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【结 构 式】

【分子编号】10019

【品名】Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate

【CA登记号】867-13-0

【 分 子 式 】C8H17O5P

【 分 子 量 】224.193742

【元素组成】C 42.86% H 7.64% O 35.68% P 13.82%
与该中间体有关的原料药合成路线共 52 条
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合成路线1

该中间体在本合成路线中的序号：(IV)

A total synthesis of (+)-sinefungin has been reported: The reaction of D-ribose (I) with acetone and methanol by means of CuSO4 and a catalytic amount of H2SO4 gives methyl 2,3-O-isopropylidene-beta-D-ribofuranoside (II), which is oxidized to the aldehyde (III) with oxalyl chloride in DMSO/dichloromethane. The Wittig condensation of (III) with triethyl phosphonoacetate (IV) by means of NaH in THF affords the unsaturated ester (V), which is hydrogenated with H2 over Pd/C in ethyl acetate and saponified with LiOH in methanol/water to give the propionic acid (VI). The condensation of (VI) with the chiral oxazolidone (VII) by means of pivaloyl chloride and triethylamine in THF yields the oxalidone (VIII). The stereoselective alkylation of (VIII) with allyl bromide by means of lithium hexamethyldisylazide in THF affords the 2(S)-allyl derivative (IX), which is hydrolyzed with LiOH in THF/water to the corresponding free acid (X). The Curtius degradation of the acid (X) by means of diphenyl phosphorazidate and benzyl alcohol gives the corresponding benzyloxycarbonylamino derivative (XI), which is benzylated with benzyl bromide to the fully protected compound (XII). The ozonolysis of the allyl double bond of (XII) with O3 in methanol/dichloromethane yields the aldehyde (XIII).

参考文献 中间体
合成目标
【1】 Ghosh, A.K.; Liu, W.M.; Total synthesis of (+)-sinefungin. J Org Chem 1996, 61, 18, 6175.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
32112 3-iodo-1-propene;3-iodo-propen;allyl iodide 556-56-9 C3H5I 详情 详情
(I) 10016 D-Ribose; (3R,4S,5R)-5-(Hydroxymethyl)tetrahydro-2,3,4-furantriol; (2R,3R,4R)-2,3,4,5-Tetrahydroxypentanal 50-69-1 C5H10O5 详情 详情
(II) 10017 [(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol 4099-85-8 C9H16O5 详情 详情
(III) 10018 (3aR,4S,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbaldehyde C9H14O5 详情 详情
(IV) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(V) 10020 Ethyl (E)-3-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2-propenoate C13H20O6 详情 详情
(VI) 10021 3-[(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]propionic acid C11H18O6 详情 详情
(VII) 10022 [(3aS,8aR)-2-Oxo-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]lithium C10H8LiNO2 详情 详情
(VIII) 10023 (3aS,8aR)-3-[3-[(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]propanoyl]-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3]oxazol-2-one C21H25NO7 详情 详情
(IX) 10024 (3aS,8aR)-3-((2S)-2-[[(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-4-pentenoyl)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3]oxazol-2-one C24H29NO7 详情 详情
(X) 10025 (2S)-2-[[(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-4-pentenoic acid C14H22O6 详情 详情
(XI) 10026 Benzyl N-((1S)-1-[[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-3-butenyl)carbamate 180776-29-8 C21H29NO6 详情 详情
(XII) 10027 Benzyl (1S)-1-[[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-3-butenyl(benzyl)carbamate C28H35NO6 详情 详情
(XIII) 10028 Benzyl (1R)-1-[[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-3-oxopropyl(benzyl)carbamate C27H33NO7 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

The Wittig condensation of 6,10,14-trimethylpentadeca-3,5,9,13-tetraen-2-one (I) with triethyl phosphonoacetate (II) by means of NaH in refluxing hexane gives ethyl 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoate (III), which is then hydrolyzed with KOH in hot isopropanol.

参考文献 中间体
合成目标
【1】 Yamatsu, I.; Tagaya, O.; Abe, S.; Abe, K.; Suzuki, K.; Yamada, K.; Suzuki, T.; Inai, Y.; Suzuki, Y. (Eisai Co., Ltd.); 3,7,11,15-Tetramethyl-2,4,6,10,14-hexadecapentaenoic acid. BE 888290; US 4917829 .
【2】 Katoh, Y.; et al. (Eisai Co., Ltd.); Method for treatment of inflammation. EP 0107188; JP 59073516 .
【3】 Prous, J.; Castaner, J.; E-5166. Drugs Fut 1986, 11, 7, 562.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 24564 (3E,5E,9E)-6,10,14-trimethyl-3,5,9,13-pentadecatetraen-2-one C18H28O 详情 详情
(II) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(III) 24566 ethyl (2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoate C22H34O2 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

The Wittig condensation of triethyl phosphonoacetate (II) with 5H-dibenzo[a,d]cyclohepten-5-one (I) by means of NaH in DMSO gives the ethyl (III), which is finally hydrolyzed with KOH in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Bergmann, E.D.; Solomonovici, A.; Fulvenes and thermochromic ethylenes. 57. Wittig-Homer reaction with fulvene ketones and related ketones. Synthesis 1970, 2, 4, 183-189.
【2】 Wolf, M. (American Home Products Corp.); Method for treating inflammation. EP 0035903; GB 2071098; JP 82500244; US 4267192 .
【3】 Serradell, M.N.; Castaner, J.; Arrigoni-Martelli, E.; WY-41770. Drugs Fut 1985, 10, 4, 309.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 29151 5H-dibenzo[a,d]cyclohepten-5-one; Dibenzosuberenone 2222-33-5 C15H10O 详情 详情
(II) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(III) 29152 ethyl 2-(5H-dibenzo[a,d]cyclohepten-5-ylidene)acetate C19H16O2 详情 详情

合成路线4

该中间体在本合成路线中的序号：(IV)

The monoprotection of acetonide dol (I) by means of Pmb-Cl and KOH in refluxing benzene gives the alcohol (II), which is submitted to a Swern oxidation, yielding the aldehyde (III). The Horner Wadswort Emmons condensation of (III) with phosphonate (IV) by means of NaH in THF affords the unsaturated ester (V), which is deprotected by means of HCl in hot ethanol to provide the diol (VI), which is reprotected by means of Tbdms-OTf and TEA in dichloromethane to gives the bis silyl ether (VII).The selective deprotection of (VII) by means of DDQ in aqueous acetonitrile yields the primary alcohol (VIII), which is submitted to a Swern oxidation to afford the corresponding aldehyde (IX). The cyclization of (IX) by means of PhCH2-S-Li in THF provides the chiral cyclopentanol (X), which is desilylated by means of HF in aqueous acetonitrile to give the trihydroxy compound (XI). The vicinal cis diols of (XI) are selectively protected with acetone and Ts-OH to yield the acetonide (XII), which is desulfurized by oxidation with NaIO4 and heating at 180 C in decalin to afford the cyclopentenol (XIII). The oxidation of (XIII) by means of PDC in dichloromethane provides the cyclopentenone (XIV), which is reduced at the ester and ketone groups by means of DIBAL in toluene to give the diol (XV). The selective silylation of the primary OH group of (XV) by means of Tbdms-Cl, TEA and DMAP in dichloromethane yields the primary silyl ether (XVI), which is condensed with adenine (XVII) by means of DIAD and PPH3 in THF to afford the protected adduct (XVIII). Finally this compound is deprotected by means of HCl in methanol to provide the target Neplanocin A.

参考文献 中间体
合成目标
【1】 Ono, M.; et al.; Total synthesis of (-)-neplanocin A by using lithium thiolate-initiated Michael-aldol tandem cyclization reaction. J Org Chem 2001, 66, 24, 8199.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 52911 [(4R,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol C7H14O4 详情 详情
(II) 58117 ((4R,5R)-5-{[(4-methoxybenzyl)oxy]methyl}-2,2-dimethyl-1,3-dioxolan-4-yl)methanol C15H22O5 详情 详情
(III) 58118 (4S,5R)-5-{[(4-methoxybenzyl)oxy]methyl}-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde C15H20O5 详情 详情
(IV) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(V) 58119 ethyl (E)-3-((4R,5R)-5-{[(4-methoxybenzyl)oxy]methyl}-2,2-dimethyl-1,3-dioxolan-4-yl)-2-propenoate C19H26O6 详情 详情
(VI) 58120 ethyl (E,4R,5R)-4,5-dihydroxy-6-[(4-methoxybenzyl)oxy]-2-hexenoate C16H22O6 详情 详情
(VII) 58121 ethyl (E,4R,5R)-4,5-bis{[tert-butyl(dimethyl)silyl]oxy}-6-[(4-methoxybenzyl)oxy]-2-hexenoate C28H50O6Si2 详情 详情
(VIII) 58122 ethyl (E,4R,5R)-4,5-bis{[tert-butyl(dimethyl)silyl]oxy}-6-hydroxy-2-hexenoate C20H42O5Si2 详情 详情
(IX) 58123 ethyl (E,4R,5S)-4,5-bis{[tert-butyl(dimethyl)silyl]oxy}-6-oxo-2-hexenoate C20H40O5Si2 详情 详情
(X) 58124 ethyl (1S,2R,3S,4R,5R)-2-(benzylsulfanyl)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxycyclopentanecarboxylate C27H48O5SSi2 详情 详情
(XI) 58125 ethyl (1S,2R,3S,4R,5R)-2-(benzylsulfanyl)-3,4,5-trihydroxycyclopentanecarboxylate C15H20O5S 详情 详情
(XII) 58126 ethyl (3aR,4S,5R,6S,6aS)-5-(benzylsulfanyl)-6-hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxylate C18H24O5S 详情 详情
(XIII) 58127 ethyl (3aR,6R,6aS)-6-hydroxy-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxylate C11H16O5 详情 详情
(XIV) 58128 ethyl (3aR,6aR)-2,2-dimethyl-6-oxo-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxylate C11H14O5 详情 详情
(XV) 58129 (3aS,4S,6aR)-6-(hydroxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol C9H14O4 详情 详情
(XVI) 58130 (3aS,4S,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol C15H28O4Si 详情 详情
(XVII) 10343 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine 73-24-5 C5H5N5 详情 详情
(XVIII) 58131 9-[(3aS,4R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-9H-purin-6-ylamine; 9-[(3aS,4R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-9H-purin-6-amine C20H31N5O3Si 详情 详情

合成路线5

该中间体在本合成路线中的序号：(IX)

The reaction of 3-bromopropionic acid (I) with triphenylphosphine (II) in refluxing acetonitrile gives (2-carboxyethyl)-triphenylphosphonium bromide (III), which by a Wittig reaction with 2-oxa-3-hydroxy-6-syn-(3alpha-tetrahydropyranyloxy-4,4-dimethyl-1-trans-octen-1-yl)-7-anti-tetrahydropyranyloxybicyclo- [3.3.0]cis-octane (IV) (prepared according to reference 2) by means of sodium dimethylsulfinate in DMSO yields 9alpha-hydroxy-11alpha,15alpha-bis(tetrahydropyranyloxy)-16,16-dimethyl-alpha-dinorprosta-5-cis-13-trans-dienoic acid (V). The reduction of (V) with H2 over Pd/C in methanol affords the 13-trans-prostenoic acid (VI), which is methylated with CH2N2 in ether yielding the methyl ester (VII). The reduction of (VII) with diisobutyl aluminum hydride in toluene affords the corresponding aldehyde (VIII), which by a Wittig reaction with triethyl phosphonoacetate (IX) by means of NaH in THF is converted into 9alpha-hydroxy-11alpha,15alpha-bis(tetrahydropyranyloxy)-16,16-dimethylprosta-2-trans-dienoic acid ethyl ester (X). The hydrolysis of the ester (X) with KOH in ethanol-water gives the corresponding acid (XI), which is oxidized with CrO3, MnSO4 and H2SO4 in ether - water yielding the protected ketoacid (XII). The hydrolysis of (XII) with acetic acid-water at 80 C gives 9-oxo-11alpha,15alpha-dihydroxy-16,16-dimethyl-prosta-2-trans-13-trans-dienoic acid (16,16-dimethyl-DELTA2-trans-PGE1) (XIII), which is finally methylated with CH2N2 in ether

参考文献 中间体
合成目标
【1】 Oshima, K.; Effect of ONO-802 on uterine activity and plasma levels of steroid hormones in japanese monkeys (Macaca Fuscata Fuscata). Acta Obs Gyn Jpn 1977, 29, 12, 1923.
【2】 Hayashi, M.; Kori, S.; Wakatsuka, H.; Prostaglandin-analoge. BE 0850084 .
【3】 Castaner, J.; Leeson, P.; ONO-802. Drugs Fut 1979, 4, 1, 38.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 15472 3-Bromopropionic acid 590-92-1 C3H5BrO2 详情 详情
(II) 12437 Triphenylphosphine; Triphenyl phosphine 603-35-0 C18H15P 详情 详情
(III) 33280 (2-carboxyethyl)(triphenyl)phosphonium bromide 51114-94-4 C21H20BrO2P 详情 详情
(IV) 33281 (2S,3aR,4S,5R,6aS)-4-[(E,3S)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-ol C29H50O6 详情 详情
(V) 33282 (Z)-5-[(1R,2S,3R,5S)-2-[(E,3S)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-hydroxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-3-pentenoic acid C32H54O7 详情 详情
(VI) 33283 5-[(1R,2S,3R,5S)-2-[(E,3S)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-hydroxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]pentanoic acid C32H56O7 详情 详情
(VII) 33284 methyl 5-[(1R,2S,3R,5S)-2-[(E,3S)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-hydroxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]pentanoate C33H58O7 详情 详情
(VIII) 33285 5-[(1R,2S,3R,5S)-2-[(E,3S)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-hydroxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]pentanal C32H56O6 详情 详情
(IX) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(X) 33286 ethyl (E)-7-[(1R,2S,3R,5S)-2-[(E,3S)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-hydroxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-2-heptenoate C36H62O7 详情 详情
(XI) 33287 (E)-7-[(1R,2S,3R,5S)-2-[(E,3S)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-hydroxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-2-heptenoic acid C34H58O7 详情 详情
(XII) 33288 (E)-7-[(1R,2S,3R)-2-[(E,3S)-4,4-dimethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-2-heptenoic acid C34H56O7 详情 详情
(XIII) 33289 (E)-7-[(1R,2R,3R)-3-hydroxy-2-[(E,3S)-3-hydroxy-4,4-dimethyl-1-octenyl]-5-oxocyclopentyl]-2-heptenoic acid C22H36O5 详情 详情

合成路线6

该中间体在本合成路线中的序号：(VI)

1) The Wittig condensation of dimetbyl 3 methyl-2-oxooct-5-inphosphonate (II) with (1R,5S,6R,7R)-3,3-ethylenedioxy 7-benzoyloxy-6-formylbicyclo[3.3.0]octane by means of NaH in dimethoxy ethane, followed by a bromination with N-bromosuccinimide (NBS), gives the brominated condensation product (III), which is reduced with NaBH4 in methanol, debenzoylated with K2CO3 in methanol and protected with dihydropyran and p-toluenesulfonic acid yielding the protected diol (IV). Dehydrobromination of (IV) with potassium tert-butoxide in DMSO THF, followed by hydrolysis with acetic acid, affords the diacetylenic ketone (V), which is submitted to a Wittig condensation with triethyl phosphonoacetate (VI) usino potassium ten butoxide as base, and to a reduction with LiAlH4 in ether yielding the pentalenylideneethanol (VII). The condensation of (VII) with bromoacetic acid (VIII), by means of NaH in THF affords the protected prostaglandin (IX), which is finally deprotected with aceto acid water THF.

参考文献 中间体
合成目标
【1】 Haberey, M.; Raduchel, B.; Schillinger, E.; Skuballa, W.; Sturzebecher, C.-S.; Town, M.H.; Vorbruggen, H. (Schering AG); Novel carbacyclins, processes for their preparation and their use as medicinal agents. EP 0119949; US 5013758 .
【2】 Castaner, J.; Prous, J.; Cicaprost. Drugs Fut 1986, 11, 11, 913.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 24200 Benzoic acid (1'R,2'R,3'aR,6'aS)-1'-formylspiro[1,3-dioxolane-2,5'-perhydropentalen]-2'-yl ester C18H20O5 详情 详情
(II) 24201 dimethyl 3-methyl-2-oxo-5-octynylphosphonate C11H19O4P 详情 详情
(III) 24202 Benzoic acid (2'R,3'aR,6'aS)-1'-(2-Bromo-4(S)-methyl-3-oxonon-1(E)-en-6-yn-1-yl)-spiro[1,3-dioxolane-2,5'-perhydropentalen]-2'-yl ester C27H31BrO5 详情 详情
(IV) 24203 2-Bromo-4(S)-methyl-1-[(2'(R),3'a(R),6'a(S))-2'-(tetrahydropyranyloxy)spiro[1,3-dioxolane-2,5'-perhydropentalen]-1-yl]non-1(E)-en-6-yn-3-one C21H29BrO3 详情 详情
(V) 24204 (3aS,5R,6aR)-4-[(3S,4S)-4-methyl-3-(tetrahydro-2H-pyran-2-yloxy)-1,6-nonadiynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenone C29H42O5 详情 详情
(VI) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(VII) 24206 2-[(3aS,4R,5R,6aR)-4-[(3S,4S)-4-methyl-3-(tetrahydro-2H-pyran-2-yloxy)-1,6-nonadiynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]-1-ethanol C31H46O5 详情 详情
(VIII) 23666 (2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-[((2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propanoyl)oxy]butyric acid C27H32N2O8 详情 详情
(IX) 24208 2-[2-[(3aS,4R,5R,6aR)-4-[(3S,4S)-4-methyl-3-(tetrahydro-2H-pyran-2-yloxy)-1,6-nonadiynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]ethoxy]acetic acid C33H48O7 详情 详情

合成路线7

该中间体在本合成路线中的序号：(VI)

2) The reduction of (III) with NaBH4 followed by debenzoylation with NaOH and deprotection with acetic acid gives the dihydroxy ketone (X), which by silviation with dimethyl-tert-butylsilyl chloride in DMF is converted to the disilylated ketone (XI). A Horner Wittig reaction of ketone (XI) with phosphonate (VI), followed by reduction with LiAlH4 as before affords the pentalenylideneethanol (XII), which is etherified with ten butyl bromoacetate (XIII) in aqueous NaOH - toluene and tetrabutylammonium sulfate with simultaneous hydrolysis of the tert-butyl group yielding the silylated prostaglandin (XIV). Finally, this compound is deprotected with tetrabutylammonium fluoride in THF.

参考文献 中间体
合成目标
【1】 Skuballa, W.; et al.; Synthesis of a new chemically and metabolically stable prostacyclin analogue with high and long-lasting oral activity. J Med Chem 1986, 29, 3, 313.
【2】 Castaner, J.; Prous, J.; Cicaprost. Drugs Fut 1986, 11, 11, 913.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 24200 Benzoic acid (1'R,2'R,3'aR,6'aS)-1'-formylspiro[1,3-dioxolane-2,5'-perhydropentalen]-2'-yl ester C18H20O5 详情 详情
(II) 24201 dimethyl 3-methyl-2-oxo-5-octynylphosphonate C11H19O4P 详情 详情
(III) 24202 Benzoic acid (2'R,3'aR,6'aS)-1'-(2-Bromo-4(S)-methyl-3-oxonon-1(E)-en-6-yn-1-yl)-spiro[1,3-dioxolane-2,5'-perhydropentalen]-2'-yl ester C27H31BrO5 详情 详情
(VI) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(X) 24212 (3aS,5R,6aR)-5-hydroxy-4-[(3S,4S)-3-hydroxy-4-methyl-1,6-nonadiynyl]hexahydro-2(1H)-pentalenone C18H24O3 详情 详情
(XI) 24213 (3aS,5R,6aR)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-((3S,4S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-1,6-nonadiynyl)hexahydro-2(1H)-pentalenone C30H52O3Si2 详情 详情
(XII) 24215 2-[(3aS,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-((3S,4S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-1,6-nonadiynyl)hexahydro-2(1H)-pentalenylidene]-1-ethanol C32H56O3Si2 详情 详情
(XIII) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(XIV) 24216 2-[2-[(3aS,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-((3S,4S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-1,6-nonadiynyl)hexahydro-2(1H)-pentalenylidene]ethoxy]acetic acid C34H58O5Si2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(IV)

The condensation of homogeranyl iodide (III) with diethyl ethoxycarbony-methylphosphonate (IV) by means of NaH in diethoxyethane gives the phosphorane (V), which by a Wittig condensation with 4-methyl-6-acetoxy-4-hexenal (VI) by means of NaH yields 7-(ethoxycarbonyl)-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol acetate (VII). Finally, this compound is reduced and hydrolyzed by treatment with LiAlH4.

参考文献 中间体
合成目标
【1】 Mishima, H.; Ogiso, A.; Kobayashi, S.; Polyprenyl derivatives. CH 629471; DE 2652256; FR 2332009; GB 1533377; JP 52062213; US 4059641 .
【2】 Castaner, J.; Serradell, M.N.; Blancafort, P.; Plaunotol. Drugs Fut 1983, 8, 11, 930.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 31112 (6E)-9-iodo-2,6-dimethyl-2,6-nonadiene C11H19I 详情 详情
(IV) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(V) 31113 ethyl (5E)-2-(diethoxyphosphoryl)-6,10-dimethyl-5,9-undecadienoate C19H35O5P 详情 详情
(VI) 31114 (E)-3-methyl-6-oxo-2-hexenyl acetate C9H14O3 详情 详情
(VII) 31115 ethyl (5E)-2-[(Z,4E)-6-(acetoxy)-4-methyl-4-hexenylidene]-6,10-dimethyl-5,9-undecadienoate C24H38O4 详情 详情

合成路线9

该中间体在本合成路线中的序号：(III)

The oxidation of 4-(benzyloxy)-1-butanol (I) with oxalyl chloride gives the corresponding aldehyde (II), which is condensed with the phosphonate (III) by means of DBU and LiCl in acetonitrile to yield the 2-hexenoate (IV). The asymmetric aminohydroxylation of (IV) by means of tert-butyl carbamate, K2[OsO2(OH)4] and a chiral catalyst ((DHQD)2PHAL) in propanol/water affords the desired regioisomer (V). The introduction of an azido group into the alpha-position with retention of the configuration was accomplished by two Mitsunobu reactions. The reaction of (V) with benzoic acid, PPh3 and DEAD in THF gives the benzoyloxy compound (VI) with inverted stereochemistry, which is hydrolyzed with K2CO3 in methanol to yield the corresponding alcohol (VII). Then the reaction of (VII) with HN3, DEAD and PPh3 in THF affords the azide (VIII) with the right stereochemistry. The hydrolysis of the ester group of (VIII) by means of K2CO3 in methanol/water, followed by cleavage of the protecting carbamate group with TFA, provides the carboxylic acid (IX). The cyclization of (IX) by means of 2-chloro-1-methylpyridinium iodide (CMPI) and TEA in acetonitrile gives the azetidinone (X), which is reduced with PPh3 in THF/water to yield the aminoazetidinone (XI). The acylation of the amino group of (XI) with 2-phenoxyacetyl chloride (A) and NaHCO3 in aqueous acetonitrile affords the amide (XII). The hydrogenation of (XII) with H2 over Pd/C in ethanol affords the primary alcohol (XIII), which is finally oxidized with the Jones reagent to provide the target carboxylic acid intermediate (XIV).

参考文献 中间体
合成目标
【1】 Lee, J.C.; et al.; An asymmetric aminohydroxylation approach to the stereoselective synthesis of cis-substituted azetidinone of loracarbef. Tetrahedron Lett 2001, 42, 27, 4519.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 12180 Phenoxyacetyl chloride; 2-Phenoxyacetyl chloride 701-99-5 C8H7ClO2 详情 详情
(I) 46169 4-(benzyloxy)-1-butanol C11H16O2 详情 详情
(II) 46170 4-(benzyloxy)butanal C11H14O2 详情 详情
(III) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(IV) 49625 ethyl (E)-6-(benzyloxy)-2-hexenoate C15H20O3 详情 详情
(V) 49626 ethyl (2S,3R)-6-(benzyloxy)-3-[(tert-butoxycarbonyl)amino]-2-hydroxyhexanoate C20H31NO6 详情 详情
(VI) 49627 (1R,2R)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-1-(ethoxycarbonyl)pentyl benzoate C27H35NO7 详情 详情
(VII) 49628 ethyl (2R,3R)-6-(benzyloxy)-3-[(tert-butoxycarbonyl)amino]-2-hydroxyhexanoate C20H31NO6 详情 详情
(VIII) 49629 ethyl (2S,3R)-2-azido-6-(benzyloxy)-3-[(tert-butoxycarbonyl)amino]hexanoate C20H30N4O5 详情 详情
(IX) 49630 (2S,3R)-3-amino-2-azido-6-(benzyloxy)hexanoic acid C13H18N4O3 详情 详情
(X) 49631 (3S,4R)-3-azido-4-[3-(benzyloxy)propyl]-2-azetidinone C13H16N4O2 详情 详情
(XI) 49632 (3S,4R)-3-amino-4-[3-(benzyloxy)propyl]-2-azetidinone C13H18N2O2 详情 详情
(XII) 49633 N-[(2R,3S)-2-[3-(benzyloxy)propyl]-4-oxoazetidinyl]-2-phenoxyacetamide C21H24N2O4 详情 详情
(XIII) 49634 N-[(2R,3S)-2-(3-hydroxypropyl)-4-oxoazetidinyl]-2-phenoxyacetamide C14H18N2O4 详情 详情
(XIV) 12182 3-[(2R,3S)-4-Oxo-3-[(2-phenoxyacetyl)amino]azetanyl]propionic acid C14H16N2O5 详情 详情

合成路线10

该中间体在本合成路线中的序号：(XLII)

3) The cyclization of benzoquinone (XXXVII) with 3-amino-4-methoxycrotonic acid methyl ester (XXXVIII) gives 5-hydroxy-2-(methoxymethyl)-1H-indole-3-carboxylic acid methyl ester (XXXIX), which is methylated to 5-methoxy-2-(methoxymethyl)-1-methylindole-3-carboxylic acid methyl ester (XL). The oxidation of (XL) with DDQ yields the corresponding aldehyde (XLI), which is submitted to a Horner-Emmonds condensation with 2-(dimethoxyphosphoryl)acetic acid ethyl ester (XLII) in a basic medium to afford the corresponding acrylic ester (XLIII). The nitration of (XLIII) gives 3-[5-methoxy-3-(methoxycarbonyl)-1-methyl-4-nitroindol-2-yl]acrylic acid ethyl ester (XLIV), the monoethyl ester analogue of compound (XVIII).The reduction of (XLIV) with Sn and 3N HCl in ethanol/water yields the corresponding 4-amino derivative (XLV), which is oxidized with Fremy's salt (nitrodisulfonic acid potassium salt) to afford 3-[5-methoxy-3-(methoxycarbonyl)-1-methyl-4,7-dioxo-4,7-dihydro-1H-indo l -2-yl]acrylic acid ethyl ester (XLVI). The reduction of (XLVI) with Na2S2O4 in CHCl3/ethanol/water gives the corresponding hydroquinone (XLVII), which is first reduced with DIBAL (diisobutylaluminum hydride) in toluene/dichloromethane and then oxidized again with FeCl3 to afford 3-(hydroxymethyl)-2-(3-hydroxy-1-propenyl)-5-methoxy-1-methyl-4,7-dihydro-1H-indole-4,7-dione (XXII). Finally, this compound is treated with aziridine (XXIII) in hot methanol.

参考文献 中间体
合成目标
【1】 Bailey, S.M.; Lohmeyer, M.; Dimbleby, R.; Castaner, J.; EO9. Drugs Fut 1996, 21, 2, 143.
【2】 Kinugawa, M.; Arai, H.; Nishikawa, H.; Masuda, Y.; Ogasa, T.; Tomioka, S.; Kasai, M.; Synthetic studies of the indoloquinone antitumor agent EO9. 13th Int Symp Med Chem (Sept 19-23, Paris) 1994, Abst P250.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXII) 12618 3-(Hydroxymethyl)-2-[(E)-3-hydroxy-1-propenyl]-5-methoxy-1-methyl-1H-indole-4,7-dione C14H15NO5 详情 详情
(XXIII) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情
(XXXVII) 12633 Quinone; Benzo-1,4-quinone; 2,5-Cyclohexadiene-1,4-dione 106-51-4 C6H4O2 详情 详情
(XXXVIII) 12634 methyl (E)-3-amino-4-methoxy-2-butenoate C6H11NO3 详情 详情
(XXXIX) 12635 methyl 5-hydroxy-2-(methoxymethyl)-1H-indole-3-carboxylate C12H13NO4 详情 详情
(XL) 12636 methyl 5-methoxy-2-(methoxymethyl)-1-methyl-1H-indole-3-carboxylate C14H17NO4 详情 详情
(XLI) 12637 methyl 2-formyl-5-methoxy-1-methyl-1H-indole-3-carboxylate C13H13NO4 详情 详情
(XLII) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(XLIII) 12639 methyl 2-[(E)-3-ethoxy-3-oxo-1-propenyl]-5-methoxy-1-methyl-1H-indole-3-carboxylate C17H19NO5 详情 详情
(XLIV) 12640 methyl 2-[(E)-3-ethoxy-3-oxo-1-propenyl]-5-methoxy-1-methyl-4-nitro-1H-indole-3-carboxylate C17H18N2O7 详情 详情
(XLV) 63466 2-propenyl 6-(1-hydroxyethyl)-3-({5-[2-(5-isothiazolyl)ethenyl]-1-[(2-propenyloxy)carbonyl]-3-pyrrolidinyl}sulfanyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C26H31N3O6S2 详情 详情
(XLVI) 63467 methyl 2-[(E)-3-ethoxy-3-oxo-1-propenyl]-5-methoxy-1-methyl-4,7-dioxo-4,7-dihydro-1H-indole-3-carboxylate C17H17NO7 详情 详情
(XLVII) 63468 methyl 2-[(E)-3-ethoxy-3-oxo-1-propenyl]-4,7-dihydroxy-5-methoxy-1-methyl-1H-indole-3-carboxylate C17H19NO7 详情 详情

合成路线11

该中间体在本合成路线中的序号：(IV)

The title compound was obtained by two related procedures. Reaction of 4-piperidone-HCl (II) with 2-(benzhydryloxy)ethyl chloride (I) in the presence of Na2CO3 and NaI provided the N-alkylated piperidone (III). Horner-Emmons condensation of (III) with triethyl phosphonoacetate (IV) and NaH gave rise to the piperidylidene acetate (V). Then, hydrogenation of the double bond of (V) using Raney Nickel yielded the target compound.

参考文献 中间体
合成目标
【1】 Buzas, A.; Merour, J.-Y.; Ollivier, R. (Laboratoires Meram SA); Benzhydryloxyethylpiperidine derivs., process for their preparation and pharmaceutical compsns., in which they are present. EP 0259227; US 4983614 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 34744 1-[(2-chloroethoxy)(phenyl)methyl]benzene; benzhydryl 2-chloroethyl ether 32669-06-0 C15H15ClO 详情 详情
(II) 27115 4-piperidinone 40064-34-4 C5H9NO 详情 详情
(III) 34745 1-[2-(benzhydryloxy)ethyl]-4-piperidinone C20H23NO2 详情 详情
(IV) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(V) 34746 ethyl 2-[1-[2-(benzhydryloxy)ethyl]-4-piperidinylidene]acetate C24H29NO3 详情 详情

合成路线12

该中间体在本合成路线中的序号：(IV)

Horner-Emmons condensation of 1-benzyl-4-piperidone (VI) with phosphonate (IV) furnished the unsaturated ester (VII). Hydrogenation of (VII) over Pd/C produced double bond reduction and simultaneous N-benzyl group cleavage to afford piperidine (VIII). This was finally alkylated with chloride (I) in the presence of K2CO3 and NaI.

参考文献 中间体
合成目标
【1】 Buzas, A.; Merour, J.-Y.; Ollivier, R. (Laboratoires Meram SA); Benzhydryloxyethylpiperidine derivs., process for their preparation and pharmaceutical compsns., in which they are present. EP 0259227; US 4983614 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 34744 1-[(2-chloroethoxy)(phenyl)methyl]benzene; benzhydryl 2-chloroethyl ether 32669-06-0 C15H15ClO 详情 详情
(IV) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(VI) 15720 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one 3612-20-2 C12H15NO 详情 详情
(VII) 34747 ethyl 2-(1-benzyl-4-piperidinylidene)acetate C16H21NO2 详情 详情
(VIII) 28087 4-Piperidineacetic acid ethyl ester; ethyl 2-(4-piperidinyl)acetate C9H17NO2 详情 详情

合成路线13

该中间体在本合成路线中的序号：(IV)

The title compound was obtained by two related procedures. Reaction of 4-piperidone-HCl (II) with 2-(benzhydryloxy)ethyl chloride (I) in the presence of Na2CO3 and NaI provided the N-alkylated piperidone (III). Horner-Emmons condensation of (III) with triethyl phosphonoacetate (IV) and NaH gave rise to the piperidylidene acetate (V). Then, hydrogenation of the double bond of (V) using Raney Nickel and hydrolysis yielded the target compound.

参考文献 中间体
合成目标
【1】 Buzas, A.; Merour, J.-Y.; Ollivier, R. (Laboratoires Meram SA); Benzhydryloxyethylpiperidine derivs., process for their preparation and pharmaceutical compsns., in which they are present. EP 0259227; US 4983614 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 34744 1-[(2-chloroethoxy)(phenyl)methyl]benzene; benzhydryl 2-chloroethyl ether 32669-06-0 C15H15ClO 详情 详情
(II) 27115 4-piperidinone 40064-34-4 C5H9NO 详情 详情
(III) 34745 1-[2-(benzhydryloxy)ethyl]-4-piperidinone C20H23NO2 详情 详情
(IV) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(V) 34746 ethyl 2-[1-[2-(benzhydryloxy)ethyl]-4-piperidinylidene]acetate C24H29NO3 详情 详情
(VI) 34748 ethyl 2-[1-[2-(benzhydryloxy)ethyl]-4-piperidinyl]acetate C24H31NO3 详情 详情

合成路线14

该中间体在本合成路线中的序号：(IV)

Horner-Emmons condensation of 1-benzyl-4-piperidone (VII) with phosphonate (IV) furnished the unsaturated ester (VIII). Hydrogenation of (VIII) over Pd/C produced double bond reduction and simultaneous N-benzyl group cleavage to afford piperidine (IX). This was finally alkylated with chloride (I) in the presence of K2CO3 and NaI and hydrolyzed to target compound.

参考文献 中间体
合成目标
【1】 Buzas, A.; Merour, J.-Y.; Ollivier, R. (Laboratoires Meram SA); Benzhydryloxyethylpiperidine derivs., process for their preparation and pharmaceutical compsns., in which they are present. EP 0259227; US 4983614 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 34744 1-[(2-chloroethoxy)(phenyl)methyl]benzene; benzhydryl 2-chloroethyl ether 32669-06-0 C15H15ClO 详情 详情
(IV) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(VI) 34748 ethyl 2-[1-[2-(benzhydryloxy)ethyl]-4-piperidinyl]acetate C24H31NO3 详情 详情
(VII) 15720 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one 3612-20-2 C12H15NO 详情 详情
(VIII) 34747 ethyl 2-(1-benzyl-4-piperidinylidene)acetate C16H21NO2 详情 详情
(IX) 28087 4-Piperidineacetic acid ethyl ester; ethyl 2-(4-piperidinyl)acetate C9H17NO2 详情 详情

合成路线15

该中间体在本合成路线中的序号：(VI)

A new synthesis of FK-453 has been published: The cyclization of 1-aminopyridinium iodide (I) with 3-phenylpropynoic acid ethyl ester (II) by means of KOH in DMF gives 2-phenylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (III), which is decarboxylated with 47% aqueous HBr yielding 2-phenylpyrazolo[1,5-a]pyridine (IV). The Vilsmayer formylation of (IV) with POCl3 and DMF affords 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (V), which by a Horner-Emmonds condensation with 2-(diethoxyphosphoryl)acetic acid ethyl ester and NaH in THF is converted into 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2(E)-propenoic acid ethyl ester (VII). The hydrolysis of (VII) with NaOH in methanol gives the free acid (VIII), which by reaction with SOCl2 in dichloromethane yields the corresponding acyl chloride (IX). The condensation of (IX) with 2-(2-hydroxyethyl)piperidine (X) by means of triethylamine in dichloromethane affords FK-453 as a racemic mixture (XI), which is finally submitted to optical resolution.

参考文献 中间体
合成目标
【1】 Kita, Y.; Akahane, A.; Kusunoki, T.; Terai, T.; Yoshida, K.; Shiokawa, Y.; Mitsunaga, T.; Katayama, H.; Discovery of FK453, a novel non-xanthine adenosine A1 receptor antagonist. Bioorg Med Chem Lett 1996, 6, 17, 2059.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 32760 1-aminopyridinium iodide C5H7IN2 详情 详情
(II) 13278 ethyl phenylpropiolate; ethyl 3-phenyl-2-propynoate 2216-94-6 C11H10O2 详情 详情
(III) 13279 ethyl 2-phenylpyrazolo[1,5-a]pyridine-3-carboxylate C16H14N2O2 详情 详情
(IV) 13280 2-Phenylpyrazolo[1,5-a]pyridine C13H10N2 详情 详情
(V) 13271 2-Phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde C14H10N2O 详情 详情
(VI) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(VII) 13283 ethyl (E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoate C18H16N2O2 详情 详情
(VIII) 13274 (E)-3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoic acid C16H12N2O2 详情 详情
(IX) 13275 (E)-3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoyl chloride C16H11ClN2O 详情 详情
(X) 17614 2-(2-piperidinyl)-1-ethanol; 2-Piperidineethanol 1484-84-0 C7H15NO 详情 详情
(XI) 13287 (E)-1-[2-(2-Hydroxyethyl)-1-piperidinyl]-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propen-1-one C23H25N3O2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(VII)

A new practical synthesis of FK-453, suitable for large scale manufacture is described: Bromination of cinnamic aldehyde (I) with Br2 in HOAc gives the dibromoderivative (II), which is treated with NaHSO3 and triethylamine yielding alpha-bromocinnamic aldehyde (III). The reaction of (III) with triethyl orthoformate affords the corresponding acetal (IV), which is treated with KOH in hot ethanol to give the acetylenic acetal (V). Acidic hydrolysis of the acetal (V) with sulfuric acid in refluxing water affords phenylpropargyl aldehyde (VI), which by a Horner-Emmons condensation with the phosphonate (VII) by means of KOH in DMSO gives 5-phenylpent-2(E)-en-4-ynoic acid ethyl ester (VIII). The 1,3-dipolar cycloaddition of (VIII) with 1-aminopyridinium iodide (IX) by means of KOH and K2CO3 in the same solvent yields 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2(E)-propenoic acid ethyl ester (X), which is hydrolyzed with NaOH in hot methanol affording the corresponding free acid (XI). Reaction of (XI) with SOCl2 and DMF gives the activated acyl chloride (XII), which is condensed with the silylated chiral piperidineethanol (XIII) [obtained by silylation of the chiral piperidineethanol (XIV) with N,N'-bis(trimethylsilyl)urea (BSU)] by means of Et3N and DMAP in CH2Cl2, yielding the silylated target compound (XV). Finally, this compound is desilylated by means of K2CO3 in methanol.

参考文献 中间体
合成目标
【1】 Morinaga, Y.; Zanka, A.; Uematsu, R.; Yamazaki, H.; Yasuda, H.; Process development of a novel-xanthine adenosine A1 receptor antagonist. Org Process Res Dev 1999, 3, 6, 389.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 41712 (E)-3-phenyl-2-propenal 14371-10-9 C9H8O 详情 详情
(II) 41735 2,3-dibromo-3-phenylpropanal C9H8Br2O 详情 详情
(III) 41736 (Z)-2-bromo-3-phenyl-2-propenal 5443-49-2 C9H7BrO 详情 详情
(IV) 41737 (Z)-2-bromo-1-ethoxy-3-phenyl-2-propenyl ethyl ether; 1-[(Z)-2-bromo-3,3-diethoxy-1-propenyl]benzene C13H17BrO2 详情 详情
(V) 41738 1-(3,3-diethoxy-1-propynyl)benzene; 1-ethoxy-3-phenyl-2-propynyl ethyl ether 6142-95-6 C13H16O2 详情 详情
(VI) 41739 3-phenyl-2-propynal 2579-22-8 C9H6O 详情 详情
(VII) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(VIII) 41740 ethyl (E)-5-phenyl-2-penten-4-ynoate C13H12O2 详情 详情
(IX) 32760 1-aminopyridinium iodide C5H7IN2 详情 详情
(X) 13273 methyl (E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoate C17H14N2O2 详情 详情
(XI) 13274 (E)-3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoic acid C16H12N2O2 详情 详情
(XII) 13275 (E)-3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoyl chloride C16H11ClN2O 详情 详情
(XIII) 41741 (2R)-2-[2-[(trimethylsilyl)oxy]ethyl]piperidine; 2-[(2R)piperidinyl]ethyl trimethylsilyl ether C10H23NOSi 详情 详情
(XIV) 13276 2-[(2R)Piperidinyl]-1-ethanol C7H15NO 详情 详情
(XV) 41742 (E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1-((2R)-2-[2-[(trimethylsilyl)oxy]ethyl]piperidinyl)-2-propen-1-one C26H33N3O2Si 详情 详情

合成路线17

该中间体在本合成路线中的序号：(II)

The Wittig condensation of 2-ethyl-2(E)-butenal (I) with triethyl phosphonoacetate (II) by means of NaH in benzene gives (2E,4E)-4-ethyl-2,4-hexadienoic acid ethyl ester (III), which is hydrolyzed with NaOH to the corresponding free acid (IV). The reaction of (IV) with ethyl chloroformate and then with ammonia affords the (2E,4E)-2-ethyl-2,4-hexadienamide (V), which is finally treated with NaNO2 in methanol adjusted at pH 3.0 with cond. HCl.

参考文献 中间体
合成目标
【1】 Okamoto, M.; Iwami, M.; Takase, S.; Uchida, I.; Umehara, K.; Kohsaka, M.; Imanaka, H. (Fujisawa Pharmaceutical Co., Ltd.); New nitro aliphatic cpds., process for preparation thereof and use thereof. EP 0113106; JP 1990160750 .
【2】 Aoki, H.; Imanaka, H.; Takase, S.; Okamoto, M.; Itoh, Y.; Hino, M.; Uchida, I.; Kohsaka, M.; FK409, a novel vasodilator isolated from the acid-treated fermentation broth of Streptomyces griseosporeus. III. Reaction mechanism and synthesis. J Antibiot 1989, 42, 44, 1589.
【3】 Hino, M.; Hosoda, J.; Iwami, M.; Yoshida, K.; Okamoto, M.; Kohsaka, M.; Imanaka, H.; Okuhara, M.; Haruta, H.; Aoki, H.; FK409, a novel vasodilator isolated from the acid-treated fermentation broth of Streptomyces griseosporeus. I. Taxonomy, fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot 1989, 42, 11, 1578.
【4】 Hino, M.; Kohsaka, M.; Uchida, I.; Hashimoto, M.; Takase, S.; Okamoto, M.; Itoh, Y.; Structure and synthesis of FK409, a novel vasodilator isolated from Streptomyces as a semi-artificial fermentation product. Chem Pharm Bull 1989, 37, 10, 2864.
【5】 Prous, J.; Castaner, J.; FK-409. Drugs Fut 1993, 18, 1, 9.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 13404 (E)-2-Ethyl-2-butenal 19780-25-7 C6H10O 详情 详情
(II) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(III) 13406 ethyl (2E,4E)-4-ethyl-2,4-hexadienoate C10H16O2 详情 详情
(IV) 13407 (2E,4E)-4-Ethyl-2,4-hexadienoic acid C8H12O2 详情 详情
(V) 13408 (2E,4E)-4-Ethyl-2,4-hexadienamide C8H13NO 详情 详情

合成路线18

该中间体在本合成路线中的序号：(II)

YM-796 can be obtained by two different ways: 1) The Wittig condensation of 1-methylpiperidin-4-one (I) with 2-(diethoxyphosphoryl)acetic acid ethyl ester (II) by means of NaH in dimethoxyethane gives 2-(1-methylpiperidin-4-ylidene) acetic acid ethyl ester (III), which is cyclized with ethyl lactate (IV) by means of NaH in DMSO yielding 2,8-dimethyl-3-oxo-1-oxa-8-azaspiro[4.5]decane-4-carboxylic acid ethyl ester (V). The decarboxylation of (V) with refluxing aqueous 1N HCl affords 2,8-dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one (VI), which is submitted to a new Wittig condensation with methyltriphenylphosphonium iodide (or bromide) (VII) by means of NaH in DMSO to give racemic 2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane (VIII). Finally, this compound is submitted to optical resolution with L-tartaric acid or with di-p-toluoyl-D-tartaric acid. 2) The Wittig condensation of 4-oxopiperidine-1-carboxylic acid ethyl ester (IX) with phosphorane (VII) as before gives the corresponding methylene derivative (X), which is submitted to alkoxybromination with N-bromosuccinimide (NBS) and (S)-3-butyn-2-ol (XI) yielding (S)-4-(bromomethyl)-4-(1-methyl-2-propynyloxy)piperidine-1-carboxylic acid ethyl ester (XII). The radical cyclization of (XII) with NaBH4 catalyzed by bis(dimethylglyoximato)(pyridine)cobalt(III) chloride [chlorocobaloxime(III)] affords (S)-2-methyl-3-methylene-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid ethyl ester (XIII), which is finally reduced with sodium bis(2-methoxyethoxy)aluminum hydride (vitride) in toluene and treated with fumaric acid to obtain the sesquifumarate salt.

参考文献 中间体
合成目标
【1】 Ngo, J.; Martel, A.M.; Castaner, J.; YM-796. Drugs Fut 1997, 22, 2, 144.
【2】 Tsukamoto, S.; Kondo, Y.; Igarashi, S.; An efficient synthesis of (S)-(-)-2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane by cobaloxime(I)-mediated radical cyclization. Heterocycles 1995, 41, 8, 1771-1778.
【3】 Tsukamoto, S.; Fujii, M.; Yasunaga, T.; Matsuda, K.; Wanibuchi, F.; Hidaka, K.; Furuya, T.; Tamura, T.; Synthesis and structure-activity studies of a series of 1-oxa-8-azaspiro[4.5]decanes as M1 muscarinic agonists. Chem Pharm Bull 1995, 43, 5, 842-852.
【4】 Tsukamoto, S.-I.; Nagaoka, H.; Usuda, S.; Harada, M.; Tamura, T. (Yamanouchi Pharmaceutical Co., Ltd.); Heterocyclic spiro cpds. and their preparation. AU 8823449; EP 0311313; JP 1990036183; US 4996210 .
【5】 Tsukamoto, S.; Kohinata, T.; Fujii, M.; Tomisawa, S. (Yamanouchi Pharmaceutical Co., Ltd.); (-)-(S)-2,8-Dimethyl-3-methylene-1-oxa-8-azaspiro[4,5]decane L-tartrate. EP 0590150; JP 1993508699; WO 9220683 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 10919 1-Methyl-4-piperidone; 1-Methyltetrahydro-4(1H)-pyridinone; N-Methyl-4-piperidone;1-methylpiperidin-4-one 1445-73-4 C6H11NO 详情 详情
(II) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(III) 13480 ethyl 2-(1-methyl-4-piperidinylidene)acetate C10H17NO2 详情 详情
(IV) 13481 ethyl lactate; ethyl 2-hydroxypropanoate 97-64-3 C5H10O3 详情 详情
(V) 13482 ethyl 2,8-dimethyl-3-oxo-1-oxa-8-azaspiro[4.5]decane-4-carboxylate C13H21NO4 详情 详情
(VI) 13483 2,8-Dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one C10H17NO2 详情 详情
(VII) 13484 Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide 2065-66-9 C19H18IP 详情 详情
(VIII) 13485 2,8-Dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane C11H19NO 详情 详情
(IX) 13486 Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone 29976-53-2 C8H13NO3 详情 详情
(X) 13487 ethyl 4-methylene-1-piperidinecarboxylate C9H15NO2 详情 详情
(XI) 13488 (2S)-3-Butyn-2-ol; (S)-(-)-3-Butyn-2-ol 2914-69-4 C4H6O 详情 详情
(XII) 13489 ethyl 4-(bromomethyl)-4-[[(1S)-1-methyl-2-propynyl]oxy]-1-piperidinecarboxylate C13H20BrNO3 详情 详情
(XIII) 13490 ethyl (2S)-2-methyl-3-methylene-1-oxa-8-azaspiro[4.5]decane-8-carboxylate C13H21NO3 详情 详情

合成路线19

该中间体在本合成路线中的序号：(III)

The epoxidation of the chiral cyclohexenone (I) with H2O2 and NaOH in methanol gives the epoxide (II), which is condensed with triethyl phosphonoacetate (III) by means of NaH in THF to yield the cyclohexylidene acetate (IV). The regioselective opening of the epoxide ring of (V) by means of formic acid, Pd2(dba)3 and Bu3P in chloroform affords the cyclohexanol derivative (V), which is silylated by means of Tbdms-Cl and imidazole to provide the fully silylated compound (VI). The reduction of the ester group of (VI) by means of DIBAL in toluene gives the primary alcohol (VII) (1), which is treated with NCS and Me2S in dichloromethane to yield the chloride compound (VIII). The reaction of (VIII) with lithium diphenylphosphide, followed by oxidation with H2O2 affords the phosphine oxide (IX), which is condensed with the known synthon (X) by means of BuLi in THF to provide the silylated precursor (XI). Finally, this compound is desilylated by means of TBAF in THF to afford the target 1-alpha,25-dihydroxy-19-nor-vitamin D3.

参考文献 中间体
合成目标
【1】 Hanazawa, T.; et al.; Efficient and practical synthesis of the A-ring precursor of 19-nor-1alpha,25-dihydroxyvitamin D3 and its (3C- or 2H-labeled derivative. Org Lett 2001, 3, 14, 2205.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 57138 (5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclohexen-1-one C12H22O2Si 详情 详情
(II) 57139 (1S,4S,6S)-4-{[tert-butyl(dimethyl)silyl]oxy}-7-oxabicyclo[4.1.0]heptan-2-one C12H22O3Si 详情 详情
(III) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(IV) 57148 ethyl 2-((1R,4R,6S)-4-{[tert-butyl(dimethyl)silyl]oxy}-7-oxabicyclo[4.1.0]hept-2-ylidene)acetate C16H28O4Si 详情 详情
(V) 57149 ethyl 2-((3R,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxycyclohexylidene)acetate C16H30O4Si 详情 详情
(VI) 49047 ethyl 2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)acetate C22H44O4Si2 详情 详情
(VII) 49048 2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)-1-ethanol C20H42O3Si2 详情 详情
(VIII) 57150 tert-butyl(dimethyl)silyl (1R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-(2-chloroethylidene)cyclohexyl ether; tert-butyl{[(1R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-(2-chloroethylidene)cyclohexyl]oxy}dimethylsilane C20H41ClO2Si2 详情 详情
(IX) 30302 [2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)ethyl(diphenyl)phosphine oxide C32H51O3PSi2 详情 详情
(X) 47151 ethyl 4-[[4-(benzyloxy)-2-hydroxy-3,6-dimethylbenzoyl]oxy]-2-hydroxy-3,6-dimethylbenzoate C27H28O7 详情 详情
(XI) 57147 [((1R,5R)-3-[2-((1R,7aR)-1-{(1R)-1,5-dimethyl-5-[(trimethylsilyl)oxy]hexyl}-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene]-5-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)oxy](tert-butyl)dimethylsilane; (5R)-5-{(1R,7aR)-4-[(E)-2-((3R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}cyclohexylidene)ethylidene]-7a-methyloctahydro-4H-inden-1-yl}-1,1-dimethylhexyl trimethylsilyl ether C41H80O3Si3 详情 详情

合成路线20

该中间体在本合成路线中的序号：(II)

The condensation of 3-(trifluoromethyl)benzaldehyde (I) with phosphonate (II) by means of NaH in THF gives the unsaturated ester (III), which is reduced with DIBAL in ethyl ether / hexane, yielding 3-[3-(trifluoromethyl)phenyl]allyl alcohol (IV). The Sharpless asymmetric epoxidation of (IV) affords the epoxyalcohol (V), which is oxidized with pyridine·SO3 to the corresponding aldehyde and condensed with phosphorane (A) to provide the unsaturated epoxyaldehyde (VI). The condensation of aldehyde (VI) with the pentylphosphonium derivative (VII) by means of NaNH2 in THF gives the corresponding adduct (VIII). The addition of 4-oxo-7-sulfanyl-4H-1-benzopyran-2-carboxylic acid methyl ester (IX) to the epoxide group of (VIII) by means of Et3N in methanol yields the expected alpha-hydroxy thioether (X), which is finally hydrolyzed with NaOH in THF/water to afford the target sodium salt. The intermediate pentylphosphonium derivative (VII) has been obtained by selective alkylation of 2,4-dihydroxy-3-propylacetophenone (XI) with 1,5-dibromopentane (XII) followed by reaction of the resulting ether with triphenylphosphine in refluxing toluene.

参考文献 中间体
合成目标
【1】 Von Sprecher, A.; Beck, A.; Sallmann, A.; Breitenstein, W.; Wiestner, H.; Kimmel, S.; Anderson, G.P.; Subramanian, N.; Bray, M.A.; Peptidoleukotriene antagonists: Structural analogs of leukotriene D4 with special emphasis on CGP 45715A. Drugs Fut 1991, 16, 9, 827.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 20110 2-(triphenylphosphoranyl)acetaldehyde C20H19OP 详情 详情
(I) 35964 3-(trifluoromethyl)benzaldehyde 454-89-7 C8H5F3O 详情 详情
(II) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(III) 42936 ethyl (E)-3-[3-(trifluoromethyl)phenyl]-2-propenoate 113048-68-3 C12H11F3O2 详情 详情
(IV) 42937 (E)-3-[3-(trifluoromethyl)phenyl]-2-propen-1-ol C10H9F3O 详情 详情
(V) 42938 [(2S,3R)-3-[3-(trifluoromethyl)phenyl]oxiranyl]methanol C10H9F3O2 详情 详情
(VI) 42939 (E)-3-[(2S,3R)-3-[3-(trifluoromethyl)phenyl]oxiranyl]-2-propenal C12H9F3O2 详情 详情
(VII) 42940 [5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl](triphenyl)phosphonium bromide C34H38BrO3P 详情 详情
(VIII) 42941 1-[2-hydroxy-3-propyl-4-[((5Z,7E)-8-[(2S,3R)-3-[3-(trifluoromethyl)phenyl]oxiranyl]-5,7-octadienyl)oxy]phenyl]-1-ethanone C28H31F3O4 详情 详情
(IX) 42942 methyl 4-oxo-7-sulfanyl-4H-chromene-2-carboxylate C11H8O4S 详情 详情
(X) 42943 methyl 7-[((1S,2E,4Z)-9-(4-acetyl-3-hydroxy-2-propylphenoxy)-1-[(R)-hydroxy[3-(trifluoromethyl)phenyl]methyl]-2,4-nonadienyl)sulfanyl]-4-oxo-4H-chromene-2-carboxylate C39H39F3O8S 详情 详情
(XI) 13137 2',4'-Dihydroxy-3'-propylacetophenone; 1-(2,4-Dihydroxy-3-propylphenyl)-1-ethanone 40786-69-4 C11H14O3 详情 详情
(XII) 30560 1,5-dibromopentane 111-24-0 C5H10Br2 详情 详情

合成路线21

该中间体在本合成路线中的序号：

The racemic compound RP 58866 was synthesized as follows: The ethyl ester of (2,3-dihydro-4H-1-benzopyran-4-ylidene)acetic acid (II) is prepared by carrying out the Wittig-Horner reaction on commercially available chromanone (I), followed by catalytic hydrogenation over 10% Pd on carbon to yield the ethyl ester of 3,4-dihydro-2H-1-benzopyran-4-acetic acid (III). Reduction of this ester with lithium aluminum hydride gives the alcohol (IV), which is converted into the corresponding bromide (V) (1, 3) by reaction with N,N'-carbonyldiimidazole and an excess of allyl bromide. Subsequent condensation of (V) with 4-(3,4-dimethoxyphenyl)piperidine (VI) by refluxing in 2-butanone, followed by the addition of (E)-2-butenedioic acid (fumaric acid), yields the salt (RS)-1-[2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4-(3,4-dimethoxyphenyl)piperidine (E)-2-butenedioate (1:1) (VII).

参考文献 中间体
合成目标
【1】 Hardy, J.-C.; Renault, C. (Aventis SA); Novel benzopyran derivs., their preparation and medicines containing them. (Rhône-Poulenc Santé). AU 8819713; EP 0300908; FR 2618437; JP 1989040476; US 4977166 .
【2】 Barreau, M.; Hardy, J.-C.; Martin, J.-P.; Renault, C. (Aventis SA); Benzopyran derivs., their preparation and pharmaceutical compsns. Containing them. (Rhône-Poulenc Santé). AU 9048584; EP 0379441; FR 2642069; JP 1990233675; US 5025013 .
【3】 Barreau, M.; Hardy, J.-C.; Renault, C. (Aventis SA); Novel benzopyran derivs., their preparation and pharmaceutical compsns. containing them. (Rhône-Poulenc Santé). AU 9048583; EP 0379440; FR 2642068; JP 1990229188; US 4994470 .
【4】 Mestre, M.; Cavero, I.; Hardy, J.-C.; Barreau, M.; Terikalant Fumarate. Drugs Fut 1992, 17, 12, 1097.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
23808 Fumaric acid; (E)-2-butenedioic acid 110-17-8 C4H4O4 详情 详情
(I) 14461 2,3-Dihydro-4H-chromen-4-one; 4-Chromanone 491-37-2 C9H8O2 详情 详情
(II) 14462 ethyl 2-(2,3-dihydro-4H-chromen-4-ylidene)acetate C13H14O3 详情 详情
(III) 14463 ethyl 2-(3,4-dihydro-2H-chromen-4-yl)acetate C13H16O3 详情 详情
(IV) 14464 2-(3,4-dihydro-2H-chromen-4-yl)-1-ethanol C11H14O2 详情 详情
(V) 14465 4-(2-bromoethyl)chromane C11H13BrO 详情 详情
(VI) 14466 4-(3,4-dimethoxyphenyl)piperidine; 2-methoxy-4-(4-piperidinyl)phenyl methyl ether C13H19NO2 详情 详情

合成路线22

该中间体在本合成路线中的序号：(II)

The Wittig condensation of cis-bicyclo[4.3.0]nona-3-en-8-one (I) with triethyl phosphonoacetate (II) by means of NaH in THF gives 2-(cis-bicyclo[4.3.0]octa-3-en-8-ylidene)acetic acid ethyl ester (III), which is reduced with Li in liquid ammonia to the corresponding ethanol derivative (IV). The condensation of (IV) with N-benzyl-2-chloro-N-phenylacetamide (V) by means of NaH in toluene affords the corresponding ethoxyacetamide (VI), which is treated with ozone in methanol to give the epoxide (VII). Cleavage of (VII) with dimethyl sulfide in the same solvent yields the dialdehyde (VIII), which is submitted to an aldol cyclization by means of NaOH in methanol/water to afford the 2beta-formyl-3alpha-hydroxy derivative (IX). The Wittig condensation of aldehyde (IX) with dimethyl 4(S)-methyl-2-oxooctylphosphonate (X) by means of NaH in THF gives the unsaturated hydroxy ketone (XI). The ketone group of (XI) is reduced with NaBH4 in methanol, and the resulting diastereomeric diols obtained are separated by column chromatography to yield the alpha,alpha-dihydroxy compound (XII). The hydrolysis of (XII) with KOH in refluxing ethanol/water yields the corresponding free acid (XIII), which is finally methylated with diazomethane in ethyl ether to obtain a mixture of the epoxy alcohol (XXIVa) and the unsaturated alcohol (XXIVb). A chromatographic separation of the mixture followed by desilylation with acetic acid in methanol gives the desired final product.

参考文献 中间体
合成目标
【1】 Mealy, N.; Castaner, J.; Pimilprost. Drugs Fut 1996, 21, 4, 369.
【2】 Muraoka, M.; Nakamura, T.; Sugie, A.; Ono, K.; Yamamoto, M. (Sumitomo Pharmaceuticals Co., Ltd.); Bicyclooctane derivs. and their production and use. EP 0115954 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 14816 (3aR,7aS)-1,3,3a,4,7,7a-hexahydro-2H-inden-2-one C9H12O 详情 详情
(II) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(III) 14818 ethyl 2-[(3aR,7aS)-1,3,3a,4,7,7a-hexahydro-2H-inden-2-ylidene]acetate C13H18O2 详情 详情
(IV) 14819 2-[(3aR,7aS)-2,3,3a,4,7,7a-hexahydro-1H-inden-2-yl]-1-ethanol C11H18O 详情 详情
(V) 14820 N-benzyl-2-chloro-N-phenylacetamide C15H14ClNO 详情 详情
(VI) 14821 2-[2-[(3aR,7aS)-2,3,3a,4,7,7a-hexahydro-1H-inden-2-yl]ethoxy]-N-benzyl-N-phenylacetamide C26H31NO2 详情 详情
(VII) 14822 2-[2-[(2aR,5aS)octahydro-1aH-indeno[5,6-b]oxiren-4-yl]ethoxy]-N-benzyl-N-phenylacetamide C26H31NO3 详情 详情
(VIII) 14823 N-benzyl-2-[2-[(3R,4S)-3,4-bis(2-oxoethyl)cyclopentyl]ethoxy]-N-phenylacetamide C26H31NO4 详情 详情
(IX) 14824 2-[2-[(2R,3aS,4R,5R,6aS)-4-formyl-5-hydroxyoctahydro-2-pentalenyl]ethoxy]-N-benzyl-N-phenylacetamide C26H31NO4 详情 详情
(X) 14825 dimethyl (4S)-4-methyl-2-oxooctylphosphonate C11H23O4P 详情 详情
(XI) 14826 2-(2-[(2R,3aS,4S,5R,6aS)-5-hydroxy-4-[(E,5S)-5-methyl-3-oxo-1-nonenyl]octahydro-2-pentalenyl]ethoxy)-N-benzyl-N-phenylacetamide C35H47NO4 详情 详情
(XII) 14827 2-(2-[(2R,3aS,4S,5R,6aS)-5-hydroxy-4-[(E,3S,5S)-3-hydroxy-5-methyl-1-nonenyl]octahydro-2-pentalenyl]ethoxy)-N-benzyl-N-phenylacetamide C35H49NO4 详情 详情
(XIII) 14828 2-(2-[(2R,3aS,4S,5R,6aS)-5-hydroxy-4-[(E,3S,5S)-3-hydroxy-5-methyl-1-nonenyl]octahydro-2-pentalenyl]ethoxy)acetic acid C22H38O5 详情 详情

合成路线23

该中间体在本合成路线中的序号：(IX)

The intermediate carboxylic acid (XIII) was prepared as follows: 2-(4-Hydroxyphenyl)ethanol (VI) was selectively protected at the phenolic hydroxyl with benzyl bromide, yielding (VII). Subsequent oxidation of the aliphatic alcohol group of (VII) with Dess-Martin periodinane reagent provided aldehyde (VIII). Wadsworth-Emmons condensation of (VIII) with the sodium derivative of phosphonate (IX) furnished adduct (X), which was further hydrogenated over Pd/C to the saturated ester (XI). The phenolic hydroxyl group of (XI), which was concomitantly debenzylated in the preceding hydrogenation step, was further reprotected as the methoxymethyl ether (XII). Acid (XIII) was then obtained by basic hydrolysis of ester (XII).

参考文献 中间体
合成目标
【1】 Takaoka, E.; et al.; Catalytic asymmetric synthesis of arbutamine. Heterocycles 1997, 46, 157.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 47355 4-(2-hydroxyethyl)phenol 501-94-0 C8H10O2 详情 详情
(VII) 33328 2-(p-Benzyloxyphenyl)ethanol; 2-[4-(Benzyloxy)phenyl]-1-ethanol C15H16O2 详情 详情
(VIII) 55597 2-[4-(benzyloxy)phenyl]acetaldehyde C15H14O2 详情 详情
(IX) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(X) 55598 ethyl (E)-4-[4-(benzyloxy)phenyl]-2-butenoate C19H20O3 详情 详情
(XI) 55599 ethyl 4-(4-hydroxyphenyl)butanoate C12H16O3 详情 详情
(XII) 55600 ethyl 4-[4-(methoxymethoxy)phenyl]butanoate C14H20O4 详情 详情
(XIII) 55601 4-[4-(methoxymethoxy)phenyl]butanoic acid C12H16O4 详情 详情

合成路线24

该中间体在本合成路线中的序号：(VII)

By condensation of 3-[2(E)-(4-(2,2,3,3-tetrafluoropropoxy)phenyl)vinyl]-1H-1,2,4-triazole (I) with (+)-(R)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-epoxypropane (II) by means of anhydrous K2CO3 in hot DMF. The starting products (I) and (II) are obtained as follows: a) The condensation of 4-chlorobenzonitrile (III) with 2,2,3,3-tetrafluoropanol (IV) by means of NaH in DMF gives 4-(2,2,3,3-tetrafluoropropoxy)benzonitrile (V), which is reduced to the corresponding benzaldehyde (VI) with diisobutylaluminum hydride in toluene. The condensation of diethoxyphosphorylacetic acid ethyl ester (VII) with aldehyde (VI) by means of KOH in THF yields (E)-4-(2,2,3,3-tetrafluoropropoxy)cinnamic acid ethyl ester (VIII), which is saponified to the corresponding acid (IX) with NaOH in ethanol-water. The reaction of (IX) first with refluxing SOCl2 and then with aqueous ammonia in toluene affords the corresponding amide (X), which is finally condensed with formyl hydrazide (XI) by means of trimethyloxonium tetrafluoroborate in CH2Cl2 to give (I). b) The reaction of 1,3-dichloroacetone (XII) with 2,4-difluorobromobenzene (XIII) by means of butyllithium in ether gives 1,3-dichloro-2-(2,4-difluorophenyl)-2-propanol (XIV), which is converted into 3-chloro-2-(2,4-difluorophenyl)-1,2-epoxypropane (XV) by treatment with NaH in DMF. The reaction of (XV) with tellurium and sodium hydroxymethylsulfinate in water yields 2-(2,4-difluorophenyl)allyl alcohol (XVI), which by stereoselective epoxidation with titanium tetraisopropoxide and diethyl (+)-tartrate in methylene chloride is converted into (R)-(-)-2-(2,4-difluorophenyl)-2,3-epoxypropanol (XVII). The reaction of (XVII) with 1,2,4-triazole (XVIII) by means of K2CO3 in THF affords (S)-(-)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazole-1-yl)-propane-1,2-diol (XIX), which is finally treated with methanesulfonyl chloride and triethylamine in ether to give (II).

参考文献 中间体
合成目标
【1】 Murakami, K.; Mochizuki, H. (AstraZeneca plc; Mochida Pharmaceutical Co., Ltd.); Optically active triazole derivs. and compsns. EP 0472392; JP 1993009183 .
【2】 Fromtling, R.A.; Castaner, J.; ICI-D0870. Drugs Fut 1993, 18, 5, 424.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 15476 2,2,3,3-tetrafluoropropyl 4-[(E)-2-(1H-1,2,4-triazol-3-yl)ethenyl]phenyl ether; 3-[(E)-2-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]ethenyl]-1H-1,2,4-triazole C13H11F4N3O 详情 详情
(II) 15477 1-[[(2R)-2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole C11H9F2N3O 详情 详情
(III) 15478 4-methylcyclohexanecarbonitrile C8H13N 详情 详情
(IV) 15479 2,2,3,3-tetrafluoro-1-propanol 76-37-9 C3H4F4O 详情 详情
(V) 15480 4-(2,2,3,3-tetrafluoropropoxy)benzonitrile C10H7F4NO 详情 详情
(VI) 15481 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde C10H8F4O2 详情 详情
(VII) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(VIII) 15483 ethyl (E)-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-propenoate C14H14F4O3 详情 详情
(IX) 15484 (E)-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-propenoic acid C12H10F4O3 详情 详情
(X) 15485 (E)-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-propenamide C12H11F4NO2 详情 详情
(XI) 15486 formic hydrazide; Formylhydrazine 624-84-0 CH4N2O 详情 详情
(XII) 63907 1,3-dichloroacetone C3H4Cl2O 详情 详情
(XIII) 15488 1-bromo-2,4-difluorobenzene 348-57-2 C6H3BrF2 详情 详情
(XIV) 15489 1,3-dichloro-2-(2,4-difluorophenyl)-2-propanol C9H8Cl2F2O 详情 详情
(XV) 15490 2-(chloromethyl)-2-(2,4-difluorophenyl)oxirane C9H7ClF2O 详情 详情
(XVI) 15491 2-(2,4-difluorophenyl)-2-propen-1-ol C9H8F2O 详情 详情
(XVII) 64587 [(2R)-2-(2,4-difluorophenyl)oxiranyl]methanol C9H8F2O2 详情 详情
(XVIII) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(XIX) 15494 (2S)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol C11H11F2N3O2 详情 详情

合成路线25

该中间体在本合成路线中的序号：(VI)

This compound was prepared by two ways starting from 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (I). Alkylation of (I) with 2-chlorocyclohexanone (II) in the presence of NaH in DMF gave diketone (V). Alternatively, condensation of (I) with epoxycyclohexane and NaH in DMF at 127 C yielded the ketoalcohol (IV) as a mixture of cis and trans isomers, which were separated by column chromatography. The major trans isomer was then oxidized with pyridinium dichromate to the diketone (V). Reaction of this diketone with the sodium salt of triethyl phosphonoacetate (VI) in toluene at 100 C afforded a mixture of unsaturated esters (VII) and (VIII), which were subsequently submitted to hydrolysis with NaOH. Then, column chromatography of the mixture provided the desired endocyclic unsaturated acid.

参考文献 中间体
合成目标
【1】 Tenda, Y.; Kinoshita, T.; Sakane, K.; Nishimura, S.; Akahane, A.; Durkin, K.; Kuroda, S.; Discovery of FR166124, a novel water-soluble pyrazolo-[1,5-a]pyridine adenosine A1 receptor antagonist. Bioorg Med Chem Lett 1999, 9, 14, 1979.
【2】 Akahane, A.; Nishimura, S.; Itani, H.; Durkin, K.P.M. (Fujisawa Pharmaceutical Co., Ltd.); Pyrazolopyridine adenosine antagonists. EP 0737193; JP 1997507485; US 5773530; WO 9518128 .
【3】 Zanka, A.; et al.; Process improvements in the production of a novel non-xanthine adenosine A1 receptopr antagonist. A "one-pot" horner-emmons isomerization reaction. Org Process Res Dev 1999, 3, 6, 394.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 17984 6-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3(2H)-pyridazinone C17H12N4O 详情 详情
(II) 17985 2-Chlorocyclohexanone 822-87-7 C6H9ClO 详情 详情
(III) 17986 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide 286-20-4 C6H10O 详情 详情
(IV) 17987 2-(2-hydroxycyclohexyl)-6-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3(2H)-pyridazinone C23H22N4O2 详情 详情
(V) 17988 2-(2-oxocyclohexyl)-6-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3(2H)-pyridazinone C23H20N4O2 详情 详情
(VI) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(VII) 17990 ethyl 2-[2-[6-oxo-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1(6H)-pyridazinyl]cyclohexylidene]acetate C27H26N4O3 详情 详情
(VIII) 17991 ethyl 2-[2-[6-oxo-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1(6H)-pyridazinyl]-1-cyclohexen-1-yl]acetate C27H26N4O3 详情 详情

合成路线26

该中间体在本合成路线中的序号：(II)

The condensation of isobutyraldehyde (I) with triethyl phosphonoacetate (II) by means of NaH in THF gives 4-methyl-2-pentenoic acid ethyl ester (III), which is reduced with DIBAL in THF to yield the allyl alcohol (IV). The Sharpless asymmetric epoxidation of (IV) by means of Ti(O-iPr)4, (+)-diethyl tartrate ((+)-DET) and tBu-OOH in toluene affords the epoxy alcohol (V), which is treated with trichloroacetonitrile and DBU to provide the acetimidate (VI). The cyclization of (VI) by means of triethyl aluminum chloride in dichloromethane gives the oxazoline (VII), which is silylated with Tbdms-OTf and TEA in dichloromethane to afford the silyl ether (VIII). The cleavage of the oxazoline ring of (VIII) by means of HCl in THF yields the chiral amino alcohol (IX), which is protected with Tbdms-OTf as before to afford the silylated amine (X). The monoalkylation of (X) with 1,3-dibromo-2-methylpropene (XI) and Cs-OH in DMF provides the secondary amine (XII). The cyclization of (XII) by means of KHMDS in toluene/ethyl ether gives the non isolated intermediate (XIII) that rearranges to the pyrroline (XIV). The reaction of (XIV) with TPAP and NMO in acetonitrile yields the cyclic imine (XV), which is oxidized with NaClO2 to the 1-chloropyrrolin-2-one (XVI). The dechlorination of (XVI) by means of NaBH4 affords the pyrrolinone (XVII), which is selectively monodesilylated with TBAF in THF to provide the primary alcohol (XVIII). The cyclization of (XVIII) with benzaldehyde dimethylacetal and Ts-OH in refluxing toluene gives the bicyclic pyrrolo oxazole (XIX), which is finally deprotected by means of TBAF in THF to yield the target bicyclic intermediate (XX) (see scheme no. 23327701c intermediate (XXXII)).

参考文献 中间体
合成目标
【1】 Green, M.P.; et al.; An enantioselective formal synthesis of the proteasome inhibitor (+)-lactacystin. Tetrahedron Lett 2002, 43, 37, 6609.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(II) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(III) 57196 ethyl (E)-4-methyl-2-pentenoate C8H14O2 详情 详情
(IV) 43593 (E)-4-methyl-2-penten-1-ol C6H12O 详情 详情
(V) 57181 [(2S,3S)-3-isopropyloxiranyl]methanol C6H12O2 详情 详情
(VI) 57182 [(2S,3S)-3-isopropyloxiranyl]methyl 2,2,2-trichloroethanimidoate C8H12Cl3NO2 详情 详情
(VII) 57183 (1S)-2-methyl-1-[(4R)-2-(trichloromethyl)-4,5-dihydro-1,3-oxazol-4-yl]-1-propanol C8H12Cl3NO2 详情 详情
(VIII) 57184 (4R)-4-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-2-(trichloromethyl)-4,5-dihydro-1,3-oxazole; tert-butyl(dimethyl)silyl (1S)-2-methyl-1-[(4R)-2-(trichloromethyl)-4,5-dihydro-1,3-oxazol-4-yl]propyl ether C14H26Cl3NO2Si 详情 详情
(IX) 57185 (2R,3S)-2-amino-3-{[tert-butyl(dimethyl)silyl]oxy}-4-methyl-1-pentanol C12H29NO2Si 详情 详情
(X) 57186 (5S,6R)-5-isopropyl-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-amine; (1R,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-methylbutylamine C18H43NO2Si2 详情 详情
(XI) 57187 (E)-1,3-dibromo-2-methyl-1-propene C4H6Br2 详情 详情
(XII) 57188 N-[(E)-3-bromo-2-methyl-2-propenyl]-N-[(1R,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-methylbutyl]amine; (5S,6R)-N-[(E)-3-bromo-2-methyl-2-propenyl]-5-isopropyl-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-amine C22H48BrNO2Si2 详情 详情
(XIII) 57189 (5S,6S)-N-[(Z)-3-bromo-2-methyl-2-propenyl]-5-isopropyl-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-amine; N-[(Z)-3-bromo-2-methyl-2-propenyl]-N-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-methylbutyl]amine C22H48BrNO2Si2 详情 详情
(XIV) 57190 (2R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-4-methyl-2,5-dihydro-1H-pyrrole; tert-butyl(dimethyl)silyl (1S)-1-[(2R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methyl-2,5-dihydro-1H-pyrrol-2-yl]-2-methylpropyl ether C22H47NO2Si2 详情 详情
(XV) 57191 tert-butyl(dimethyl)silyl (1S)-1-[(2R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methyl-2H-pyrrol-2-yl]-2-methylpropyl ether; (2R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-4-methyl-2H-pyrrole C22H45NO2Si2 详情 详情
(XVI) 57192 (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-1-chloro-3-methyl-1,5-dihydro-2H-pyrrol-2-one C22H44ClNO3Si2 详情 详情
(XVII) 57193 (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-3-methyl-1,5-dihydro-2H-pyrrol-2-one C22H45NO3Si2 详情 详情
(XVIII) 57194 (5R)-5-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-5-(hydroxymethyl)-3-methyl-1,5-dihydro-2H-pyrrol-2-one C16H31NO3Si 详情 详情
(XIX) 57195 (3S,7aS)-7a-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-6-methyl-3-phenyl-1,7a-dihydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one C23H35NO3Si 详情 详情
(XX) 43612 (3S,7aR)-7a-[(1S)-1-hydroxy-2-methylpropyl]-6-methyl-3-phenyl-1,7a-dihydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one C17H21NO3 详情 详情

合成路线27

该中间体在本合成路线中的序号：(A)

Wittig reaction between aldehyde (I) and bromo derivative (II) by means of triethyl phosphonoacetate and NaH in 1,2-dimethoxyethane (A) affords a mixture of isomeric acrylates (IIIa-b), which are hydrogenated over Pd/C in EtOH to yield derivative (IV). Hydrolysis of ethyl ester (IV) by means of KOH or NaOH provides carboxylic acid (V), which is then converted into N-protected derivative (VI) by first treatment with diphenylphosphoryl azide (DPPA) and Et3N in refluxing benzene, followed by reaction with refluxing t-butanol. Boc removal of (VI) with TFA in CH2Cl2 furnishes free amine (VII), which is finally alkylated with propyl bromide (VIII) by means of K2CO3 in DMF to yield the target product.

参考文献 中间体
合成目标
【1】 Tomisawa, K.; Ohta, K.; Nakazato, A.; Kumagai, T.; Chaki, S.; Okuyama, S.; Synthesis and SAR of 1-alkyl-2-phenylethylamine derivatives designed from N,N-dipropyl-4-methoxy-3-(2-phenylethoxy)phenylethylamine to discover sigma1 ligands. J Med Chem 1999, 42, 19, 3965.
【2】 Nakazato, A.; Kumagai, T.; Miyazawa, T.; Ohta, K.; Kawashima, Y.; Hatayama, K. (Taisho Pharmaceutical Co., Ltd.); Optically active substd. phenylalkylamine derivs.. EP 0870758; JP 1997059230; US 5990151; WO 9700238 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(IIIa) 46235 ethyl (Z)-2-isopentyl-3-[4-methoxy-3-(phenethyloxy)phenyl]-2-propenoate C25H32O4 详情 详情
(IIIb) 46236 ethyl (E)-2-isopentyl-3-[4-methoxy-3-(phenethyloxy)phenyl]-2-propenoate C25H32O4 详情 详情
(I) 23679 4-methoxy-3-(phenethyloxy)benzaldehyde C16H16O3 详情 详情
(II) 46234 1-bromo-3-methylbutane C5H11Br 详情 详情
(IV) 46237 ethyl 2-[4-methoxy-3-(phenethyloxy)benzyl]-5-methylhexanoate C25H34O4 详情 详情
(V) 46238 2-[4-methoxy-3-(phenethyloxy)benzyl]-5-methylhexanoic acid C23H30O4 详情 详情
(VI) 46239 tert-butyl 1-[4-methoxy-3-(phenethyloxy)benzyl]-4-methylpentylcarbamate C27H39NO4 详情 详情
(VII) 46240 1-[4-methoxy-3-(phenethyloxy)benzyl]-4-methylpentylamine; 1-[4-methoxy-3-(phenethyloxy)phenyl]-5-methyl-2-hexanamine C22H31NO2 详情 详情
(VIII) 19502 Propyl bromide; 1-Bromopropane 106-94-5 C3H7Br 详情 详情

合成路线28

该中间体在本合成路线中的序号：(V)

The intermediate N-Boc-amino acid (VII) was synthesized as shown in Scheme 25409101a. Treatment of 3-(tert-butoxycarbonylamino)-3-methylbutanoic acid (I) with ethyl chloroformate and Et3N, followed by reduction of the resulting mixed anhydride (II) with LiBH4, provided alcohol (III). Then, oxidation of (III) under Swern conditions yielded aldehyde (IV). Subsequent Horner-Emmons condensation of (IV) with triethyl phosphonoacetate (V) in the presence of potassium tert-butoxide gave ester (VI), which was saponified with LiOH to provide the required carboxylic acid (VII).

参考文献 中间体
合成目标
【1】 Hansen, T.K.; Ankersen, M.; Hansen, B.S.; Raun, K.; Nielsen, K.K.; Lau, J.; Peschke, B.; Lundt, B.F.; Thogersen, H.; Johansen, N.L.; Madsen, K.; Andersen, P.H.; Novel orally active growth hormone secretagogues. J Med Chem 1998, 41, 19, 3705.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
29841 Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride 79-37-8 C2Cl2O2 详情 详情
(I) 22193 3-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(II) 27229 3-(Tert-butoxycarbonylamino)-3-methyl butyric acid ethoxycarbonyl anhydride C13H23NO6 详情 详情
(III) 22194 tert-butyl 3-hydroxy-1,1-dimethylpropylcarbamate C10H21NO3 详情 详情
(IV) 22195 tert-butyl 1,1-dimethyl-3-oxopropylcarbamate C10H19NO3 详情 详情
(V) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(VI) 27230 ethyl (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoate C14H25NO4 详情 详情
(VII) 22191 (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoic acid C12H21NO4 详情 详情

合成路线29

该中间体在本合成路线中的序号：(VII)

The cyclization of 3-methyl-2-buten-1-ol (I) with acetonitrile (II) gives 2,4,4-trimethyl-5,6-dihydro-4H-1,3-oxazine (III), which is hydrolyzed with NaOH to yield 3-amino-3-methyl-1-butanol (IV). The protection of the amino group of (IV) with (Boc)2O in isopropanol affords the carbamate (V), which is oxidized at the primary OH group with SO3/pyridine and TEA to provide the aldehyde (VI). The condensation of (VI) with triethyl phosphonoacetate (VII) by means of potassium tert-butoxide in hot toluene gives the desired hexenoic ester (intermediate 27230), which is hydrolyzed with NaOH in refluxing ethanol to yield the corresponding acid intermediate (intermediate 22191).

参考文献 中间体
合成目标
【1】 Jessen, C.U.; et al.; Synthesis of N-protected 14C-labelled (2E)-5-amino-5-methylhex-2-enoic acid analogues. J Label Compd Radiopharm 2001, 44, 4, 265.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 37754 3-methyl-2-buten-1-ol 556-82-1 C5H10O 详情 详情
(II) 37210 acetonitrile 75-05-8 C2H3N 详情 详情
(III) 46630 2,4,4-trimethyl-5,6-dihydro-4H-1,3-oxazine C7H13NO 详情 详情
(IV) 46631 3-amino-3-methyl-1-butanol C5H13NO 详情 详情
(V) 22194 tert-butyl 3-hydroxy-1,1-dimethylpropylcarbamate C10H21NO3 详情 详情
(VI) 22195 tert-butyl 1,1-dimethyl-3-oxopropylcarbamate C10H19NO3 详情 详情
(VII) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(VIII) 27230 ethyl (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoate C14H25NO4 详情 详情
(IX) 22191 (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoic acid C12H21NO4 详情 详情

合成路线30

该中间体在本合成路线中的序号：(IV)

The reaction of 2,3-dihydrobenzofuran (I) with dichloromethyl methyl ether (II) by means of TiCl4 in dichloromethane gives 2,3-dihydrobenzofuran-5-carbaldehyde (III), which is condensed with the phosphonate (IV) by means of NaH in THF to yield the propenoic ester (V). The reduction of (V) with H2 over Pd/C in ethanol affords the saturated propionic ester (VI), which is brominated with Br2 in HOAc providing the 7-bromo derivative (VII). Further bromination of (VII) with Br2 and Fe in HOAc gives the 6,7-dibromo derivative (VIII), which is hydrolyzed with NaOH in THF/water to yield the propionic acid derivative (IX). The reaction of (IX) with hot SOCl2 affords the corresponding acyl chloride (X), which is cyclized by means of AlCl3 in dichloroethane to provide 4,5-dibromo-2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-one (XI). The debromination of (XI) by means of H2 over Pd/C in Ac-OH gives 2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-one (XII), which is condensed with the phosphorane (XIII) by means of NaH in THF to yield 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ylidene)acetonitrile (XIV). The selective reduction of the cyano group of (XIV) by means of H2 over Raney cobalt in ethanol/NH3 affords 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ylidene)ethylamine (XV), which is condensed with propionyl chloride (XVI) by means of TEA in THF to provide the propionamide (XVII). Finally this compound is enantioselectively reduced with H2 over a chiral Ru catalyst (Ru(OAc)2-(S)-BINAP) in methanol to give rise to the target (S)-enantiomer. Alternatively, the reduction of 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ylidene)acetonitrile (XIV) with H2 over RaNi in ethanol/NH3 gives 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-yl)ethylamine (XVIII), which is acylated with propionyl chloride (XVI) and TEA in DMF to yield the racemic propionamide (XIX). Finally this compound is submitted to optical resolution by means of chiral HPLC to afford the target (S)-enantiomer.

参考文献 中间体
合成目标
【1】 Chilman-Blair, K.; Castaner, J.; Silvestre, J.S.; Bayes, M.; TAK-375. Drugs Fut 2003, 28, 10, 950.
【2】 Ohkawa, S.; Uchikawa, O.; Fukatsu, K.; Miyamoto, M. (Takeda Chemical Industries, Ltd.); Tricyclic cpds., their production and use. EP 0885210; JP 1998287665; JP 1999152281; WO 9732871 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 14499 2,3-Dihydrobenzofuran; 2,3-dihydro-1-benzofuran 496-16-2 C8H8O 详情 详情
(II) 40668 dichloro(methoxy)methane; dichloromethyl methyl ether 4885-02-3 C2H4Cl2O 详情 详情
(III) 52198 2,3-Dihydrobenzo[b]furan-5-carboxaldehyde C9H8O2 详情 详情
(IV) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(V) 57393 ethyl (E)-3-(2,3-dihydro-1-benzofuran-5-yl)-2-propenoate C13H14O3 详情 详情
(VI) 57394 ethyl 3-(2,3-dihydro-1-benzofuran-5-yl)propanoate C13H16O3 详情 详情
(VII) 57395 ethyl 3-(7-bromo-2,3-dihydro-1-benzofuran-5-yl)propanoate C13H15BrO3 详情 详情
(VIII) 57396 ethyl 3-(6,7-dibromo-2,3-dihydro-1-benzofuran-5-yl)propanoate C13H14Br2O3 详情 详情
(IX) 57397 3-(6,7-dibromo-2,3-dihydro-1-benzofuran-5-yl)propanoic acid C11H10Br2O3 详情 详情
(X) 57398 3-(6,7-dibromo-2,3-dihydro-1-benzofuran-5-yl)propanoyl chloride C11H9Br2ClO2 详情 详情
(XI) 57399 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one C11H8Br2O2 详情 详情
(XII) 57400 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one C11H10O2 详情 详情
(XIII) 10045 Diethyl cyanomethylphosphonate 2537-48-6 C6H12NO3P 详情 详情
(XIV) 57401 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitrile C13H11NO 详情 详情
(XV) 57402 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)-1-ethanamine; 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ethylamine C13H15NO 详情 详情
(XVI) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(XVII) 57403 N-[2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ethyl]propanamide C16H19NO2 详情 详情
(XVIII) 57404 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)-1-ethanamine; 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine C13H17NO 详情 详情
(XIX) 57405 N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propanamide C16H21NO2 详情 详情

合成路线31

该中间体在本合成路线中的序号：(IV)

The reaction of 2,3-dihydrobenzofuran (I) with DMF (II) and POCl3 gives 2,3-dihydrobenzofuran-5-carbaldehyde (III), which is condensed with the phosphonate (IV) by means of t-BuONa in toluene to yield the acrylate (V). The reduction of (V) with H2 over Pd/C in AcOH affords the corresponding propionate (VI), which is brominated with Br2 in AcOH to provide the dibromo derivative (VII). The hydrolysis of the ester group of (VII) in acidic medium gives the expected propionic acid derivative (VIII), which is treated with SOCl2 in dichloromethane to yield the propionyl chloride (IX). The cyclization of (IX) by means of AlCl3 in dichloromethane affords the 4,5-dibromo-2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-one (X), which is submitted to an hydrogenolytic debromination with H2 over Pd/C in methanol to provide the 2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-one (XI). The Wittig condensation of (XI) with phosphonate (XII) by means of NaOMe in toluene gives 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ylidene)acetonitrile (XIII), which is reduced with H2 and Raney-Co in toluene/MeOH to yield 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ylidene)ethylamine (XIV). The asymmetric reduction of (XIV) with H2 and a chiral Ru catalyst in toluene/MeOH affords the 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8(S)-yl)ethylamine (XV), which is finally acylated with propionyl chloride (XVI) and NaOH in aq. THF to provide the target chiral propionamide.

参考文献 中间体
合成目标
【1】 Ohkawa, S.; Discovery of the novel melatonin agonist TAK-375. 22nd Symp Med Chem (Nov 27 2002, Shizuoka) 2002, Abst IL 11.
【2】 Chilman-Blair, K.; Castaner, J.; Silvestre, J.S.; Bayes, M.; TAK-375. Drugs Fut 2003, 28, 10, 950.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 14499 2,3-Dihydrobenzofuran; 2,3-dihydro-1-benzofuran 496-16-2 C8H8O 详情 详情
(II) 45439 dimethylformamide C3H7NO 详情 详情
(III) 52198 2,3-Dihydrobenzo[b]furan-5-carboxaldehyde C9H8O2 详情 详情
(IV) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(V) 57393 ethyl (E)-3-(2,3-dihydro-1-benzofuran-5-yl)-2-propenoate C13H14O3 详情 详情
(VI) 57394 ethyl 3-(2,3-dihydro-1-benzofuran-5-yl)propanoate C13H16O3 详情 详情
(VII) 57396 ethyl 3-(6,7-dibromo-2,3-dihydro-1-benzofuran-5-yl)propanoate C13H14Br2O3 详情 详情
(VIII) 57397 3-(6,7-dibromo-2,3-dihydro-1-benzofuran-5-yl)propanoic acid C11H10Br2O3 详情 详情
(IX) 57398 3-(6,7-dibromo-2,3-dihydro-1-benzofuran-5-yl)propanoyl chloride C11H9Br2ClO2 详情 详情
(X) 57399 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one C11H8Br2O2 详情 详情
(XI) 57400 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one C11H10O2 详情 详情
(XII) 10045 Diethyl cyanomethylphosphonate 2537-48-6 C6H12NO3P 详情 详情
(XIII) 57401 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitrile C13H11NO 详情 详情
(XIV) 57402 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)-1-ethanamine; 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ethylamine C13H15NO 详情 详情
(XV) 62217 2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]-1-ethanamine; 2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethylamine C13H17NO 详情 详情
(XVI) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情

合成路线32

该中间体在本合成路线中的序号：(VIII)

The indenone intermediate (XIII) has been obtained as follows: The silylation of 3-methyl-1-pentyn-3-ol (I) with Tes-Cl and DMAP in DMF gives the silyl ether (II), which is condensed with paraformaldehyde and n-BuLi in THF to yield the propargyl alcohol (III). Partial reduction of (III) with Red-Al in THF affords the allyl alcohol (IV), which is treated with Ts-Cl and DMAP in dichloromethane to provide the allyl chloride (V). The condensation of (V) with the unsaturated ester (VI) (obtained by Wittig condensation of perhydroindanone (VII) with triethyl phosphonoacetate (VIII) by means of EtONa) by means of BuLi and dicyclohexylamine in HMPA gives the octenoic ester (IX), which is reduced with LiAlH4, yielding the corresponding primary alcohol (X). The reaction of (X) with TsCl and pyridine affords the tosylate (XI), which is reduced with LiBEt3H in THF with simultaneous opening of the epoxide ring to provide the hexahydroindenol (XII). Finally, this compound is oxidized with pyridinium dichromate (PDC), yielding the target hexahydroindenone intermediate (XIII).

参考文献 中间体
合成目标
【1】 Radinov, R.N.; Daniewski, A.R. (F. Hoffmann-La Roche AG); Process for preparing anti-osteoporotic agents. EP 1048661; JP 2000336094 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 46664 3-ethyl-1-pentyn-3-ol 6285-06-9 C7H12O 详情 详情
(II) 46665 [(1,1-diethyl-2-propynyl)oxy](triethyl)silane; 1,1-diethyl-2-propynyl triethylsilyl ether C13H26OSi 详情 详情
(III) 46666 4-ethyl-4-[(triethylsilyl)oxy]-2-hexyn-1-ol C14H28O2Si 详情 详情
(IV) 46667 (E)-4-ethyl-4-[(triethylsilyl)oxy]-2-hexen-1-ol C14H30O2Si 详情 详情
(V) 46668 (E)-4-chloro-1,1-diethyl-2-butenyl triethylsilyl ether; [[(E)-4-chloro-1,1-diethyl-2-butenyl]oxy](triethyl)silane C14H29ClOSi 详情 详情
(VI) 46669 ethyl 2-[(1aS,3aS,6aR,6bR)-3a-methyloctahydro-4H-indeno[4,5-b]oxiren-4-ylidene]acetate C14H20O3 详情 详情
(VII) 45538 (1aS,3aS,6aR,6bR)-3a-methyloctahydro-4H-indeno[4,5-b]oxiren-4-one C10H14O2 详情 详情
(VIII) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(IX) 46670 ethyl (2S,4E)-2-[(1aS,3aS,6aR,6bR)-3a-methyl-2,3,3a,6,6a,6b-hexahydro-1aH-indeno[4,5-b]oxiren-4-yl]-6-ethyl-6-[(triethylsilyl)oxy]-4-octenoate C28H48O4Si 详情 详情
(X) 46671 (3aS,7S,7aR)-3-[(1S,3E)-5-ethyl-1-(hydroxymethyl)-5-[(triethylsilyl)oxy]-3-heptenyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol C26H48O3Si 详情 详情
(XI) 46672 (2S,4E)-2-[(3aS,7S,7aR)-7-hydroxy-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]-6-ethyl-6-[(triethylsilyl)oxy]-4-octenyl 4-methylbenzenesulfonate C33H54O5SSi 详情 详情
(XII) 46673 (3aS,7S,7aR)-3-[(1S,3E)-5-ethyl-1-methyl-5-[(triethylsilyl)oxy]-3-heptenyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol C26H48O2Si 详情 详情
(XIII) 46674 (3aR,7aS)-1-[(1S,3E)-5-ethyl-1-methyl-5-[(triethylsilyl)oxy]-3-heptenyl]-7a-methyl-3,3a,5,6,7,7a-hexahydro-4H-inden-4-one C26H46O2Si 详情 详情

合成路线33

该中间体在本合成路线中的序号：(II)

The Wadsworth-Emmons condensation of 3-pentanone (I) with phosphonate (II) affords the conjugated ester adduct (III). Subsequent double bond hydrogenation in (III), in the presence of Pd/C, leads to the saturated ester (IV). After basic hydrolysis of the ethyl ester group of (IV), the resultant carboxylic acid (V) is activated as the corresponding acid chloride (VI) upon treatment with SOCl2. Then, acylation of the silver acetylide of methyl propiolate (VII) with acid chloride (VI) gives rise to the oxo ester intermediate (VIII).

参考文献 中间体
合成目标
【1】 Mori, S.; Takechi, S.; Kida, S.; Mizui, T.; Ichihashi, T. (Shionogi & Co. Ltd.); Lignan analog, production thereof, and hypolipidemic drug. EP 0597107; EP 0701991; JP 1993310634; US 5731455; WO 9308155 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 32415 Propione; Dimethylacetone; Diethyl ketone; 3-Pentanone 96-22-0 C5H10O 详情 详情
(II) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(III) 57428 ethyl 3-ethyl-2-pentenoate C9H16O2 详情 详情
(IV) 57429 ethyl 3-ethylpentanoate C9H18O2 详情 详情
(V) 57433 3-ethylpentanoic acid C7H14O2 详情 详情
(VI) 57430 3-ethylpentanoyl chloride C7H13ClO 详情 详情
(VII) 57431 (3-methoxy-3-oxo-1-propynyl)silver C4H3AgO2 详情 详情
(VIII) 57432 methyl 6-ethyl-4-oxo-2-octynoate C11H16O3 详情 详情

合成路线34

该中间体在本合成路线中的序号：(V)

(3,4-Dichlorophenyl)alanine methyl ester (I) was converted to the N-Boc amino ester (II), which was subsequently alkylated with iodomethane in the presence of Ag2O, yielding the N-methyl derivative (III). Partial reduction of the ester group of (III) to the aldehyde (IV) was carried out using DIBAL in toluene at -78 C. Horner-Emmons reaction of aldehyde (IV) with triethyl phosphonoacetate (V) furnished the arylpentenoate ester (VI), which was further hydrolyzed to acid (VII) with LiOH. Coupling of acid (VII) with D-3-amino-epsilon-caprolactam (VIII) gave rise to amide (IX). The N-Boc group of (IX) was removed by treatment with trifluoroacetic acid, and the resulting amine (X) was finally acylated with 3,5-bis(trifluoromethyl)benzoyl chloride to produce the target amide.

参考文献 中间体
合成目标
【1】 Gerspacher, M.; Von Sprecher, A.; Mah, R.; Roggo, S.; Stutz, S. (Novartis AG); Acylaminoalkenylene-amide derivs. as NK1 and NK2 antagonists. EP 0923550; JP 2001503387; US 6319917; WO 9807694 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51615 methyl (2R)-2-amino-3-(3,4-dichlorophenyl)propanoate C10H11Cl2NO2 详情 详情
(II) 51616 methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(3,4-dichlorophenyl)propanoate C15H19Cl2NO4 详情 详情
(III) 51617 methyl (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(3,4-dichlorophenyl)propanoate C16H21Cl2NO4 详情 详情
(IV) 51618 tert-butyl (1R)-1-(3,4-dichlorobenzyl)-2-oxoethyl(methyl)carbamate C15H19Cl2NO3 详情 详情
(V) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(VI) 51619 ethyl (E,4R)-4-[(tert-butoxycarbonyl)(methyl)amino]-5-(3,4-dichlorophenyl)-2-pentenoate C19H25Cl2NO4 详情 详情
(VII) 51620 (E,4R)-4-[(tert-butoxycarbonyl)(methyl)amino]-5-(3,4-dichlorophenyl)-2-pentenoic acid C17H21Cl2NO4 详情 详情
(VIII) 51621 (3R)-3-amino-2-azepanone C6H12N2O 详情 详情
(IX) 51622 tert-butyl (1R,2E)-1-(3,4-dichlorobenzyl)-4-oxo-4-[[(3R)-2-oxoazepanyl]amino]-2-butenyl(methyl)carbamate C23H31Cl2N3O4 详情 详情
(X) 51623 (E,4R)-5-(3,4-dichlorophenyl)-4-(methylamino)-N-[(3R)-2-oxoazepanyl]-2-pentenamide C18H23Cl2N3O2 详情 详情
(XI) 18290 3,5-Bis(trifluoromethyl)benzoyl chloride 785-56-8 C9H3ClF6O 详情 详情

合成路线35

该中间体在本合成路线中的序号：(IX)

Condensation of dichloronitrotoluene (I) with diethyl oxalate in the presence of KOEt afforded phenylpyruvate (II), and subsequent reductive cyclization gave indole-2-carboxylate (VI). Alternatively, condensation of 3,4-dichlorophenyl hydrazine (III) with ethyl pyruvate (IV) provided hydrazone (V). Then, Fischer indole synthesis with p-TsOH in refluxing toluene yielded a mixture of 5,6-dichloroindole (VI) and the corresponding 4,5-dichloroindole. Ester reduction using LiAlH4 in THF afforded alcohol (VII), which was subsequently oxidized to aldehyde (VIII) with MnO2 in Et2O. Condensation of (VIII) with phosphonate (IX) in the presence of NaH provided E-indolylpropenoate (X). Then, the sequence of DIBAH reduction, followed by oxidation of the resulting allyl alcohol (XI) with MnO2 in EtOAc furnished aldehyde (XII).

参考文献 中间体
合成目标
【1】 Consolandi, E.; Nadler, G.; Gagliardi, S.; et al.; 5-(5,6-Dichloro-2-indolyl)-2-methoxy-2, 4-pentadienamides: Novel and selective inhibitors of the vacuolar H+-ATPase of osteoclasts with bone antiresorptive activity. J Med Chem 1998, 41, 10, 1568.
【2】 Farina, C.; Gagliardi, S.; Parini, C.; Pinza, M.; Nadler, G.M.M.G.; Morvan, M.J.-M. (SmithKline Beecham SpA); Indole derivs. useful in the treatment of osteoporosis. JP 1998512251; WO 9621644 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 19088 1,2-dichloro-4-methyl-5-nitrobenzene C7H5Cl2NO2 详情 详情
(II) 19089 ethyl 3-(4,5-dichloro-2-nitrophenyl)-2-oxopropanoate C11H9Cl2NO5 详情 详情
(III) 19090 1-(3,4-dichlorophenyl)hydrazine C6H6Cl2N2 详情 详情
(IV) 12135 ethyl 2-oxopropanoate; Ethyl pyruvate 617-35-6 C5H8O3 详情 详情
(V) 19092 ethyl 2-[(Z)-2-(3,4-dichlorophenyl)hydrazono]propanoate C11H12Cl2N2O2 详情 详情
(VI) 19093 ethyl 5,6-dichloro-1H-indole-2-carboxylate C11H9Cl2NO2 详情 详情
(VII) 19094 (5,6-dichloro-1H-indol-2-yl)methanol C9H7Cl2NO 详情 详情
(VIII) 19095 5,6-dichloro-1H-indole-2-carbaldehyde C9H5Cl2NO 详情 详情
(IX) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(X) 19097 ethyl (E)-3-(5,6-dichloro-1H-indol-2-yl)-2-propenoate C13H11Cl2NO2 详情 详情
(XI) 19098 (E)-3-(5,6-dichloro-1H-indol-2-yl)-2-propen-1-ol C11H9Cl2NO 详情 详情
(XII) 19099 (E)-3-(5,6-dichloro-1H-indol-2-yl)-2-propenal C11H7Cl2NO 详情 详情

合成路线36

该中间体在本合成路线中的序号：(V)

The condensation of the protected L-glutamine (I) with N,O-dimethylhydroxylamine (II) by means of isobutyl chloroformate and NMM in dichloromethane gives the methoxyamide (III), which is reduced with DIBAL in THF to the aldehyde (IV). The condensation of (IV) with phosphonate (V) by means of NaN(SiMe3)2 in THF yields the carbamoylhexenoate (VI), which is selectively deprotected with HCl in dioxane and condensed with the dipeptide (VII) by means of HOBT, NMM and EDC in dichloromethane to afford the tritylated target compound (VIII). Finally, the trityl group of (VIII) is eliminated with TFA and Et3SiH in dichloromethane.

参考文献 中间体
合成目标
【1】 Dragovich, P.S.; Babine, R.E.; Webber, S.E.; et al.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 1. Michael acceptor structure-activity studies. J Med Chem 1998, 41, 15, 2806.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 31045 (2S)-2-[(tert-butoxycarbonyl)amino]-5-oxo-5-(tritylamino)pentanoic acid C29H32N2O5 详情 详情
(II) 13361 (Methoxyamino)methane; N,O-Dimethylhydroxylamine 1117-97-1 C2H7NO 详情 详情
(III) 31046 tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-4-oxo-4-(tritylamino)butylcarbamate C31H37N3O5 详情 详情
(IV) 31047 tert-butyl (1S)-1-formyl-4-oxo-4-(tritylamino)butylcarbamate C29H32N2O4 详情 详情
(V) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(VI) 31048 ethyl (E,4S)-4-[(tert-butoxycarbonyl)amino]-7-oxo-7-(tritylamino)-2-heptenoate C33H38N2O5 详情 详情
(VII) 31052 (2S)-2-[((2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)amino]-3-phenylpropionic acid C23H28N2O5 详情 详情
(VII) 31053 ethyl (5S,8S,11S,12E)-11-(3-amino-3-oxopropyl)-8-benzyl-5-isobutyl-3,6,9-trioxo-1-phenyl-2-oxa-4,7,10-triaza-12-tetradecen-14-oate C32H42N4O7 详情 详情

合成路线37

该中间体在本合成路线中的序号：

Horner-Emmons condensation of benzazepinone (I) with triethyl phosphonoacetate gave unsaturated ester (II). Subsequent reductive treatment of (II) with Mg in MeOH produced the saturated ester (III) with concomitant cleavage of the tosyl group. 2-Chloro-4-(1-pyrrolidinyl)benzoyl chloride (V) (prepared by reaction of the corresponding carboxylic acid (IV) with SOCl2) was then condensed with benzazepine (III) to produce benzamide (VI). Hydrolysis of the methyl ester function of (VI) yielded the racemic carboxylic acid (VII), which was resolved by means of esterification with (R)-2-heptanol, followed by chromatographic separation of the diastereomeric mixture. After saponification of the required diastereoisomeric ester (VIII), the resulting (R)-carboxylic acid was finally coupled with isopropylamine using diethylcyanophosphate as the condensing reagent.

参考文献 中间体
合成目标
【1】 Kondo, K.; et al.; Characterization of orally active nonpeptide vasopressin V2 receptor agonist. Synthesis and biological evaluation of both the (5R)- and (5S)-enantioisomers of 2-[1-(2-chloro-4-pyrrolidin-1yl-benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]-N-isopropylace. J Med Chem 2002, 45, 17, 3805.
【2】 Ogawa, H.; Kondo, K.; Shinohara, T.; Kan, K.; Tanada, Y.; Kurimura, M.; Morita, S.; Uchida, M.; Mori, T.; Tominaga, M.; Yabuuchi, Y. (Otsuka Pharmaceutical Co., Ltd.); Benzazepine derivs. with vasopressin agonistic activity. EP 0877736; JP 1998081668; US 6096736; WO 9722591 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
42235 Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC 2942-58-7 C5H10NO3P 详情 详情
(I) 14763 1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one C17H17NO3S 详情 详情
(II) 27544 ethyl 2-[1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene]acetate C21H23NO4S 详情 详情
(III) 27545 methyl 2-(2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl)acetate C13H17NO2 详情 详情
(IV) 27546 2-chloro-4-(1-pyrrolidinyl)benzoic acid C11H12ClNO2 详情 详情
(V) 27547 2-chloro-4-(1-pyrrolidinyl)benzoyl chloride C11H11Cl2NO 详情 详情
(VI) 27548 methyl 2-[1-[2-chloro-4-(1-pyrrolidinyl)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]acetate C24H27ClN2O3 详情 详情
(VII) 27549 2-[1-[2-chloro-4-(1-pyrrolidinyl)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]acetic acid C23H25ClN2O3 详情 详情
(VIII) 27550 (1R)-1-methylhexyl 2-[(5R)-1-[2-chloro-4-(1-pyrrolidinyl)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]acetate C30H39ClN2O3 详情 详情

合成路线38

该中间体在本合成路线中的序号：(VII)

3,4-Dichlorotoluene (I) was nitrated with HNO3 in H2SO4, and the resulting nitrotoluene (II) was condensed with diethyl oxalate in the presence of KOEt to give the phenylpyruvic derivative (III). Then, reductive cyclization of (III) with Fe and AcOH produced ethyl 5,6-dichloroindole-2-carboxylate (IV). Further reduction of (IV) with LiAlH4 yielded alcohol (V), which was oxidized to aldehyde (VI) with MnO2 in Et2O. Horner-Emmons reaction of (VI) with triethyl phosphonoacetate (VII) afforded the indolylpropenoate (VIII). This was reduced to the allyl alcohol (IX) with DIBAL-H, and subsequently oxidized with MnO2 to afford the propenaldehyde (X). In a shorter procedure, Wittig reaction of (VI) with formylmethylene triphenylphosphorane (XI) yielded also propenaldehyde (X) along with the homologated pentadienaldehyde. Phosphonium bromide (XIV) was prepared by bromination of methyl methoxyacetate (XII) with NBS in the presence of dibenzoyl peroxide, followed by condensation of the resulting bromide (XIII) with PPh3. Wittig reaction of this phosphonium reagent with aldehyde (X) in the presence of DBU in boiling THF gave ester (XV). Subsequent saponification of (XV) with ethanolic KOH yielded acid (XVI). The aminopiperidine (XX) was synthesized by N-methylation of tetramethylpiperidone (XVII), followed by formation of the oxime (XIX) and catalytic reduction over Rh/C. Then, condensation of amine (XX) with acid (XVI) using 1-ethyl-3-(dimethylaminopropyl)carbodiimide-HCl (EDC) and 1-hydroxy-7-azabenzotriazole (HOAt) in DMF furnished the target compound.

参考文献 中间体
合成目标
【1】 Consolandi, E.; Nadler, G.; Gagliardi, S.; et al.; 5-(5,6-Dichloro-2-indolyl)-2-methoxy-2, 4-pentadienamides: Novel and selective inhibitors of the vacuolar H+-ATPase of osteoclasts with bone antiresorptive activity. J Med Chem 1998, 41, 10, 1568.
【2】 Nadler, G.; Morvan, M.; Delimoge, I.; Belfiore, P.; Zocchetti, A.; James, I.; Zembryki, D.; Lee-Rycakzewski, E.; Parini, C.; Consolandi, E.; Gagliardi, S.; Farina, C.; (2Z,4E)-5-(5,6-Dichloro-2-indolyl)-2-methoxy-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pentadienamide, a novel, potent and selective inhibitor of the osteoclast V-ATPase. Bioorg Med Chem Lett 1998, 8, 24, 3621.
【3】 Yu, M.S.; et al.; Synthesis of 2-dienylindole, SB 242784, by a three-component palladium-catalyzed coupling reaction. Tetrahedron Lett 1998, 39, 51, 9347.
【4】 Farina, C.; Nadler, G.M.M.G.; Gagliardi, S. (GlaxoSmithKline SpA); Indole derivs. for the treatment of osteoporosis. US 2002173659 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 20100 1,2-dichloro-4-methylbenzene 95-75-0 C7H6Cl2 详情 详情
(II) 19088 1,2-dichloro-4-methyl-5-nitrobenzene C7H5Cl2NO2 详情 详情
(III) 19089 ethyl 3-(4,5-dichloro-2-nitrophenyl)-2-oxopropanoate C11H9Cl2NO5 详情 详情
(IV) 19093 ethyl 5,6-dichloro-1H-indole-2-carboxylate C11H9Cl2NO2 详情 详情
(V) 19094 (5,6-dichloro-1H-indol-2-yl)methanol C9H7Cl2NO 详情 详情
(VI) 19095 5,6-dichloro-1H-indole-2-carbaldehyde C9H5Cl2NO 详情 详情
(VII) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(VIII) 19097 ethyl (E)-3-(5,6-dichloro-1H-indol-2-yl)-2-propenoate C13H11Cl2NO2 详情 详情
(IX) 19098 (E)-3-(5,6-dichloro-1H-indol-2-yl)-2-propen-1-ol C11H9Cl2NO 详情 详情
(X) 19099 (E)-3-(5,6-dichloro-1H-indol-2-yl)-2-propenal C11H7Cl2NO 详情 详情
(XI) 20110 2-(triphenylphosphoranyl)acetaldehyde C20H19OP 详情 详情
(XII) 19100 methyl 2-methoxyacetate 6290-49-9 C4H8O3 详情 详情
(XIII) 19101 methyl 2-bromo-2-methoxyacetate C4H7BrO3 详情 详情
(XIV) 19102 (1,2-dimethoxy-2-oxoethyl)(triphenyl)phosphonium bromide C22H22BrO3P 详情 详情
(XV) 19103 methyl (2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoate C15H13Cl2NO3 详情 详情
(XVI) 19104 (2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoic acid C14H11Cl2NO3 详情 详情
(XVII) 20116 2,2,6,6-tetramethyl-4-piperidinone 826-36-8 C9H17NO 详情 详情
(XVIII) 20117 1,2,2,6,6-pentamethyl-4-piperidinone C10H19NO 详情 详情
(XIX) 20118 1,2,2,6,6-pentamethyl-4-piperidinone oxime C10H20N2O 详情 详情
(XX) 20119 1,2,2,6,6-pentamethyl-4-piperidinamine; 1,2,2,6,6-pentamethyl-4-piperidinylamine C10H22N2 详情 详情

合成路线39

该中间体在本合成路线中的序号：(I)

Treatment of triethyl phosphoacetate (I) with NaH and 4-bromobenzyl bromide (II) in DMF provides the 2-substituted triethyl phosphoacetate (III), which then undergoes reaction with formaldehyde and K2CO3 to afford acrylate derivative (IV). Michael condensation of (IV) with phosphinic acid (V) in N,O-bistrimethylsilylacetamide (BSA) yields intermediate (VI), which then undergoes Suzuki condensation in toluene with phenylboronic acid (VII) and NaHCO3 in MeOH catalyzed by Pd(PPh3)4 to give (VIII). Hydrolysis of ethyl ester (VIII) by means of NaOH in EtOH furnishes carboxylic acid (IX), which is then coupled to L-alanine (X) by means of BOP and DIEA or Et3N in DMF to yield methyl ester (XI). Compound (XI) is then hydrolyzed by treatment with NaOH or LiOH in EtOH and, finally, the Z-protecting group is removed with BBr3 in dichloromethane.

参考文献 中间体
合成目标
【1】 Chen, H.; Noble, F.; Coric, P.; Fournie-Zaluski, M.-C.; Roques, B.P.; Aminophosphinic inhibitors as transition state analogues of enkephalin-degrading enzymes: A class of central analgesics. Proceedings of the National Academy of Sciences of the United States of America 1998, 95, 20, 12028.
【2】 Noble, F.; Morthé, A.; Chen, H.; et al.; Phosphinic derivatives as new dual enkephalin-degrading enzyme inhibitors: Synthesis, biological properties, and antinociceptive activities. J Med Chem 2000, 43, 7, 1398.
【3】 Fournie-Zaluski, M.-C.; Chen, H.; Roques, B.P. (INSERM (Institut National de la Sante et de la Recherche Medicale)); Novel (alpha-aminophosphino) peptide derivs., method for making same and therapeutic applications thereof. EP 1009750; WO 9818803 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(II) 16109 1-bromo-4-(bromomethyl)benzene; 4-Bromobenzyl bromide 589-15-1 C7H6Br2 详情 详情
(III) 42984 ethyl 3-(4-bromophenyl)-2-(diethoxyphosphoryl)propanoate C15H22BrO5P 详情 详情
(IV) 42985 ethyl 2-(4-bromobenzyl)acrylate C12H13BrO2 详情 详情
(V) 42986 1-[[(benzyloxy)carbonyl]amino]ethylphosphinic acid C10H14NO4P 详情 详情
(VI) 42987 1-[[(benzyloxy)carbonyl]amino]ethyl[2-(4-bromobenzyl)-3-ethoxy-3-oxopropyl]phosphinic acid C22H27BrNO6P 详情 详情
(VII) 16593 Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide 98-80-6 C6H7BO2 详情 详情
(VIII) 42988 1-[[(benzyloxy)carbonyl]amino]ethyl[2-([1,1'-biphenyl]-4-ylmethyl)-3-ethoxy-3-oxopropyl]phosphinic acid; 4-(2-[[(1-[[(benzyloxy)carbonyl]amino]ethyl)(hydroxy)phosphoryl]methyl]-3-ethoxy-3-oxopropyl)-1,1'-biphenyl C28H32NO6P 详情 详情
(IX) 42989 3-[(1-[[(benzyloxy)carbonyl]amino]ethyl)(hydroxy)phosphoryl]-2-([1,1'-biphenyl]-4-ylmethyl)propionic acid C26H28NO6P 详情 详情
(X) 20694 methyl (2S)-2-aminopropanoate C4H9NO2 详情 详情
(XI) 42990 1-[[(benzyloxy)carbonyl]amino]ethyl(2-([1,1'-biphenyl]-4-ylmethyl)-3-[[(1S)-2-methoxy-1-methyl-2-oxoethyl]amino]-3-oxopropyl)phosphinic acid; 4-(2-[[(1-[[(benzyloxy)carbonyl]amino]ethyl)(hydroxy)phosphoryl]methyl]-3-[[(1S)-2-methoxy-1-methyl-2-oxoethyl]amino]-3-oxopropyl)-1,1'-biphenyl C30H35N2O7P 详情 详情

合成路线40

该中间体在本合成路线中的序号：

(R)-4-hydroxy-2-pyrrolidinone (I) was protected as the tert-butyldimethylsilyl ether, and then converted to tert-butyl carbamate (II) by means of Boc2O. Subsequent condensation of (II) with Grignard reagent (III), followed by reduction with NaBH4, and acetal hydrolysis yielded the pyrrolidinyl benzaldehyde (IV). Horner-Emmons reaction of (IV) with phosphonate (V) produced the cinnamic acid derivative (VI), and further Michael addition to (VI) of the chiral lithium amide (VII) furnished aminoester (VIII). After hydrogenolysis of both N-benzyl groups of (VIII), the resulting primary amine (IX) was protected with Boc2O, and the silyl ether was then cleaved by means of tetrabutylammonium fluoride to give the hydroxypyrrolidine derivative (X). This was converted to the required thiol (XI), which was then coupled with the carbapenem phosphate (XII). Finally, hydrogenolysis of the 4-nitrobenzyl ester of (XII) provided the title compound.

参考文献 中间体
合成目标
【1】 Imamura, H.; et al.; Discovery of novel trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenems. Bioorg Med Chem 2000, 8, 8, 1969.
【2】 Imamura, H.; Sato, H.; Shimizu, A.; et al.; J-114,870 and J-114,871, novel trans-3,5-disubstituted pyrrolidinylthio 1beta-methylcarbapenems: Synthesis and physicochemical properties. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-56.
【3】 Sato, H.; Shimizu, A.; Imamura, H.; et al.; J-111,225, a novel trans-3,5-disubstituted pyrrolidinylthio 1beta-methylcarbapenem; synthesis and physicochemical properties. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-61.
【4】 Imamura, H.; Ohtake, N.; Shimizu, A.; et al.; Structure-activity relationships of trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenems. Part 2: J-111,225, J-114,870, J-114,871 and related compounds. Bioorg Med Chem Lett 2000, 10, 2, 115.
【5】 Ushijima, R.; Sugimoto, Y.; Shimizu, A.; Kiyonaga, H.; Nagano, R.; Nakagawa, S.; Sakuraba, S.; Sato, H.; Hashizume, T.; Nakano, M.; Imamura, H.; Fukatsu, H. (Banyu Pharmaceutical Co., Ltd.); Carbapenem derivs.. EP 1048669; JP 2000143512; WO 9931106 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(I) 30864 N-Benzyl-N-(1(R)-phenylethyl)amide lithium salt C15H16LiN 详情 详情
(II) 30850 tert-butyl (4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-oxo-1-pyrrolidinecarboxylate C15H29NO4Si 详情 详情
(III) 30851 bromo[4-(dimethoxymethyl)phenyl]magnesium C9H11BrMgO2 详情 详情
(IV) 30852 tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-formylphenyl)-1-pyrrolidinecarboxylate C22H35NO4Si 详情 详情
(VI) 30853 tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[4-[(E)-3-ethoxy-3-oxo-1-propenyl]phenyl]-1-pyrrolidinecarboxylate C26H41NO5Si 详情 详情
(VII) 30854 N-Benzyl-N-(1(S)-phenylethyl)amide lithium salt C15H16LiN 详情 详情
(VIII) 30855 tert-butyl (2R,4R)-2-[4-((1R)-1-[benzyl[(1S)-1-phenylethyl]amino]-3-ethoxy-3-oxopropyl)phenyl]-4-[[tert-butyl(dimethyl)silyl]oxy]-1-pyrrolidinecarboxylate C41H58N2O5Si 详情 详情
(IX) 30856 tert-butyl (2R,4R)-2-[4-[(1R)-1-amino-3-ethoxy-3-oxopropyl]phenyl]-4-[[tert-butyl(dimethyl)silyl]oxy]-1-pyrrolidinecarboxylate C26H44N2O5Si 详情 详情
(X) 30857 tert-butyl (2R,4R)-2-(4-[(1R)-1-[(tert-butoxycarbonyl)amino]-3-ethoxy-3-oxopropyl]phenyl)-4-hydroxy-1-pyrrolidinecarboxylate C25H38N2O7 详情 详情
(XI) 30858 (3R)-3-amino-3-[4-[(2R,4S)-4-sulfanylpyrrolidinyl]phenyl]propanamide C13H19N3OS 详情 详情
(XII) 13224 4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate 90776-59-3 C29H27N2O10P 详情 详情

合成路线41

该中间体在本合成路线中的序号：(XXV)

Pyrrolidinone (XXVI): The selective hydrolysis of the known methyl ester (XIV) with NaOH in methanol/water gives the corresponding carboxylic acid (XV), which is coupled with the chiral oxazolidinone (XVI) by means of pivaloyl chloride and Et3N in THF to yield the amide (XVII). The regiocontrolled alkylation of (XVII) with allyl iodide and NaN(SiMe3)2 in THF affords the allyl derivative (XVIII), which is submitted to ozonolysis in dichloromethane to provide the aldehyde (XIX). The condensation of (XIX) with 2,4-dimethoxybenzylamine (XX) yields imine (XXI), which by a reductive cyclization with NaBH3CN in THF/EtOH affords pyrrolidinone (XXII). Cleavage of the oxazolidine ring of (XXII) with TsOH in hot methanol gives the amino alcohol (XXIII), which is oxidized with oxalyl chloride in DMSO to the aldehyde (XXIV). Finally, this compound is condensed with triethyl phosphonoacetate (XXV) by means of NaN(SiMe3)2 in THF to provide the desired pyrrolidinone (XXVI).

参考文献 中间体
合成目标
【1】 Dragovich, P.S.; Prins, T.J.; Zhou, R.; et al.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements. J Med Chem 1999, 42, 7, 1213.
【2】 Graul, A.; Castañer, J.; AG-7088. Drugs Fut 2000, 25, 1, 9.
【3】 Meyer, M.D.; Daanen, J.F.; Ehrlich, P.P.; Ralston, J.W. (Abbott Laboratories Inc.); 3-Phenylpyrrole alpha-1 adrenergic cpds.. WO 9957122 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
32112 3-iodo-1-propene;3-iodo-propen;allyl iodide 556-56-9 C3H5I 详情 详情
(XIV) 32109 tert-butyl (4S)-4-(3-methoxy-3-oxopropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate C14H25NO5 详情 详情
(XV) 32110 3-[(4S)-3-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-oxazolidin-4-yl]propionic acid C13H23NO5 详情 详情
(XVI) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(XVII) 32111 tert-butyl (4S)-4-[3-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxopropyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate C23H32N2O6 详情 详情
(XVIII) 32113 tert-butyl (4S)-4-((2S)-2-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-4-pentenyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate C26H36N2O6 详情 详情
(XIX) 32114 tert-butyl (4S)-4-((2R)-2-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-4-oxobutyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate C25H34N2O7 详情 详情
(XX) 32115 (2,4-dimethoxyphenyl)methanamine; 2,4-dimethoxybenzylamine 20781-21-9 C9H13NO2 详情 详情
(XXI) 32116 tert-butyl (4S)-4-[(2R)-2-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-4-[(2,4-dimethoxybenzyl)imino]butyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate C34H45N3O8 详情 详情
(XXII) 32117 tert-butyl (4S)-4-[[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate C24H36N2O6 详情 详情
(XXIII) 32118 tert-butyl (1S)-2-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-1-(hydroxymethyl)ethylcarbamate C21H32N2O6 详情 详情
(XXIV) 32119 tert-butyl (1S)-2-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-1-formylethylcarbamate C21H30N2O6 详情 详情
(XXV) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(XXVI) 32105 ethyl (E,4S)-4-[(tert-butoxycarbonyl)amino]-5-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-2-pentenoate C25H36N2O7 详情 详情

合成路线42

该中间体在本合成路线中的序号：

Amino acid (II) (obtained by N-alkylation of N-Boc-D-phenylalanine (I) with MeI), was coupled to (S)-1-amino-2-propanol (III) using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-HCl (EDC) and 1-hydroxybenzotriazole to give amide (IV). The N-Boc group of (IV) was then deprotected with trifluoroacetic acid in CH2Cl2 to afford (V). Further coupling of (V) with D-naphthylalanine derivative (VI), followed by Boc deprotection with trifluoroacetic acid, provided dipeptide amide (VII). This dipeptide was coupled to intermediate amino acid (VIII) using EDC and 1-hydroxy-7-azabenzotriazole yielding tripeptide (IX). Finally, trifluoroacetic acid-promoted Boc-deprotection of (IX) provided the target compound. Intermediate amino acid (VIII) was prepared from 3-(tert-butoxycarbonylamino)-3-methylbutanoic acid (X) upon conversion to the mixed anhydride with ethyl chloroformate, followed by reduction to alcohol (XI) with LiBH4. Subsequent Swern oxidation of the alcohol (XI) furnished aldehyde (XII). This was condensed with triethyl phosphonoacetate, and then saponified with LiOH to produce the intermediate (VIII).

参考文献 中间体
合成目标
【1】 Hansen, T.K.; Ankersen, M.; Hansen, B.S.; Raun, K.; Nielsen, K.K.; Lau, J.; Peschke, B.; Lundt, B.F.; Thogersen, H.; Johansen, N.L.; Madsen, K.; Andersen, P.H.; Novel orally active growth hormone secretagogues. J Med Chem 1998, 41, 19, 3705.
【2】 Eriksen, E.F.; Kappelgaard, A.-M. (Novo Nordisk A/S); Growth hormone component and bone anti-resorptive agent in cyclic (coherence) treatment of osteoporosis. WO 9746252 .
【3】 Hansen, T.K.; Peschke, B.; Lau, J.; Lundt, B.F.; Ankersen, M.; Watson, B.; Madsen, K. (Novo Nordisk A/S); Cpds. with growth hormone releasing properties. JP 1999209336; JP 1999501054; JP 2000143613; US 6127391; WO 9723508 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(I) 22184 (2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid C14H19NO4 详情 详情
(II) 22185 (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-phenylpropionic acid 37553-65-4 C15H21NO4 详情 详情
(III) 22186 (S)-(+)-1-Amino-2-propanol; (2S)-1-amino-2-propanol 2799-17-9 C3H9NO 详情 详情
(IV) 22187 tert-butyl (1R)-1-benzyl-2-[[(2S)-2-hydroxypropyl]amino]-2-oxoethyl(methyl)carbamate C18H28N2O4 详情 详情
(V) 22188 (2R)-N-[(2S)-2-hydroxypropyl]-2-(methylamino)-3-phenylpropanamide C13H20N2O2 详情 详情
(VI) 22189 (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(2-naphthyl)propionic acid 147577-61-5 C19H23NO4 详情 详情
(VII) 22190 (2R)-N-((1R)-1-benzyl-2-[[(2S)-2-hydroxypropyl]amino]-2-oxoethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propanamide C27H33N3O3 详情 详情
(VIII) 22191 (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoic acid C12H21NO4 详情 详情
(IX) 22192 tert-butyl (E)-5-[[(1R)-2-[((1R)-1-benzyl-2-[[(2S)-2-hydroxypropyl]amino]-2-oxoethyl)(methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl](methyl)amino]-1,1-dimethyl-5-oxo-3-pentenylcarbamate C39H52N4O6 详情 详情
(X) 22193 3-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(XI) 22194 tert-butyl 3-hydroxy-1,1-dimethylpropylcarbamate C10H21NO3 详情 详情
(XII) 22195 tert-butyl 1,1-dimethyl-3-oxopropylcarbamate C10H19NO3 详情 详情

合成路线43

该中间体在本合成路线中的序号：(XIII)

1) The reaction of undecanal (I) with vinylmagnesium bromide (II) in THF gives 1-tridecen-3-ol (III), which is condensed with propionic acid (IV) by means of triethyl orthoacetate in refluxing xylene yielding 4(E)-pentadecenoic acid ethyl ester (V). The reaction of (V) with AD-mix-beta and methanesulfonamide in tert-butanol affords (R,R)-5-(1-hydroxyundecyl)tetrahydrofuran-2-one (VI), which by reaction with p-nitrobenzoic acid and triphenylphosphine in benzene gives the corresponding ester (VII). The reaction of (VII) first with LiAlH4 in ether, followed by a treatment with acetone and p-toluenesulfonic acid yields the acetonide (VIII), which by oxidation of its primary alcohol with pyridinium chlorochromate (PCC) in dichloromethane affords the corresponding aldehyde (IX). The reaction of (IX) with vinylmagnesium bromide (II) in ether gives the allyl alcohol (X), which by condensation with proionic acid (IV) and triethyl orthoacetate yields (4E,8R,9S)-8,9-(isopropylidenedioxy)-4-nonadecenoic acid ethyl ester (XI), The reduction of (XI) with diisobutylaluminum hydride (DIBAL) in toluene affords the corresponding aldehyde (XII), which is condensed with triethyl phosphonoacetate (XIII) by means of NaH in toluene giving (2E,6E,10R,11S)-10,11-(isopropylidenedioxy)-heneicosa-2,6-dienoic acid ethyl ester (XIV).

参考文献 中间体
合成目标
【1】 Yazbak, A.; et al.; Total synthesis of uvaricin. J Org Chem 1998, 63, 17, 5863.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 20175 undecanal 112-44-7 C11H22O 详情 详情
(II) 10386 Allyl(bromo)magnesium 1730-25-2 C3H5BrMg 详情 详情
(III) 20177 1-tridecen-3-ol C13H26O 详情 详情
(IV) 20178 propionic acid 79-09-4 C3H6O2 详情 详情
(V) 20179 ethyl (E)-4-pentadecenoate C17H32O2 详情 详情
(VI) 20180 (5R)-5-[(1R)-1-hydroxyundecyl]dihydro-2(3H)-furanone C15H28O3 详情 详情
(VII) 20181 (1R)-1-[(2S)-4-oxo-1,3-dioxolan-2-yl]undecyl 4-nitrobenzoate C21H29NO7 详情 详情
(VIII) 20182 3-[(4R,5S)-5-decyl-2,2-dimethyl-1,3-dioxolan-4-yl]-1-propanol C18H36O3 详情 详情
(IX) 20183 3-[(4R,5S)-5-decyl-2,2-dimethyl-1,3-dioxolan-4-yl]propanal C18H34O3 详情 详情
(X) 20184 (3S)-5-[(4R,5S)-5-decyl-2,2-dimethyl-1,3-dioxolan-4-yl]-1-penten-3-ol C20H38O3 详情 详情
(XI) 20185 ethyl (E)-7-[(4R,5S)-5-decyl-2,2-dimethyl-1,3-dioxolan-4-yl]-4-heptenoate C24H44O4 详情 详情
(XII) 20186 (E)-7-[(4R,5S)-5-decyl-2,2-dimethyl-1,3-dioxolan-4-yl]-4-heptenal C22H40O3 详情 详情
(XIII) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(XIV) 20188 ethyl (2E,6E)-9-[(4R,5S)-5-decyl-2,2-dimethyl-1,3-dioxolan-4-yl]-2,6-nonadienoate C26H46O4 详情 详情

合成路线44

该中间体在本合成路线中的序号：(VII)

Friedel-Crafts acylation of benzene with 6-chloronicotinyl chloride (I) using AlCl3 afforded ketone (II). Subsequent displacement of the chlorine atom of (II) by means of ethanolic ammonia at 145 C in a pressure reactor led to the aminopyridine (III), which was converted to sulfonamide (IV) by means of tosyl chloride in pyridine. Alkylation of the pyridine N of (IV) with iodoacetamide gave (V), and further cyclization in the presence of trifluoroacetic anhydride produced the imidazopyridine (VI). Phosphonate (VIII) was prepared by treatment of triethyl phosphonoacetate (VII) with methylamine. Horner-Emmons condensation of this phosphonate with ketone (VI) yielded the E-propenamide (IX). Selective iodination of (IX) at position 3 using N-iodosuccinimide furnished iodide (X). This compound was first deprotonated with PhLi, then subjected to a halogen-metal exchange reaction with tert-butyllithium, and the resulting trianion was reacted with isopropyl isopropanethiolsulfonate to give sulfide (XI). Finally, smooth hydrolysis of the trifluoroacetamide group of (XI) employing MeOH-CH2Cl2 in the presence of silica gel provided the title compound.

参考文献 中间体
合成目标
【1】 Hamdouchi, C.; de Blas, J.; del Prado, M.; Gruber, J.; Heinz, B.A.; Vance, L.; 2-Amino-3-substituted-6-[(E)-1-phenyl-2-(N-methylcarbamoyl)vinyl]imidazo[1,2-a]pyridines as a novel class of inhibitors of human rhinovirus: Stereospecific synthesis and antiviral activity. J Med Chem 1999, 42, 1, 50.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 30256 6-chloronicotinoyl chloride 58757-38-3 C6H3Cl2NO 详情 详情
(II) 30257 (6-chloro-3-pyridinyl)(phenyl)methanone C12H8ClNO 详情 详情
(III) 30258 (6-amino-3-pyridinyl)(phenyl)methanone C12H10N2O 详情 详情
(IV) 30259 N-(5-benzoyl-2-pyridinyl)-4-methylbenzenesulfonamide C19H16N2O3S 详情 详情
(V) 30260 2-(5-benzoyl-2-[[(4-methylphenyl)sulfonyl]imino]-1-pyridinyl)acetamide C21H19N3O4S 详情 详情
(VI) 30261 N-(6-benzoylimidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroacetamide C16H10F3N3O2 详情 详情
(VII) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(VIII) 30262 diethyl 2-(methylamino)-2-oxoethylphosphonate C7H16NO4P 详情 详情
(IX) 30263 (E)-N-methyl-3-phenyl-3-[2-[(2,2,2-trifluoroacetyl)amino]imidazo[1,2-a]pyridin-6-yl]-2-propenamide C19H15F3N4O2 详情 详情
(X) 30264 (E)-3-[3-iodo-2-[(2,2,2-trifluoroacetyl)amino]imidazo[1,2-a]pyridin-6-yl]-N-methyl-3-phenyl-2-propenamide C19H14F3IN4O2 详情 详情
(XI) 30265 (E)-3-[3-(isopropylsulfanyl)-2-[(2,2,2-trifluoroacetyl)amino]imidazo[1,2-a]pyridin-6-yl]-N-methyl-3-phenyl-2-propenamide C22H21F3N4O2S 详情 详情

合成路线45

该中间体在本合成路线中的序号：(VII)

Horner-Emmons condensation of 1-naphthaldehyde (VI) with triethyl phosphonoacetate (VII) using DBU as the base afforded naphthylacrylate (VIII). This was reacted with tosylmethylisocyanide and potassium tert-butoxide to produce pyrrole (IX). Hydrolysis of the ester group of (IX) with KOH gave rise to the carboxylic acid (X), which was coupled with N-methylpiperazine (XI) employing EDC and HOBt or, alternatively, by previous conversion to the corresponding acid chloride with SOCl2. The resulting amide (XII) was finally alkylated at the pyrrole N atom with chloride (V) in the presence of NaH.

参考文献 中间体
合成目标
【1】 Lee, J.; Lee, H.; Shin, Y.; et al.; Synthesis and structure-activity relationships of 1-(1(3)H-imidazole-5(4)-yl)-methylpyrroles as farnesyl protein transferase inhibitors (FTPI). 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 210.
【2】 Lee, J.H.; Yoo, J.K.; Koh, J.S.; Choi, T.S.; Shin, Y.S.; Kim, K.H.; Jung, W.H.; Kim, J.H.; Lee, S.H.; Ahn, I.A.; Ro, S.G.; Lee, H.I.; Kim, H.S.; Chung, H.H.; Jeong, S.W.; Kwak, T.H. (LG Chem Ltd.); Imidazole derivs. having an inhibitory activity for farnesyl transferase and process for preparation thereof. WO 9928315 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 33672 1-(1,3-benzodioxol-5-ylmethyl)-5-(chloromethyl)-1H-imidazole C12H11ClN2O2 详情 详情
(VI) 12314 1-Naphthaldehyde 66-77-3 C11H8O 详情 详情
(VII) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(VIII) 25405 ethyl (E)-3-(1-naphthyl)-2-propenoate C15H14O2 详情 详情
(IX) 33673 ethyl 4-(1-naphthyl)-1H-pyrrole-3-carboxylate C17H15NO2 详情 详情
(X) 33674 4-(1-naphthyl)-1H-pyrrole-3-carboxylic acid C15H11NO2 详情 详情
(XI) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(XII) 33675 (4-methyl-1-piperazinyl)[4-(1-naphthyl)-1H-pyrrol-3-yl]methanone C20H21N3O 详情 详情

合成路线46

该中间体在本合成路线中的序号：(IV)

Reduction of N-Boc-3-amino-3-methylbutanoic acid (I) to alcohol (II) was achieved via formation of the corresponding mixed anhydride with ethyl chloroformate, followed by treatment with LiBH4. Swern oxidation then produced aldehyde (III), which was subjected to a Horner-Emmons condensation with triethyl phosphonoacetate (IV) to afford unsaturated ester (V). Ester hydrolysis with LiOH yielded carboxylic acid (VI). Subsequent alkylation of (VI) with methyl iodide and NaH furnished de N-methyl derivative (VII).

参考文献 中间体
合成目标
【1】 Madsen, K.; Kruse hansen, T.; Watson, B.; Peschke, B.; Langeland Johansen, N.; Sehested Hansen, B.; Lau, J.; Thogersen, H.; Ankersen, M.; Petersen, H.; Synthesis and in vitro characterization of new growth hormone secretagogues derived form ipamorelin with dipeptidomimetic N-terminals. Eur J Med Chem 1999, 34, 5, 363.
【2】 Hansen, T.K.; Peschke, B.; Lau, J.; Lundt, B.F.; Ankersen, M.; Watson, B.; Madsen, K. (Novo Nordisk A/S); Cpds. with growth hormone releasing properties. JP 1999209336; JP 1999501054; JP 2000143613; US 6127391; WO 9723508 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 22193 3-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(II) 22194 tert-butyl 3-hydroxy-1,1-dimethylpropylcarbamate C10H21NO3 详情 详情
(III) 22195 tert-butyl 1,1-dimethyl-3-oxopropylcarbamate C10H19NO3 详情 详情
(IV) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(V) 27230 ethyl (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoate C14H25NO4 详情 详情
(VI) 22191 (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoic acid C12H21NO4 详情 详情
(VII) 37820 (E)-5-[(tert-butoxycarbonyl)(methyl)amino]-5-methyl-2-hexenoic acid C13H23NO4 详情 详情

合成路线47

该中间体在本合成路线中的序号：(II)

Several improved synthetic procedures have been described for the synthesis of the title compound, using estrone-3-methyl ether (I) as the starting compound. Horner-Emmons condensation of ketone (I) with triethyl phosphonoacetate (II) provided the unsaturated ester (III). Birch reduction of aromatic ring and ester functions of (III) afforded, after acidic hydrolysis of the intermediate enol ether, enone (IV). Protection of the hydroxyl group of (IV) with dihydropyran, followed by air oxidation and treatment with isopropyl bromide, furnished the isopropoxy ketone (V). Methylation of the lithium enolate of ketone (V) and subsequent acidic cleavage of the tetrahydropyranyl protecting group gave the alpha-methyl ketone (VI). The free hydroxyl group of (VI) was then converted to the corresponding mesylate, which was further condensed with vanillic acid diethylamide (VII) in the presence of Cs2CO3, yielding ether (VIII). Cleavage of the isopropyl ether in the presence of AlCl3, followed by simultaneous reduction of the amide and ketone functions with LiAlH4-AlCl3, afforded the title compound, which was isolated after formation of the corresponding citrate salt. The intermediate alpha-methyl ketone (VIII) was also obtained through a related reaction sequence. Alcohol (IV) was initially condensed with vanillic acid diethylamide (VII), via activation as the mesylate (IX), to afford the corresponding ether, which was further oxidized in the presence of isopropyl bromide, producing the isopropoxy ketone (XI). This was then methylated at the alpha position employing iodomethane and LDA to furnish intermediate (VIII).

参考文献 中间体
合成目标
【1】 Peters, R.H.; Tanabe, M.; Chao, W.-R.; Johansson, J.G.; Ryan, K.J.; Liu, J. (SRI International); Synthesis of anti-estrogenic acid and other therapeutic steroids from 21-hydroxy-19-norpregna-4-en-3-one. WO 0158919 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 52999 (8R,9S,13S,14S)-3-methoxy-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one 1624-62-0 C19H24O2 详情 详情
(II) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(III) 53000 ethyl 2-[(8R,9S,13S,14S)-3-methoxy-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-ylidene]acetate n/a C23H30O3 详情 详情
(IV) 53001 (8R,9S,13R,14S,17R)-17-(2-hydroxyethyl)-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one n/a C20H30O2 详情 详情
(V) 53002 (8S,9S,13R,14S,17R)-3-isopropoxy-13-methyl-17-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-6-one n/a C28H40O4 详情 详情
(VI) 53003 (7S,8S,9S,13R,14S,17R)-17-(2-hydroxyethyl)-3-isopropoxy-7,13-dimethyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-6-one n/a C24H34O3 详情 详情
(VII) 53004 N,N-diethyl-4-hydroxy-3-methoxybenzamide n/a C12H17NO3 详情 详情
(VIII) 53005 N,N-diethyl-4-{2-[(7S,8S,9S,13R,14S,17R)-3-isopropoxy-7,13-dimethyl-6-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl]ethoxy}-3-methoxybenzamide n/a C36H49NO5 详情 详情
(IX) 53006 2-[(8R,9S,13R,14S,17R)-13-methyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]ethyl methanesulfonate n/a C21H32O4S 详情 详情
(XI) 53007 N,N-diethyl-4-{2-[(8S,9S,13R,14S,17R)-3-isopropoxy-13-methyl-6-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl]ethoxy}-3-methoxybenzamide n/a C35H47NO5 详情 详情

合成路线48

该中间体在本合成路线中的序号：(B)

Synthesis of intermediate (3S)-(XI): Iodination of 4-chloro-2-nitrotoluene (I) with NaI, I2 and H2SO4 yields (II), which is then treated with dimethyl oxalate (A) in toluene in presence of KOMe or alternatively NaOMe, in MeOH to afford (III). Cyclization of (III) is performed by a first treatment with SnCl2 in dimethoxyethane followed by TiCl3/H2O to provide indole (IV), which is converted into (VI) by reaction with alcohol (V) in presence of NaHCO3, benzyltriethyl ammonium chloride and Pd(OAc)2, followed by a treatment with sodium thiosulfate. The reaction of aldehyde (VI) with KOtBu and triethyl phosphonoacetate (B) in THF yields ethyl ester (VIIa-b), which is then converted into iodo derivative (VIIIa-b) by means of NaI and NCS in DMF. Cyclization of (VIIIa-b) by treatment with Pd(PPh3)4 in DMF and Ag3PO4/H2O affords tetrahydrobenzindole (IX), which is reduced by means of Sm, and I2 in MeOH/THF to give (X). Alternatively (X) is obtained by simultaneous cyclization and reduction of (VIIIa-b) by treatment with SnBu3H and AIBN in chlorobenzene. Finally ethyl ester (X) is selectively hydrolyzed with HCl in HOAc to provide (XI) in its racemic form. Enantiomer (3S)-(XI) can be isolated by separation of the corresponding diasteromers obtained by reaction of (XI) with L-(-) norphedrine in isopropanol followed by hydrolysis with HCl in EtOAc and THF.

参考文献 中间体
合成目标
【1】 Katayama, S.; Kishimoto, H.; Ae, N.; Nagata, R. (Sumitomo Pharmaceuticals Co., Ltd.); Tricyclic indole-2-carboxylic acid cpd. used as NMDA receptor antagonist. WO 0056711 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(A) 37412 methyl 2-methoxy-2-oxoacetate;dimethyl oxalate;Methyl oxalate 553-90-2 C4H6O4 详情 详情
(VIIa) 41490 methyl 6-chloro-4-[(E)-5-ethoxy-5-oxo-3-pentenyl]-1H-indole-2-carboxylate C17H18ClNO4 详情 详情
(VIIb) 41491 methyl 6-chloro-4-[(Z)-5-ethoxy-5-oxo-3-pentenyl]-1H-indole-2-carboxylate n/a C17H18ClNO4 详情 详情
(VIIIa) 41492 methyl 6-chloro-4-[(E)-5-ethoxy-5-oxo-3-pentenyl]-3-iodo-1H-indole-2-carboxylate n/a C17H17ClINO4 详情 详情
(VIIIb) 41493 methyl 6-chloro-4-[(Z)-5-ethoxy-5-oxo-3-pentenyl]-3-iodo-1H-indole-2-carboxylate n/a C17H17ClINO4 详情 详情
(3S)-(XI) 41497 2-[(3S)-7-chloro-2-(methoxycarbonyl)-1,3,4,5-tetrahydrobenzo[cd]indol-3-yl]acetic acid C15H14ClNO4 详情 详情
(I) 41485 4-chloro-1-methyl-2-nitrobenzene；4-chloro-2-nitrotoluene;4-chloro-1-methyl-2-nitro-benzene 89-59-8 C7H6ClNO2 详情 详情
(II) 41486 5-chloro-1-iodo-2-methyl-3-nitrobenzene n/a C7H5ClINO2 详情 详情
(III) 41487 methyl 3-(4-chloro-2-iodo-6-nitrophenyl)-2-oxopropanoate C10H7ClINO5 详情 详情
(IV) 41488 methyl 6-chloro-4-iodo-1H-indole-2-carboxylate C10H7ClINO2 详情 详情
(V) 12234 2-Propen-1-ol; Allyl alcohol 107-18-6 C3H6O 详情 详情
(VI) 41489 methyl 6-chloro-4-(3-oxopropyl)-1H-indole-2-carboxylate C13H12ClNO3 详情 详情
(IX) 41494 methyl 7-chloro-3-[(Z)-2-ethoxy-2-oxoethylidene]-4,5-dihydrobenzo[cd]indole-2(1H)-carboxylate C17H16ClNO4 详情 详情
(X) 41495 methyl 7-chloro-3-(2-ethoxy-2-oxoethyl)-1,3,4,5-tetrahydrobenzo[cd]indole-2-carboxylate C17H18ClNO4 详情 详情
(XI) 41496 2-[7-chloro-2-(methoxycarbonyl)-1,3,4,5-tetrahydrobenzo[cd]indol-3-yl]acetic acid C15H14ClNO4 详情 详情

合成路线49

该中间体在本合成路线中的序号：(IX)

Horner-Emmons condensation of 2,3-isopropylidene-D-glyceraldehyde (I) with phosphonate (II) produced the unsaturated ester (IIIa-b). Ketal deprotection and lactone ring closure of (II) under acidic conditions, followed by O-silylation afforded (IV). The lactone function of (IV) was reduced with DIBAL and then with NaBH4-CeCl3 to produce the corresponding diol. Further silylation of the primary hydroxyl group furnished (V). Condensation of (V) with triethyl orthoacetate followed by Claisen rearrangement gave rise to the gamma,delta-unsaturated ester (VI). This was reduced to alcohol with LiAlH4 and then alkylated with benzyl bromide to yield benzyl ether (VII). Ozonization of (VII) in methanol at -78 C, followed by decomposition of the ozonide with dimethyl sulfide gave aldehyde (VIII). Horner-Emmons condensation of (VIII) with the sodium salt of triethyl phosphonoacetate (IX) produced the alpha,beta-unsaturated ester (X). Double bond hydrogenation in (X) with simultaneous benzyl group cleavage afforded hydroxy ester (XI), which was then converted to mesylate (XII). This was cyclized to the cyclopentane (XIIIa-b) by means of NaH in refluxing THF.

参考文献 中间体
合成目标
【1】 Hong, J.H.; et al.; Enantiomeric synthesis of 3'-fluoro-apionucleosides using claisen rearrangement. Tetrahedron Lett 1998, 39, 21, 3443.
【2】 Gumina, G.; et al.; Stereoselective synthesis of carbocyclic L-4'-fluoro-2',3'-dideoxyadenosine. Org Lett 2000, 2, 9, 1229.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(XIIIa) 36757 ethyl (1S,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentanecarboxylate C15H29FO3Si 详情 详情
(XIIIb) 36758 ethyl (1R,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentanecarboxylate C15H29FO3Si 详情 详情
(IIIa) 36760 ethyl (E)-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-fluoro-2-propenoate C10H15FO4 详情 详情
(IIIb) 36761 ethyl (E)-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-fluoro-2-propenoate C10H15FO4 详情 详情
(I) 36759 (4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde 15186-48-8 C6H10O3 详情 详情
(II) 18192 ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate 2356-16-3 C8H16FO5P 详情 详情
(IV) 36762 (5S)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluoro-2(5H)-furanone C11H19FO3Si 详情 详情
(V) 36750 (6S,7E)-8-fluoro-2,2,3,3,11,11,12,12-octamethyl-4,10-dioxa-3,11-disila-7-tridecen-6-ol C17H37FO3Si2 详情 详情
(VI) 36751 ethyl (3S,4E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluoro-4-hexenoate C21H43FO4Si2 详情 详情
(VII) 36752 benzyl (3S,4E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluoro-4-hexenyl ether; (E,8S)-8-[2-(benzyloxy)ethyl]-8-fluoro-2,2,3,3,11,11,12,12-octamethyl-4,10-dioxa-3,11-disila-6-tridecene C26H47FO3Si2 详情 详情
(VIII) 36753 (2R)-4-(benzyloxy)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-fluorobutanal C18H29FO3Si 详情 详情
(IX) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(X) 36754 ethyl (E,4S)-6-(benzyloxy)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-fluoro-2-hexenoate C22H35FO4Si 详情 详情
(XI) 36755 ethyl (4R)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-fluoro-6-hydroxyhexanoate C15H31FO4Si 详情 详情
(XII) 36756 ethyl (4R)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-fluoro-6-[(methylsulfonyl)oxy]hexanoate C16H33FO6SSi 详情 详情

合成路线50

该中间体在本合成路线中的序号：(IV)

The reduction of 1-indanone (I) with NaBH4 in methanol gives 1-indanol (II), which is brominated with Tms-Br in chloroform to yield 1-bromoindane (III) (1). The condensation of (III) with triethyl phosphonoacetate (IV) and NaH in DMF affords 2-(diethoxyphosphoryl)-2-(1-indanyl)acetic acid ethyl ester (V), which is treated with paraformaldehyde and K2CO3 in refluxing THF to provide 2-(1-indanyl)acrylic acid ethyl ester (VI). The hydrolysis of (VI) with NaOH in acetone/water gives the corresponding acrylic acid (VII), which is condensed with thioacetic acid (VIII) in refluxing chloroform to yield 3-(acetylsulfanyl)-2-(1-indanyl)propionic acid ethyl ester (IX) as a mixture of the two (R,R)+(S,S) and (R,S)+(S,R) racemates. These two racemates are easily separated by HPLC affording the desired (R,R)+(S,S)-(X) racemate. The condensation of (X) with L-tryptophan methyl ester (XI) by means of EDC and HOBT in THF/chloroform to provide a diastereomeric mixture (R,R,S)+(S,S,S) of compounds that is separated by HPLC to provide the desired (R,R,S) diastereomer (XII). Finally, this compound is hydrolyzed with NaOH in methanol/water to furnish the target tryptophan derivative.

参考文献 中间体
合成目标
【1】 Inguimbert, N.; Roques, B.P.; Meudal, H.; Teffot, F.; Poras, H.; Fournié-Zaluski, M.-C.; Coric, P.; Toward an optimal joint recognition of the S1' subsites of endothelin converting enzyme-1 (ECE-1), angiotensin converting enzyme (ACE), and neutral endopeptidase (NEP). J Med Chem 2002, 45, 7, 1477.
【2】 Roques, B.P.; Renard, P.; Scalbert, E.; Bennejean, C.; Fournie-Lazuski, M.-C.; Inguimbert, N.; Poras, H. (ADIR et Cie.; INSERM (Institut National de la Sante et de la Recherche Medicale)); Amino acid derivs. and use thereof as NEP, ACE and ECE inhibitors. FR 2805259; WO 0160822 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 23857 1-indanone 83-33-0 C9H8O 详情 详情
(II) 53590 1-Hydroxyhydrindene; 1-Hydroxyindan; 1-Indanol 6351-10-6 C9H10O 详情 详情
(III) 53591 1-bromoindane n/a C9H9Br 详情 详情
(IV) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(V) 53592 ethyl 2-(diethoxyphosphoryl)-2-(2,3-dihydro-1H-inden-1-yl)acetate n/a C17H25O5P 详情 详情
(VI) 53593 ethyl 2-(2,3-dihydro-1H-inden-1-yl)acrylate n/a C14H16O2 详情 详情
(VII) 53594 2-(2,3-dihydro-1H-inden-1-yl)acrylic acid n/a C12H12O2 详情 详情
(VIII) 12893 Ethanethioic S-acid C2H4OS 详情 详情
(IX) 53595 3-(acetylsulfanyl)-2-(2,3-dihydro-1H-inden-1-yl)propanoic acid n/a C14H16O3S 详情 详情
(X) 53596 (2R)-3-(acetylsulfanyl)-2-[(1R)-2,3-dihydro-1H-inden-1-yl]propanoic acid n/a C14H16O3S 详情 详情
(XI) 30387 2-amino-6-isopropyl-4-pyrimidinol C7H11N3O 详情 详情
(XII) 53597 methyl (2S)-2-({(2R)-3-(acetylsulfanyl)-2-[(1R)-2,3-dihydro-1H-inden-1-yl]propanoyl}amino)-3-(1H-indol-3-yl)propanoate n/a C26H28N2O4S 详情 详情

合成路线51

该中间体在本合成路线中的序号：(A)

Horner-Emmons condensation of benzophenone (I) with triethyl phosphonoacetate provides the unsaturated ester (II), which is further reduced with DIBAL in toluene to the allylic alcohol (III). Reaction of alcohol (III) with methanesulfonyl chloride and Et3N leads to chloride (IV). Finally, alkylation of 3-propionyl-3,9-diazabicyclo[3.3.1]nonane (V) with the allyl chloride (IV) furnishes the title compound.

参考文献 中间体
合成目标
【1】 Pinna, G.A.; Cignarella, G.; Loriga, G.; Murineddu, G.; Mussinu, J.-M.; Ruiu, S.; Fadda, P.; Fratta, W.; N-3(9)-Arylpropenyl-N-9(3)-propionyl-3,9-diazabicyclo[3.3.1]nonanes as mu-opioid receptor agonists. Effects on mu-affinity of arylalkenyl chain modifications. Bioorg Med Chem 2002, 10, 6, 1929.
【2】 Cignarella, G.; Pinna, G.A. (Centro Consortile Ricerche Neuropsicofarmacologiche a.r.l); 3,9-Diazabicyclo[3.3.1]nonane derivs. with analgesic activity. EP 1259511; WO 0160823 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(I) 18732 benzophenone 119-61-9 C13H10O 详情 详情
(II) 61015 ethyl 3,3-diphenylacrylate C17H16O2 详情 详情
(III) 61016 3,3-diphenyl-2-propen-1-ol C15H14O 详情 详情
(IV) 61017 1-(3-chloro-1-phenyl-1-propenyl)benzene C15H13Cl 详情 详情
(V) 61018 1-(3,9-diazabicyclo[3.3.1]non-3-yl)-1-propanone C10H18N2O 详情 详情

合成路线52

该中间体在本合成路线中的序号：(XXI)

Jones oxidation of 2-fluoro-4-methyl-1-nitrobenzene (XVIII) with CrO3 and H2SO4, followed by acetylation with Ac2O in AcOH yields the gemdiacetate (XIX), which by deacetylation with HCl in AcOH at 115 °C provides 3-fluoro-4-nitrobenzaldehyde (XX). Horner-Wadsworth-Emmons reaction of aldehyde (XX) with ethyl (diethoxyphosphoryl)acetate (XXI) using NaH in THF affords the unsaturated ester (XXII), which by fluoride substitution with methylamine (XXIII) in DMSO provides the nitro-aniline derivative (XXIVa) . Alternatively, condensation of 2,4-dichloro-1-nitrobenzene (XXV) with methylamine (XXIII) using Et3N in DMSO or THF yields 5-chloro-N-methyl-2-nitroaniline (XXVI), which is then subjected to Heck coupling with ethyl acrylate (XXVIIa), methyl acrylate (XXVIIb) or butyl acrylate (XXVIIa) in the presence of Pd(OAc)2, LiCl and DIEA in DMAc at 110 °C , or Pd2dba3, t-Bu3P and (c-Hex)2NMe at 110 °C to give the corresponding arylacrylates (XXIVa), (XXIVb) or (XXIVc). Reduction of the nitro group in compounds (XXIVa), (XXIVb) or (XXIVc) by means of SnCl2.2H2O in EtOH at 80 °C , H2 over Raney-Ni in toluene/MeOH or Na2S2O4 and K2CO3 in EtOH/H2O produces the corresponding diaminophenylacrylates (XXVIIIa) , (XXVIIIb) or (XXVIIIc) , which are finally condensed with 1-aminocyclo-butanecarboxylic acid hydrochloride (XXIX) in CH2Cl2 to provide the benzimidazole intermediates (IIIa) , (IIIb) or (XXX), the free base of intermediate (II) .
Similarly, intermediate (II) can be obtained by condensation of the diaminophenylacrylate (XXVIIIc) with N-Boc-1-aminocyclobutanecarboxylic acid (XXXI) using DCC in toluene, followed by N-deprotection and cyclization of the resulting amino amide (XXXII) with HCl in BuOH at 75 °C .

参考文献 中间体
合成目标
【1】 Boecher, W., Haefner, C., Kukolj, G. (Boehringer Ingelheim Pharma GmbH & Co. KG). Combination therapy for treating HCV infection. CN 103228278, EP 2621495, JP 2013540112, KR 2013116245, US 2012135949, WO 2012041771.
【2】 Brickl, R.-S., Chen, S., Chung, J. et al. (Boehringer Ingelheim Pharma GmbH & Co. KG). Solid state forms of a potent HCV inhibitor. CN 103153987, EP 2621921, JP 2013543495, KR 2013108326, US 2012122887, US 8598183, US 2014057928, WO 2012044520.
【3】 Mensa, F., Nehmiz, G. (Boehringer Ingelheim Pharma GmbH & Co. KG). Oral combination therapy for treating HCV infection in specific patient subgenotype populations. WO 2013147749.
【4】 Mensa, F. (Boehringer Ingelheim Pharma GmbH & Co. KG). Oral combination therapy for treating HCV infection in specific patient sub-population. WO 2013147750.
【5】 LaPlante, S.R., Boes, M., Brochu, C. et al. Conformation-based restrictions and scaffold replacements in the design of hepatitis C virus polymerase inhibitors. Discovery of deleobuvir (BI 207127). J Med Chem 2014, 57(5): 1845-54.
【6】 Tsantrizos, Y.S., Chabot, C., Beaulieu, P. et al. (Boehringer Ingelheim Pharma GmbH & Co. KG). Viral polymerase inhibitors. CN 102911161, CN 103304541, CN 103319464, CN 103333162, EP 1718608, EP 2626354, JP 2007523094, JP 2010195818, JP 2010280740, KR 2012091276, US 2005222236, US 8030309, WO 2005080388.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIVa) 67786 (E)-ethyl 3-(3-(methylamino)-4-nitrophenyl)acrylate 　 C12H14N2O4 详情 详情
(XXIVb) 67787 (E)-methyl 3-(3-(methylamino)-4-nitrophenyl)acrylate 　 C11H12N2O4 详情 详情
(XXIVc) 67788 (E)-butyl 3-(3-(methylamino)-4-nitrophenyl)acrylate 　 C14H18N2O4 详情 详情
(XXVIIa) 10164 ethyl acrylate 140-88-5 C5H8O2 详情 详情
(XXVIIb) 14156 methyl acrylate 96-33-3 C4H6O2 详情 详情
(XXVIIc) 67789 butyl acrylate 　 C7H12O2 详情 详情
(XXVIIIa) 67791 (E)-ethyl 3-(4-amino-3-(methylamino)phenyl)acrylate 　 C12H16N2O2 详情 详情
(XXVIIIb) 67792 (E)-methyl 3-(4-amino-3-(methylamino)phenyl)acrylate 　 C11H14N2O2 详情 详情
(XXVIIIc) 67790 (E)-butyl 3-(4-amino-3-(methylamino)phenyl)acrylate C14H20N2O2 详情 详情
(IIIa) 67765 (E)-methyl 3-(2-(1-aminocyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate 　 C16H19N3O2 详情 详情
(IIIb) 67766 (E)-ethyl 3-(2-(1-aminocyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate 　 C17H21N3O2 详情 详情
(II) 67764 (E)-butyl 3-(2-(1-aminocyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate dihydrochloride 　 C19H25N3O2.2HCl 详情 详情
(XVIII) 39366 2-fluoro-4-methyl-1-nitrobenzene 446-34-4 C7H6FNO2 详情 详情
(XIX) 67783 (3-fluoro-4-nitrophenyl)methylene diacetate 　 C11H10FNO6 详情 详情
(XX) 67784 3-fluoro-4-nitrobenzaldehyde 　 C7H4FNO3 详情 详情
(XXI) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(XXII) 67785 (E)-ethyl 3-(3-fluoro-4-nitrophenyl)acrylate 　 C11H10FNO4 详情 详情
(XXIII) 11021 Methanamine; Methylamine 74-89-5 CH5N 详情 详情
(XXV) 21787 2,4-dichloro-1-nitrobenzene 611-06-3 C6H3Cl2NO2 详情 详情
(XXVI) 46715 5-chloro-N-methyl-2-nitroaniline; N-(5-chloro-2-nitrophenyl)-N-methylamine 35966-84-8 C7H7ClN2O2 详情 详情
(XXIX) 67793 1-aminocyclo-butanecarboxylic acid hydrochloride 98071-16-0 C5H9NO2.HCl 详情 详情
(XXX) 67794 (E)-butyl 3-(2-(1-aminocyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate 　 C19H25N3O2 详情 详情
(XXXI) 67795 1-((tert-butoxycarbonyl)amino)cyclobutanecarboxylic acid 　 C10H17NO4 详情 详情
(XXXII) 67796 (E)-butyl 3-(4-amino-3-(1-((tert-butoxycarbonyl)amino)-N-methylcyclobutanecarboxamido)phenyl)acrylate 　 C24H35N3O5 详情 详情
Extended Information