【结 构 式】 |
【分子编号】12437 【品名】Triphenylphosphine; Triphenyl phosphine 【CA登记号】603-35-0 |
【 分 子 式 】C18H15P 【 分 子 量 】262.290862 【元素组成】C 82.43% H 5.76% P 11.81% |
合成路线1
该中间体在本合成路线中的序号:(II)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
【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2
该中间体在本合成路线中的序号:(IV)The esterification of bromoacetic acid (I) with benzyl alcohol (II) gives the corresponding ester (III), which by reaction with triphenylphosphine (IV) in hot toluene yields the phosphonium bromide (V). The reaction of (V) with NaOH in water-dichloromethane affords benzyl(triphenylphosphoranylidene) acetate (VI), which is submitted to a Wittig condensation with 5-(hydroxymethyl)-2-pyrrolidone (VII) in the presence of Dess-Martin periodinane (DMPI) giving benzyl 3-(5-oxo-2-pyrrolidinyl)-2(E) propenoate (VIII). The acylation of (VIII) with 4-methoxybenzoyl chloride (IX) by means of triethylamine in hot toluene yields the corresponding amide (X), which is finally hydrogenated and deprotected with H2 over Pd/C in THF.
【1】 Huang, C.C.; Synthesis of carbon-14 labeled 1-(4-methoxybenzoyl. J Label Compd Radiopharm 1987, 24, 6, 675. |
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) | 23660 | 2-Bromoacetic acid | 79-08-3 | C2H3BrO2 | 详情 | 详情 |
(II) | 18710 | Benzyl alcohol; Phenylmethanol | 100-51-6 | C7H8O | 详情 | 详情 |
(III) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
(IV) | 12437 | Triphenylphosphine; Triphenyl phosphine | 603-35-0 | C18H15P | 详情 | 详情 |
(V) | 22667 | [2-(benzyloxy)-2-oxoethyl](triphenyl)phosphonium bromide | C27H24BrO2P | 详情 | 详情 | |
(VI) | 22668 | benzyl 2-(triphenylphosphoranylidene)acetate | C27H23O2P | 详情 | 详情 | |
(VII) | 10079 | 5-(Hydroxymethyl)-2-pyrrolidinone | 62400-75-3 | C5H9NO2 | 详情 | 详情 |
(VIII) | 22670 | benzyl (E)-3-(5-oxo-2-pyrrolidinyl)-2-propenoate | C14H15NO3 | 详情 | 详情 | |
(IX) | 22671 | 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride | 100-07-2 | C8H7ClO2 | 详情 | 详情 |
(X) | 22672 | benzyl (E)-3-[1-(4-methoxybenzoyl)-5-oxo-2-pyrrolidinyl]-2-propenoate | C22H21NO5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(XIII)The treatment with NaHCO3 of the corresponding mixture of the 6(R)- and 6(S)-SO2-aldehydic adducts (VIII) gives a mixture of the 20(R) and 20(S) epimeric aldehydes (IX). The Wittig condensation of the aldehyde mixture (IX) with cyclopropylcarbonylmethylenetriphenylphosphorane (X) [prepared from acetylcyclopropane (XI) by bromination to bromoacetylcyclopropane (XII), reaction with triphenylphosphine (XIII) to the phosphonium salt (XIV) and treatment with NaOH] in DMSO at 105 C, followed by chromatographic separation yields the epimeric 20(R)-enone (XV). The reduction of (XV) with NaBH4 and CeCl3 in THF-methanol, followed by chromatographic purification affords the epimeric 3'(R)-allylic alcohol (XVI), which is isomerized by irradiation with UV-light from a TQ 718Z2 Hanau lamp in toluene in the presence of anthracene to give the corresponding 5(Z)-derivative (XVII). Finally, this compound is deprotected by a treatment with tetrabutylammonium fluoride in THF at 60 C.
【1】 Calverley, M.J.; Synthesis of MC 903, a biologically active vitamin D metabolite analogue. Tetrahedron 1987, 43, 20, 4609-19. |
【2】 Binderup, E.; CALCIPOTRIOL. Drugs Fut 1990, 15, 1, 15. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VIII) | 12432 | (2S)-2-[(1R,3aR,7aR)-4-[(E)-((4S,6R)-4,6-bis[[tert-Butyl(dimethyl)silyl]oxy]-2,2-dioxooctahydro-1H-2-benzothiophen-1-yl)methylidene]-7a-methyloctahydro-1H-inden-1-yl]propanal | C34H62O5SSi2 | 详情 | 详情 | |
(IX) | 12433 | 2-[(1R,3aS,7aR)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-Butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]propanal | C34H60O3Si2 | 详情 | 详情 | |
(X) | 12434 | 1-cyclopropyl-2-(triphenylphosphoranylidene)-1-ethanone | C23H21OP | 详情 | 详情 | |
(XI) | 12435 | Acetylcyclopropane; 1-Cyclopropyl-1-ethanone; Cyclopropylmethylketone | 765-43-5 | C5H8O | 详情 | 详情 |
(XII) | 12436 | 2-Bromo-1-cyclopropyl-1-ethanone | 69267-75-0 | C5H7BrO | 详情 | 详情 |
(XIII) | 12437 | Triphenylphosphine; Triphenyl phosphine | 603-35-0 | C18H15P | 详情 | 详情 |
(XIV) | 12438 | (2-Cyclopropyl-2-oxoethyl)(triphenyl)phosphonium bromide | 112849-15-7 | C23H22BrOP | 详情 | 详情 |
(XV) | 12439 | (E,4R)-4-[(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-Bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]-1-cyclopropyl-2-penten-1-one | C39H66O3Si2 | 详情 | 详情 | |
(XVI) | 12440 | (1S,2E,4R)-4-[(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-Bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]-1-cyclopropyl-2-penten-1-ol | C39H68O3Si2 | 详情 | 详情 | |
(XVII) | 12441 | (1S,2E,4R)-4-[(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-Bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]-1-cyclopropyl-2-penten-1-ol | C39H68O3Si2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(IX)The condensation of 4-methoxypyridine-3-carbaldehyde (I) with 2-azidoacetic acid ethyl ester (II) by means of NaOMe in ethanol gives 2-azido-3-(4-methoxypyridin-3-yl)acrylic acid ethyl ester (III), which is cyclized in refluxing o-xylene to yield the pyrrolopyridine (IV). The reaction of the NH group of (IV) with Sem-Cl and NaH in DMF affords the N-protected compound (V), whose ester group is reduced with LiAlH4 in refluxing THF to provide the carbinol (VI). The oxidation of (VI) with MnO2 in dichloromethane gives the corresponding carbaldehyde (VII), which is condensed with 2-azidoacetic acid ethyl ester (II) as before to yield the azido acrylic ester (VIII). The condensation of (VIII) with triphenylphosphine (IX) in dichloromethane affords the iminophosphorane (X), which is N-deprotected by means of TBAF in THF to provide the deprotected iminophosphorane (XI). The cyclization of (XI) with alpha-methylbenzyl isocyanate (XII) in THF gives the tricyclic pyrimidopyrrolopyridine (XIII), which is brominated with Br2 in pyridine to yield intermediate (XIV). The reaction of (XIV) with 1-ethoxyvinyl trimethyl tin (XV) by means of PdCl2(PPh3)2 in DMF affords the acetyl derivative (XVI), which is condensed with dimethylformamide di-tert-butyl acetal (XVII) in hot DMF to provide the dimethyl enaminone (XVIII). The cyclization of (XVIII) with guanidine (XIX) by means of K2CO3 in refluxing 2-methoxyethanol gives the 2-aminopyrimidine derivative (XX), with simultaneous hydrolysis of the ester group. The decarboxylation of (XX), with simultaneous demethylation, by heating at 260 C in diphenyl ether yields the N-protected precursor (XXI), which is finally treated with triflic acid to afford the target variolin B.
【1】 Molina, P.; et al.; Synthesis of the potent antitumoral marine alkaloid variolin B. Tetrahedron Lett 2002, 43, 6, 1005. |
【2】 Fresneda, P.M.; et al.; Synthetic studies towards the 2-aminopyrimidine alkaloids variolins and meridianins from marine origin. Tetrahedron Lett 2000, 41, 24, 4777. |
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) | 55718 | 4-methoxynicotinaldehyde | C7H7NO2 | 详情 | 详情 | |
(II) | 32916 | ethyl 2-azidoacetate | 637-81-0 | C4H7N3O2 | 详情 | 详情 |
(III) | 55719 | ethyl (Z)-2-azido-3-(4-methoxy-3-pyridinyl)-2-propenoate | C11H12N4O3 | 详情 | 详情 | |
(IV) | 55720 | ethyl 4-methoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylate | C11H12N2O3 | 详情 | 详情 | |
(V) | 55721 | ethyl 4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxylate | C17H26N2O4Si | 详情 | 详情 | |
(VI) | 55722 | (4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-2-yl)methanol | C15H24N2O3Si | 详情 | 详情 | |
(VII) | 55723 | 4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde | C15H22N2O3Si | 详情 | 详情 | |
(VIII) | 55724 | ethyl (Z)-2-azido-3-(4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-propenoate | C19H27N5O4Si | 详情 | 详情 | |
(IX) | 12437 | Triphenylphosphine; Triphenyl phosphine | 603-35-0 | C18H15P | 详情 | 详情 |
(X) | 55725 | ethyl (Z)-3-(4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-[(triphenylphosphoranylidene)amino]-2-propenoate | C37H42N3O4PSi | 详情 | 详情 | |
(XI) | 55726 | ethyl (Z)-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-[(triphenylphosphoranylidene)amino]-2-propenoate | C31H28N3O3P | 详情 | 详情 | |
(XII) | 55734 | (S)-(-)-1-Phenylethyl isocyanate; (S)-(-)-Phenylethyl Isocyanate; Isocyanic acid (S)-(-)-alpha-phenylethyl ester; S-(-)-alpha-Methylbenzyl isocyanate | 14649-03-7 | C9H9NO | 详情 | 详情 |
(XIII) | 55727 | ethyl 4-methoxy-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine-7-carboxylate | C22H22N4O3 | 详情 | 详情 | |
(XIV) | 55728 | ethyl 5-bromo-4-methoxy-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine-7-carboxylate | C22H21BrN4O3 | 详情 | 详情 | |
(XV) | 55729 | ethyl 1-(trimethylstannyl)vinyl ether; (1-ethoxyvinyl)(trimethyl)stannane | C7H16OSn | 详情 | 详情 | |
(XVI) | 55730 | ethyl 5-acetyl-4-methoxy-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine-7-carboxylate | C24H24N4O4 | 详情 | 详情 | |
(XVII) | 21059 | N-[di(tert-butoxy)methyl]-N,N-dimethylamine; di(tert-butoxy)-N,N-dimethylmethanamine | 36805-97-7 | C11H25NO2 | 详情 | 详情 |
(XVIII) | 55731 | ethyl 5-[(E)-3-(dimethylamino)-2-propenoyl]-4-methoxy-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine-7-carboxylate | C27H29N5O4 | 详情 | 详情 | |
(XIX) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
(XX) | 55732 | 5-(2-amino-4-pyrimidinyl)-4-methoxy-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine-7-carboxylic acid | C24H21N7O3 | 详情 | 详情 | |
(XXI) | 55733 | 5-(2-amino-4-pyrimidinyl)-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-4-ol | C22H19N7O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号: (I)
【1】 Morieux P,Stables JP, Kohn H. 2008. Synthesis and anticonvulsant activities of N-benzyl(2R)-2-acetamido-3-oxysubstituted propionamide derivatives. Bioorganic & Medicinal Chemistry, 16(19): 8968~8975. |
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) | 12437 | Triphenylphosphine; Triphenyl phosphine | 603-35-0 | C18H15P | 详情 | 详情 |
(II) | 67198 | ethanol, sodium salt | C2H6O.Na | 详情 | 详情 | |
(III) | 67199 | diethoxytriphenylphosphorane | 18509-25-6 | C22H25O2P | 详情 | 详情 |
(IV) | 67200 | (R)-methyl 2-amino-3-hydroxypropanoate | 24184-43-8 | C4H9NO3 | 详情 | 详情 |
(V) | 67201 | (R)-ethyl aziridine-2-carboxylate | C5H9NO2 | 详情 | 详情 | |
(VI) | 67202 | (R)-methyl aziridine-2-carboxylate | 103539-32-8 | C4H7NO2 | 详情 | 详情 |
(VII) | 67203 | (R)-ethyl 1-acetylaziridine-2-carboxylate | C7H11NO3 | 详情 | 详情 | |
(VIII) | 67204 | (R)-methyl 1-acetylaziridine-2-carboxylate | C6H9NO3 | 详情 | 详情 | |
(IX) | 67205 | (R)-ethyl 2-acetamido-3-methoxypropanoate | C8H15NO4 | 详情 | 详情 | |
(X) | 67206 | (R)-methyl 2-acetamido-3-methoxypropanoate | C7H13NO4 | 详情 | 详情 | |
(XI) | 67190 | (R)-2-acetamido-3-methoxypropanoic acid | C6H11NO4 | 详情 | 详情 | |
(XII) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
(XIII) | 67207 | 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride | C10H17ClN4O3 | 详情 | 详情 |