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【结 构 式】 
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【分子编号】12869 【品名】benzyl 2-bromoacetate 【CA登记号】5437-45-6 |
【 分 子 式 】C9H9BrO2 【 分 子 量 】229.07326 【元素组成】C 47.19% H 3.96% Br 34.88% O 13.97% |
合成路线1
该中间体在本合成路线中的序号：(V)The reaction of 2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (I) with PCl5 in hot xylene gives 3,3-dichloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (II), which is treated with sodium acetate and reduced with H2 over Pd/C in acetic acid yielding 3-chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (III). The reaction of (III) with sodium azide in DMSO affords 3-azido-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (IV), which is condensed with benzyl bromoacetate (V) by means of NaH in DMF giving 3-azido-1-(benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VI). The treatment of (VI) with Raney-Ni in ethanol-water yields 3-amino-1-(benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol affording 3-amino-1-(carboxymethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VIII). Finally, this compound is condensed with ethyl 3-benzylpyruvate (IX) by means of sodium cyanoborohydride in methanol acetic acid.
| 【1】 Watthey, J.W.H. (Novartis AG); Benzazepin-2-ones, process for their preparation, pharmaceutical preparations containing these compounds and the compounds for therapeutical use. EP 0072352; GB 2103614; JP 8338260 . |
| 【2】 Castaner, J.; Serradell, M.N.; CGS-14824 A. Drugs Fut 1984, 9, 5, 317. |
| 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) | 30511 | 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H11NO | 详情 | 详情 | |
| (II) | 30512 | 3,3-dichloro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H9Cl2NO | 详情 | 详情 | |
| (III) | 30513 | 3-chloro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10ClNO | 详情 | 详情 | |
| (IV) | 20891 | 3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10N4O | 详情 | 详情 | |
| (V) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (VI) | 30514 | benzyl 2-(3-azido-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C19H18N4O3 | 详情 | 详情 | |
| (VII) | 30515 | benzyl 2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C19H20N2O3 | 详情 | 详情 | |
| (VIII) | 30516 | 2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetic acid | C12H14N2O3 | 详情 | 详情 | |
| (IX) | 20896 | Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester | 64920-29-2 | C12H14O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(A)1) By condensation of 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid (II) with benzyl bromoacetate (A) by means of K2CO3 in DMF. 2) By cyclocondensation of a mixture of N-(p-methoxyphenyl)-N-(p-chlorobenzoyl)hydrazine (III) and benzyl levulinate (IV) at 80 C in acetic acid.
| 【1】 Boltze, K.; Brendler, O.; Dell, H.-D.; Jacobi, H.; Novel substituted indole compound, process for the preparation and therapeutic compositions containing it.. DE 2234651; ES 416877; FR 2192828; JP 49043970; US 3910952 . |
| 【2】 Leeson, P.A.; Castaner, J.; Acemetacin. Drugs Fut 1977, 2, 7, 423. |
| 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) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (I) | 33962 | 2-(benzyloxy)-2-oxoethyl 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetate | C28H24ClNO6 | 详情 | 详情 | |
| (II) | 22930 | 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid | C19H16ClNO4 | 详情 | 详情 | |
| (III) | 24319 | 4-chloro-N-(4-methoxyphenyl)benzohydrazide | C14H13ClN2O2 | 详情 | 详情 | |
| (IV) | 33963 | 2-(benzyloxy)-2-oxoethyl 4-oxopentanoate | C14H16O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)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4
该中间体在本合成路线中的序号：(II)Alkylation of the sodium salt of diclofenac (I) with benzyl bromoacetate (II) in hot DMF yielded the (arylacetoxy)acetate (III). Subsequent hydrogenolysis of the benzyl ester of (III) in the presence of Pd/C gave the title carboxylic acid. Alternatively, the benzyl ester group of (III) was cleaved by means of the combination of chlorotrimethylsilane and sodium iodide. This method of selective ester hydrolysis with in situ generated iodotrimethylsilane was also applied to the corresponding methyl (IV) and tert-butyl (V) esters. In a related procedure, tert-butyl ester (V) was prepared by alkylation of diclofenac (VI) with tert-butyl bromoacetate (VII) in the presence of tertiary amines. Selective cleavage of the tert-butyl ester group of (V) was then performed by treatment with either trifluoroacetic or formic acid.
| 【1】 Casas, A.V. (Almirall Prodesfarma, SA); 2-[(2,6-Dichlorophenyl)amino]phenylacetoxyacetyl derivs. and therapeutic compsns. containing same. EP 0119932; US 4548952 . |
| 【2】 Ginebreda Martí, A.; Agustí Cruz, A. (Almirall Prodesfarma, SA); Process for obtaining 2-[(2,6-dichlorophenyl)amino]phenylacetoxyacetic acid. ES 2020146 . |
| 【3】 Schickaneder, H.; Nikolopoulos, A.; Murphy, T.; Process for the preparation of aceclofenac. WO 9955660 . |
| 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) | 56535 | sodium 2-[2-(2,6-dichloroanilino)phenyl]acetate | C14H10Cl2NNaO2 | 详情 | 详情 | |
| (II) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (III) | 56536 | 2-(benzyloxy)-2-oxoethyl 2-[2-(2,6-dichloroanilino)phenyl]acetate | C23H19Cl2NO4 | 详情 | 详情 | |
| (IV) | 56537 | 2-methoxy-2-oxoethyl 2-[2-(2,6-dichloroanilino)phenyl]acetate | C17H15Cl2NO4 | 详情 | 详情 | |
| (V) | 56538 | 2-(tert-butoxy)-2-oxoethyl 2-[2-(2,6-dichloroanilino)phenyl]acetate | C20H21Cl2NO4 | 详情 | 详情 | |
| (VI) | 33701 | Diclofenac; 2-[2-(2,6-Dichloroanilino)phenyl]acetic acid | C14H11Cl2NO2 | 详情 | 详情 | |
| (VII) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)The starting product (I) is obtained as follows: The acylation of 4(S)-isopropyloxazolidin-2-one (IV) with 3-(1-naphthyl)propionyl chloride (III) by means of butyllithium in THF-hexane yields 4(S)-isopropyl-3-[3-(1-naphthyl)propionyl]oxazolidin-2-one (V), which is condensed with benzyl bromoacetate (VI) by means of lithium diisopropylamide in THF to afford 3-[3-(benzyloxycarbonyl)-2(R)-(1-naphthylmethyl)propionyl]-4(S)-isoprop yloxazolidin-2-one (VII). The hydrogenolysis of (VII) with H2 over Pd/C in ethanol gives the carboxylic acid (VIII), which is condensed with morpholine (IX) by means of triethylamine and diethylphosphoryl cyanide in THF yielding 4(S)-isopropyl-3-[3-(morpholinocarbonyl)-2(R)-(1-naphthylmethyl)propion yl]oxazolidin-2-one (X). Finally, this compound is hydrolyzed with LiOH in THF - water to afford the acid (I).
| 【1】 Nishi, T.; Nagahori, H.; Saito, F.; et al.; Syntheses and biological activities of renin inhibitors containing statine analogues. Chem Pharm Bull 1990, 38, 1, 103-9. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 12866 | 3-(1-Naphthyl)propanoyl chloride | C13H11ClO | 详情 | 详情 | |
| (IV) | 12867 | (4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone | 17016-83-0 | C6H11NO2 | 详情 | 详情 |
| (V) | 12868 | (4S)-4-Isopropyl-3-[3-(1-naphthyl)propanoyl]-1,3-oxazolidin-2-one | C19H21NO3 | 详情 | 详情 | |
| (VI) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (VII) | 12870 | benzyl (3R)-4-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-3-(1-naphthylmethyl)-4-oxobutanoate | C28H29NO5 | 详情 | 详情 | |
| (VIII) | 12871 | (3R)-4-[(4S)-4-Isopropyl-2-oxo-1,3-oxazolidin-3-yl]-3-(1-naphthylmethyl)-4-oxobutyric acid | C21H23NO5 | 详情 | 详情 | |
| (IX) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (X) | 12873 | Boc-L-phenylalanine;N-[(1,1-Dimethylethoxy)carbonyl]-L-phenylalanine;N-(tert-Butoxycarbonyl)-L-phenylalanine;(R)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid;N-Boc-Lhomophenylalanine；(2R)-1-[(4S)-4-Isopropyl-2-oxo-1,3-oxazolidin-3-yl]-4-(4-morpholinyl)-2-(1-naphthylmethyl)-1,4-butanedione | C25H30N2O5 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XII)The reaction of L-tyrosine (I) with methyl chloroformate (II) by means of NaOH in water gives the carbamate (III), which is methylated at the remaining phenol and carboxylic groups with dimethyl sulfate and K2CO3 in refluxing acetone to yield the 4-O-methyl tyrosine derivative (IV). The hydrolysis of the methyl ester of (IV) with NaOH in dioxane/water, followed by reaction with O-methylhydroxylamine by means of DCC and HOBT, affords the methyl hydroxamate (V). The cyclization of (V) by means of bis(trifluoroacetoxy)iodobenzene in dichloromethane/methanol provides the spirodienone (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate to give the saturated ketone (VII). The protection of the ketonic group of (VII) with ethyleneglycol and PPTS yields the cyclic ketal (VIII), which is reduced with LiAlH4 in THF to afford the methoxyamine (IX). The protection of the N-methylamine of (IX) with benzyl chloroformate and TEA provides the carbamate (X), which is treated with Zn in acetic acid in order to cleave the N-methoxyamine group and yield the spiropyrrolidine (XI). The alkylation of the pyrrolidine NH with benzyl chloroformate (XII) and K2CO3 in warm acetonitrile affords the adduct (XIII), which is treated with H2 over Pd/C in methanol in order to remove the benzyl and benzyloxycarbonyl protecting groups, providing the amino acid (XIV). The cyclization of (XIV) by means of DPPA and NaHCO3 in DMF/dichloromethane gives the tetracyclic compound (XV), which is condensed with 4-(prenyloxy)benzaldehyde (XVI) by means of LDA in THF yielding the aldol condensation product (XVII).
| 【1】 Basak, A.; Wardrop, D.J.; N-methoxy-N-acylnitrenium ions: Application to the formal synthesis of (-)-TAN1251A. Org Lett 2001, 3, 7, 1053. |
| 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) | 48794 | (S)-(-)-Tyrosine; (S)-2-Amino-3-(4-hydroxyphenyl)propionic acid; 3-(4-Hydroxyphenyl)-L-alanine; L-(-)-Tyrosine; L-3-(4-Hydroxyphenyl)alanine; L-4-Hydroxy-17O-phenylalanine; L-beta-(p-Hydroxyphenyl)alanine; L-Hydroxy Phenyl Alanine; L-tyrosine | 60-18-4 | C9H11NO3 | 详情 | 详情 |
| (II) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (III) | 48795 | (2S)-3-(4-hydroxyphenyl)-2-[(methoxycarbonyl)amino]propionic acid | C11H13NO5 | 详情 | 详情 | |
| (IV) | 48796 | methyl (2S)-2-[(methoxycarbonyl)amino]-3-(4-methoxyphenyl)propanoate | C13H17NO5 | 详情 | 详情 | |
| (V) | 48797 | methyl (1S)-2-(methoxyamino)-1-(4-methoxybenzyl)-2-oxoethylcarbamate | C13H18N2O5 | 详情 | 详情 | |
| (VI) | 48798 | methyl (3S)-1-methoxy-2,8-dioxo-1-azaspiro[4.5]deca-6,9-dien-3-ylcarbamate | C12H14N2O5 | 详情 | 详情 | |
| (VII) | 48799 | methyl (3S)-1-methoxy-2,8-dioxo-1-azaspiro[4.5]dec-3-ylcarbamate | C12H18N2O5 | 详情 | 详情 | |
| (VIII) | 48800 | methyl (11S)-9-methoxy-10-oxo-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-ylcarbamate | C14H22N2O6 | 详情 | 详情 | |
| (IX) | 48801 | (11S)-9-methoxy-N-methyl-1,4-dioxa-9-azadispiro[4.2.4.2]tetradecan-11-amine; N-[(11S)-9-methoxy-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-yl]-N-methylamine | C13H24N2O3 | 详情 | 详情 | |
| (X) | 48802 | benzyl (11S)-9-methoxy-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-yl(methyl)carbamate | C21H30N2O5 | 详情 | 详情 | |
| (XI) | 48803 | benzyl (11S)-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-yl(methyl)carbamate | C20H28N2O4 | 详情 | 详情 | |
| (XII) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (XIII) | 48804 | benzyl 2-[(11S)-11-[[(benzyloxy)carbonyl](methyl)amino]-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]acetate | C29H36N2O6 | 详情 | 详情 | |
| (XIV) | 48805 | 2-[(11S)-11-(methylamino)-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]acetic acid | C14H24N2O4 | 详情 | 详情 | |
| (XV) | 48806 | C14H22N2O3 | 详情 | 详情 | ||
| (XVI) | 19019 | 4-[(3-methyl-2-butenyl)oxy]benzaldehyde | C12H14O2 | 详情 | 详情 | |
| (XVII) | 19020 | (1R,4S)-4-[1-Hydroxy-1-[4-(3-methyl-2-butenyloxy)phenyl]methyl]-2-methyldispiro[2,5-diazabicyclo[3,2,1]octane-6,1'-cyclohexane-4',2''-[1,3]-dioxolan]-3-one | C26H36N2O5 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XL)Keto ester (XLI) was obtained by Reformatskii condensation of the organozinc reagent generated from benzyl bromoacetate (XL) with n-undecyl cyanide (XXXIX). Subsequent hydrogenolysis of the benzyl ester of (XLI) in the presence of Pearlman's catalyst furnished keto acid (XLII). Acylation of the diamino compound (XXXVIII) with ketoacid (XLII), by means of DCC, provided diamide (XLIII). Then, desilylation of (XLIII) to afford alcohol (XLIV) was accomplished employing HF in acetonitrile.
| 【1】 Christ, W.J.; Kawata, T.; Hawkins, L.D.; Kobayashi, S.; Asano, O.; Rossignol, D.P. (Eisai Co., Ltd.); Anti-endotoxin cpds.. EP 0536969; JP 1993194470; US 5530113 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXVIII) | 59104 | (1R)-1-(2-{[(2R,3R,4R,5S,6R)-2-[((2R,3S,4R,5R,6S)-3-{[(allyloxy)carbonyl]oxy}-4-[((3R)-3-{[(allyloxy)carbonyl]oxy}decyl)oxy]-5-amino-6-{[tert-butyl(dimethyl)silyl]oxy}tetrahydro-2H-pyran-2-yl)methoxy]-3-amino-5-{[bis(allyloxy)phosphoryl]oxy}-6-(methoxymethyl)tetrahydro-2H-pyran-4-yl]oxy}ethyl)octyl (Z)-5-dodecenoate | C65H117N2O19PSi | 详情 | 详情 | |
| (XXXIX) | 59105 | lauronitrile | C12H23N | 详情 | 详情 | |
| (XL) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (XLI) | 59106 | benzyl 3-oxotetradecanoate | C21H32O3 | 详情 | 详情 | |
| (XLII) | 59107 | 3-oxotetradecanoic acid | C14H26O3 | 详情 | 详情 | |
| (XLIII) | 59108 | (1R)-1-[2-({(2R,3R,4R,5S,6R)-2-({(2R,3S,4R,5R,6S)-3-{[(allyloxy)carbonyl]oxy}-4-[((3R)-3-{[(allyloxy)carbonyl]oxy}decyl)oxy]-6-{[tert-butyl(dimethyl)silyl]oxy}-5-[(3-oxotetradecanoyl)amino]tetrahydro-2H-pyran-2-yl}methoxy)-5-{[bis(allyloxy)phosphoryl]oxy}-6-(methoxymethyl)-3-[(3-oxotetradecanoyl)amino]tetrahydro-2H-pyran-4-yl}oxy)ethyl]octyl (Z)-5-dodecenoate | C93H165N2O23PSi | 详情 | 详情 | |
| (XLIV) | 59109 | (1R)-1-[2-({(2R,3R,4R,5S,6R)-2-({(2R,3S,4R,5R)-3-{[(allyloxy)carbonyl]oxy}-4-[((3R)-3-{[(allyloxy)carbonyl]oxy}decyl)oxy]-6-hydroxy-5-[(3-oxotetradecanoyl)amino]tetrahydro-2H-pyran-2-yl}methoxy)-5-{[bis(allyloxy)phosphoryl]oxy}-6-(methoxymethyl)-3-[(3-oxotetradecanoyl)amino]tetrahydro-2H-pyran-4-yl}oxy)ethyl]octyl (Z)-5-dodecenoate | C87H151N2O23P | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(V)1) The reaction of 4-methylpentanoic acid (I) with SOCl2 in refluxing chloroform gives the acyl chloride (II), which is condensed with the chiral oxazolidinone (III) by means of BuLi in THF, yielding the corresponding N-acyl derivative (IV). The regioselective alkylation of (IV) with benzyl bromoacetate (V) by means of LDA in THF affords the (S)-adduct (VI) with >95% e.e. purity. The elimination of the chiral auxiliary with LiOH and H2O2 gives the glutaric acid monoester (VII), which is reduced with BH3/SMe2 in THF, yielding compound (VIII). The reaction of (VIII) with tosyl chloride in pyridine yields the tosylate (IX), which is treated with sodium azide in DMSO, affording the azide (X). Finally, this compound is reduced and debenzylated with H2 over Pd/C in THF.
| 【1】 Bryans, J.S.; Wustrow, D.J.; 3-Substituted GABA analogs with central nervous system activity: A review. Med Res Rev 1999, 19, 2, 149. |
| 【2】 Newhouse, B.J.; Ibrahim, P.; Burgess, L.E.; et al.; Potent selective nonpeptidic inhibitors of human lung tryptase. Proc Natl Acad Sci USA 1999, 96, 15, 8348. |
| 【3】 Sobieray, D.M.; Hoekstra, M.S.; Schwindt, M.A.; et al.; Chemical development of CI-1008, an enantiomerically pure anticonvulsant. Org Process Res Dev 1997, 1, 1, 26. |
| 【4】 Taylor, C.P.; Kanter, G.D.; Vartanian, M.G.; Yuen, P.; Enantioselective synthesis of PD144723: A potent stereospecific anticonvulsant. Bioorg Med Chem Lett 1994, 4, 6, 823. |
| 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) | 25389 | 4-methylpentanoic acid | 646-07-1 | C6H12O2 | 详情 | 详情 |
| (II) | 25390 | 4-methylpentanoyl chloride | 38136-29-7 | C6H11ClO | 详情 | 详情 |
| (III) | 26040 | (4R,5S)-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C10H11NO2 | 详情 | 详情 | |
| (IV) | 26041 | (4R,5S)-4-methyl-3-(4-methylpentanoyl)-5-phenyl-1,3-oxazolidin-2-one | C16H21NO3 | 详情 | 详情 | |
| (V) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (VI) | 26042 | benzyl (3S)-5-methyl-3-[[(4R,5S)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]carbonyl]hexanoate | C25H29NO5 | 详情 | 详情 | |
| (VII) | 26043 | (2S)-2-[2-(benzyloxy)-2-oxoethyl]-4-methylpentanoic acid | C15H20O4 | 详情 | 详情 | |
| (VIII) | 26044 | benzyl (3S)-3-(hydroxymethyl)-5-methylhexanoate | C15H22O3 | 详情 | 详情 | |
| (IX) | 26045 | benzyl (3S)-5-methyl-3-([[(4-methylphenyl)sulfonyl]oxy]methyl)hexanoate | C22H28O5S | 详情 | 详情 | |
| (X) | 26046 | benzyl (3S)-3-(azidomethyl)-5-methylhexanoate | C15H21N3O2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XIV)Reduction of the phenyl ring of N-(tert-butoxycarbonyl)-(R)-phenylglycine (VI) with H2 over Rh/Al2O3 in methanol gives the protected (R)-cyclohexylglycine (VII), which is condensed with azetidine (VIII) by means of EDC in acetonitrile to yield the dipeptide (IX). Hydrolysis of the ester group of (IX) affords the carboxylic acid (X), which is condensed with the amino group of the previous intermediate (V) by means of EDC and DMAP in acetonitrile or ethyl acetate/acetonitrile to provide adduct (XI). Cleavage of the Boc-protecting group of (XI) with HCl or methanesulfonic acid gives (XII) with a terminal amino group that is condensed with benzyl 2-(2-nitrophenylsulfonyloxy)acetate (XIII) or benzyl 2-bromoacetate (XIV) by means of K2CO3 in the same solvent to yield the melagatran precursor (XV). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in methanol.
| 【1】 Bayes, M.; Silvestre, J.S.; Sorbera, L.A.; Castaner, J.; Melagatran and Ximelagatran. Drugs Fut 2001, 26, 12, 1155. |
| 【2】 Antonsson, K.T.; Bylund, R.E.; Gustafsson, N.D.; Nilsson, N.O.I. (AstraZeneca plc); New peptide derivs.. EP 0701568; JP 1996511018; JP 2001322974; US 5602253; US 5723444; WO 9429336 . |
| 【3】 Hedstrom, L.; Lundblad, A.; Nagard, S. (AstraZeneca AB); A substantially crystalline form of melagatran. WO 0102426 . |
| 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) | 50386 | benzyl [4-(aminomethyl)phenyl](imino)methylcarbamate | C16H17N3O2 | 详情 | 详情 | |
| (VI) | 22613 | (2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid | 2900-27-8 | C13H17NO4 | 详情 | 详情 |
| (VII) | 35619 | (2S)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoic acid | C13H23NO4 | 详情 | 详情 | |
| (VIII) | 50387 | methyl (2S)-2-azetidinecarboxylate | C5H9NO2 | 详情 | 详情 | |
| (IX) | 50388 | tert-butyl (1R)-1-cyclohexyl-2-[(2S)-2-[(methylamino)carbonyl]azetidinyl]-2-oxoethylcarbamate | C18H31N3O4 | 详情 | 详情 | |
| (X) | 50389 | (2S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl]-2-azetidinecarboxylic acid | C17H28N2O5 | 详情 | 详情 | |
| (XI) | 50376 | benzyl [4-([[((2S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl]azetidinyl)carbonyl]amino]methyl)phenyl](imino)methylcarbamate | C33H43N5O6 | 详情 | 详情 | |
| (XII) | 50390 | benzyl (4-[[([(2S)-1-[(2R)-2-amino-2-cyclohexylethanoyl]azetidinyl]carbonyl)amino]methyl]phenyl)(imino)methylcarbamate | C28H35N5O4 | 详情 | 详情 | |
| (XIII) | 50391 | benzyl 2-[[(2-nitrophenyl)sulfonyl]oxy]acetate | C15H13NO7S | 详情 | 详情 | |
| (XIV) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (XV) | 50392 | benzyl 2-[((1R)-2-[(2S)-2-[([4-[[[(benzyloxy)carbonyl]amino](imino)methyl]benzyl]amino)carbonyl]azetidinyl]-1-cyclohexyl-2-oxoethyl)amino]acetate | C37H43N5O6 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XIV)Reaction of 4-cyanobenzyl bromide (I) with bis(tert-butoxycarbonyl)imine (XVI) by means of NaH in THF gives the protected benzylamine (XVII), which is treated with hydroxylamine and Na2CO3 in ethanol/water to yield the N-hydroxybenzamidine (XVIII). Reduction of compound (XVIII) with H2 over Pd/C in HOAc/Ac2O affords the protected benzamidine (XIX), which is treated with benzyl chloroformate and NaOH in THF in order to obtain the fully protected compound (XX). Selective deprotection of (XX) with HCl gives 4-(benzyloxycarbonylamidino)benzylamine (V), which is condensed with the protected azetidine-2-carboxylic acid (XXI) to afford the corresponding amide (XXII). Boc-deprotection of (XXII) provides azetidine (XXIII), which is condensed with N-Boc-(R)-cyclohexylglycine (VII) to give the protected dipeptide (XI). Boc-deprotection of (XI) affords intermediate (XII), which is condensed with benzyl 2-bromoacetate (XIV) to give the melagatran precursor (XV). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C as before.
| 【2】 Hervé, Y.; Fournier, J.; De Nanteuil, G.; Leborgne, F.; Verbeuren, T.J.; Lila, C.; Gloanec, P.; Cadet, L.; Large scale preparation of protected 4-aminomethylbenzamidine. Application to the synthesis of the thrombin inhibitor melagatran. Synth Commun 1998, 28, 23, 4419. |
| 【1】 Bayes, M.; Silvestre, J.S.; Sorbera, L.A.; Castaner, J.; Melagatran and Ximelagatran. Drugs Fut 2001, 26, 12, 1155. |
| 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) | 14200 | 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile | 17201-43-3 | C8H6BrN | 详情 | 详情 |
| (V) | 50386 | benzyl [4-(aminomethyl)phenyl](imino)methylcarbamate | C16H17N3O2 | 详情 | 详情 | |
| (VII) | 35619 | (2S)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoic acid | C13H23NO4 | 详情 | 详情 | |
| (XI) | 50376 | benzyl [4-([[((2S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl]azetidinyl)carbonyl]amino]methyl)phenyl](imino)methylcarbamate | C33H43N5O6 | 详情 | 详情 | |
| (XII) | 50390 | benzyl (4-[[([(2S)-1-[(2R)-2-amino-2-cyclohexylethanoyl]azetidinyl]carbonyl)amino]methyl]phenyl)(imino)methylcarbamate | C28H35N5O4 | 详情 | 详情 | |
| (XIV) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (XV) | 50392 | benzyl 2-[((1R)-2-[(2S)-2-[([4-[[[(benzyloxy)carbonyl]amino](imino)methyl]benzyl]amino)carbonyl]azetidinyl]-1-cyclohexyl-2-oxoethyl)amino]acetate | C37H43N5O6 | 详情 | 详情 | |
| (XVI) | 48447 | Di-tert-butyl iminodicarboxylate; Iminodicarboxylic acid di-tert-butyl ester | 51779-32-9 | C10H19NO4 | 详情 | 详情 |
| (XVII) | 50393 | 1-[[bis(tert-butoxycarbonyl)amino]methyl]-4-cyanobenzene | C18H24N2O4 | 详情 | 详情 | |
| (XVIII) | 50394 | 1-[amino(hydroxyimino)methyl]-4-[[bis(tert-butoxycarbonyl)amino]methyl]benzene | C18H27N3O5 | 详情 | 详情 | |
| (XIX) | 50395 | 1-[amino(imino)methyl]-4-[[bis(tert-butoxycarbonyl)amino]methyl]benzene | C18H27N3O4 | 详情 | 详情 | |
| (XX) | 50396 | 1-[[[(benzyloxy)carbonyl]amino](imino)methyl]-4-[[bis(tert-butoxycarbonyl)amino]methyl]benzene | C26H33N3O6 | 详情 | 详情 | |
| (XXI) | 26205 | (2S)-1-(tert-butoxycarbonyl)-2-azetidinecarboxylic acid | C9H15NO4 | 详情 | 详情 | |
| (XXII) | 50397 | tert-butyl (2S)-2-[([4-[[[(benzyloxy)carbonyl]amino](imino)methyl]benzyl]amino)carbonyl]-1-azetidinecarboxylate | C25H30N4O5 | 详情 | 详情 | |
| (XXIII) | 50398 | benzyl [4-([[(2S)azetidinylcarbonyl]amino]methyl)phenyl](imino)methylcarbamate | C20H22N4O3 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(X)The piperazine (IX) was alkylated with benzyl bromoacetate (X) to give ester (XI), which was converted to carboxylic acid (XII) by catalytic hydrogenolysis of the benzyl ester group. Then, coupling of (XII) with 1-amino-4-methylpiperazine (XIII) produced the corresponding hydrazide. Finally, treatment with fumaric acid in EtOH generated the title fumarate salt.
| 【1】 Matsuo, M.; Hagiwara, D.; Manabe, T.; Konishi, N.; Shigenaga, S.; Murano, K.; Matsuda, H.; Miyake, H. (Fujisawa Pharmaceutical Co., Ltd.); 1-Benzoyl-2-(indolyl-3-alkyl)-piperazine derivs. as neurokinin receptor antagonists. EP 0846116; JP 1999505830; WO 9637489 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 44730 | [3,5-bis(trifluoromethyl)phenyl][(2R)-2-(1H-indol-3-ylmethyl)piperazinyl]methanone | C22H19F6N3O | 详情 | 详情 | |
| (X) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (XI) | 44732 | benzyl 2-[(3R)-4-[3,5-bis(trifluoromethyl)benzoyl]-3-(1H-indol-3-ylmethyl)piperazinyl]acetate | C31H27F6N3O3 | 详情 | 详情 | |
| (XII) | 44733 | 2-[(3R)-4-[3,5-bis(trifluoromethyl)benzoyl]-3-(1H-indol-3-ylmethyl)piperazinyl]acetic acid | C24H21F6N3O3 | 详情 | 详情 | |
| (XIII) | 40655 | 4-Methyl-1-piperazinamine; 1-Amino-4-methylpiperazine; 4-Methyl-1-piperazinylamine | 6928-85-4 | C5H13N3 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(VI)The reaction of N-Boc-L-serine (I) with 2-fluoronitrobenzene (II) by means of NaH in DMF gives N-Boc-O-(2-nitrophenyl)-L-serine (III), which is reduced with H2 over Pd/C in methanol yielding the 2-aminophenyl derivative (IV). The cyclization of (IV) by means of EDAC in DMF affords the benzoxazepinone (V), which is condensed with benzyl 2-bromoacetate (VI) by means of LHMDS in THF providing the benzoxazepinone acetic ester (VII). The deprotection of the carbamate group of (VII) with HCl in dioxane affords (VIII) with a free amino group that is condensed with 2-benzyl-3-[N-(benzyloxy)-N-formylamino]propionic acid (IX) by means of EDAC in dichloromethane giving the corresponding amide (X). The deprotection of the benzyl groups of (X) with H2 over Pd/C in methanol yields the expected mixture of diastereomers that is resolved by preparative HPLC to afford the target compound.
| 【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257. |
| 【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 . |
| 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) | 20126 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropionic acid | C8H15NO5 | 详情 | 详情 | |
| (II) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (III) | 37271 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-nitrophenoxy)propionic acid | C14H18N2O7 | 详情 | 详情 | |
| (IV) | 37272 | (2S)-3-(2-aminophenoxy)-2-[(tert-butoxycarbonyl)amino]propionic acid | C14H20N2O5 | 详情 | 详情 | |
| (V) | 37273 | tert-butyl (3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-ylcarbamate | C14H18N2O4 | 详情 | 详情 | |
| (VI) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (VII) | 37274 | benzyl 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C23H26N2O6 | 详情 | 详情 | |
| (VIII) | 37275 | benzyl 2-[(3S)-3-amino-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C18H18N2O4 | 详情 | 详情 | |
| (IX) | 37276 | 2-benzyl-N-(benzyloxy)-N-formyl-beta-alanine | C18H19NO4 | 详情 | 详情 | |
| (X) | 37278 | benzyl 2-[(3S)-3-([2-benzyl-3-[(benzyloxy)(formyl)amino]propanoyl]amino)-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C36H35N3O7 | 详情 | 详情 | |
| (XI) | 37280 | 2-benzylmalonic acid | 616-75-1 | C10H10O4 | 详情 | 详情 |
| (XII) | 37279 | 2-benzylacrylic acid | C10H10O2 | 详情 | 详情 | |
| (XIII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XIV) | 37277 | 2-benzyl-N-(benzyloxy)-beta-alanine | C17H19NO3 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(VI)The reaction of N-Boc-L-serine (I) with 2-fluoronitrobenzene (II) by means of NaH in DMF gives N-Boc-O-(2-nitrophenyl)-L-serine (III), which is reduced with H2 over Pd/C in methanol yielding the 2-aminophenyl derivative (IV). The cyclization of (IV) by means of EDAC in DMF affords the benzoxazepinone (V), which is condensed with benzyl 2-bromoacetate (VI) by means of LHMDS in THF providing the benzoxazepinone acetic ester (VII). The deprotection of the carbamate group of (VII) with HCl in dioxane affords (VIII) with a free amino group that is condensed with 2-benzyl-3-[N-(benzyloxy)-N-formylamino]propionic acid (IX) by means of EDAC in dichloromethane giving the corresponding amide (X). The deprotection of the benzyl groups of (X) with H2 over Pd/C in methanol yields the expected mixture of diastereomers that is resolved by preparative HPLC to afford the target compound. The intermediate 2-benzyl-3-[N-(benzyloxy)-N-formylamino]propionic acid (IX) has been obtained as follows: The reaction of benzylmalonic acid (XI) with aqueous formaldehyde and dimethylamine gives 2-benzyl-2-propenoic acid (XII), which is condensed with O-benzylhydroxylamine (XIII) in refluxing ethanol yielding 2-benzyl-3-(benzyloxyamino)propionic acid (XIV). Finally, this compound is N-formylated with formic acid/acetic anhydride to afford the desired intermediate (IX).
| 【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257. |
| 【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 . |
| 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) | 20126 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropionic acid | C8H15NO5 | 详情 | 详情 | |
| (II) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (III) | 37271 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-nitrophenoxy)propionic acid | C14H18N2O7 | 详情 | 详情 | |
| (IV) | 37272 | (2S)-3-(2-aminophenoxy)-2-[(tert-butoxycarbonyl)amino]propionic acid | C14H20N2O5 | 详情 | 详情 | |
| (V) | 37273 | tert-butyl (3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-ylcarbamate | C14H18N2O4 | 详情 | 详情 | |
| (VI) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (VII) | 37274 | benzyl 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C23H26N2O6 | 详情 | 详情 | |
| (VIII) | 37275 | benzyl 2-[(3S)-3-amino-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C18H18N2O4 | 详情 | 详情 | |
| (IX) | 37276 | 2-benzyl-N-(benzyloxy)-N-formyl-beta-alanine | C18H19NO4 | 详情 | 详情 | |
| (X) | 37278 | benzyl 2-[(3S)-3-([2-benzyl-3-[(benzyloxy)(formyl)amino]propanoyl]amino)-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C36H35N3O7 | 详情 | 详情 | |
| (XI) | 37280 | 2-benzylmalonic acid | 616-75-1 | C10H10O4 | 详情 | 详情 |
| (XII) | 37279 | 2-benzylacrylic acid | C10H10O2 | 详情 | 详情 | |
| (XIII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XIV) | 37277 | 2-benzyl-N-(benzyloxy)-beta-alanine | C17H19NO3 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(X)The reaction of 2,5-dimethoxytetrahydrofuran-3-carbaldehyde (I) with 2-(trimethylsilyl)-1,3-dithiane (II) by means of BuLi in THF gives the expected condensation product (III), which is treated with HgCl2 and methanol in THF/water yielding 2-(2,5-dimethoxytetrahydrofuran-3-yl)acetic acid methyl ester (IV). The cyclization of (IV) with 4'-aminobiphenyl-4-carbonitrile (V) by means of CDE in hot trifluorocetic acid affords the biphenylylpyrrole (VI), which is hydrolyzed with LiOH and condensed with the chiral auxiliary 4(S)- benzyloxazolidin-2-one (VII) by means of pivaloyl chloride, BuLi and TEA in THF giving the acylated thiazolidine (VIII). The stereocontrolled reaction of (VIII) with benzyl bromoacetate (IX) by means of sodium hexamethyldisylazane (NaHMDS) in THF yields the succinamic ester (X), which is hydrolyzed with LiOH in THF/water to afford the succinic acid monoester (XI). The amidation of (XI) with 3(S)-amino-4,4-dimethyltetrahydrofuran-2-one (XII) by means of TBTU and NMM in DMF provides the succinamic ester derivative (XIII), which is debenzylated by hydrogenation with H2 over Pd/C in methanol.
| 【1】 Deal, J.G.; Bender, S.L.; Chong, W.K.M.; et al.; Preparation of various P1'-heterocyclic succinamide inhibitors of matrix metalloproteases (MMP's). 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 197. |
| 【2】 Bender, S.L.; Castelhano, A.L.; Chong, W.K.M.; Abreo, M.A.; Billedeau, R.J.; Chen, J.J.; Deal, J.G. (Agouron Pharmaceuticals, Inc.; Syntex (USA), Inc.); Heteroaryl succinamides and their use as metalloproteinase inhibitors. EP 0937042; JP 2000511201; US 6008243; WO 9817643 . |
| 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) | 26664 | 2,5-dimethoxytetrahydro-3-furancarbaldehyde | C7H12O4 | 详情 | 详情 | |
| (II) | 16517 | 1,3-dithian-2-yl(trimethyl)silane; 2-Trimethylsilyl-1,3-dithiane | 13411-42-2 | C7H16S2Si | 详情 | 详情 |
| (III) | 26665 | 3-(1,3-dithian-2-ylidenemethyl)-2,5-dimethoxytetrahydrofuran | C11H18O3S2 | 详情 | 详情 | |
| (IV) | 26666 | methyl 2-(2,5-dimethoxytetrahydro-3-furanyl)acetate | C9H16O5 | 详情 | 详情 | |
| (V) | 26667 | 4'-amino[1,1'-biphenyl]-4-carbonitrile | 4854-84-6 | C13H10N2 | 详情 | 详情 |
| (VI) | 26668 | methyl 2-[1-(4'-cyano[1,1'-biphenyl]-4-yl)-1H-pyrrol-3-yl]acetate | C20H16N2O2 | 详情 | 详情 | |
| (VII) | 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 |
| (VIII) | 26669 | 4'-(3-[2-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethyl]-1H-pyrrol-1-yl)[1,1'-biphenyl]-4-carbonitrile | C29H23N3O3 | 详情 | 详情 | |
| (IX) | 26670 | benzyl (3S)-4-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-[1-(4'-cyano[1,1'-biphenyl]-4-yl)-1H-pyrrol-3-yl]-4-oxobutanoate | C38H31N3O5 | 详情 | 详情 | |
| (X) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (XI) | 26671 | (2S)-4-(benzyloxy)-2-[1-(4'-cyano[1,1'-biphenyl]-4-yl)-1H-pyrrol-3-yl]-4-oxobutyric acid | C28H22N2O4 | 详情 | 详情 | |
| (XII) | 26672 | (3S)-3-amino-4,4-dimethyldihydro-2(3H)-furanone | C6H11NO2 | 详情 | 详情 | |
| (XIII) | 26673 | benzyl (3S)-3-[1-(4'-cyano[1,1'-biphenyl]-4-yl)-1H-pyrrol-3-yl]-4-[[(3S)-4,4-dimethyl-2-oxotetrahydro-3-furanyl]amino]-4-oxobutanoate | C34H31N3O5 | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(XI)Azepinone (X) was obtained by cyclization of Boc-L-lysine (IX) in the presence of NaHCO3 and BOP reagent. Subsequent alkylation of the lactam nitrogen of (X) with benzyl bromoacetate (XI) afforded (XII). After Boc deprotection of (XII) with trifluoroacetic acid, coupling with Boc-L-alanine (XIII) gave dipeptide (XIV). This was subjected to a further deprotection and coupling sequence with Boc-L-tryptophan (XV) to give tripeptide (XVI), and then with Boc-L-glutamine (XVII), yielding (XVIII). Acid deprotection of the Boc group of (XVIII), followed by coupling with p-hydroxyphenylpropionic acid (XIX) provided the peptide amide (XX).
| 【1】 Cristau, M.; et al.; Synthesis and biological evaluation of bombesin constrained analogues. J Med Chem 2000, 43, 12, 2356. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 42809 | (2S)-6-amino-2-[(tert-butoxycarbonyl)amino]hexanoic acid | C11H22N2O4 | 详情 | 详情 | |
| (X) | 42810 | L-(-)-N-alpha-Boc-amino-epsilon-caprolactam; tert-butyl (3S)-2-oxoazepanylcarbamate | 76944-95-1 | C11H20N2O3 | 详情 | 详情 |
| (XI) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (XII) | 42811 | benzyl 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-2-oxoazepanyl]acetate | n/a | C20H28N2O5 | 详情 | 详情 |
| (XIII) | 26450 | Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid | 15761-38-3 | C8H15NO4 | 详情 | 详情 |
| (XIV) | 42812 | benzyl 2-[(3S)-3-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-2-oxoazepanyl]acetate | C23H33N3O6 | 详情 | 详情 | |
| (XV) | 16114 | N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid | 13139-14-5 | C16H20N2O4 | 详情 | 详情 |
| (XVI) | 42813 | benzyl 2-[(3S)-3-[((2S)-2-[[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoyl]amino]propanoyl)amino]-2-oxoazepanyl]acetate | C34H43N5O7 | 详情 | 详情 | |
| (XVII) | 31820 | (2S)-5-amino-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid | 13726-85-7 | C10H18N2O5 | 详情 | 详情 |
| (XVIII) | 42814 | benzyl 2-((3S)-3-[[(2S,5S,8S)-8-(3-amino-3-oxopropyl)-5-(1H-indol-3-ylmethyl)-2,12,12-trimethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatridec-1-anoyl]amino]-2-oxoazepanyl)acetate | C39H51N7O9 | 详情 | 详情 | |
| (XIX) | 25691 | 3-(4-hydroxyphenyl)propionic acid | 501-97-3 | C9H10O3 | 详情 | 详情 |
| (XX) | 42815 | benzyl 2-[(3S)-3-[((2S)-2-[[(2S)-2-[((2S)-5-amino-2-[[3-(4-hydroxyphenyl)propanoyl]amino]-5-oxopentanoyl)amino]-3-(1H-indol-3-yl)propanoyl]amino]propanoyl)amino]-2-oxoazepanyl]acetate | C43H51N7O9 | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(II)The reaction of pyrimidine-2,4(1H,3H)-dione (I) with benzyl 2-bromoacetate (II) by means of K2CO3 in DMF gives the pyrimidine-1-acetic acid benzyl ester (III), which is condensed with tert-butyl 2-bromoacetate (IV) by means of NaH in DMF to yield the pyrimidine bis acetate (V). Selective deprotection of the benzyl ester of (V) by means of H2 over Pd(OH)2 in ethyl acetate affords the mono acetic acid derivative (VI), which is condensed with the free amino group of the tripeptide analogue (VII) by means of EDC in pyridine to provide the acylated tripeptide analogue (VIII). The oxidation of the secondary OH group of (VIII) by means of DMP in dichloromethane furnishes the acylated 2-(L-valyl-L-prolyl-L-valyl)benzoxazole derivative (IX), which is finally deprotected with TFA in dichloromethane to give the target tripeptide analogue.
| 【1】 Sato, F.; Inoue, Y.; Honda, S.; Komiya, M.; Takemura, T.; Omodani, T.; Shiratake, R. (Dainippon Pharmaceutical Co., Ltd.); Heterocyclic cpds., intermediates thereof and elastase inhibitors. EP 1157998; JP 2000256396; WO 0052032 . |
| 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) | 30912 | (2R,3S)-N,6-dimethoxy-2-(4-methoxyphenyl)-N-methyl-2,3-dihydro-1-benzothiophene-3-carboxamide | C19H21NO4S | 详情 | 详情 | |
| (II) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (III) | 55789 | benzyl 2-[2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]acetate | C13H12N2O4 | 详情 | 详情 | |
| (IV) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (V) | 55790 | tert-butyl 2-[3-[2-(benzyloxy)-2-oxoethyl]-2,6-dioxo-1(2H,6H)-pyrimidinyl]acetate | C19H22N2O6 | 详情 | 详情 | |
| (VI) | 55791 | 2-[3-[2-(tert-butoxy)-2-oxoethyl]-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]acetic acid | C12H16N2O6 | 详情 | 详情 | |
| (VII) | 55792 | (2S)-1-[(2S)-2-amino-3-methylbutanoyl]-N-{(1S)-1-[(S)-1,3-benzoxazol-2-yl(hydroxy)methyl]-2-methylpropyl}-2-pyrrolidinecarboxamide | C22H32N4O4 | 详情 | 详情 | |
| (VIII) | 55793 | tert-butyl 2-[3-(2-{[(1S)-1-({(2S)-2-[({(1S)-1-[(S)-1,3-benzoxazol-2-yl(hydroxy)methyl]-2-methylpropyl}amino)carbonyl]pyrrolidinyl}carbonyl)-2-methylpropyl]amino}-2-oxoethyl)-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]acetate | C34H46N6O9 | 详情 | 详情 | |
| (IX) | 55794 | tert-butyl 2-[3-{2-[((1S)-1-{[(2S)-2-({[(1S)-1-(1,3-benzoxazol-2-ylcarbonyl)-2-methylpropyl]amino}carbonyl)pyrrolidinyl]carbonyl}-2-methylpropyl)amino]-2-oxoethyl}-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]acetate | C34H44N6O9 | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：(II)Alkylation of the previously reported 2',5'-bis-silylated nucleoside (I) with benzyl bromoacetate (II) in the presence of K2CO3 in acetone provided the N-3-substituted derivative (III). The benzyl ester group was then removed by catalytic hydrogenation over Pd/C to furnish the target carboxylic acid.
| 【1】 Chamorro, C.; Lobatón, E.; Bonache, M.-C.; De Clercq, E.; Balzarini, J.; Velázquez, S.; San-Félix, A.; Camarasa, M.-J.; Identification of a novel family of nucleosides that specifically inhibit HIV-1 reverse transcriptase. Bioorg Med Chem Lett 2001, 11, 23, 3085. |
| 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) | 59913 | 1-[(2R,3R,4R,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-hydroxytetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | C22H42N2O6Si2 | 详情 | 详情 | |
| (II) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (III) | 59914 | benzyl 2-[3-[(2R,3R,4R,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-hydroxytetrahydro-2-furanyl]-5-methyl-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]acetate | C31H50N2O8Si2 | 详情 | 详情 |