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【结 构 式】 
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【分子编号】13955 【品名】(3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide 【CA登记号】 |
【 分 子 式 】C14H26N2O 【 分 子 量 】238.37332 【元素组成】C 70.54% H 10.99% N 11.75% O 6.71% |
合成路线1
该中间体在本合成路线中的序号：(XI)Various new routes for the large-scale synthesis of Ro-31-8959 have been described: 1) The condensation of N-protected-L-phenylalanine (I) with the Mg salt of malonic acid monoethyl ester (II) gives the keto ester (III), which is enantioselectively reduced with NaBH4 to yield the hydroxy ester (IV). The reaction of (IV) with 2,2-dimethoxypropane (V) by means of p-toluenesulfonic acid affords the oxazolidine (VI), which is hydrolyzed with NaOH in ethanol/water to the corresponding acid (VII). The treatment of (VII) with oxalyl chloride, mercaptopyridine-N-oxide (MPO) and bromotrichloromethane affords the bromomethyloxazolidine (VIII), which, without isolation, is treated with acetic acid to give the N-protected 3(S)-amino-2-bromo-4-phenyl-2(S)-butanol (IX). The reaction of (IX) with KOH in methanol yields the epoxide (X), which is condensed with (3S,4aS,8aS)-N-tert-butyldecahydroisoquinoline-3-carboxamide (XI), yielding the protected condensation product (XII). The deprotection of the amino group of (XII) by hydrogenation with H2 over Pd/C affords the amino derivative (XIII), which is condensed with N-benzyloxycarbonyl-asparagine (XIV) in the usual way, giving the protected peptide (XV). The deprotection of (XV) as before yields compound (XVI), with a free amino group that is finally condensed with quinoline-2-carboxylic acid (XVII) by means of dicyclohexylcarbodiimide and hydroxybenzotriazole.
| 【1】 Parkes, K.E.B.; Bushnell, D.J.; Crackett, P.H.; et al.; Studies toward the large-scale synthesis of the HIV proteinase inhibitor Ro 31-8959. J Org Chem 1994, 59, 13, 3656. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Va) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (Ib) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (IIIb) | 12876 | ethyl (4S)-4-[(tert-butoxycarbonyl)amino]-3-oxo-5-phenylpentanoate | C18H25NO5 | 详情 | 详情 | |
| (Ia) | 14505 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropionic acid; N-Carbobenzyloxy-L-phenylalanine; N-Cbz-L-Phenylalanine | 1161-13-3 | C17H17NO4 | 详情 | 详情 |
| (IIIa) | 14508 | ethyl (4S)-4-[[(benzyloxy)carbonyl]amino]-3-oxo-5-phenylpentanoate | C21H23NO5 | 详情 | 详情 | |
| (IVa) | 14510 | ethyl (3R,4S)-4-[[(benzyloxy)carbonyl]amino]-3-hydroxy-5-phenylpentanoate | C21H25NO5 | 详情 | 详情 | |
| (VIa) | 14514 | benzyl (4S,5R)-4-benzyl-5-(2-ethoxy-2-oxoethyl)-2,2-dimethyl-1,3-oxazolane-3-carboxylate | C24H29NO5 | 详情 | 详情 | |
| (VIb) | 14515 | ethyl 2-[(4S,5R)-4-benzyl-3-[(2,2-dimethylpropanoyl)oxy]-2,2-dimethyl-1,3-oxazolan-5-yl]acetate | C21H31NO5 | 详情 | 详情 | |
| (VIIa) | 14516 | 2-[(4S,5R)-4-benzyl-3-[(benzyloxy)carbonyl]-2,2-dimethyl-1,3-oxazolan-5-yl]acetic acid | C22H25NO5 | 详情 | 详情 | |
| (VIIb) | 14517 | 2-[(4S,5R)-4-benzyl-3-[(2,2-dimethylpropanoyl)oxy]-2,2-dimethyl-1,3-oxazolan-5-yl]acetic acid | C19H27NO5 | 详情 | 详情 | |
| (VIIIa) | 14518 | benzyl (4S,5S)-4-benzyl-5-(bromomethyl)-2,2-dimethyl-1,3-oxazolane-3-carboxylate | C21H24BrNO3 | 详情 | 详情 | |
| (VIIIb) | 14519 | (4S,5S)-4-benzyl-5-(bromomethyl)-3-[(2,2-dimethylpropanoyl)oxy]-2,2-dimethyl-1,3-oxazolane | C18H26BrNO3 | 详情 | 详情 | |
| (IXa) | 14520 | benzyl N-[(1S,2S)-1-benzyl-3-bromo-2-hydroxypropyl]carbamate | C18H20BrNO3 | 详情 | 详情 | |
| (IXb) | 14521 | (2S,3S)-1-bromo-3-[[(2,2-dimethylpropanoyl)oxy]amino]-4-phenyl-2-butanol | C15H22BrNO3 | 详情 | 详情 | |
| (Xa) | 14522 | benzyl N-[(1S)-1-[(2S)oxiranyl]-2-phenylethyl]carbamate | C18H19NO3 | 详情 | 详情 | |
| (XIIa) | 14526 | benzyl (1S,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-benzyl-2-hydroxypropylcarbamate | C32H45N3O4 | 详情 | 详情 | |
| (XIIb) | 14527 | (3S,4aS,8aS)-N-(tert-butyl)-2-((2R,3S)-3-[[(2,2-dimethylpropanoyl)oxy]amino]-2-hydroxy-4-phenylbutyl)decahydro-3-isoquinolinecarboxamide | C29H47N3O4 | 详情 | 详情 | |
| (IXb) | 19730 | tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate | 98737-29-2 | C15H21NO3 | 详情 | 详情 |
| (IVb) | 25725 | 2-[(4S,5R)-4-benzyl-3-(tert-butoxycarbonyl)-1,3-oxazolidin-5-yl]acetic acid | C17H23NO5 | 详情 | 详情 | |
| (II) | 14507 | Malonic acid monoethyl ester magnesium salt | C5H6MgO4 | 详情 | 详情 | |
| (XI) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
| (XIII) | 14528 | (3S,4aS,8aS)-2-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(tert-butyl)decahydro-3-isoquinolinecarboxamide | C24H39N3O2 | 详情 | 详情 | |
| (XIV) | 14529 | (2S)-4-amino-2-[[(benzyloxy)carbonyl]amino]-4-oxobutyric acid | 2304-96-3 | C12H14N2O5 | 详情 | 详情 |
| (XV) | 14530 | benzyl (1S)-1-[([(1S,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-benzyl-2-hydroxypropyl]amino)carbonyl]-3-amino-3-oxopropylcarbamate | C36H51N5O6 | 详情 | 详情 | |
| (XVI) | 14531 | (2S)-N(1)-[(1S,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-benzyl-2-hydroxypropyl]-2-aminobutanediamide | C28H45N5O4 | 详情 | 详情 | |
| (XVII) | 14532 | 2-Quinolinecarboxylic acid; Quinaldic Acid | 93-10-7 | C10H7NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)2) The condensation of N-phthaloyl-L-phenylalaninyl chloride (XVIII) with 1,1,2-tris(trimethylsilyloxy)ethylene (TMS) (XIX) at 90-100 C followed by acidic hydrolysis with HCl gives the acid (XX), which, without isolation, is decarboxylated, yielding 1-hydroxy-3(S)-phthalimido-4-phenyl-2-butanone (XXI). Sequential protection of the OH- group with dihydropyran, reduction of the CO group with NaBH4, mesylation of the resulting OH group with methanesulfonyl chloride and deprotection of the primary OH group gives 2(R)-(methanesulfonyloxy)-4-phenyl-3(S)-phthalimido-1-butanol (XXII). The epoxidation of (XXII) with potassium tert-butoxide yields the epoxide (XXIII), which is condensed with the decahydroisoquinoline (XI) as before, affording the protected condensation product (XXIV). The elimination of the phthalimido group of (XXIV) with methylamine and HCl gives the amino derivative (XIII), already obtained in scheme 16810301a.
| 【1】 Parkes, K.E.B.; Bushnell, D.J.; Crackett, P.H.; et al.; Studies toward the large-scale synthesis of the HIV proteinase inhibitor Ro 31-8959. J Org Chem 1994, 59, 13, 3656. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
| (XIII) | 14528 | (3S,4aS,8aS)-2-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(tert-butyl)decahydro-3-isoquinolinecarboxamide | C24H39N3O2 | 详情 | 详情 | |
| (XVIII) | 56756 | diethyl 2-[(2R)-4-chloro-2-methyl-4-oxobutyl]malonate | C12H19ClO5 | 详情 | 详情 | |
| (XIX) | 14534 | 2,2,7,7-tetramethyl-4-[(trimethylsilyl)oxy]-3,6-dioxa-2,7-disila-4-octene; 1,2-bis[(trimethylsilyl)oxy]vinyl trimethylsilyl ether; TRIS(TRIMETHYLSILYLOXY)ETHYLENE | 69097-20-7 | C11H28O3Si3 | 详情 | 详情 |
| (XX) | 14535 | (4S)-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-hydroxy-3-oxo-5-phenylpentanoic acid | C19H15NO6 | 详情 | 详情 | |
| (XXI) | 14536 | 2-[(1S)-1-benzyl-3-hydroxy-2-oxopropyl]-1H-isoindole-1,3(2H)-dione | C18H15NO4 | 详情 | 详情 | |
| (XXII) | 14537 | (1R,2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-(hydroxymethyl)-3-phenylpropyl methanesulfonate | C19H19NO6S | 详情 | 详情 | |
| (XXIII) | 14538 | 2-[(1S)-1-[(2S)oxiranyl]-2-phenylethyl]-1H-isoindole-1,3(2H)-dione | C18H15NO3 | 详情 | 详情 | |
| (XXIV) | 14539 | (3S,4aS,8aS)-N-(tert-butyl)-2-[(2R,3S)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-hydroxy-4-phenylbutyl]decahydro-3-isoquinolinecarboxamide | C32H41N3O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)4) The selective esterification of 3(S)-azido-4-phenylbutane-1,2(S)-diol (XXIX) with 2,4,6-triiosopropylbenzenesulfonyl chloride (XXX) gives the sulfonate ester (XXXI), which by treatment with KOH is converted to the azido epoxide (XXXII). The condensation of (XXXII) with decahydroisoquinoline (XI) affords the azido condensation product (XXXIII), which is finally hydrogenated with H2 over Pd/C to the amino condensation product (XIII), already obtained in scheme 16810301a. 5) The reaction of (XXIX) with SOCl2 and RuCl3 gives the dioxathiole dioxide (XXXIV), which is condensed with decahydroisoquinoline (XI) to afford the azido condensation product (XXXIII), already obtained.
| 【1】 Parkes, K.E.B.; Bushnell, D.J.; Crackett, P.H.; et al.; Studies toward the large-scale synthesis of the HIV proteinase inhibitor Ro 31-8959. J Org Chem 1994, 59, 13, 3656. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
| (XIII) | 14528 | (3S,4aS,8aS)-2-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(tert-butyl)decahydro-3-isoquinolinecarboxamide | C24H39N3O2 | 详情 | 详情 | |
| (XXIX) | 14544 | (2S,3S)-3-azido-4-phenyl-1,2-butanediol | C10H13N3O2 | 详情 | 详情 | |
| (XXX) | 14545 | 2,4,6-triisopropylbenzenesulfonyl chloride | 6553-96-4 | C15H23ClO2S | 详情 | 详情 |
| (XXXI) | 14546 | (2S,3S)-3-azido-2-hydroxy-4-phenylbutyl 2,4,6-triisopropylbenzenesulfonate | C25H35N3O4S | 详情 | 详情 | |
| (XXXII) | 14547 | (1S)-1-[(2S)oxiranyl]-2-phenylethyl azide; (2S)-2-[(1S)-1-azido-2-phenylethyl]oxirane | C10H11N3O | 详情 | 详情 | |
| (XXXIII) | 14548 | (3S,4aS,8aS)-2-[(2R,3S)-3-(1-azanylhydrazino)-2-hydroxy-4-phenylbutyl]-N-(tert-butyl)decahydro-3-isoquinolinecarboxamide | C24H41N5O2 | 详情 | 详情 | |
| (XXXIV) | 14549 | (4S)-4-[(1S)-1-azido-2-phenylethyl]-1,3,2lambda(6)-dioxathiolane-2,2-dione | C10H11N3O4S | 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 synthesis of Ro-31-8959/003 (X) was carried out as follows: Condensation of L-phenylalanine (I) with formaldehyde in concentrated hydrochloric acid gave the tetrahydroisoquinoline (II), which was hydrogenated in 90% acetic acid over rhodium on carbon to yield the decahydroisoquinoline (III) as a mixture of diastereoisomers. Treatment of (III) with benzyl chloroformate in aqueous sodium hydroxide solution gave a mixture of N-protected amino acids which was separated by fractional crystallization of the cyclohexylamine salts to give the (S,S,S)-isomer. Reaction with dicyclohexylcarbodiimide and N-hydroxysuccinimide in dimethoxyethane, followed by treatment of the activated ester with tert-butylamine in dichloromethane and subsequent hydrogenolysis of the benzyloxycarbonyl protecting group gave the decahydroisoquinoline (IV). In the other branch of the synthesis L-phenylalanine was treated with benzyl chloroformate in aqueous sodium hydroxide solution to give the N-protected amino acid. This was converted to the corresponding mixed anhydride with isobutyl chloroformate and N-ethylmorpholine in tetrahydrofuran and immediately reacted with diazomethane in diethyl ether to give the diazomethyl ketone (V). Treatment of (V) with ethereal hydrogen chloride gave the chloromethyl ketone (VI), which on reduction with sodium borohydride in aqueous tetrahydrofuran gave a mixture of diastereoisomeric chlorohydrins. Solvent extraction with boiling n-hexane followed by recrystallization of the less soluble isomer from isopropanol gave pure chlorohydrin (VII), which on treatment with ethanolic potassium hydroxide gave the epoxide (VIII). Condensation of (VIII) with (IV) in ethanol gave the hydroxyethylamine (IX). Hydrogenolysis of (IX) was followed by condensation with N-benzyloxycarbonyl-L-asparagine in tetrahydrofuran in the presence of 1-hydroxybenzotriazole and dicyclohexylcarbodiimide. Hydrogenolysis in ethanol over palladium on charcoal, followed by condensation with quinoline-2-carboxylic acid in tetrahydrofuran in the presence of dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, gave the free base, Ro-31-8959/000. Treatment with methanesulfonic acid in aqueous ethanol then afforded the mesylate salt (X), Ro-31-8959/003.
| 【1】 Martin, J.A.; Ro-31-8959/003. Drugs Fut 1991, 16, 3, 210. |
| 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) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (II) | 13953 | (3S)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid; (S)-(-)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid | 74163-81-8 | C10H11NO2 | 详情 | 详情 |
| (III) | 13954 | (3S)Decahydro-3-isoquinolinecarboxylic acid | C10H17NO2 | 详情 | 详情 | |
| (IV) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
| (V) | 13956 | (3S)-1-Imino-4-phenyl-3-[[(2-phenylacetyl)oxy]amino]-2-butanone | C18H18N2O3 | 详情 | 详情 | |
| (VI) | 13957 | (3S)-1-Chloro-4-phenyl-3-[[(2-phenylacetyl)oxy]amino]-2-butanone | C18H18ClNO3 | 详情 | 详情 | |
| (VII) | 13958 | (2S,3S)-1-Chloro-4-phenyl-3-[[(2-phenylacetyl)oxy]amino]-2-butanol | C18H20ClNO3 | 详情 | 详情 | |
| (VIII) | 13959 | N-[(1S)-1-[(2S)Oxiranyl]-2-phenylethyl]-N-[(2-phenylacetyl)oxy]amine; (1S)-1-[(2S)Oxiranyl]-2-phenyl-N-[(2-phenylacetyl)oxy]-1-ethanamine | C18H19NO3 | 详情 | 详情 | |
| (IX) | 13960 | (3S,4aS,8aS)-N-(tert-Butyl)-2-((2R,3S)-2-hydroxy-4-phenyl-3-[[(2-phenylacetyl)oxy]amino]butyl)decahydro-3-isoquinolinecarboxamide | C32H45N3O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)The addition of thiophenol (II) to N-(benzyloxycarbonyl)-L-serine beta-lactone (I) by means of NaH in THF gives N-(benzyloxycarbonyl)-(S-phenyl)-L-cysteine (III), which is treated with isobutyl chloroformate, diazomethane and N-nitro-N-nitrosoguanidine in ethyl acetate/ethyl ether to yield the diazo intermediate (IV). The treatment of (IV) with dry HCl in ethyl ether affords the chloromethyl derivative (V), which is reduced with NaBH4 in THF giving the secondary alcohol (VI). The dehydrochlorination of (VI) with KOH in ethanol yields the corresponding epoxide (VII), which is submitted to ring opening with (3S,4aS,8aS)-N-(tert-butyl)decahydroisoquinoline-3-carboxamide (VIII) in hot isopropanol to afford the condensation product (IX). The deprotection of (IX) with 30% HBr in acetic acid gives compound (X) with a free amino group, which is finally acylated with 3-hydroxy-2-methylbenzoic acid (XI) by means of dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBT) in THF. The benzoic acid (XI) has been obtained by the following sequence: The condensation of 3-methoxybenzoyl chloride (XII) with aniline (XIII) gives the corresponding anilide (XIV), which is methylated with butyllithium and methyl iodide in THF yielding 2-methyl-3-methoxybenzanilide (XV). Finally, this compound is treated with 5N HCl and 30% HBr in refluxing acetic acid.
| 【1】 Rabasseda, X.; Martel, A.M.; Castañer, J.; Nelfinavir Mesylate. Drugs Fut 1997, 22, 4, 371. |
| 【2】 Dressman, B.A.; Fritz, J.E.; Hammond, M.; Hornback, W.J.; Kaldor, S.W.; Kalish, V.J.; Munroe, J.E.; Reich, S.H.; Tatlock, J.H.; Shepherd, T.A.; Rodriguez, M.J. (Agouron Pharmaceuticals, Inc.); HIV protease inhibitors. EP 0889036; JP 1997501443; JP 1999310573; US 5484926; WO 9509843 . |
| 【3】 Jungheim, L.N.; Shepherd, T.A. (Eli Lilly and Company); Intermediate and process for making. WO 9521164 . |
| 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) | 16749 | benzyl N-[(3S)-2-oxooxetanyl]carbamate | C11H11NO4 | 详情 | 详情 | |
| (II) | 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 |
| (III) | 16751 | (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(phenylsulfanyl)propionic acid | 159453-24-4 | C17H17NO4S | 详情 | 详情 |
| (IV) | 16752 | benzyl N-[(1R)-3-diazo-2-oxo-1-[(phenylsulfanyl)methyl]propyl]carbamate | C18H17N3O3S | 详情 | 详情 | |
| (V) | 16753 | benzyl N-[(1R)-3-chloro-2-oxo-1-[(phenylsulfanyl)methyl]propyl]carbamate | C18H18ClNO3S | 详情 | 详情 | |
| (VI) | 16754 | benzyl N-[(1R,2S)-3-chloro-2-hydroxy-1-[(phenylsulfanyl)methyl]propyl]carbamate | C18H20ClNO3S | 详情 | 详情 | |
| (VII) | 16755 | benzyl N-[(1R)-1-[(2S)oxiranyl]-2-(phenylsulfanyl)ethyl]carbamate | C18H19NO3S | 详情 | 详情 | |
| (VIII) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
| (IX) | 16757 | benzyl (1R,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-2-hydroxy-1-[(phenylsulfanyl)methyl]propylcarbamate | C32H45N3O4S | 详情 | 详情 | |
| (X) | 16758 | (3S,4aS,8aS)-2-[(2R,3R)-3-amino-2-hydroxy-4-(phenylsulfanyl)butyl]-N-(tert-butyl)decahydro-3-isoquinolinecarboxamide | C24H39N3O2S | 详情 | 详情 | |
| (XI) | 16759 | 3-hydroxy-2-methylbenzoic acid | 603-80-5 | C8H8O3 | 详情 | 详情 |
| (XII) | 16760 | 3-methoxybenzoyl chloride | 1711-05-3 | C8H7ClO2 | 详情 | 详情 |
| (XIII) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (XIV) | 16762 | 3-methoxy-N-phenylbenzamide | C14H13NO2 | 详情 | 详情 | |
| (XV) | 16763 | 3-methoxy-2-methyl-N-phenylbenzamide | C15H15NO2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(X)A new synthesis of nelfinavir has been described: The protection of the amino group of the dioxolane derivative (I) with benzyl chloroformate and K2CO3 in toluene gives the carbamate (II), which is mesylated with MsCl and triethylamine in toluene yielding the mesylate (III). Reaction of compound (III) with thiophenol (IV) by means of tetrabutylammonium bromide and NaOH in toluene/water affords the thioether (V), which is treated with HCl in methanol/water to provide diol (VI). Protection of the primary OH group of (VI) with p-nitrobenzoyl chloride and 2-picoline yields the p-nitrobenzoate (VII), which is mesylated as before to afford the protected compound (VIII). The reaction of (VIII) with KOH in dioxane gives epoxide (IX), which is condensed with N-tert-butylperhydroisoquinoline-3-carboxamide (X) in refluxing methanol to yield the addition product (XI). This compound (XI) can also be obtained by direct condensation of compound (VIII) with isoquinoline (X) by means of K2CO3 in methanol/water. Removal of the benzyloxycarbonyl group of (XI) with KOH in hot isopropanol affords compound (XII), which is condensed with 3-acetoxy-2-methylbenzoyl chloride (XIII) by means of NaHCO3 in ethyl acetate to give the corresponding amide (XIV). Finally, this compound is deacetylated with ammonia in methanol.
| 【1】 Schaus, S.E.; et al.; Practical synthesis of enantiopure cyclic 1,2-amino alcohols via catalytic asymmetric ring opening of meso epoxides. J Org Chem 1997, 62, 12, 4197. |
| 【2】 Busse, J.K.; Borer, B.C.; Zook, S.E.; A concise synthesis of the HIV-protease inhibitor nelfinavir via an unusual tetrahydrofuran rearrangement. Tetrahedron Lett 2000, 41, 36, 7017. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 | |
| (I) | 46589 | (2S)-2-amino-2-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-ethanol | C7H15NO3 | 详情 | 详情 | |
| (II) | 46590 | benzyl (1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethylcarbamate | C15H21NO5 | 详情 | 详情 | |
| (III) | 46591 | (2S)-2-[[(benzyloxy)carbonyl]amino]-2-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl methanesulfonate | C16H23NO7S | 详情 | 详情 | |
| (IV) | 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 |
| (V) | 46592 | benzyl (1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(phenylsulfanyl)ethylcarbamate | C21H25NO4S | 详情 | 详情 | |
| (VI) | 46593 | benzyl (1R,2R)-2,3-dihydroxy-1-[(phenylsulfanyl)methyl]propylcarbamate | C18H21NO4S | 详情 | 详情 | |
| (VII) | 46594 | (2R,3R)-3-[[(benzyloxy)carbonyl]amino]-2-hydroxy-4-(phenylsulfanyl)butyl 4-nitrobenzoate | C25H24N2O7S | 详情 | 详情 | |
| (VIII) | 46595 | (2R,3R)-3-[[(benzyloxy)carbonyl]amino]-2-[(methylsulfonyl)oxy]-4-(phenylsulfanyl)butyl 4-nitrobenzoate | C26H26N2O9S2 | 详情 | 详情 | |
| (IX) | 16755 | benzyl N-[(1R)-1-[(2S)oxiranyl]-2-(phenylsulfanyl)ethyl]carbamate | C18H19NO3S | 详情 | 详情 | |
| (X) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
| (XI) | 16757 | benzyl (1R,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-2-hydroxy-1-[(phenylsulfanyl)methyl]propylcarbamate | C32H45N3O4S | 详情 | 详情 | |
| (XII) | 16758 | (3S,4aS,8aS)-2-[(2R,3R)-3-amino-2-hydroxy-4-(phenylsulfanyl)butyl]-N-(tert-butyl)decahydro-3-isoquinolinecarboxamide | C24H39N3O2S | 详情 | 详情 | |
| (XIII) | 46596 | 3-(chlorocarbonyl)-2-methylphenyl acetate | C10H9ClO3 | 详情 | 详情 | |
| (XIV) | 46597 | 3-[([(1R,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-2-hydroxy-1-[(phenylsulfanyl)methyl]propyl]amino)carbonyl]-2-methylphenyl acetate | C34H47N3O5S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IX)A new concise synthesis of nelfinavir has been reported: The asymmetric desymmetrization of the meso-epoxide (I) by means of azidotrimethylsilane and a chiral (R,R)-(salen)chromium(III) complex as catalyst gives the chiral 3-(trimethylsilyloxy)-4-azidotetrahydrofuran (II), which is deprotected with TFA in methanol yielding the chiral 4-azidotetrahydrofuran-3-ol (III). Hydrogenation of (III) with H2 over PtO2 affords the chiral 4-aminotetrahydrofuran-3-ol (IV), which is condensed with 3-acetoxy-2-methylbenzoyl chloride (V) by means of NaHCO3 in dichloromethane to provide amide (VI). The mesylation of the OH group of (VI) with Ms-Cl gives mesylate (VII), which is isomerized with Ac2O and H2SO4 to yield oxazoline (VIII). Condensation of compound (VIII) with the perhydroisoquinoline-3-carboxamide derivative (IX) by means of K2CO3 in methanol affords the oxazoline-adduct (X). Finally, the oxazoline-ring opening of compound (X) is performed with thiophenol (XI) and KHCO3.
| 【1】 Inaba, T.; Cho, H.; Yamada, Y.; Sagawa, S.; Abe, H.; (1S)-1-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethylammonium benzoate, a versatile building block for chiral 2-aminoalkanols: Concise synthesis and application to nelfinavir, a potent HIV-protease inhibitor. J Org Chem 2000, 65, 6, 1623. |
| 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) | 46598 | 3,6-dioxabicyclo[3.1.0]hexane | C4H6O2 | 详情 | 详情 | |
| (II) | 46599 | [[(3R,4S)-4-azidotetrahydro-3-furanyl]oxy](trimethyl)silane; (3R,4S)-4-azidotetrahydro-3-furanyl trimethylsilyl ether | C7H15N3O2Si | 详情 | 详情 | |
| (III) | 46600 | (3R,4S)-4-azidotetrahydro-3-furanol | C4H7N3O2 | 详情 | 详情 | |
| (IV) | 46601 | (3R,4S)-4-aminotetrahydro-3-furanol | C4H9NO2 | 详情 | 详情 | |
| (V) | 46596 | 3-(chlorocarbonyl)-2-methylphenyl acetate | C10H9ClO3 | 详情 | 详情 | |
| (VI) | 46602 | 3-([[(3S,4R)-4-hydroxytetrahydro-3-furanyl]amino]carbonyl)-2-methylphenyl acetate | C14H17NO5 | 详情 | 详情 | |
| (VII) | 46603 | 2-methyl-3-[([(3S,4R)-4-[(methylsulfonyl)oxy]tetrahydro-3-furanyl]amino)carbonyl]phenyl acetate | C15H19NO7S | 详情 | 详情 | |
| (VIII) | 46604 | (2R)-2-[(4S)-2-[3-(acetoxy)-2-methylphenyl]-4,5-dihydro-1,3-oxazol-4-yl]-2-[(methylsulfonyl)oxy]ethyl acetate | C17H21NO8S | 详情 | 详情 | |
| (IX) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
| (X) | 46605 | (3S,4aS,8aS)-N-(tert-butyl)-2-[(2R)-2-hydroxy-2-[(4S)-2-(3-hydroxy-2-methylphenyl)-4,5-dihydro-1,3-oxazol-4-yl]ethyl]decahydro-3-isoquinolinecarboxamide | C26H39N3O4 | 详情 | 详情 | |
| (XI) | 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XV)The reaction of D-tartaric acid (I) with 2,2-dimethoxypropane (II) and Ts-OH gives the acetonide (III), which is reduced with NaBH4 in ethanol to yield the diol (IV). The reaction of (IV) with Ts-OH and TEA affords the ditosylate (V), whose acetonide is cleaved with HCl to provide the diol (VI). The reaction of (VI) with SOCl2 in dichloromethane gives the cyclic sulfite (VII), which is oxidized with NaIO4 and RuCl3 to yield the cyclic sulfate (VIII). The reaction of (VIII) with sodium azide in acetone/water affords the azide (IX), which is treated with sulfuric acid in THF/water to provide the azido alcohol (X). The reduction of the azido group of (X) with H2 over Pd/C affords the amino alcohol (XI), which is condensed with 3-acetoxy-2-methylbenzoyl chloride (XII) by means of TEA in THF, providing the intermediate amide (XIII). Spontaneous cyclization of the amide (XIII) under the reaction conditions gives the oxazoline (XIV), which is condensed with the perhydroisoquinoline (XV) by means of K2CO3 in isopropanol to yield the oxazoline intermediate (XVI). Finally, the cleavage of the oxazoline ring of (XVI) by means of thiophenol (XVII) affords the target compound.
| 【1】 Albizati, K.F.; et al.; A synthesis of the HIV-protease inhibitor nelfinavir from D-tartaric acid. Tetrahedron Lett 2001, 42, 37, 6481. |
| 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) | 16695 | (2S,3S)-2,3-dihydroxybutanedioic acid; D-(-)-Tartaric Acid; D-Tartaric Acid; (2S,3S)-2,3-dihydroxysuccinic acid | 147-71-7 | C4H6O6 | 详情 | 详情 |
| (II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (III) | 55018 | (4S,5S)-1,3-dioxolane-4,5-dicarboxylic acid | C5H6O6 | 详情 | 详情 | |
| (IV) | 55019 | [(4R,5R)-5-(hydroxymethyl)-1,3-dioxolan-4-yl]methanol | C5H10O4 | 详情 | 详情 | |
| (V) | 55020 | [(4R,5R)-5-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate | C19H22O8S2 | 详情 | 详情 | |
| (VI) | 55021 | (2R,3R)-2,3-dihydroxy-4-{[(4-methylphenyl)sulfonyl]oxy}butyl 4-methylbenzenesulfonate | C18H22O8S2 | 详情 | 详情 | |
| (VII) | 55022 | [(4R,5R)-5-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2-oxo-1,3,2lambda~4~-dioxathiolan-4-yl]methyl 4-methylbenzenesulfonate | C18H20O9S3 | 详情 | 详情 | |
| (VIII) | 55023 | [(4R,5R)-5-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2,2-dioxo-1,3,2lambda~6~-dioxathiolan-4-yl]methyl 4-methylbenzenesulfonate | C18H20O10S3 | 详情 | 详情 | |
| (IX) | 55024 | C18H20N3NaO10S3 | 详情 | 详情 | ||
| (X) | 55025 | (2S,3S)-3-azido-2-hydroxy-4-{[(4-methylphenyl)sulfonyl]oxy}butyl 4-methylbenzenesulfonate | C18H21N3O7S2 | 详情 | 详情 | |
| (XI) | 55026 | (2S,3S)-2-amino-3-hydroxy-4-{[(4-methylphenyl)sulfonyl]oxy}butyl 4-methylbenzenesulfonate | C18H23NO7S2 | 详情 | 详情 | |
| (XII) | 46596 | 3-(chlorocarbonyl)-2-methylphenyl acetate | C10H9ClO3 | 详情 | 详情 | |
| (XIII) | 55027 | 3-({[(1S,2S)-2-hydroxy-3-{[(4-methylphenyl)sulfonyl]oxy}-1-({[(4-methylphenyl)sulfonyl]oxy}methyl)propyl]amino}carbonyl)-2-methylphenyl acetate | C28H31NO10S2 | 详情 | 详情 | |
| (XIV) | 55028 | 3-[(4S)-4-((1S)-1-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)-4,5-dihydro-1,3-oxazol-2-yl]-2-methylphenyl acetate | C21H23NO7S | 详情 | 详情 | |
| (XV) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
| (XVI) | 46605 | (3S,4aS,8aS)-N-(tert-butyl)-2-[(2R)-2-hydroxy-2-[(4S)-2-(3-hydroxy-2-methylphenyl)-4,5-dihydro-1,3-oxazol-4-yl]ethyl]decahydro-3-isoquinolinecarboxamide | C26H39N3O4 | 详情 | 详情 | |
| (XVII) | 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XV)Alternatively, the reaction of the cyclic sulfate (VIII) with potassium phthalimide (XVIII) gives the N-substituted phthalimide (XIX), whose sulfate group is cleaved with sulfuric acid to yield the alcohol (XX). The reaction of (XX) with the perhydroisoquinoline (XV) by means of K2CO3 in acetonitrile/methanol affords the oxazoline (XXI), whose ring is opened with thiophenol (XVII) and KHCO3 in THF, providing a mixture of the two sulfides (XXII) and (XXIII) that are not isolated. The cleavage of the phthalimido group with refluxing ethanolamine followed by a treatment with benzoic acid gives a mixture of ammonium salts that is separated by crystallization, yielding the desired isomer (XXIV). The reaction of (XXIV) with acid chloride (XII) affords the precursor (XXV), which is finally deacetylated with NaOH to provide the target compound.
| 【1】 Albizati, K.F.; et al.; A synthesis of the HIV-protease inhibitor nelfinavir from D-tartaric acid. Tetrahedron Lett 2001, 42, 37, 6481. |
| 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) | 55023 | [(4R,5R)-5-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2,2-dioxo-1,3,2lambda~6~-dioxathiolan-4-yl]methyl 4-methylbenzenesulfonate | C18H20O10S3 | 详情 | 详情 | |
| (XII) | 46596 | 3-(chlorocarbonyl)-2-methylphenyl acetate | C10H9ClO3 | 详情 | 详情 | |
| (XV) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
| (XVII) | 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 |
| (XVIII) | 27890 | Potassium phthalimide | 1074-82-4 | C8H4KNO2 | 详情 | 详情 |
| (XIX) | 55029 | potassium 2-[(1S,2S)-3-{[(4-methylphenyl)sulfonyl]oxy}-1-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2-(sulfonatooxy)propyl]-1,3-dioxoisoindoline | C26H24KNO12S3 | 详情 | 详情 | |
| (XX) | 55030 | (2S,3S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-hydroxy-4-{[(4-methylphenyl)sulfonyl]oxy}butyl 4-methylbenzenesulfonate | C26H25NO9S2 | 详情 | 详情 | |
| (XXI) | 55031 | methyl 2-((4S)-4-{(1R)-2-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-hydroxyethyl}-4,5-dihydro-1,3-oxazol-2-yl)benzoate | C27H39N3O5 | 详情 | 详情 | |
| (XXII) | 55032 | (3S,4aS,8aS)-N-(tert-butyl)-2-[(2R,3R)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-hydroxy-4-(phenylsulfanyl)butyl]decahydro-3-isoquinolinecarboxamide | C32H41N3O4S | 详情 | 详情 | |
| (XXIII) | 55033 | (3S,4aS,8aS)-N-(tert-butyl)-2-[(2S,3S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-hydroxy-4-(phenylsulfanyl)butyl]decahydro-3-isoquinolinecarboxamide | C32H41N3O4S | 详情 | 详情 | |
| (XXIV) | 55034 | (2R,3R)-4-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-3-hydroxy-1-(phenylsulfanyl)-2-butanaminium benzoate | C31H45N3O4S | 详情 | 详情 | |
| (XXV) | 46497 | 4-[(3aR,9bR)-9-methoxy-1,3a,4,9b-tetrahydrochromeno[3,4-c]pyrrol-2(3H)-yl]butanenitrile | C16H20N2O2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(IX)The reaction of the unsaturated acetonide (I) with ammonia gives a diastereomeric, not separable mixture, of amino derivatives (II) + (III), which is reduced with BF3/Et2O and NaI to yield a mixture of sulfanyl derivatives (IV)+ (V). The condensation of this mixture with 3-acetoxy-2-methylbenzoic acid (VI) by means of EDC and HOBT affords a separable mixture of amides, from which the desired diastereomer (VII) is isolated. The hydrolysis of the acetonide group of (VII) by means of HCl in methanol provide the dihydroxyamide (VIII), which is finally condensed with the perhydroisoquinoline (IX) by means of Tes-Cl and TEA to furnish the target Nelfinavir.
| 【1】 Ma, D.; et al.; A short synthesis of the HIV-protease inhibitor nelfinavir via a diastereoselective addition of ammonia to the alpha,beta-unsaturated sulfoxide derived from (R)-glyceraldehyde acetonide. Tetrahedron Lett 2002, 43, 47, 8511. |
| 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) | 60477 | (4S)-2,2-dimethyl-4-[(E)-2-(phenylsulfinyl)ethenyl]-1,3-dioxolane; (E)-2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethenyl phenyl sulfoxide | C13H16O3S | 详情 | 详情 | |
| (II) | 60478 | (1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(phenylsulfinyl)-1-ethanamine; (1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(phenylsulfinyl)ethylamine | C13H19NO3S | 详情 | 详情 | |
| (III) | 60479 | (1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(phenylsulfinyl)-1-ethanamine; (1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(phenylsulfinyl)ethylamine | C13H19NO3S | 详情 | 详情 | |
| (IV) | 60480 | (1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(phenylsulfanyl)-1-ethanamine; (1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(phenylsulfanyl)ethylamine | C13H19NO2S | 详情 | 详情 | |
| (V) | 60481 | (1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(phenylsulfanyl)-1-ethanamine; (1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(phenylsulfanyl)ethylamine | C13H19NO2S | 详情 | 详情 | |
| (VI) | 34785 | 3-([[(1S,2S)-1-benzyl-3-((4R)-5,5-dimethyl-4-[[(2-methylbenzyl)amino]carbonyl]-1,3-thiazolidin-3-yl)-2-methyl-3-oxopropyl]amino]carbonyl)-2-methylphenyl acetate | C35H41N3O5S | 详情 | 详情 | |
| (VII) | 60482 | 3-({[(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(phenylsulfanyl)ethyl]amino}carbonyl)-2-methylphenyl acetate | C23H27NO5S | 详情 | 详情 | |
| (VIII) | 60483 | 3-[({(1R,2S)-2,3-dihydroxy-1-[(phenylsulfanyl)methyl]propyl}amino)carbonyl]-2-methylphenyl acetate | C20H23NO5S | 详情 | 详情 | |
| (IX) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 |