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【结 构 式】 
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【分子编号】19730 【品名】tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate 【CA登记号】98737-29-2 |
【 分 子 式 】C15H21NO3 【 分 子 量 】263.33668 【元素组成】C 68.42% H 8.04% N 5.32% O 18.23% |
合成路线1
该中间体在本合成路线中的序号：(IXb)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：(I)The reaction of the chiral epoxide (I) with isobutylamine (II) in refluxing ethanol gives the secondary amine (III), which is protected with benzyl chloroformate (IV) and TEA, yielding the dicarbamate (V). Selective deprotection of (V) with dry HCl in ethyl acetate affords the primary amine (VI), which is treated with 3(S)-tetrahydrofuryl N-succinimidinyl carbonate (VII) (prepared by condensation of tetrahydrofuran-3(S)-ol (VIII) with phosgene and N-hydroxysuccinimide (IX)) and DIEA in acetonitrile to provide the corresponding carbamate (X). The deprotection of (X) by hydrogenation with H2 over Pd/C in ethanol gives the secondary amine (XI), which is condensed with 4-nitrophenylsulfonyl chloride (XII) by means of NaHCO3 in dichloromethane/water to yield the sulfonamide (XIII). Finally, the nitro group of (XIII) is reduced with H2 over Pd/C in ethyl acetate to afford the target compound.
| 【1】 Tung, R.D.; Murcko, M.A.; Bhisetti, G.R. (Vertex Pharmaceuticals Inc.); Sulfonamide inhibitors of HIV-aspartyl protease. EP 0659181; EP 0885887; JP 1996501299; US 5585397; WO 9405639 . |
| 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) | 19730 | tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate | 98737-29-2 | C15H21NO3 | 详情 | 详情 |
| (II) | 13306 | 2-Methyl-1-propanamine; Isobutylamine | 78-81-9 | C4H11N | 详情 | 详情 |
| (III) | 44417 | tert-butyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate | 160232-08-6 | C19H32N2O3 | 详情 | 详情 |
| (IV) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (V) | 44418 | benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl(isobutyl)carbamate | C27H38N2O5 | 详情 | 详情 | |
| (VI) | 44419 | benzyl (2R,3S)-3-amino-2-hydroxy-4-phenylbutyl(isobutyl)carbamate | C22H30N2O3 | 详情 | 详情 | |
| (VII) | 39664 | 1-([[(3S)tetrahydro-3-furanyloxy]carbonyl]oxy)-2,5-pyrrolidinedione | C9H11NO6 | 详情 | 详情 | |
| (VIII) | 44420 | (3S)-tetrahydro-3-furanol; (S)-3-Hydroxytetrahydrofuran | 86087-23-2 | C4H8O2 | 详情 | 详情 |
| (IX) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
| (X) | 44421 | benzyl (2R,3S)-2-hydroxy-4-phenyl-3-([[(3S)tetrahydro-3-furanyloxy]carbonyl]amino)butyl(isobutyl)carbamate | C27H36N2O6 | 详情 | 详情 | |
| (XI) | 44422 | (3S)tetrahydro-3-furanyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate | C19H30N2O4 | 详情 | 详情 | |
| (XII) | 15809 | 4-nitrobenzenesulfonyl chloride | 98-74-8 | C6H4ClNO4S | 详情 | 详情 |
| (XIII) | 44423 | (3S)tetrahydro-3-furanyl (1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]propylcarbamate | C25H33N3O8S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Reaction of the chiral epoxide (I) with isobutylamine (II) in refluxing ethanol gives the secondary amine (III), which is condensed with 4-nitrophenylsulfonyl chloride (IV) and TEA in hot toluene to yield the sulfonamide (V). Deprotection of (V) with HCl hot toluene/water affords the primary amine (VI), which is condensed with imidazole-1-carboxylic acid 3(S)-tetrahydrofuryl ester (VII) [prepared by reaction of tetrahydrofuran-3(S)-ol (VIII) with carbonyldiimidazole (CDI) in ethyl acetate] to provide the corresponding carbamate (IX). Finally, the nitro group of (IX) is reduced with H2 over Pd/C in ethyl acetate to afford the target compound.
| 【1】 Deininger, D.D.; O'Callaghan, J.; McGuie, S.; Singh, H.; Robertson, M.S.; Rodgers, K.; Tung, R.D.; Al-Farhan, E.; Rout, S.J. (Glaxo Group Ltd.); Process for the synthesis of HIV protease inhibitors. WO 9948885 . |
| 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) | 19730 | tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate | 98737-29-2 | C15H21NO3 | 详情 | 详情 |
| (II) | 13306 | 2-Methyl-1-propanamine; Isobutylamine | 78-81-9 | C4H11N | 详情 | 详情 |
| (III) | 44417 | tert-butyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate | 160232-08-6 | C19H32N2O3 | 详情 | 详情 |
| (IV) | 15809 | 4-nitrobenzenesulfonyl chloride | 98-74-8 | C6H4ClNO4S | 详情 | 详情 |
| (V) | 44938 | tert-butyl (1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]propylcarbamate | C25H35N3O7S | 详情 | 详情 | |
| (VI) | 44939 | N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutyl-4-nitrobenzenesulfonamide | 590-90-9 | C20H27N3O5S | 详情 | 详情 |
| (VII) | 44940 | (3S)tetrahydro-3-furanyl 1H-imidazole-1-carboxylate | C8H10N2O3 | 详情 | 详情 | |
| (VIII) | 44420 | (3S)-tetrahydro-3-furanol; (S)-3-Hydroxytetrahydrofuran | 86087-23-2 | C4H8O2 | 详情 | 详情 |
| (IX) | 44423 | (3S)tetrahydro-3-furanyl (1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]propylcarbamate | C25H33N3O8S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)The reaction of tert-butoxycarbonyl-L-phenylalanine (I) with isobutyl chloroformate in THF gives the expected mixed anhydride which is treated with diazomethane and HCl yielding the corresponding chloromethyl ketone (II). The reduction of (II) with NaBH4 in THF affords the (S)-chlorohydrin (IV), which is treated with KOH in ethanol to obtain the chiral epoxide (V)(1,2). Ring opening of (V) with (±)(cis)-N-tert-butyl-4-(4-pyridylmethoxy)piperidine-2-carboxamide (VI) by a treatment with LiCl in refluxing ethanol gives a mixture of diastereomers that is separated by chromatography giving the pure isomer (VII). The reaction of (VII) with tert-butoxycarbonyl-L-valine (VIII) by treatment first with trifluoroacetic acid (TFA), and condesation by means of BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate) and NMM (N-methylmorpholine) affords the expected condensation product (IX). Finally, this compound is condensed with quinoline-2-carboxylic acid (X) by means of BOP and NMM as before. 2) The piperidine (VI) has been obtained by condensation of (±)(cis)-N-(tert-butoxycarbonyl)-4-hydroxypiperidine-2-carboxamide (XI) with 4-(chloromethyl)pyridine (XII) by means of NaH in DMS, followed by hydrolysis with HCl.
| 【1】 Beaulieu, P.L.; et al.; Practical, stereoselective synthesis of palinavir, a potent HIV protease inhibitor. J Org Chem 1997, 62, 11, 3440. |
| 【2】 Gillard, J.; et al.; Preparation of (2S,4R)-4-hydroxypipecolic acid and derivatives. J Org Chem 1996, 61, 6, 2226. |
| 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) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (II) | 19727 | tert-butyl (1S)-1-benzyl-3-diazo-2-oxopropylcarbamate | C15H19N3O3 | 详情 | 详情 | |
| (III) | 19728 | tert-butyl (1S)-1-benzyl-3-chloro-2-oxopropylcarbamate | C15H20ClNO3 | 详情 | 详情 | |
| (IV) | 19729 | (1S,2S)-[3-chloro-2-hydroxy-1-benzylpropyl]carbamic acid, 1,1-dimethylethyl ether; tert-butyl (1S,2S)-1-benzyl-3-chloro-2-hydroxypropylcarbamate | 165727-45-7 | C15H22ClNO3 | 详情 | 详情 |
| (V) | 19730 | tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate | 98737-29-2 | C15H21NO3 | 详情 | 详情 |
| (VI) | 19731 | (2S,4R)-N-(tert-butyl)-4-(4-pyridinylmethoxy)-2-piperidinecarboxamide | C16H25N3O2 | 详情 | 详情 | |
| (VII) | 19732 | tert-butyl (1S,2R)-1-benzyl-3-[(2S,4R)-2-[(tert-butylamino)carbonyl]-4-(4-pyridinylmethoxy)piperidinyl]-2-hydroxypropylcarbamate | C31H46N4O5 | 详情 | 详情 | |
| (VIII) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (IX) | 19734 | tert-butyl (1S)-1-[([(1S,2R)-1-benzyl-3-[(2S,4R)-2-[(tert-butylamino)carbonyl]-4-(4-pyridinylmethoxy)piperidinyl]-2-hydroxypropyl]amino)carbonyl]-2-methylpropylcarbamate | C36H55N5O6 | 详情 | 详情 | |
| (X) | 14532 | 2-Quinolinecarboxylic acid; Quinaldic Acid | 93-10-7 | C10H7NO2 | 详情 | 详情 |
| (XI) | 19736 | tert-butyl (2S,4R)-2-[(tert-butylamino)carbonyl]-4-hydroxy-1-piperidinecarboxylate | C15H28N2O4 | 详情 | 详情 | |
| (XII) | 10844 | 4-(Chloromethyl)pyridine | 10445-91-7 | C6H6ClN | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)Palinavir can also be obtained as follows: The controlled oxidation of 2(S)-(dibenzylamino)-3-phenyl-1-propanol (XIII) with pyridine-SO3 complex in DMSO gives the corresponding aldehyde (XIV), which is condensed with bromochloromethane (XV) by means of Li in THF followed by hydrolysis with HCl yielding regioselectively the 1-chloro-2-butanol (XVI). The debenzylation of (XVI) by hydrogenation over Pd/C affords the free amine (XVII), which is treated with tert-butoxycarbonyl anhydride/triethylamine and dehydrochlorinated with KOH in methanol to give the desired chiral epoxide (V).
| 【1】 Beaulieu, P.L.; et al.; Practical, stereoselective synthesis of palinavir, a potent HIV protease inhibitor. J Org Chem 1997, 62, 11, 3440. |
| 【2】 Gillard, J.; et al.; Preparation of (2S,4R)-4-hydroxypipecolic acid and derivatives. J Org Chem 1996, 61, 6, 2226. |
| 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) | 19730 | tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate | 98737-29-2 | C15H21NO3 | 详情 | 详情 |
| (XIII) | 19738 | (2S)-2-[bis(4-methylphenyl)amino]-3-phenyl-1-propanol | C23H25NO | 详情 | 详情 | |
| (XIV) | 19739 | (2S)-2-[bis(4-methylphenyl)amino]-3-phenylpropanal | C23H23NO | 详情 | 详情 | |
| (XV) | 19740 | bromo(chloro)methane | 74-97-5 | CH2BrCl | 详情 | 详情 |
| (XVI) | 19741 | (2S,3S)-3-[bis(4-methylphenyl)amino]-1-chloro-4-phenyl-2-butanol | C24H26ClNO | 详情 | 详情 | |
| (XVII) | 19742 | (2S,3S)-3-amino-1-chloro-4-phenyl-2-butanol | C10H14ClNO | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(V)The condendsation of epoxide (V) with (2S,4R)(VI) by means of basic alumina in THF, followed by elimination of the protecting group with HCl and NaOH yields directly the condensation product (XVIII) as a pure diastereomer and with a free amino group. Finally, this compound is condensed with N-(2-quinolylcarbonyl)-L-valine (XIX) through its activation compound with isobutyl chloroformate (the 4(S)-isopropyl-2-(2-quinolyl)oxazol-5(4H)-one (XX)). The N-acyl-L-valine (XIX) has been obtained by acylation of L-valine (XXI) with quinoline-2-carboxylic acid (X) through its acyl chloride obtained with SOCl2.
| 【1】 Beaulieu, P.L.; et al.; Practical, stereoselective synthesis of palinavir, a potent HIV protease inhibitor. J Org Chem 1997, 62, 11, 3440. |
| 【2】 Gillard, J.; et al.; Preparation of (2S,4R)-4-hydroxypipecolic acid and derivatives. J Org Chem 1996, 61, 6, 2226. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14532 | 2-Quinolinecarboxylic acid; Quinaldic Acid | 93-10-7 | C10H7NO2 | 详情 | 详情 | |
| (V) | 19730 | tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate | 98737-29-2 | C15H21NO3 | 详情 | 详情 |
| (VI) | 19731 | (2S,4R)-N-(tert-butyl)-4-(4-pyridinylmethoxy)-2-piperidinecarboxamide | C16H25N3O2 | 详情 | 详情 | |
| (XVIII) | 19750 | (2S,4R)-1-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(tert-butyl)-4-(4-pyridinylmethoxy)-2-piperidinecarboxamide | C26H38N4O3 | 详情 | 详情 | |
| (XIX) | 19751 | (2S)-2-[(3-isoquinolinylcarbonyl)amino]-3-methylbutyric acid | C15H16N2O3 | 详情 | 详情 | |
| (XX) | 19752 | (4S)-4-isopropyl-2-(2-quinolinyl)-1,3-oxazol-5(4H)-one | C15H14N2O2 | 详情 | 详情 | |
| (XXI) | 37828 | L-2-Amino-3-methylbutyric acid; L-2-Aminoisovaleric acid; 2-Aminoisovaleric acid; L-2-Amino-3-methylbutyric acid; L-alpha-Aminoisovaleric acid; L-valine; (S)-(+)-Valine; (S)-alpha-Aminoisovaleric acid | 72-18-4 | C5H11NO2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VIII)The reaction of (2S,4R)-1-(tert-butoxycarbonyl)-N-tert-butyl-4-hydroxypiperidine-2-carboxamide (I) with MsCl and TEA gives the mesylate (II), which is treated with tetrabutylammonium bromide in refluxing THF to yield the corresponding 4-bromo derivative (III). The reaction of (III) with potassium thioacetate, followed by hydrolysis with NaOH affords the sodium thiolate (IV), which is condensed with 4-chloropyridine (V) to provide (2S,4R)-1-(tert-butoxycarbonyl)-N-tert-butyl-4-(4-pyridylsulfanyl)piperidine-2-carboxamide (VI). The deprotection of (VI) with TFA or HCl in dioxane gives intermediate (VII), which is condensed with epoxide (VIII) in refluxing ethanol to obtain the expected addition compound (IX). The deprotection of (IX) with TFA or HCl as before yields the amide (X), which is finally condensed with 2-(2,6-dimethylphenoxy)acetic acid (XI) by means of BOP and DIEA to furnish the target diamide.
| 【1】 Anderson, P.C.; Beaulieu, P.L.; Cameron, D.R.; et al.; 2'6'-Dimethylphenoxyacetyl: A new achiral high affinity P3-P2 ligand for peptidomimetic-based HIV protease inhibitors. J Med Chem 2000, 43, 6, 1094. |
| 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) | 19736 | tert-butyl (2S,4R)-2-[(tert-butylamino)carbonyl]-4-hydroxy-1-piperidinecarboxylate | C15H28N2O4 | 详情 | 详情 | |
| (II) | 38756 | tert-butyl (2S,4R)-2-[(tert-butylamino)carbonyl]-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1-piperidinecarboxylate | C18H34N2O4S | 详情 | 详情 | |
| (III) | 38757 | tert-butyl (2S,4S)-4-bromo-2-[(tert-butylamino)carbonyl]-1-piperidinecarboxylate | C15H27BrN2O3 | 详情 | 详情 | |
| (IV) | 38762 | C15H27N2NaO3S | 详情 | 详情 | ||
| (V) | 32889 | 4-chloropyridine | 7379-35-3 | C5H4ClN | 详情 | 详情 |
| (VI) | 38758 | tert-butyl (2S,4R)-2-[(tert-butylamino)carbonyl]-4-(4-pyridinylsulfanyl)-1-piperidinecarboxylate | C20H31N3O3S | 详情 | 详情 | |
| (VII) | 38759 | (2S,4R)-N-(tert-butyl)-4-(4-pyridinylsulfanyl)-2-piperidinecarboxamide | C15H23N3OS | 详情 | 详情 | |
| (VIII) | 19730 | tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate | 98737-29-2 | C15H21NO3 | 详情 | 详情 |
| (IX) | 38760 | tert-butyl (1S,2R)-1-benzyl-3-[(2S,4R)-2-[(tert-butylamino)carbonyl]-4-(4-pyridinylsulfanyl)piperidinyl]-2-hydroxypropylcarbamate | C30H44N4O4S | 详情 | 详情 | |
| (X) | 38761 | (2S,4R)-1-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(tert-butyl)-4-(4-pyridinylsulfanyl)-2-piperidinecarboxamide | C25H36N4O2S | 详情 | 详情 | |
| (XI) | 38270 | 2-(2,6-dimethylphenoxy)acetic acid | C10H12O3 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)The reaction of the chiral epoxide (I) with isobutylamine (II) in refluxing ethanol gives the secondary amine (III), which is protected with benzyl chloroformate (IV) and TEA, yielding dicarbamate (V). Selective deprotection of (V) with dry HCl in ethyl acetate affords the primary amine (VI), which is treated with 3(S)-tetrahydrofuryl N-succinimidinyl carbonate (VII) -- obtained by reaction of tetrahydrofuran-3(S)-ol (VIII) first with phosgene and then with N-hydroxysuccinimide (IX) -- and DIEA in acetonitrile to provide the corresponding carbamate (X). Deprotection of (X) by hydrogenation with H2 over Pd/C in ethanol gives the secondary amine (XI), which is condensed with 4-nitrophenylsulfonyl chloride (XII) by means of NaHCO3 in dichloromethane/water to yield the sulfonamide intermediate (XIII).
| 【1】 Martin, L.; Castaner, R.M.; Sorbera, L.A.; Castaner, J.; Fosamprenavir. Drugs Fut 2001, 26, 3, 224. |
| 【2】 Tung, R.D.; Murcko, M.A.; Bhisetti, G.R. (Vertex Pharmaceuticals Inc.); Sulfonamide inhibitors of HIV-aspartyl protease. EP 0659181; EP 0885887; JP 1996501299; US 5585397; WO 9405639 . |
| 【3】 Tung, R.D. (Vertex Pharmaceuticals Inc.); THF-containing sulfonamide inhibitors of aspartyl protease. EP 0846110; WO 9633184 . |
| 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) | 19730 | tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate | 98737-29-2 | C15H21NO3 | 详情 | 详情 |
| (II) | 13306 | 2-Methyl-1-propanamine; Isobutylamine | 78-81-9 | C4H11N | 详情 | 详情 |
| (III) | 44417 | tert-butyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate | 160232-08-6 | C19H32N2O3 | 详情 | 详情 |
| (IV) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (V) | 44418 | benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl(isobutyl)carbamate | C27H38N2O5 | 详情 | 详情 | |
| (VI) | 44419 | benzyl (2R,3S)-3-amino-2-hydroxy-4-phenylbutyl(isobutyl)carbamate | C22H30N2O3 | 详情 | 详情 | |
| (VII) | 39664 | 1-([[(3S)tetrahydro-3-furanyloxy]carbonyl]oxy)-2,5-pyrrolidinedione | C9H11NO6 | 详情 | 详情 | |
| (VIII) | 44420 | (3S)-tetrahydro-3-furanol; (S)-3-Hydroxytetrahydrofuran | 86087-23-2 | C4H8O2 | 详情 | 详情 |
| (IX) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
| (X) | 44421 | benzyl (2R,3S)-2-hydroxy-4-phenyl-3-([[(3S)tetrahydro-3-furanyloxy]carbonyl]amino)butyl(isobutyl)carbamate | C27H36N2O6 | 详情 | 详情 | |
| (XI) | 44422 | (3S)tetrahydro-3-furanyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate | C19H30N2O4 | 详情 | 详情 | |
| (XII) | 15809 | 4-nitrobenzenesulfonyl chloride | 98-74-8 | C6H4ClNO4S | 详情 | 详情 |
| (XIII) | 44423 | (3S)tetrahydro-3-furanyl (1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]propylcarbamate | C25H33N3O8S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(I)The reaction of the chiral epoxide (I) with isobutylamine (II) in refluxing ethanol gives the secondary amine (III), which is condensed with 4-nitrophenylsulfonyl chloride (XII) and TEA in hot toluene, yielding sulfonamide (XIV). Deprotection of (XIV) with HCl in hot toluene/water affords the primary amine (XV), which is condensed with imidazole-1-carboxylic acid 3(S)-tetrahydrofuryl ester (XVI) -- prepared by reaction of tetrahydrofuran-3(S)-ol (VIII) with carbonyldiimidazole (CDI) in ethyl acetate -- to provide intermediate (XIII).
| 【1】 Martin, L.; Castaner, R.M.; Sorbera, L.A.; Castaner, J.; Fosamprenavir. Drugs Fut 2001, 26, 3, 224. |
| 【2】 Deininger, D.D.; O'Callaghan, J.; McGuie, S.; Singh, H.; Robertson, M.S.; Rodgers, K.; Tung, R.D.; Al-Farhan, E.; Rout, S.J. (Glaxo Group Ltd.); Process for the synthesis of HIV protease inhibitors. WO 9948885 . |
| 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) | 19730 | tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate | 98737-29-2 | C15H21NO3 | 详情 | 详情 |
| (II) | 13306 | 2-Methyl-1-propanamine; Isobutylamine | 78-81-9 | C4H11N | 详情 | 详情 |
| (III) | 44417 | tert-butyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate | 160232-08-6 | C19H32N2O3 | 详情 | 详情 |
| (VIII) | 44420 | (3S)-tetrahydro-3-furanol; (S)-3-Hydroxytetrahydrofuran | 86087-23-2 | C4H8O2 | 详情 | 详情 |
| (XII) | 15809 | 4-nitrobenzenesulfonyl chloride | 98-74-8 | C6H4ClNO4S | 详情 | 详情 |
| (XIII) | 44423 | (3S)tetrahydro-3-furanyl (1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]propylcarbamate | C25H33N3O8S | 详情 | 详情 | |
| (XIV) | 44938 | tert-butyl (1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]propylcarbamate | C25H35N3O7S | 详情 | 详情 | |
| (XV) | 44939 | N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutyl-4-nitrobenzenesulfonamide | 590-90-9 | C20H27N3O5S | 详情 | 详情 |
| (XVI) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |