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【结 构 式】

【分子编号】38264

【品名】(2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butyric acid

【CA登记号】

【 分 子 式 】C9H16N2O3

【 分 子 量 】200.23772

【元素组成】C 53.99% H 8.05% N 13.99% O 23.97%

与该中间体有关的原料药合成路线共 4 条

合成路线1

该中间体在本合成路线中的序号:(XIII)

The reaction of L-phenylalanine (I) with benzyl bromide and K2CO3 in hot ethanol/water gives N,N,O-tribenzyl derivative (II), which is condensed with acetonitrile (III) by means of NaNH2 in THF yielding the pentanenitrile (IV). The reaction of nitrile (IV) with benzylmagnesium chloride (V) in THF affords the diphenylhexenone (VI), which is reduced with NaBH4 in THF to give the diphenylhexanol (VII). The protection of the amino group of (VII) with Boc2O and K2CO3 in methyl tert-butyl ether yields the carbamate (VIII), which is debenzylated with ammonium formate over Pd/C in methanol affording the amino compound (IX). The condensation of (IX) with 2-(2,6-dimethylphenoxy)acetic acid (X) by means of EDAC in DMF provides the corresponding amide (XI), which is deprotected at the carbamate group with TFA in dichloromethane to give (XII) with a free amino group. Finally, this compound is condensed with 3-methyl 2(S)-(2-oxoperhydropyrimidin-1-yl)butyric acid (XIII) by means of EDAC in DMF or SOCl2 and imidazole to furnish the target compound. The intermediate 2-(2,6-dimethylphenoxy)acetic acid (X) has been obtained by condensation of 2,6-dimethylphenol (XIV) with ethyl 2-bromoacetate (XV) by means of Cs2CO3 in refluxing dioxane to give the acetate ester (XVI), which is hydrolyzed with LiOH ethanol/water to afford the target intermediate (X).

1 Stoner, E.J.; et al.; Synthesis of ABT-378, an HIV protease inhibitor candidate: Avoiding the use of carbodiimides in a difficult peptide coupling. Org Process Res Dev 1999, 3, 2, 145.
2 Sham, H.L.; Stewart, K.D.; Kempf, D.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds.. EP 0876353; JP 2000502997; WO 9721683 .
3 Retroviral protease inhibiting cpds.. EP 0882024; JP 2000502085; US 5914332; WO 9721685 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情
(I) 13952 (S)-(-)-Phenylalanine; L-Phenylalanine 63-91-2 C9H11NO2 详情 详情
(II) 37670 benzyl (2S)-2-(dibenzylamino)-3-phenylpropanoate C30H29NO2 详情 详情
(III) 37210 acetonitrile 75-05-8 C2H3N 详情 详情
(IV) 38263 (4S)-4-(dibenzylamino)-3-oxo-5-phenylpentanenitrile C25H24N2O 详情 详情
(V) 18327 benzyl(chloro)magnesium 6921-34-2 C7H7ClMg 详情 详情
(VI) 37671 (2S,4E)-5-amino-2-(dibenzylamino)-1,6-diphenyl-4-hexen-3-one C32H32N2O 详情 详情
(VII) 37672 (2S,3S,5S)-5-amino-2-(dibenzylamino)-1,6-diphenyl-3-hexanol C32H36N2O 详情 详情
(VIII) 38542 tert-butyl (1S,3S,4S)-1-benzyl-4-(dibenzylamino)-3-hydroxy-5-phenylpentylcarbamate C37H44N2O3 详情 详情
(IX) 38543 tert-butyl (1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentylcarbamate C23H32N2O3 详情 详情
(X) 38270 2-(2,6-dimethylphenoxy)acetic acid C10H12O3 详情 详情
(XI) 38545 tert-butyl (1S,3S,4S)-1-benzyl-4-[[2-(2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenylpentylcarbamate C33H42N2O5 详情 详情
(XII) 38546 N-[(1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-phenylpentyl]-2-(2,6-dimethylphenoxy)acetamide C28H34N2O3 详情 详情
(XIII) 38264 (2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butyric acid C9H16N2O3 详情 详情
(XIV) 38388 4-[(5-formyl-1H-imidazol-1-yl)methyl]benzonitrile C12H9N3O 详情 详情
(XV) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(XVI) 38544 ethyl 2-(2,6-dimethylphenoxy)acetate C12H16O3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XIII)

The intermediate 3-methyl 2(S)-(2-oxoperhydropyrimidin1-yl)butyric acid (XIII) has been obtained as follows: The oxidation of 3-(benzyloxycarbonylamino)-1-propanol (XVII) with oxalyl chloride in dichloromethane gives the corresponding aldehyde (XVIII), which is reductocondensed with L-valine methyl ester (XIX) by means NaBH3CN in methanol yielding the N-substituted valine (XX). The cyclization of (XX) by elimination of the benzyloxycarbonyl group by hydrogenation with H2 over Pd/C in dichloromethane, followed by reaction with carbonyldiimidazole (CDI) affords the 3-methyl 2(S)-(2-oxoperhydropyrimidin-1-yl)butyric acid methyl ester (XXI). Finally, this compound is hydrolyzed with LiOH in dioxane/water to afford the target intermediate (XIII).

1 Retroviral protease inhibiting cpds.. EP 0882024; JP 2000502085; US 5914332; WO 9721685 .
2 Sham, H.L.; Stewart, K.D.; Kempf, D.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds.. EP 0876353; JP 2000502997; WO 9721683 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIII) 38264 (2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butyric acid C9H16N2O3 详情 详情
(XVII) 38547 benzyl 3-hydroxypropylcarbamate C11H15NO3 详情 详情
(XVIII) 38548 benzyl 3-oxopropylcarbamate C11H13NO3 详情 详情
(XIX) 16613 methyl (2S)-2-amino-3-methylbutanoate C6H13NO2 详情 详情
(XX) 38549 methyl (2S)-2-[(3-[[(benzyloxy)carbonyl]amino]propyl)amino]-3-methylbutanoate C17H26N2O4 详情 详情
(XXI) 38550 methyl (2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butanoate C10H18N2O3 详情 详情

合成路线3

该中间体在本合成路线中的序号:(IX)

The reaction of L-phenylalanine (I) with benzyl bromide and K2CO3 in hot EtOH/H2O gives N,N,O-tribenzyl derivative (II), which is condensed with acetonitrile (III) by means of NaNH2 in THF yielding the pentanenitrile (IV). The reaction of nitrile (IV) with benzylmagnesium chloride (V) in THF affords the diphenylhexenone (VI), which is reduced with NaBH4 in THF to give the diphenylhexanol (VII) (slightly impurified (~10%) with other diastereomers that are not eliminated at this stage). The condensation of (VII) with acid chloride (VIII) (obtained by reaction of acid (IX) with SOCl2) in the presence of imidazole yields the amide (X), which is debenzylated with ammonium formate over Pd/C in methanol affording the amine (XI). At this stage the purification (elimination of the diastereomers) has been performed by crystallization of its salt with L-pyroglutamic acid (XII) in EtOH/DMF, pure salt (XIII) being obtained. Finally, this compound is condensed with the acid chloride (XIV) (obtained by reaction of acid (XV) with SOCl2) by means of NaHCO3 in ethyl acetate/water. The intermediates, the acids (IX) and (XV), have been obtained as indicated in schemes 24659001a and 24659001b (intermediates (XIII) and (X) of these schemes, respectively).

1 Stoner, E.J.; et al.; Synthesis of HIV protease inhibitor ABT-378 (lopinavir). Org Process Res Dev 2000, 4, 4, 264.
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) 37670 benzyl (2S)-2-(dibenzylamino)-3-phenylpropanoate C30H29NO2 详情 详情
(III) 37210 acetonitrile 75-05-8 C2H3N 详情 详情
(IV) 38263 (4S)-4-(dibenzylamino)-3-oxo-5-phenylpentanenitrile C25H24N2O 详情 详情
(V) 18327 benzyl(chloro)magnesium 6921-34-2 C7H7ClMg 详情 详情
(VI) 37671 (2S,4E)-5-amino-2-(dibenzylamino)-1,6-diphenyl-4-hexen-3-one C32H32N2O 详情 详情
(VII) 37672 (2S,3S,5S)-5-amino-2-(dibenzylamino)-1,6-diphenyl-3-hexanol C32H36N2O 详情 详情
(VIII) 38265 (2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butanoyl chloride C9H15ClN2O2 详情 详情
(IX) 38264 (2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butyric acid C9H16N2O3 详情 详情
(X) 38266 (2S)-N-[(1S,3S,4S)-1-benzyl-4-(dibenzylamino)-3-hydroxy-5-phenylpentyl]-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butanamide C41H50N4O3 详情 详情
(XI) 38267 (2S)-N-[(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentyl]-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butanamide C27H38N4O3 详情 详情
(XII) 32406 (2S)-5-oxo-2-pyrrolidinecarboxylic acid 98-79-3 C5H7NO3 详情 详情
(XIII) 38268 (2S,3S,5S)-3-hydroxy-5-([(2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butanoyl]amino)-1,6-diphenyl-2-hexanaminium (2S)-5-oxo-2-pyrrolidinecarboxylate C32H45N5O6 详情 详情
(XIV) 38269 2-(2,6-dimethylphenoxy)acetyl chloride C10H11ClO2 详情 详情
(XV) 38270 2-(2,6-dimethylphenoxy)acetic acid C10H12O3 详情 详情

合成路线4

该中间体在本合成路线中的序号:(IV)

 

1 Bose P.2006. Process for the preparation of lopinavir and its intermediate-(S)-tetrahydro-alaha-(1-methylethyl)-2-oxo-1(2H)-pyrimidineeacetic acid. WO 2006100552[本专利为Ranbaxy laboratories Ltd(IN)所有]
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 66513 (S)-2-((2-cyanoethyl)amino)-3-methylbutanoic acid   C8H14N2O2 详情 详情
(I) 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
(III) 66514 (S)-2-((2-cyanoethyl)(methoxycarbonyl)amino)-3-methylbutanoic acid   C10H16N2O4 详情 详情
(IV) 38264 (2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butyric acid C9H16N2O3 详情 详情
(V) 38265 (2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butanoyl chloride C9H15ClN2O2 详情 详情
Extended Information