|
【结 构 式】 
|
【分子编号】37671 【品名】(2S,4E)-5-amino-2-(dibenzylamino)-1,6-diphenyl-4-hexen-3-one 【CA登记号】 |
【 分 子 式 】C32H32N2O 【 分 子 量 】460.61896 【元素组成】C 83.44% H 7% N 6.08% O 3.47% |
合成路线1
该中间体在本合成路线中的序号：(XXXI)A new method for the preparation of a key diaminoalcohol intermediate in the synthesis of ritonavir has been described: The reaction of L-phenylalanine (XXIX) with benzyl chloride by means of K2CO3 and KOH in hot water gives N,N-dibenzyl-L-phenylalanine benzyl ester (XXX), which is condensed first with acetonitrile by means of NaNH2 and then with benzylmagnesium chloride, both reactions in methyl tert-butyl ether, yielding 5-amino-2-(dibenzylamino)-1,6-diphenylhex-4-en-3-one (XXXI). The reduction of (XXXI) with NaBH4 with an accurate control of the solvent and acidity, results in an enhanced enantioselectivity towards the desired (S,S,S)-enantiomer of 5-amino-2-(dibenzylamino)-1,6-diphenyl-3-hexanol (XXXII). Finally, this compound is deprotected by hydrogenation with ammonium formate over Pd/C in methanol/water to provide the target chiral diaminoalcohol (VIII).
| 【1】 Allen, M.S.; Stuk, T.L.; Haight, A.R.; et al.; Reduction of an enaminone: Synthesis of the diamino alcohol core of ritonavir. Org Process Res Dev 1999, 3, 2, 94. |
| 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) | 16592 | (2S,3S,5S)-2,5-diamino-1,6-diphenyl-3-hexanol | C18H24N2O | 详情 | 详情 | |
| (XXIX) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (XXX) | 37670 | benzyl (2S)-2-(dibenzylamino)-3-phenylpropanoate | C30H29NO2 | 详情 | 详情 | |
| (XXXI) | 37671 | (2S,4E)-5-amino-2-(dibenzylamino)-1,6-diphenyl-4-hexen-3-one | C32H32N2O | 详情 | 详情 | |
| (XXXII) | 37672 | (2S,3S,5S)-5-amino-2-(dibenzylamino)-1,6-diphenyl-3-hexanol | C32H36N2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)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3
该中间体在本合成路线中的序号：(VI)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)The reaction of L-phenylalanine (I) with benzyl chloride and K2CO3 gives the tribenzylated compound (II), which is condensed with acetonitrile by means of NaNH2 yielding 4(S)-(dibenzylamino)-3-oxo-4-phenylbutyronitrile (III). The reaction of (III) with benzylmagnesium chloride in THF affords the unsaturated, partially protected diaminohexenone (IV), which is reduced with NaBH4 and NaBH3(OTf) to provide a mixture of diastereomeric diaminohexanones, from which the desired diastereomer (V) is isolated by crystallization. The acylation of the free amino group of (V) with acylated anthranilic acid (VI) by means of HOBT gives the expected amide (VII), which is debenzylated by treatment with Pd/C and ammonium formate yielding intermediate (VIII). Finally this compound is acylated with the activated N-succinylcarbamate (IX) to afford the desired target compound.
| 【1】 Stuk, T.L.; et al.; An efficient stereocontrolled strategy for the synthesis of hydroxyethylene dipeptide isosteres. J Org Chem 1994, 59, 15, 4040. |
| 【2】 Randad, R.S.; Lubkowska, L.; Eissenstat, M.A.; Gulnik, S.V.; Yu, B.; Bhat, T.N.; Clanton, D.J.; House, T.; Stinson, S.F.; Erickson, J.W.; Unsymmetric nonpeptidic HIV protease inhibitors containing anthranilamide as a P2' ligand. Bioorg Med Chem Lett 1998, 8, 24, 3537. |
| 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) | 38263 | (4S)-4-(dibenzylamino)-3-oxo-5-phenylpentanenitrile | C25H24N2O | 详情 | 详情 | |
| (IV) | 37671 | (2S,4E)-5-amino-2-(dibenzylamino)-1,6-diphenyl-4-hexen-3-one | C32H32N2O | 详情 | 详情 | |
| (V) | 37672 | (2S,3S,5S)-5-amino-2-(dibenzylamino)-1,6-diphenyl-3-hexanol | C32H36N2O | 详情 | 详情 | |
| (V) | 41850 | 2-[[(2-pyridinylmethoxy)carbonyl]amino]benzoic acid | C14H12N2O4 | 详情 | 详情 | |
| (VI) | 41851 | 2-pyridinylmethyl 2-([[(1S,3S,4S)-1-benzyl-4-(dibenzylamino)-3-hydroxy-5-phenylpentyl]amino]carbonyl)phenylcarbamate | C46H46N4O4 | 详情 | 详情 | |
| (VII) | 41852 | 2-pyridinylmethyl 2-([[(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentyl]amino]carbonyl)phenylcarbamate | C32H34N4O4 | 详情 | 详情 | |
| (VIII) | 41853 | 1,3-thiazol-5-ylmethyl 2,5-dioxo-1-pyrrolidinecarboxylate | C9H8N2O4S | 详情 | 详情 |