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【结 构 式】 
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【分子编号】50591 【品名】(4S)-4-benzyl-3-[(2S,4E)-5-chloro-2-isopropyl-4-pentenoyl]-1,3-oxazolidin-2-one 【CA登记号】 |
【 分 子 式 】C18H22ClNO3 【 分 子 量 】335.83032 【元素组成】C 64.38% H 6.6% Cl 10.56% N 4.17% O 14.29% |
合成路线1
该中间体在本合成路线中的序号：(XLIX)Alternatively, the chiral azido intermediate (XXXIV) can also be synthesized as follows: Alkylation of oxazolidinone (V) with 1-chloro-3-iodopropene (XLVIII) by means of LiHMDS in THF gives compound (XLIX), which is condensed with the magnesium derivative of the phenylpropyl chloride (XXX) to yield, after working up, amide (L). Bromination of (L) with NBS and phosphoric acid affords the bromolactone (LI), which by treatment with NaN3 in tripropylene glycol/water provides the azido derivative (XXXIV).
| 【1】 Mealy, N.E.; Castañer, R.M.; Silvestre, J.S.; Castañer, J.; Aliskiren Fumarate. Drugs Fut 2001, 26, 12, 1139. |
| 【2】 Stutz, S.; Herold, P. (Speedel Pharma Inc.); 2-Alkyl-5-halogen-pent-4-ene carboxylic acids and their production. WO 0109079; WO 0109083 . |
| 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) | 28131 | (4S)-4-benzyl-3-(3-methylbutanoyl)-1,3-oxazolidin-2-one | C15H19NO3 | 详情 | 详情 | |
| (XXX) | 50574 | 4-[(2R)-2-(chloromethyl)-3-methylbutyl]-1-methoxy-2-(3-methoxypropoxy)benzene; 3-[5-[(2R)-2-(chloromethyl)-3-methylbutyl]-2-methoxyphenoxy]propyl methyl ether | 324763-39-5 | C17H27ClO3 | 详情 | 详情 |
| (XXXIV) | 50578 | (3S,5S)-5-[(1S,3S)-1-azido-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl]-3-isopropyldihydro-2(3H)-furanone | C25H39N3O5 | 详情 | 详情 | |
| (XLVIII) | 50590 | (E)-1-chloro-3-iodo-1-propene | C3H4ClI | 详情 | 详情 | |
| (XLIX) | 50591 | (4S)-4-benzyl-3-[(2S,4E)-5-chloro-2-isopropyl-4-pentenoyl]-1,3-oxazolidin-2-one | C18H22ClNO3 | 详情 | 详情 | |
| (L) | 50592 | (4S)-4-benzyl-3-[(2S,4E,7R)-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methyl-4-nonenoyl]-1,3-oxazolidin-2-one | C35H49NO6 | 详情 | 详情 | |
| (LI) | 50593 | (3S,5S)-5-[(1R,3S)-1-bromo-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl]-3-isopropyldihydro-2(3H)-furanone | C25H39BrO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)The condensation of ethyl isovalerate (I) with 1,3-dichloropropene (II) by means of BuLi and DIA in THF gives 5-chloro-2-isopropyl-4-pentenoic acid ethyl ester (III), which is hydrolyzed with NaOH in ethanol to yield the corresponding racemic acid (IV). The optical resolution of (IV) is carried out by means of cinchonidine and TEA in THF to afford 5-chloro-2(S)-isopropyl-4-pentenoic acid (V), which can also be obtained by asymmetric synthesis as follows: Condensation of 4(S)-benzyl-3-(3-methylbutyryl)oxazolidin-2-one (VI) with 3-iodo-1-propenyl chloride (VII) by means of LiHMDS in THF gives 4(S)-benzyl-3-(2(S)-isopropyl-3-methylbutyryl)oxazolidin-2-one (VIII), which is hydrolyzed with LiOH in THF/water to afford the chiral pentanoic acid (V). The reaction of (V) with oxalyl chloride in toluene gives the corresponding acyl chloride (IX), which is treated with dimethylamine and pyridine in dichloromethane to yield the dimethylamide (X). The condensation of (X) with the chiral chloro derivative (XI) (obtained by reaction of the corresponding alcohol (XII) with CCl4 and trioctylphosphine) by means of Mg and 1,2-dibromoethane in THF affords the octenamide (XIII). The cyclization of (XIII) by means of phosphoric acid and simultaneous bromination with NBS in THF provides the chiral bromolactone (XIV), which is opened by means of dimethylamine and Et2AlCl in dichloromethane to give the chiral 5-bromo-4-hydroxy-2,7-diisopropyloctanamide (XV). The reaction of (XV) with acetic anhydride and pyridine in dichloromethane yields the acetoxy derivative (XVI), which is treated with LiN3 to afford the 5(S)-azido derivative (XVII).
| 【1】 Herold, P.; Stutz, S. (Speedel Pharma Inc.); Process for the preparation of substd. octanoyl amides. WO 0208172 . |
| 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) | 61601 | ethyl isovalerate; Ethyl 3-methylbutanoate; Ethyl beta-methyl butyrate; Ethyl isovalerianate; ETHYL ISOVALERATE, NATURAL; Ethyl Isovalerate, Fcc; Isovaleriansaeure ethylester; Isovaleric Acid Ethyl Ester; iso-Valeric Acid Ethyl Ester; Ethyl isopentanoate; Ethyl isovalerate with G.C.; Ethyl Iso Valerate; Iso C-5 Ethyl Ester; Ethyl isopentanoate; 3-Methylbutyric acid ethyl ester | 108-64-5 | C7H14O2 | 详情 | 详情 |
| (II) | 61605 | 1,3-Dichloropropene; cis-1,3-Dichloropropylene; trans-1,3-Dichloropropene; 3-Chloroallyl Chloride; 3-Chloropropenyl Chloride; Telone; Telone II Soil Fumigant; 1,3-Dichloropropylene; alpha-Chloroallyl Chloride; Chloroallyl Chloride; 1,3-Dichloro-1-Propene; Telone II; cis-1,3-Dichloropropene; alpha,gamma-Dichloropropylene; gamma-chloroallyl chloride; cis-1,3-dichloro-1-propene; trans-1,3-dichloro-1-propene; 1,3-Dichloropropene (mixed isomers); (E)-1,3-dichloro-1-Propene; (Z)-1,3-dichloro-1-Propene; D-D92; (Z)-1,3-dichloropropene; 1,3-Dichloro-1-propene (Z); trans-1,3-dichloropropylene; E-1,3-Dichloropropene; 1,3-dichloro-1-propylene; 1,3-dichloropropene-1; dorlone ii; Tri-Form; 1,3-D; Telone IIR; Chloropropenyl chloride; 1,3-Dichloro-2-propene; 1,3-Dichloropropene, E,Z-; 1,3-Dichloropropene (mixed); 1,3-Dichloropropene (cis+trans); Cis-1,3-Dichloro-1-Propene, Te Ch; Trans-1,3-Dichloro-1-Propene,tech; 1,3-Dichloropropene, Mixture Of Isomers, 92%; 1,3-Dichloropropene, mixture of isomers; G | 542-75-6 | C3H4Cl2 | 详情 | 详情 |
| (III) | 61602 | ethyl (E)-5-chloro-2-isopropyl-4-pentenoate | C10H17ClO2 | 详情 | 详情 | |
| (IV) | 61603 | (E)-5-chloro-2-isopropyl-4-pentenoic acid | C8H13ClO2 | 详情 | 详情 | |
| (V) | 61604 | (2S,4E)-5-chloro-2-isopropyl-4-pentenoic acid | 324519-66-6 | C8H13ClO2 | 详情 | 详情 |
| (VI) | 61606 | (4S)-4-benzyl-3-(3-methylbutanoyl)-1,3-oxazolidin-2-one | C15H19NO3 | 详情 | 详情 | |
| (VII) | 50590 | (E)-1-chloro-3-iodo-1-propene | C3H4ClI | 详情 | 详情 | |
| (VIII) | 50591 | (4S)-4-benzyl-3-[(2S,4E)-5-chloro-2-isopropyl-4-pentenoyl]-1,3-oxazolidin-2-one | C18H22ClNO3 | 详情 | 详情 | |
| (IX) | 61607 | (2S,4E)-5-chloro-2-isopropyl-4-pentenoyl chloride | C8H12Cl2O | 详情 | 详情 | |
| (X) | 61608 | (2S,4E)-5-chloro-2-isopropyl-N,N-dimethyl-4-pentenamide | 324519-68-8 | C10H18ClNO | 详情 | 详情 |
| (XI) | 50574 | 4-[(2R)-2-(chloromethyl)-3-methylbutyl]-1-methoxy-2-(3-methoxypropoxy)benzene; 3-[5-[(2R)-2-(chloromethyl)-3-methylbutyl]-2-methoxyphenoxy]propyl methyl ether | 324763-39-5 | C17H27ClO3 | 详情 | 详情 |
| (XII) | 50573 | (2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methyl-1-butanol | C17H28O4 | 详情 | 详情 | |
| (XIII) | 61609 | (2S,4E,7R)-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-N,N,8-trimethyl-4-nonenamide | C27H45NO4 | 详情 | 详情 | |
| (XIV) | 50593 | (3S,5S)-5-[(1R,3S)-1-bromo-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl]-3-isopropyldihydro-2(3H)-furanone | C25H39BrO5 | 详情 | 详情 | |
| (XV) | 61610 | (2S,4S,5R,7S)-5-bromo-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-N,N,8-trimethylnonanamide | C27H46BrNO5 | 详情 | 详情 | |
| (XVI) | 61611 | (1S,2R,4S)-2-bromo-1-{(2S)-2-[(dimethylamino)carbonyl]-3-methylbutyl}-4-[4-methoxy-3-(3-methoxypropoxy)benzyl]-5-methylhexyl acetate | C29H48BrNO6 | 详情 | 详情 | |
| (XVII) | 61612 | (1S,2S,4S)-2-azido-1-{(2S)-2-[(dimethylamino)carbonyl]-3-methylbutyl}-4-[4-methoxy-3-(3-methoxypropoxy)benzyl]-5-methylhexyl acetate | C29H48N4O6 | 详情 | 详情 |