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【结 构 式】

【药物名称】

【化学名称】11-[1-(2,4-Dichlorobenzyl)-4(S)-(3-thienyl)pyrrolidin-3(S)-ylmethyl]-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15(S)-carboxylic acid

【CA登记号】

【 分 子 式 】C29H36Cl2N2O4S

【 分 子 量 】579.59127

【开发单位】Merck & Co. (Originator)

【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, RESPIRATORY DRUGS, Chemokine CCR3 Antagonists

合成路线1

Acid-catalyzed cycloaddition of the chiral acryloyl oxazolidine derivative (I) with amine (II) affords a diastereomeric mixture of trans pyrrolidines (III) and (IV). The desired isomer (IV) is then reduced by DIBAL to the intermediate aldehyde (V)

1 Pyrrolidine antagonists of the CCR3 chemokine receptor. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 250.
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) 63496 4-(phenylmethyl)-3-[3-(3-thiophenyl)acryloyl]-1,3-oxazolidin-2-one C17H15NO3S 详情 详情
(II) 25556 N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine; N-benzyl-N-(methoxymethyl)(trimethylsilyl)methanamine 1871-96-1 C13H23NOSi 详情 详情
(III) 63498 4-(phenylmethyl)-3-{[1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinyl]carbonyl}-1,3-oxazolidin-2-one C26H26N2O3S 详情 详情
(IV) 63499 4-(phenylmethyl)-3-{[1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinyl]carbonyl}-1,3-oxazolidin-2-one C26H26N2O3S 详情 详情
(V) 63500 1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinecarbaldehyde C16H17NOS 详情 详情

合成路线2

Alkylation of the spiro lactone (VI) with dibromide (VII) in the presence of lithium hexamethyldisilazide gives rise to the tricyclic spiro compound (VIII). After acidic Boc group cleavage in (VIII), the resultant secondary amine (IX) is reductively alkylated with aldehyde (V) to produce (X) as a diastereomeric mixture. Partial reduction of lactone (X) with DIBAL provides lactol (XI), which is further converted to nitrile (XII) upon treatment with cyanotrimethylsilane and boron trifluoride. Acidic hydrolysis of nitrile (XII), followed by esterification of the resultant carboxylic acid (XIII) furnishes the methyl ester (XIV)

1 Pyrrolidine antagonists of the CCR3 chemokine receptor. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 250.
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) 63500 1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinecarbaldehyde C16H17NOS 详情 详情
(VI) 63501 1,1-dimethylethyl 2-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate C13H21NO4 详情 详情
(VII) 63502 1-bromo-2-[(2-bromoethyl)oxy]ethane; bis(2-bromoethyl) ether 5414-19-7 C4H8Br2O 详情 详情
(VIII) 63503 1,1-dimethylethyl 15-oxo-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-11-carboxylate C17H27NO5 详情 详情
(IX) 63504 3,14-dioxa-11-azadispiro[5.1.5.2]pentadecan-15-one C12H19NO3 详情 详情
(X) 63505 11-{[1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecan-15-one C28H36N2O3S 详情 详情
(XI) 63506 11-{[1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecan-15-ol C28H38N2O3S 详情 详情
(XII) 63507 11-{[1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carbonitrile C29H37N3O2S 详情 详情
(XIII) 63508 11-{[1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carboxylic acid C29H38N2O4S 详情 详情
(XIV) 63509 methyl 11-{[1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carboxylate C30H40N2O4S 详情 详情

合成路线3

The N-benzyl group of (XIV) is removed by catalytic hydrogenolysis to yield the secondary amine (XV). Subsequent reductive alkylation of amine (XV) with 2,4-dichlorobenzaldehyde (XVI) leads to the dichlorobenzyl amine (XVII). After alkaline hydrolysis of the methyl ester (XVII), the obtained carboxylic acid (XVIII) is converted to the PMB ester (XIX) employing p-methoxybenzyl chloride and Cs2CO3. The diastereomeric mixture of PMB esters (XIX) is then chromatographically separated by means of a chiral column, and the desired isomer is finally deprotected with trifloroacetic acid to yield the target carboxylic acid

1 Pyrrolidine antagonists of the CCR3 chemokine receptor. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 250.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIV) 63509 methyl 11-{[1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carboxylate C30H40N2O4S 详情 详情
(XV) 63511 methyl 11-{[4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carboxylate C23H34N2O4S 详情 详情
(XVI) 22196 2,4-dichlorobenzaldehyde 874-42-0 C7H4Cl2O 详情 详情
(XVII) 63513 methyl 11-{[1-[(2,4-dichlorophenyl)methyl]-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carboxylate C30H38Cl2N2O4S 详情 详情
(XVIII) 63514 11-{[1-[(2,4-dichlorophenyl)methyl]-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carboxylic acid C29H36Cl2N2O4S 详情 详情
(XIX) 63515 [4-(methyloxy)phenyl]methyl 11-{[1-[(2,4-dichlorophenyl)methyl]-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carboxylate C37H44Cl2N2O5S 详情 详情
(XX) 63510 [4-(methyloxy)phenyl]methyl 11-{[1-[(2,4-dichlorophenyl)methyl]-4-(3-thiophenyl)-3-pyrrolidinyl]methyl}-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15-carboxylate C37H44Cl2N2O5S 详情 详情
Extended Information