【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 |