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【结 构 式】 
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【药物名称】SCH-62373 【化学名称】1-Benzyl-N-[2-[2-(3,4-dichlorophenyl)-4-(3,5-dimethylbenzoyl)piperazin-1-yl]-2-oxoethyl]piperidin-4-amine 【CA登记号】185108-18-3 【 分 子 式 】C33H38Cl2N4O2 【 分 子 量 】593.60241 |
【开发单位】Schering-Plough (Originator) 【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, RESPIRATORY DRUGS, Tachykinin NK1 Antagonists, Tachykinin NK2 Antagonists |
合成路线1
Reaction of 2-chloropyrazine (I) with 3,4-dichlorophenylmagnesium bromide (II) in the presence of [1,2-bis(diphenylphosphino)ethane]nickel(II) chloride produced the 2-arylpyrazine (III), which was reduced to the corresponding piperazine (IV) by means of DIBAL in THF. In a different procedure, bromination of methyl 3,4-dichlorophenylacetate (V) using N-bromosuccinimide, followed by reaction of the resulting bromo ester (VI) with ethylenediamine (VII) afforded the piperazinone (VIII), which was further reduced to (IV) by using LiAlH4 in Et2O.
| 【1】 Anthes, J.C.; McPhail, A.T.; Blythin, D.J.; Shue, H.-J.; Chen, X.; Piwinski, J.J.; shih, N.-Y.; Discovery of Sch 62373 and analogs, of novel series of 2-phenylpiperazines exhibiting potent dual NK1/NK2 antagonist activity. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 244. |
| 【2】 Shue, H.-J.; Shih, N.-Y.; Blythin, D.J.; Chen, X.; Tom, W.C.; Piwinski, J.J.; McCormick, K.D. (Schering Corp.); Piperazino derivs. as neurokinin antagonists. EP 0823906; US 5719156; WO 9634864 . |
| 【3】 Piwinski, J.J.; McCormick, K.D.; Shue, H.-J.; Chen, X.; Shih, N.-Y.; Blythin, D.J. (Schering Corp.); Piperazino derivs. as neurokinin antagonists. EP 0850236; JP 2000344766; US 5795894; US 5892039; WO 9708166 . |
| 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) | 24075 | 2-chloropyrazine | 14508-49-7 | C4H3ClN2 | 详情 | 详情 |
| (II) | 10069 | Bromo(3,4-dichlorophenyl)magnesium | 79175-35-2 | C6H3BrCl2Mg | 详情 | 详情 |
| (III) | 47945 | 2-(3,4-dichlorophenyl)pyrazine | C10H6Cl2N2 | 详情 | 详情 | |
| (IV) | 47946 | 2-(3,4-dichlorophenyl)piperazine | C10H12Cl2N2 | 详情 | 详情 | |
| (V) | 47947 | methyl 2-(3,4-dichlorophenyl)acetate | C9H8Cl2O2 | 详情 | 详情 | |
| (VI) | 47948 | methyl 2-bromo-2-(3,4-dichlorophenyl)acetate | C9H7BrCl2O2 | 详情 | 详情 | |
| (VII) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
| (VIII) | 47949 | 3-(3,4-dichlorophenyl)-2-piperazinone | C10H10Cl2N2O | 详情 | 详情 |
合成路线2
Regioselective coupling of the 2-arylpiperazine (IV) with 3,5-dimethylbenzoic acid (IX) at the less hindered N atom by means of EDC and HOBt afforded the 4-benzoyl piperazine (X). This was subsequently acylated with bromoacetyl bromide (XI) to yield the bromo amide (XII). Bromide displacement in (XII) with 4-amino-1-benzylpiperidine (XIII) then gave the title compound.
| 【1】 Shue, H.-J.; Shih, N.-Y.; Blythin, D.J.; Chen, X.; Tom, W.C.; Piwinski, J.J.; McCormick, K.D. (Schering Corp.); Piperazino derivs. as neurokinin antagonists. EP 0823906; US 5719156; WO 9634864 . |
| 【2】 Piwinski, J.J.; McCormick, K.D.; Shue, H.-J.; Chen, X.; Shih, N.-Y.; Blythin, D.J. (Schering Corp.); Piperazino derivs. as neurokinin antagonists. EP 0850236; JP 2000344766; US 5795894; US 5892039; WO 9708166 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 47946 | 2-(3,4-dichlorophenyl)piperazine | C10H12Cl2N2 | 详情 | 详情 | |
| (IX) | 26775 | 3,5-dimethylbenzoic acid | 499-06-9 | C9H10O2 | 详情 | 详情 |
| (X) | 47950 | [3-(3,4-dichlorophenyl)-1-piperazinyl](3,5-dimethylphenyl)methanone | C19H20Cl2N2O | 详情 | 详情 | |
| (XI) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (XIII) | 34808 | 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine | 50541-93-0 | C12H18N2 | 详情 | 详情 |
合成路线3
In a related method, the 2-arylpiperazine (IV) was first protected as the 4-tert-butyl carbamate (XIV) upon treatment with di-tert-butyl dicarbonate in MeOH at -78 C. Subsequent acylation of (XIV) with bromoacetyl bromide (XI) produced the bromo amide (XV), which was then condensed with the aminopiperidine (XIII), yielding the glycinamide derivative (XVI). Acidic cleavage of the Boc group of (XVI) afforded the 1-acyl piperazine (XVII). This was finally coupled with 3,5-dimethylbenzoic acid using EDC and HOBt.
| 【1】 Anthes, J.C.; McPhail, A.T.; Blythin, D.J.; Shue, H.-J.; Chen, X.; Piwinski, J.J.; shih, N.-Y.; Discovery of Sch 62373 and analogs, of novel series of 2-phenylpiperazines exhibiting potent dual NK1/NK2 antagonist activity. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 244. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 47946 | 2-(3,4-dichlorophenyl)piperazine | C10H12Cl2N2 | 详情 | 详情 | |
| (IX) | 26775 | 3,5-dimethylbenzoic acid | 499-06-9 | C9H10O2 | 详情 | 详情 |
| (XI) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (XIII) | 34808 | 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine | 50541-93-0 | C12H18N2 | 详情 | 详情 |
| (XIV) | 47952 | tert-butyl 3-(3,4-dichlorophenyl)-1-piperazinecarboxylate | C15H20Cl2N2O2 | 详情 | 详情 | |
| (XV) | 47953 | tert-butyl 4-(2-bromoacetyl)-3-(3,4-dichlorophenyl)-1-piperazinecarboxylate | C17H21BrCl2N2O3 | 详情 | 详情 | |
| (XVI) | 47954 | tert-butyl 4-[2-[(1-benzyl-4-piperidinyl)amino]acetyl]-3-(3,4-dichlorophenyl)-1-piperazinecarboxylate | C29H38Cl2N4O3 | 详情 | 详情 | |
| (XVII) | 47955 | 2-[(1-benzyl-4-piperidinyl)amino]-1-[2-(3,4-dichlorophenyl)-1-piperazinyl]-1-ethanone | C24H30Cl2N4O | 详情 | 详情 |