SR-144190, -Drug Synthesis Database

【结构式】

【药物名称】SR-144190

【化学名称】(+)-(R)-N-[1-[2-[4-Benzoyl-2-(3,4-difluorophenyl)morpholin-2-yl]ethyl]-4-phenylpiperidin-4-yl]-N',N'-dimethylurea

【CA登记号】

【分子式】C₃₃H₃₈F₂N₄O₃

【分子量】576.69261

【开发单位】Sanofi-synthélabo (Originator)

【药理作用】Antidepressants, Anxiolytics, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, Tachykinin NK2 Antagonists

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

Cyanohydrin (II) was prepared by addition of KCN to 3,4-difluorobenzaldehyde (I) in the presence of sodium bisulfite. After protection of the hydroxyl group of (II) as the tetrahydropyranyl ether (III), alkylation with bromoethyl benzoate (IV) in the presence of LDA furnished adduct (V). Catalytic hydrogenation of the cyano group to give (VI), followed by tetrahydropyranyl group cleavage under acidic conditions, afforded amino alcohol (VII). Subsequent acylation of (VII) with chloroacetyl chloride produced the chloroacetamide (VIII). Intramolecular cyclization of (VIII) upon treatment with K2CO3 in boiling toluene yielded a racemic morpholinone that was resolved into the enantiomers by using L-tartaric acid. The desired (R)-morpholinone (IX) was then reduced to the corresponding morpholine (X) employing borane in THF.

参考文献中间体

【1】 Emonds-Alt, X.; Grossriether, I.; Gueule, P.; Proietto, V.; Van Broeck, D. (Sanofi-Synthélabo); Substd. heterocyclic cpds., preparation method therefor and pharmaceutical compsns. containing same. EP 1156049; FR 2729952; FR 2729953; FR 2729954; JP 1999507324; JP 2001131171; US 5641777; WO 9623787 .

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)	26654	3,4-difluorobenzaldehyde	34036-07-2	C₇H₄F₂O	详情	详情
(II)	54981	2-(3,4-difluorophenyl)-2-hydroxyacetonitrile		C₈H₅F₂NO	详情	详情
(III)	54982	2-(3,4-difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)acetonitrile		C₁₃H₁₃F₂NO₂	详情	详情
(IV)	54983	2-Bromoethyl benzoate; Benzoic acid 2-bromoethyl ester	939-54-8	C₉H₉BrO₂	详情	详情
(V)	54984	3-cyano-3-(3,4-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)propyl benzoate		C₂₂H₂₁F₂NO₄	详情	详情
(VI)	54985	4-amino-3-(3,4-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)butyl benzoate		C₂₂H₂₅F₂NO₄	详情	详情
(VII)	54986	4-amino-3-(3,4-difluorophenyl)-3-hydroxybutyl benzoate		C₁₇H₁₇F₂NO₃	详情	详情
(VIII)	54987	4-[(2-chloroacetyl)amino]-3-(3,4-difluorophenyl)-3-hydroxybutyl benzoate		C₁₉H₁₈ClF₂NO₄	详情	详情
(IX)	54988	2-[(2R)-2-(3,4-difluorophenyl)-5-oxomorpholinyl]ethyl benzoate		C₁₉H₁₇F₂NO₄	详情	详情
(X)	54989	2-[(2R)-2-(3,4-difluorophenyl)morpholinyl]ethyl benzoate		C₁₉H₁₉F₂NO₃	详情	详情

合成路线2

Benzamide (XII) was prepared by acylation of morpholine (X) with benzoyl chloride (XI). The benzoate ester of (XII) was subsequently hydrolyzed under basic conditions to the alcohol (XIII), which was further converted to the mesylate ester (XIV) by means of methanesulfonyl chloride and triethylamine.

参考文献中间体

【1】 Emonds-Alt, X.; Grossriether, I.; Gueule, P.; Proietto, V.; Van Broeck, D. (Sanofi-Synthélabo); Substd. heterocyclic cpds., preparation method therefor and pharmaceutical compsns. containing same. EP 1156049; FR 2729952; FR 2729953; FR 2729954; JP 1999507324; JP 2001131171; US 5641777; WO 9623787 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	54989	2-[(2R)-2-(3,4-difluorophenyl)morpholinyl]ethyl benzoate		C₁₉H₁₉F₂NO₃	详情	详情
(XI)	10463	Benzoyl chloride	98-88-4	C₇H₅ClO	详情	详情
(XII)	54990	2-[(2R)-4-benzoyl-2-(3,4-difluorophenyl)morpholinyl]ethyl benzoate		C₂₆H₂₃F₂NO₄	详情	详情
(XIII)	54991	[(2R)-2-(3,4-difluorophenyl)-2-(2-hydroxyethyl)morpholinyl](phenyl)methanone		C₁₉H₁₉F₂NO₃	详情	详情
(XIV)	54992	2-[(2R)-4-benzoyl-2-(3,4-difluorophenyl)morpholinyl]ethyl methanesulfonate		C₂₀H₂₁F₂NO₅S	详情	详情

合成路线3

Acetamide (XVI) was obtained by the Ritter reaction of 1-benzyl-4-phenyl-piperidin-4-ol (XV) with acetonitrile. Acidic hydrolysis of amide (XVI) provided the aminopiperidine (XVII), which was converted into urea (XVIII) upon treatment with N,N-dimethylcarbamoyl chloride. Hydrogenolytic cleavage of the N-benzyl group of (XVIII) gave piperidine (XIX), which was finally alkylated with the mesylate (XIV) to furnish the title compound.

参考文献中间体

【1】 Emonds-Alt, X.; Grossriether, I.; Gueule, P.; Proietto, V.; Van Broeck, D. (Sanofi-Synthélabo); Substd. heterocyclic cpds., preparation method therefor and pharmaceutical compsns. containing same. EP 1156049; FR 2729952; FR 2729953; FR 2729954; JP 1999507324; JP 2001131171; US 5641777; WO 9623787 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIV)	54992	2-[(2R)-4-benzoyl-2-(3,4-difluorophenyl)morpholinyl]ethyl methanesulfonate	C₂₀H₂₁F₂NO₅S	详情	详情
(XV)	29470	1-benzyl-4-phenyl-4-piperidinol	C₁₈H₂₁NO	详情	详情
(XVI)	54993	N-(1-benzyl-4-phenyl-4-piperidinyl)acetamide	C₂₀H₂₄N₂O	详情	详情
(XVII)	54994	1-benzyl-4-phenyl-4-piperidinylamine; 1-benzyl-4-phenyl-4-piperidinamine	C₁₈H₂₂N₂	详情	详情
(XVIII)	54995	N'-(1-benzyl-4-phenyl-4-piperidinyl)-N,N-dimethylurea	C₂₁H₂₇N₃O	详情	详情
(XIX)	54996	N,N-dimethyl-N'-(4-phenyl-4-piperidinyl)urea	C₁₄H₂₁N₃O	详情	详情

合成路线4

In an alternative process, the chiral morpholino alcohol (XIII) was activated as the sulfonate ester (XX) employing benzenesulfonyl chloride under phase-transfer conditions. Condensation of the alkyl sulfonate (XX) with 4-(tert-butoxycarbonylamino)-4-phenylpiperidine (XXI) afforded the N-substituted piperidine (XXII). The Boc protecting group of (XXII) was then removed by means of a methanolic solution of HCl, yielding the primary amine (XXIII). Alternatively, amine (XXIII) was synthesized by condensation of sulfonate (XX) with 4-amino-4-phenylpiperidine (XXIV) (obtained by catalytic hydrogenolysis of the N-benzyl piperidine (XVII)). Aminopiperidine (XXIII) was finally converted to the title urea by reaction with phosgene, followed by condensation with dimethylamine.

参考文献中间体

【1】 Bonnefoy, S.; Aulombard, A.; Lucas, E.; Bernon, F.; Burgos, A.; Cabos, C. (Sanofi-Synthélabo); Method for preparing (R)-(+)-3-[1-[2-(4-benzoyl-2-(2,3-difluorophenyl)morpholin-2-yl)ethyl]-4-phenylpiperidin-4-yl]-1,1-dimethylurea, its salts solvates and/or hydrates. FR 2787790; US 6392039; WO 0039126 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIII)	54991	[(2R)-2-(3,4-difluorophenyl)-2-(2-hydroxyethyl)morpholinyl](phenyl)methanone	C₁₉H₁₉F₂NO₃	详情	详情
(XVII)	54994	1-benzyl-4-phenyl-4-piperidinylamine; 1-benzyl-4-phenyl-4-piperidinamine	C₁₈H₂₂N₂	详情	详情
(XX)	54997	2-[(2R)-4-benzoyl-2-(3,4-difluorophenyl)morpholinyl]ethyl benzenesulfonate	C₂₅H₂₃F₂NO₅S	详情	详情
(XXI)	54998	tert-butyl 4-phenyl-4-piperidinylcarbamate	C₁₆H₂₄N₂O₂	详情	详情
(XXII)	54999	tert-butyl 1-{2-[(2R)-4-benzoyl-2-(3,4-difluorophenyl)morpholinyl]ethyl}-4-phenyl-4-piperidinylcarbamate	C₃₅H₄₁F₂N₃O₄	详情	详情
(XXIII)	55000	[(2R)-2-[2-(4-amino-4-phenyl-1-piperidinyl)ethyl]-2-(3,4-difluorophenyl)morpholinyl](phenyl)methanone	C₃₀H₃₃F₂N₃O₂	详情	详情
(XXIV)	55001	4-phenyl-4-piperidinylamine; 4-phenyl-4-piperidinamine	C₁₁H₁₆N₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)