Osanetant, SR-142806((S)-isomer), SR-142801(monoHCl), -Drug Synthesis Database

【结构式】

【药物名称】Osanetant, SR-142806((S)-isomer), SR-142801(monoHCl)

【化学名称】N-[1-[3-[1-Benzoyl-3(R)-(3,4-dichlorophenyl)piperidin-3-yl]propyl]-4-phenylpiperidin-4-yl]-N-methylacetamide

【CA登记号】160492-56-8, 173050-51-6 (monoHCl)

【分子式】C₃₅H₄₁Cl₂N₃O₂

【分子量】606.64192

【开发单位】Sanofi-synthélabo (Originator)

【药理作用】Antidepressants, Antipsychotic Drugs, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, Tachykinin NK3 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5 合成路线6 合成路线7

合成路线1

N-Benzyl-4-hydroxy-4-phenylpiperidine (II) was prepared by addition of phenyllithium to N-benzyl-4-piperidone (I). Carbinol (II) was then converted to acetamide (III) by acid-catalyzed Ritter reaction with acetonitrile. Replacement of the acetamido for an N-Boc group in (III) was effected by acidic hydrolysis of amide (III) to give (IV), followed by treatment with di-tert-butyl dicarbonate. The resultant 1-benzyl-4-(Boc-amino)-4-phenylpiperidine (V) was subjected to catalytic hydrogenolysis in the presence of Pd/C, and the N-debenzylated piperidine (VI) was reprotected as the N-trityl derivative (VII) by treatment with triphenylmethyl chloride and triethylamine. Reduction of the N-Boc group of (VII) by LiAlH4, yielded the N-methyl amine (VIII). After acylation of (VIII) with acetyl chloride to acetamide (IX), its N-trityl group was cleaved by treatment with hot aqueous formic acid to produce the intermediate piperidine (X).

参考文献中间体

【1】 Bichon, D.; Van Broeck, D.; Proietto, V.; Gueule, P.; Emonds-Alt, X. (Sanofi-Synthélabo); Novel N-(3,4-dichlorophenyl-propyl)-piperidine derivs. as selective human NK3-receptor antagonists. EP 0673928; FR 2717477; FR 2717478; FR 2719311; JP 1996048669; US 5741910; US 5942523; US 6124316 .

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)	15720	1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one	3612-20-2	C₁₂H₁₅NO	详情	详情
(II)	29470	1-benzyl-4-phenyl-4-piperidinol		C₁₈H₂₁NO	详情	详情
(III)	54993	N-(1-benzyl-4-phenyl-4-piperidinyl)acetamide		C₂₀H₂₄N₂O	详情	详情
(IV)	54994	1-benzyl-4-phenyl-4-piperidinylamine; 1-benzyl-4-phenyl-4-piperidinamine		C₁₈H₂₂N₂	详情	详情
(V)	59263	tert-butyl 1-benzyl-4-phenyl-4-piperidinylcarbamate		C₂₃H₃₀N₂O₂	详情	详情
(VI)	54998	tert-butyl 4-phenyl-4-piperidinylcarbamate		C₁₆H₂₄N₂O₂	详情	详情
(VII)	59264	tert-butyl 4-phenyl-1-trityl-4-piperidinylcarbamate		C₃₅H₃₈N₂O₂	详情	详情
(VIII)	59265	N-methyl-4-phenyl-1-trityl-4-piperidinamine; N-methyl-N-(4-phenyl-1-trityl-4-piperidinyl)amine		C₃₁H₃₂N₂	详情	详情
(IX)	59266	N-methyl-N-(4-phenyl-1-trityl-4-piperidinyl)acetamide		C₃₃H₃₄N₂O	详情	详情
(X)	59267	N-methyl-N-(4-phenyl-4-piperidinyl)acetamide		C₁₄H₂₀N₂O	详情	详情

合成路线2

Michael addition of methyl acrylate (XII) to (3,4-dichlorophenyl)acetonitrile (XI) produced the cyano diester adduct (XIII). Catalytic hydrogenation of the cyano group of (XIII) over Raney nickel with concomitant intramolecular cyclization gave rise to the piperidinone (XIV). After basic hydrolysis of the methyl ester function of (XIV), the resultant piperidone propionic acid (XV) was reduced to piperidino alcohol (XVI) by means of borane in THF. Resolution of the racemic piperidine (XVI) employing (+)-camphorsulfonic acid provided the dextro enantiomer (XVII). After N-protection of (XVII) as the Boc derivative (XVIII), its primary alcohol was activated as the corresponding mesylate (XIX) with methanesulfonyl chloride and Et3N. Condensation between mesylate (XIX) and intermediate piperidine (X) in acetonitrile at 60 C, produced (XX). The title benzamido derivative was then obtained by acid-promoted Boc group cleavage in (XX), followed by acylation with benzoyl chloride.

参考文献中间体

【1】 Bichon, D.; Van Broeck, D.; Proietto, V.; Gueule, P.; Emonds-Alt, X. (Sanofi-Synthélabo); Novel N-(3,4-dichlorophenyl-propyl)-piperidine derivs. as selective human NK3-receptor antagonists. EP 0673928; FR 2717477; FR 2717478; FR 2719311; JP 1996048669; US 5741910; US 5942523; US 6124316 .

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)	59267	N-methyl-N-(4-phenyl-4-piperidinyl)acetamide		C₁₄H₂₀N₂O	详情	详情
(XI)	26935	2-(3,4-dichlorophenyl)acetonitrile	3218-49-3	C₈H₅Cl₂N	详情	详情
(XII)	14156	methyl acrylate	96-33-3	C₄H₆O₂	详情	详情
(XIII)	59268	dimethyl 4-cyano-4-(3,4-dichlorophenyl)heptanedioate		C₁₆H₁₇Cl₂NO₄	详情	详情
(XIV)	59269	methyl 3-[3-(3,4-dichlorophenyl)-6-oxo-3-piperidinyl]propanoate		C₁₅H₁₇Cl₂NO₃	详情	详情
(XV)	59270	3-[3-(3,4-dichlorophenyl)-6-oxo-3-piperidinyl]propanoic acid		C₁₄H₁₅Cl₂NO₃	详情	详情
(XVI)	29465	3-[3-(3,4-dichlorophenyl)-3-piperidinyl]-1-propanol		C₁₄H₁₉Cl₂NO	详情	详情
(XVII)	29466	3-[(3S)-3-(3,4-dichlorophenyl)piperidinyl]-1-propanol		C₁₄H₁₉Cl₂NO	详情	详情
(XVIII)	59271	tert-butyl (3S)-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)-1-piperidinecarboxylate		C₁₉H₂₇Cl₂NO₃	详情	详情
(XIX)	59272	tert-butyl (3S)-3-(3,4-dichlorophenyl)-3-{3-[(methylsulfonyl)oxy]propyl}-1-piperidinecarboxylate		C₂₀H₂₉Cl₂NO₅S	详情	详情
(XX)	59273	tert-butyl (3R)-3-(3-{4-[acetyl(methyl)amino]-4-phenyl-1-piperidinyl}propyl)-3-(3,4-dichlorophenyl)-1-piperidinecarboxylate		C₃₃H₄₅Cl₂N₃O₃	详情	详情

合成路线3

In a related synthesis, (3,4-dichlorophenyl)acetonitrile (XI) was alkylated with bromide (XXII) --prepared by protection of 3-bromopropanol (XXI) with dihydropyran-- to afford (XXIII). Subsequent Michael addition of methyl acrylate (XII) to (XXIII) in the presence of Triton B® gave the cyanoacid (XXIV). This was cyclized to the glutarimide (XXV) by refluxing in HOAc in the presence of H2SO4. Reduction of (XXV) using borane-dimethylsulfide complex produced the already reported racemic piperidinoalcohol (XVI). After acylation of the amine group of (XVI) with benzoyl chloride to yield (XXVI), its hydroxyl group was converted into the target mesylate precursor (XXVII) with methanesulfonyl chloride and Et3N.

参考文献中间体

【1】 Giardina, G.A.M.; et al.; A reliable and efficient synthesis of SR 142801. Bioorg Med Chem Lett 1996, 6, 19, 2307.
【2】 Chen, H.G.; et al.; A practical and scalable synthesis of SR 142801, a tachykinin NK3 antagonist. Bioorg Med Chem Lett 1997, 7, 5, 555.
【3】 Grugni, M.; Rigolio, R.; Erhard, K.F. (GlaxoSmithKline Inc.; GlaxoSmithKline SpA); Process for the preparation of 3,3-disubstd. piperidines. WO 9805640 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	26935	2-(3,4-dichlorophenyl)acetonitrile	3218-49-3	C₈H₅Cl₂N	详情	详情
(XII)	14156	methyl acrylate	96-33-3	C₄H₆O₂	详情	详情
(XVI)	29465	3-[3-(3,4-dichlorophenyl)-3-piperidinyl]-1-propanol		C₁₄H₁₉Cl₂NO	详情	详情
(XXI)	12573	3-Bromo-1-propanol; 3-Bromopropanol	627-18-9	C₃H₇BrO	详情	详情
(XXII)	42252	3-bromopropyl tetrahydro-2H-pyran-2-yl ether; 2-(3-bromopropoxy)tetrahydro-2H-pyran		C₈H₁₅BrO₂	详情	详情
(XXIII)	59274	2-(3,4-dichlorophenyl)-5-(tetrahydro-2H-pyran-2-yloxy)pentanenitrile		C₁₆H₁₉Cl₂NO₂	详情	详情
(XXIV)	59275	4-cyano-4-(3,4-dichlorophenyl)-7-(tetrahydro-2H-pyran-2-yloxy)heptanoic acid		C₁₉H₂₃Cl₂NO₄	详情	详情
(XXV)	59276	3-[3-(3,4-dichlorophenyl)-2,6-dioxo-3-piperidinyl]propyl acetate		C₁₆H₁₇Cl₂NO₄	详情	详情
(XXVI)	59277	[3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)-1-piperidinyl](phenyl)methanone		C₂₁H₂₃Cl₂NO₂	详情	详情
(XXVII)	59278	3-[1-benzoyl-3-(3,4-dichlorophenyl)-3-piperidinyl]propyl methanesulfonate		C₂₂H₂₅Cl₂NO₄S	详情	详情

合成路线4

In a further procedure, nitrile (XXIII) was alkylated with ethyl 3-bromopropionate (XXVIII) to give cyano ester (XXIX). Catalytic hydrogenation of the cyano group of (XXIX) gave rise to the piperidinone (XXX), which was further reduced to piperidine (XXXI) with LiAlH4 in THF. Acid deprotection of the tetrahydropyranyl group of (XXXI), followed by resolution with (+)-camphorsulfonic acid, furnished the desired (S)-piperidinoalcohol camphorsulfonate salt (XXXII). Treatment of piperidine (XXXII) with benzoyl chloride in the presence of DIEA yielded benzamide (XXXIII). Conversion of the primary alcohol of (XXXIII) into the desired alkyl iodide (XXXV) was achieved via formation of the mesylate ester (XXXIV), followed by displacement of the mesylate group with KI in refluxing acetone.

参考文献中间体

【1】 Chen, H.G.; et al.; A practical and scalable synthesis of SR 142801, a tachykinin NK3 antagonist. Bioorg Med Chem Lett 1997, 7, 5, 555.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXIII)	59274	2-(3,4-dichlorophenyl)-5-(tetrahydro-2H-pyran-2-yloxy)pentanenitrile		C₁₆H₁₉Cl₂NO₂	详情	详情
(XXVIII)	29132	ethyl 3-bromopropanoate	539-74-2	C₅H₉BrO₂	详情	详情
(XXIX)	59279	ethyl 4-cyano-4-(3,4-dichlorophenyl)-7-(tetrahydro-2H-pyran-2-yloxy)heptanoate		C₂₁H₂₇Cl₂NO₄	详情	详情
(XXX)	59280	5-(3,4-dichlorophenyl)-5-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-2-piperidinone		C₁₉H₂₅Cl₂NO₃	详情	详情
(XXXI)	59281	3-[3-(3,4-dichlorophenyl)-3-piperidinyl]propyl tetrahydro-2H-pyran-2-yl ether; 3-(3,4-dichlorophenyl)-3-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]piperidine		C₁₉H₂₇Cl₂NO₂	详情	详情
(XXXII)	59282			C₂₄H₃₅Cl₂NO₅S	详情	详情
(XXXIII)	29467	[(3S)-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidinyl](phenyl)methanone		C₂₁H₂₃Cl₂NO₂	详情	详情
(XXXIV)	29468	3-[(3S)-1-benzoyl-3-(3,4-dichlorophenyl)piperidinyl]propyl methanesulfonate		C₂₂H₂₅Cl₂NO₄S	详情	详情
(XXXV)	29469	[(3S)-3-(3,4-dichlorophenyl)-3-(3-iodopropyl)piperidinyl](phenyl)methanone		C₂₁H₂₂Cl₂INO	详情	详情

合成路线5

An alternative preparation of the precursor 4-(N-methyl-N-acetyl)amino-4-phenylpiperidine (XXXIX) has been reported. The N-benzyl protecting group of piperidine (III) was replaced with an N-Boc group by catalytic hydrogenolysis to (XXXVI), followed by treatment with Boc2O to yield (XXXVII). Amide (XXXVII) alkylation with iodomethane under phase-transfer conditions gave the N-methyl derivative (XXXVIII). Subsequent N-Boc group cleavage in (XXXVIII) was accomplished by using zinc chloride in CH2Cl2 to afford the piperidine-ZnCl2 complex (XXXIX). This was then alkylated with mesylate (XXVII), and the title compound was finally isolated from the racemic mixture by means of preparative chiral HPLC.

参考文献中间体

【1】 Giardina, G.A.M.; et al.; A reliable and efficient synthesis of SR 142801. Bioorg Med Chem Lett 1996, 6, 19, 2307.
【2】 Grugni, M.; Rigolio, R.; Erhard, K.F. (GlaxoSmithKline Inc.; GlaxoSmithKline SpA); Process for the preparation of 3,3-disubstd. piperidines. WO 9805640 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(III)	54993	N-(1-benzyl-4-phenyl-4-piperidinyl)acetamide	C₂₀H₂₄N₂O	详情	详情
(XXVII)	59278	3-[1-benzoyl-3-(3,4-dichlorophenyl)-3-piperidinyl]propyl methanesulfonate	C₂₂H₂₅Cl₂NO₄S	详情	详情
(XXXVI)	59283	N-(4-phenyl-4-piperidinyl)acetamide	C₁₃H₁₈N₂O	详情	详情
(XXXVII)	59284	tert-butyl 4-(acetylamino)-4-phenyl-1-piperidinecarboxylate	C₁₈H₂₆N₂O₃	详情	详情
(XXXVIII)	59285	tert-butyl 4-[acetyl(methyl)amino]-4-phenyl-1-piperidinecarboxylate	C₁₉H₂₈N₂O₃	详情	详情
(XXXIX)	59267	N-methyl-N-(4-phenyl-4-piperidinyl)acetamide	C₁₄H₂₀N₂O	详情	详情

合成路线6

In a further method, aminopiperidine (IV) was converted to the formamide (XL) by heating in ethyl formate. Formyl group reduction in (XL) with LiAlH4 provided the N-metyl amine (XLI). The N-benzyl group of (XLI) was then removed by catalytic hydrogenation over Pd/C. Alkylation of the resultant piperidine (XLII) with mesylate (XXVII) gave adduct (XLIII). After acetylation of (XLIII) in neat Ac2O, the racemic mixture was separated by chiral HPLC.

参考文献中间体

【1】 Giardina, G.A.M.; et al.; A reliable and efficient synthesis of SR 142801. Bioorg Med Chem Lett 1996, 6, 19, 2307.
【2】 Grugni, M.; Rigolio, R.; Erhard, K.F. (GlaxoSmithKline Inc.; GlaxoSmithKline SpA); Process for the preparation of 3,3-disubstd. piperidines. WO 9805640 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IV)	54994	1-benzyl-4-phenyl-4-piperidinylamine; 1-benzyl-4-phenyl-4-piperidinamine	C₁₈H₂₂N₂	详情	详情
(XXVII)	59278	3-[1-benzoyl-3-(3,4-dichlorophenyl)-3-piperidinyl]propyl methanesulfonate	C₂₂H₂₅Cl₂NO₄S	详情	详情
(XL)	59286	1-benzyl-4-phenyl-4-piperidinylformamide	C₁₉H₂₂N₂O	详情	详情
(XLI)	59287	1-benzyl-N-methyl-4-phenyl-4-piperidinamine; N-(1-benzyl-4-phenyl-4-piperidinyl)-N-methylamine	C₁₉H₂₄N₂	详情	详情
(XLII)	59288	N-methyl-4-phenyl-4-piperidinamine; N-methyl-N-(4-phenyl-4-piperidinyl)amine	C₁₂H₁₈N₂	详情	详情
(XLIII)	59289	(3-(3,4-dichlorophenyl)-3-{3-[4-(methylamino)-4-phenyl-1-piperidinyl]propyl}-1-piperidinyl)(phenyl)methanone	C₃₃H₃₉Cl₂N₃O	详情	详情

合成路线7

A new method has been reported. Formamide (XL) was prepared form carbinol (II) by a modified Ritter reaction with cyanotrimethylsilane. Subsequent reduction of (XL) with LiAlH4 gave the N-methyl amine (XLI), which was converted to acetamide (XLIV) by treatment with acetyl chloride. Benzyl group hydrogenolysis in (XLIV) afforded the piperidine (X). Finally, alkylation of piperidine (X) with the chiral alkyl iodide (XXXV) provided the title compound.

参考文献中间体

【1】 Chen, H.G.; et al.; A practical and scalable synthesis of SR 142801, a tachykinin NK3 antagonist. Bioorg Med Chem Lett 1997, 7, 5, 555.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(II)	29470	1-benzyl-4-phenyl-4-piperidinol	C₁₈H₂₁NO	详情	详情
(X)	59267	N-methyl-N-(4-phenyl-4-piperidinyl)acetamide	C₁₄H₂₀N₂O	详情	详情
(XXXV)	29469	[(3S)-3-(3,4-dichlorophenyl)-3-(3-iodopropyl)piperidinyl](phenyl)methanone	C₂₁H₂₂Cl₂INO	详情	详情
(XL)	59286	1-benzyl-4-phenyl-4-piperidinylformamide	C₁₉H₂₂N₂O	详情	详情
(XLI)	59287	1-benzyl-N-methyl-4-phenyl-4-piperidinamine; N-(1-benzyl-4-phenyl-4-piperidinyl)-N-methylamine	C₁₉H₂₄N₂	详情	详情
(XLIV)	59290	N-(1-benzyl-4-phenyl-4-piperidinyl)-N-methylacetamide	C₂₁H₂₆N₂O	详情	详情

Extended Information