CI-1007, PD-143188, -Drug Synthesis Database

【结构式】

【药物名称】CI-1007, PD-143188

【化学名称】(+)-(R)-4-Phenyl-1-(2,3,4,5-tetrahydrobiphenyl-3-ylmethyl)-1,2,3,6-tetrahydropyridine

【CA登记号】150013-70-0

【分子式】C₂₄H₂₇N

【分子量】329.48949

【开发单位】Pfizer (Originator)

【药理作用】Antipsychotic Drugs, PSYCHOPHARMACOLOGIC DRUGS, Dopamine Autoreceptor Agonists, Dopamine Receptor Agonists

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1

Ethyl 3-oxocyclohexanecarboxylate (I) was protected as the ethylene ketal (II) and its ethyl ester group was subsequently hydrolyzed to carboxylic acid (III). After activation of acid (III) as the mixed anhydride (IV) with isobutyl chloroformate, coupling with 4-phenyl-1,2,3,6-tetrahydropyridine (V) gave amide (VI). Reduction of amide (VI) to the corresponding amine (VII) was accomplished by treatment with LiAlH4 in the presence of AlCl3. Addition of phenylmagnesium bromide to the ketone (VIII), obtained by acidic hydrolysis of ketal (VII), provided the tertiary alcohol (IX). Dehydration of alcohol (IX) by means of trifluoroacetic acid gave rise to a mixture of isomeric cyclohexene derivatives (X) and (XI), which were separated by column chromatography. The racemic 3-cyclohexenyl isomer (XI) was then resolved via formation of the salts with (R)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate to furnish the title (R)-(+)-enantiomer.

参考文献中间体

【1】 Caprathe, B.W.; Downing, D.M.; Jaen, J.C.; Johnson, S.J.; Smith, W.J. III; Wise, L.D.; Wright, J.; Wustrow, D.J. (Pfizer Inc.); 1,3-Substd. cycloalkenes and cycloalkanes as central nervous system agents. EP 0545095; EP 0613465; JP 1995501075; US 5314896; WO 9310092 .

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)	54933	ethyl 3-oxocyclohexanecarboxylate		C₉H₁₄O₃	详情	详情
(II)	54934	ethyl 1,4-dioxaspiro[4.5]decane-7-carboxylate		C₁₁H₁₈O₄	详情	详情
(III)	54935	1,4-dioxaspiro[4.5]decane-7-carboxylic acid		C₉H₁₄O₄	详情	详情
(IV)	54936			C₁₄H₂₂O₆	详情	详情
(V)	13002	4-Phenyl-1,2,3,6-tetrahydropyridine; 1,2,3,6-Tetrahydro-4-phenyl-pyridine	10338-69-9	C₁₁H₁₃N	详情	详情
(VI)	54937	1,4-dioxaspiro[4.5]dec-7-yl[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]methanone	n/a	C₂₀H₂₅NO₃	详情	详情
(VII)	54938	1-(1,4-dioxaspiro[4.5]dec-7-ylmethyl)-4-phenyl-1,2,3,6-tetrahydropyridine		C₂₀H₂₇NO₂	详情	详情
(VIII)	54939	3-{[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]methyl}cyclohexanone		C₁₈H₂₃NO	详情	详情
(IX)	54940	1-phenyl-3-{[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]methyl}cyclohexanol		C₂₄H₂₉NO	详情	详情
(X)	54941	4-phenyl-1-[(3-phenyl-2-cyclohexen-1-yl)methyl]-1,2,3,6-tetrahydropyridine		C₂₄H₂₇N	详情	详情
(XI)	54942	4-phenyl-1-[(3-phenyl-3-cyclohexen-1-yl)methyl]-1,2,3,6-tetrahydropyridine		C₂₄H₂₇N	详情	详情

合成路线2

Racemic amide (VI) was also prepared by a closely related procedure. Coupling of keto acid (XII) with tetrahydropyridine (V) using DCC gave keto amide (XIII), which was then protected as the ethylene ketal (VI) upon treatment with 2-methoxy-1,3-dioxolane (XIV) in the presence of methanesulfonic acid.

参考文献中间体

【1】 Wright, J.L.; et al.; The discovery and structure-activity relationships of 1,2,3, 6-tetrahydro-4-phenyl-1-[(arylcyclohexenyl)alkyl]pyridines. Dopamine autoreceptor agonists and potential antipsychotic agents. J Med Chem 1994, 37, 21, 3523.

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)	54943	3-oxocyclohexanecarboxylic acid		C₇H₁₀O₃	详情	详情
(II)	13002	4-Phenyl-1,2,3,6-tetrahydropyridine; 1,2,3,6-Tetrahydro-4-phenyl-pyridine	10338-69-9	C₁₁H₁₃N	详情	详情
(III)	54944	3-{[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]carbonyl}cyclohexanone		C₁₈H₂₁NO₂	详情	详情
(IV)	54945	2-Methoxy-1,3-dioxolane	19693-75-5	C₄H₈O₃	详情	详情
(V)	54957	3-(4-morpholinyl)-1-propanol		C₇H₁₅NO₂	详情	详情

合成路线3

The analogous asymmetric synthesis starting from the (R)-enantiomer of 3-oxocyclohexanecarboxylic acid (XV) was also reported. The chiral (R)-keto acid (XV), prepared by resolution of the racemic acid (XII) with brucine, was coupled with tetrahydropyridine (V) to give keto amide (XVI). Protection as the ethylene ketal (XVII), followed by amide reduction and acidic ketal hydrolysis, furnished the (R)-amino ketone (XVIII). This was converted into the title compound by addition of phenylmagnesium bromide, followed by acidic dehydration and separation of isomers as in Scheme 19758501a.

参考文献中间体

【1】 Wright, J.L.; et al.; The discovery and structure-activity relationships of 1,2,3, 6-tetrahydro-4-phenyl-1-[(arylcyclohexenyl)alkyl]pyridines. Dopamine autoreceptor agonists and potential antipsychotic agents. J Med Chem 1994, 37, 21, 3523.

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)	13002	4-Phenyl-1,2,3,6-tetrahydropyridine; 1,2,3,6-Tetrahydro-4-phenyl-pyridine	10338-69-9	C₁₁H₁₃N	详情	详情
(XII)	54943	3-oxocyclohexanecarboxylic acid		C₇H₁₀O₃	详情	详情
(XIV)	54948	(7R)-1,4-dioxaspiro[4.5]dec-7-yl[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]methanone		C₂₀H₂₅NO₃	详情	详情
(XV)	54946	(1R)-3-oxocyclohexanecarboxylic acid		C₇H₁₀O₃	详情	详情
(XVI)	54947	(3R)-3-{[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]carbonyl}cyclohexanone		C₁₈H₂₁NO₂	详情	详情
(XVII)	54948	(7R)-1,4-dioxaspiro[4.5]dec-7-yl[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]methanone		C₂₀H₂₅NO₃	详情	详情
(XVIII)	54949	(3R)-3-{[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]methyl}cyclohexanone		C₁₈H₂₃NO	详情	详情

合成路线4

A further procedure employed the chiral keto acid (XXII) as the key intermediate. The cyclohexenone carboxylic acid (XXI) was synthesized via aldol condensation between 3-benzoylacrylic acid (XIX) and ethyl acetoacetate (XX), followed by cyclization and decarboxylation under Robinson annulation reaction conditions. Resolution of (XXI) to furnish the desired (S)-enantiomer (XXII) was accomplished either via formation of the diastereomeric salts with cinchonidine or, alternatively, by esterification of (XXI) with n-butanol --yielding the isomeric mixture (XXIII)--, followed by enantioselective hydrolysis of the (S)-butyl ester from in the presence of alpha-chymotrypsin. Coupling of keto acid (XXII) with tetrahydropyridine (V) provided keto amide (XXIV). The keto group of (XXIV) was then reduced with NaBH4 to form a diastereomeric mixture of allylic alcohols (XXV), which were further reduced employing NaBH3CN in the presence of ZnCl2 to furnish the target (R)-cyclohexenecarboxamide (XXVI). The amide function of (XXVI) was finally reduced to the title amine by means of LiAlH4 in methyl tert-butyl ether.

参考文献中间体

【1】 Butler, D.E.; Wustrow, D.J.; Smith, W.J. III; Gailey, J. (Pfizer Inc.); Improved process for R (+) 1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine, a central nervous system agent. WO 9608473 .

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)	13002	4-Phenyl-1,2,3,6-tetrahydropyridine; 1,2,3,6-Tetrahydro-4-phenyl-pyridine	10338-69-9	C₁₁H₁₃N	详情	详情
(XIX)	28661	(E)-4-oxo-4-phenyl-2-butenoic acid	583-06-2	C₁₀H₈O₃	详情	详情
(XX)	11819	ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate	141-97-9	C₆H₁₀O₃	详情	详情
(XXI)	54950	5-oxo-3-phenyl-3-cyclohexene-1-carboxylic acid		C₁₃H₁₂O₃	详情	详情
(XXII)	54952	(1S)-5-oxo-3-phenyl-3-cyclohexene-1-carboxylic acid		C₁₃H₁₂O₃	详情	详情
(XXIII)	54951	butyl 5-oxo-3-phenyl-3-cyclohexene-1-carboxylate		C₁₇H₂₀O₃	详情	详情
(XXIV)	54953	(5S)-3-phenyl-5-{[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]carbonyl}-2-cyclohexen-1-one		C₂₄H₂₃NO₂	详情	详情
(XXV)	54954	[(1S)-5-hydroxy-3-phenyl-3-cyclohexen-1-yl][4-phenyl-3,6-dihydro-1(2H)-pyridinyl]methanone		C₂₄H₂₅NO₂	详情	详情
(XXVI)	50955	2-[7-fluoro-4-(2-hydroxyethyl)-2-oxo-1(2H)-quinolinyl]acetamide		C₁₃H₁₃FN₂O₃	详情	详情

合成路线5

Swern oxidation of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (I) with oxalyl chloride in DMSO/dichloromethane gives the corresponding piperidone (II), which is submitted to a Grignard reaction with [U-14C]phenylmagnesium bromide (III) in THF to yield 4-hydroxy-4-phenylpiperidine-1-carboxylic acid tert-butyl ester (IV). The reaction of (IV) with BF3/Et2O in dichloromethane affords labeled 4-phenyl-1,2,3,6-tetrahydropyridine (V), which is condensed with 3-phenyl-3-cyclohexene-1(R)-carboxylic acid (VI) by means of HOBT, DCC and TEA in ethyl acetate to provide the labeled 1-(3-phenyl-3-cyclohexen-1(R)-yl)-1-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)methanone (VII). Finally, this compound is reduced with LiAlH4 and AlCl3 in THF to obtain the target tetrahydropyridine derivative.

参考文献中间体

【1】 Ekhato, I.V.; Huang, C.C.; Synthesis of (R)-(+)-1,2,3,6-tetrahydro-4-[U-14C]phenyl-1[(3-phenyl-3-cyclohexenyl-1-yl)methyl]pyridine, a potential antipsychotic agent. J Label Compd Radiopharm 1995, 36, 1, 57.

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)	18625	tert-butyl 4-hydroxy-1-piperidinecarboxylate		C₁₀H₁₉NO₃	详情	详情
(II)	18620	tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone	79099-07-3	C₁₀H₁₇NO₃	详情	详情
(II)	45167			C₆H₅BrMg	详情	详情
(III)	17616	bromo(phenyl)magnesium; Phenyl Magnesium Bromide	100-58-3	C₆H₅BrMg	详情	详情
(IV)	57878	tert-butyl 4-hydroxy-4-phenyl-1-piperidinecarboxylate		C₁₆H₂₃NO₃	详情	详情
(IV)	64702	tert-butyl 4-hydroxy-4-phenyl-1-piperidinecarboxylate		C₁₆H₂₃NO₃	详情	详情
(V)	13002	4-Phenyl-1,2,3,6-tetrahydropyridine; 1,2,3,6-Tetrahydro-4-phenyl-pyridine	10338-69-9	C₁₁H₁₃N	详情	详情
(V)	64703	4-Phenyl-1,2,3,6-tetrahydro-pyridine	10338-69-9	C₁₁H₁₃N	详情	详情
(VI)	57879	(1R)-3-phenyl-3-cyclohexene-1-carboxylic acid		C₁₃H₁₄O₂	详情	详情
(VII)	54955	[(1R)-3-phenyl-3-cyclohexen-1-yl][4-phenyl-3,6-dihydro-1(2H)-pyridinyl]methanone		C₂₄H₂₅NO	详情	详情
(VII)	64704	[(1R)-3-phenyl-3-cyclohexen-1-yl][4-phenyl-3,6-dihydro-1(2H)-pyridinyl]methanone		C₂₄H₂₅NO	详情	详情

Extended Information