(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline -Drug Synthesis Database

【结构式】

【分子编号】26011

【品名】(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline

【CA登记号】

【分子式】C₁₅H₁₅N

【分子量】209.29084

【元素组成】C 86.08% H 7.22% N 6.69%

与该中间体有关的原料药合成路线共 4 条

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

该中间体在本合成路线中的序号：(IX)

YM-905 has been obtained by two related ways: 1) The benzoylation of 2-phenylethylamine (I) with benzoyl chloride (II) and triethylamine in chloroform, or with benzoic acid (III), DPPA and triethylamine in DMF, gives the corresponding benzamide (IV), which is cyclized by means of POCl3 and P2O5 in refluxing xylene and reduced with NaBH4 in ethanol, yielding racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline (V). The reaction of (V) with ethyl chloroformate by means of K2CO3 in chloroform affords racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid ethyl ester (VI), which is transesterified with quinuclidine-3(R)-ol (VII) by means of NaH in refluxing toluene to provide the quinuclidinyl ester (VIII) as a diastereomeric mixture. This mixture is resolved by chiral HPLC, giving the target compound as a pure enantiomer. 2) The racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline (V) can also be submitted to optical resolution with (+)-tartaric acid to give 1(S)-phenyl-1,2,3,4-tetrahydroisoquinoline (IX), which is condensed with ethyl chloroformate by means of K2CO3 in chloroform to afford 1(S)-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid ethyl ester (VI). This compound is transesterified with quinuclidine-3(R)-ol (VII) by means of NaH in refluxing toluene to directly provide the pure enantiomer.

参考文献中间体

合成目标

【1】 Mealy, N.; Castañer, J.; YM-905. Drugs Fut 1999, 24, 8, 871.
【2】 Takeuchi, M.; Naito, R.; Hayakawa, M.; Okamoto, Y.; Yonetoku, Y.; Ikeda, K.; Isomura, Y. (Yamanouchi Pharmaceutical Co., Ltd.); Novel quinuclidine derivs. and medicinal compsn. thereof. EP 0801067; US 6017927; WO 9620194 .

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)	18333	Phenethylamine; 2-Phenyl-1-ethanamine	64-04-0	C₈H₁₁N	详情	详情
(II)	10463	Benzoyl chloride	98-88-4	C₇H₅ClO	详情	详情
(III)	10202	Benzoic acid	65-85-0	C₇H₆O₂	详情	详情
(IV)	26007	N-phenethylbenzamide		C₁₅H₁₅NO	详情	详情
(V)	26008	1-phenyl-1,2,3,4-tetrahydroisoquinoline		C₁₅H₁₅N	详情	详情
(VI)	26009	ethyl 1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate		C₁₈H₁₉NO₂	详情	详情
(VII)	16152	(3R)-1-azabicyclo[2.2.2]octan-3-ol; (R)-(-)-Quinuclidinol	42437-96-7	C₇H₁₃NO	详情	详情
(VIII)	26010	(3R)-1-azabicyclo[2.2.2]oct-3-yl 1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate		C₂₃H₂₆N₂O₂	详情	详情
(IX)	26011	(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline		C₁₅H₁₅N	详情	详情
(X)	26012	ethyl (1S)-1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate		C₁₈H₁₉NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

参考文献中间体

合成目标

【1】 Naito R. Yonetoku Y, Okamoto Y, et aL. 2005. Synthesis and antimuscarinic properties of quinuclidin-3-yl 1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives as novel muscarinic receptor antagonists. J Med Chem, 48(21):6597～6606

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)	26007	N-phenethylbenzamide		C₁₅H₁₅NO	详情	详情
(II)	66735	1-phenyl-3,4-dihydroisoquinoline	52250-50-7	C₁₅H₁₃N	详情	详情
(III)	66736	1-phenyl-1,2,3,4-tetrahydroisoquinoline		C₁₅H₁₅N	详情	详情
(IV)	66737			C₁₅H₁₅N.C₄H₆O₆	详情	详情
(V)	26011	(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline		C₁₅H₁₅N	详情	详情
(VI)	26012	ethyl (1S)-1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate		C₁₈H₁₉NO₂	详情	详情
(VII)	16152	(3R)-1-azabicyclo[2.2.2]octan-3-ol; (R)-(-)-Quinuclidinol	42437-96-7	C₇H₁₃NO	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

参考文献中间体

合成目标

【1】 Naito R. Yonetoku Y, Okamoto Y, et aL. 2005. Synthesis and antimuscarinic properties of quinuclidin-3-yl 1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives as novel muscarinic receptor antagonists. J Med Chem, 48(21):6597～6606

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)	26011	(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline		C₁₅H₁₅N	详情	详情
(II)	66738	(R)-quinuclidin-3-yl carbonochloridate hydrochloride		C₈H₁₂ClNO₂.HCl	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

参考文献中间体

合成目标

【1】 Perlman N, Nidam T. 2007. Processes for preparation of solifenacin. W0 2007076116

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)	26011	(1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline		C₁₅H₁₅N	详情	详情
(II)	66739	(R)-2-chloroethyl 1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate		C₁₈H₁₈ClNO₂	详情	详情
(III)	16152	(3R)-1-azabicyclo[2.2.2]octan-3-ol; (R)-(-)-Quinuclidinol	42437-96-7	C₇H₁₃NO	详情	详情
(IV)	66740	(R)-2-chloroethyl quinuclidin-3-yl carbonate		C₁₀H₁₆ClNO₃	详情	详情

Extended Information