{1-[2-(aminomethyl)phenyl]-4-piperidinyl}methanol -Drug Synthesis Database

【结构式】

【分子编号】54825

【品名】{1-[2-(aminomethyl)phenyl]-4-piperidinyl}methanol

【CA登记号】

【分子式】C₁₃H₂₀N₂O

【分子量】220.31468

【元素组成】C 70.87% H 9.15% N 12.72% O 7.26%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(IV)

The condensation between 2-fluorobenzonitrile (I) and ethyl isonipecotate (II) produced the piperidino benzonitrile (III). Reduction of nitrile and ester functions of (III) to afford the intermediate amino alcohol (IV) was accomplished using either LiAlH4 or, in a more practical, scalable procedure, using NaBH4/ZnCl2.

参考文献中间体

合成目标

【1】 Fujino, K.; et al.; Development of a practical synthetic route of a PDE V inhibitor KF31327. Org Process Res Dev 2001, 5, 4, 426.
【2】 Fujino, K.; et al.; Process development of a PDE V inhibitor KF31327. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst ORGN 612.
【3】 Onoda, Y.; Nomoto, Y.; Ohno, T.; Yamada, K.; Ichimura, M. (Kyowa Hakko Kogyo Co., Ltd.); Imidazoquinazoline derivs.. EP 0863144; WO 9808848 .

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)	41199	2-fluorobenzonitrile	394-47-8	C₇H₄FN	详情	详情
(II)	17410	Ethyl isonipecotate; ethyl 4-piperidinecarboxylate	1126-09-6	C₈H₁₅NO₂	详情	详情
(III)	54824	ethyl 1-(2-cyanophenyl)-4-piperidinecarboxylate		C₁₅H₁₈N₂O₂	详情	详情
(IV)	54825	{1-[2-(aminomethyl)phenyl]-4-piperidinyl}methanol		C₁₃H₂₀N₂O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

Quinazolinone (VI) was prepared by condensation of 4-chloroanthranilic acid (V) with hot formamide. Subsequent electrophilic nitration of (VI) provided the 6-nitroquinazolinone (VII) as the major regioisomer. Displacement of the 7-chloro of (VII) upon heating with ethylamine in a sealed tube gave rise to the nitro amine (VIII). The 4-chloroquinazoline derivative (IX) was then obtained by chlorination of (VIII) with phosphorus oxychloride. Condensation of (IX) with the intermediate benzylamine (IV) furnished adduct (X). The nitro group of (X) was then reduced by catalytic hydrogenation to yield the phenylenediamine derivative (XI). Finally, condensation of phenylenediamine (XI) with carbon disulfide in the presence of Et3N generated the target imidazoquinazoline, which was isolated as the dihydrochloride salt.

参考文献中间体

合成目标

【1】 Fujino, K.; et al.; Development of a practical synthetic route of a PDE V inhibitor KF31327. Org Process Res Dev 2001, 5, 4, 426.
【2】 Fujino, K.; et al.; Process development of a PDE V inhibitor KF31327. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst ORGN 612.
【3】 Onoda, Y.; Nomoto, Y.; Ohno, T.; Yamada, K.; Ichimura, M. (Kyowa Hakko Kogyo Co., Ltd.); Imidazoquinazoline derivs.. EP 0863144; WO 9808848 .

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)	54825	{1-[2-(aminomethyl)phenyl]-4-piperidinyl}methanol		C₁₃H₂₀N₂O	详情	详情
(V)	52504	4-Chloro-2-aminobenzoic acid; 2-Amino-4-chlorobenzoic acid; 2-Carboxy-5-chloroaniline; 3-Amino-4-carboxy-1-chlorobenzene; 4-Chloroanthranilic acid	89-77-0	C₇H₆ClNO₂	详情	详情
(VI)	50077	7-chloro-4(3H)-quinazolinone		C₈H₅ClN₂O	详情	详情
(VII)	50078	7-chloro-6-nitro-4(3H)-quinazolinone		C₈H₄ClN₃O₃	详情	详情
(VIII)	54826	7-(ethylamino)-6-nitro-4(3H)-quinazolinone		C₁₀H₁₀N₄O₃	详情	详情
(IX)	54827	4-chloro-N-ethyl-6-nitro-7-quinazolinamine; N-(4-chloro-6-nitro-7-quinazolinyl)-N-ethylamine		C₁₀H₉ClN₄O₂	详情	详情
(X)	54828	{1-[2-({[7-(ethylamino)-6-nitro-4-quinazolinyl]amino}methyl)phenyl]-4-piperidinyl}methanol		C₂₃H₂₈N₆O₃	详情	详情
(XI)	54829	{1-[2-({[6-amino-7-(ethylamino)-4-quinazolinyl]amino}methyl)phenyl]-4-piperidinyl}methanol		C₂₃H₃₀N₆O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

In an improved procedure, commercial 7-chloroquinazolinedione (XII) was nitrated to (XIII) using 60% HNO3 in the presence of H2SO4. Subsequent chloro displacement in (XIII) with ethylamine in hot DMSO furnished nitro amine (XIV). Chlorination of quinazolinedione (XIV) to the dichloro derivative (XV) was carried out by means of POCl3 in the presence of diisopropylethylamine in hot toluene. The 4-chloro group of (XV) was regioselectively displaced by the intermediate benzylamine (IV) yielding (XVI). Simultaneous reduction of the nitro and chloro groups of (XVI) by transfer hydrogenation provided the phenylenediamine (XI). The imidazothione ring was finally constructed by condensation of (XI) with phenyl isothiocyanate.

参考文献中间体

合成目标

【1】 Fujino, K.; et al.; Development of a practical synthetic route of a PDE V inhibitor KF31327. Org Process Res Dev 2001, 5, 4, 426.
【2】 Fujino, K.; et al.; Process development of a PDE V inhibitor KF31327. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst ORGN 612.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IV)	54825	{1-[2-(aminomethyl)phenyl]-4-piperidinyl}methanol	C₁₃H₂₀N₂O	详情	详情
(XI)	54829	{1-[2-({[6-amino-7-(ethylamino)-4-quinazolinyl]amino}methyl)phenyl]-4-piperidinyl}methanol	C₂₃H₃₀N₆O	详情	详情
(XII)	54830	7-chloro-2,4(1H,3H)-quinazolinedione	C₈H₅ClN₂O₂	详情	详情
(XIII)	54831	7-chloro-6-nitro-2,4(1H,3H)-quinazolinedione	C₈H₄ClN₃O₄	详情	详情
(XIV)	54832	7-(ethylamino)-6-nitro-2,4(1H,3H)-quinazolinedione	C₁₀H₁₀N₄O₄	详情	详情
(XV)	54833	N-(2,4-dichloro-6-nitro-7-quinazolinyl)-N-ethylamine; 2,4-dichloro-N-ethyl-6-nitro-7-quinazolinamine	C₁₀H₈Cl₂N₄O₂	详情	详情
(XVI)	54834	{1-[2-({[2-chloro-7-(ethylamino)-6-nitro-4-quinazolinyl]amino}methyl)phenyl]-4-piperidinyl}methanol	C₂₃H₂₇ClN₆O₃	详情	详情

Extended Information