Midalcipran hydrochloride, Milnacipran hydrochloride, TN-912, F-2207, Ixel, Toledomin, Dalcipran, -Drug Synthesis Database

【结构式】

【药物名称】Midalcipran hydrochloride, Milnacipran hydrochloride, TN-912, F-2207, Ixel, Toledomin, Dalcipran

【化学名称】(±)-cis-2-(Aminomethyl)-N,N-diethyl-1-phenylcyclopropane-1-carboxamide hydrochloride

【CA登记号】101152-94-7, 86181-08-0 (cis-isomer), 92623-85-3 (free base)

【分子式】C₁₅H₂₂N₂O.HCl

【分子量】282.81636

【开发单位】Pierre Fabre (Originator), Forest (Marketer), Almirall Prodesfarma (Licensee), Asahi Kasei (Licensee), Cypress Bioscience (Licensee), Janssen-Kyowa (Codevelopment)

【药理作用】Antidepressants, Fibromyalgia, Treatment of, GASTROINTESTINAL DRUGS, Irritable Bowel Syndrome, Agents for, Mood Disorders, Treatment of, NEUROLOGIC DRUGS, Neurologic Drugs (Miscellaneous), PSYCHOPHARMACOLOGIC DRUGS, Sensation Disorders, Treatment of, 5-HT Reuptake Inhibitors, Norepinephrine Reuptake Inhibitors

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

This compound can be prepared in several ways from the lactone (I), which is obtained by treatment of benzyl cyanide (A) and epichlorhydrin (B) with sodium amide: 1) The opening of lactone (I) with SOBr2-ethanol gives a bromo ester, which is treated successively by ammonia and sodium hydroxide to yield the amino acid (II). The reaction of (II) with SOCl2 and diethylamine in ethanol gives the final product, which is converted to the hydrochloric salt by treatment with HCl ethanol. 2) Lactone (I), opened with 33% HBr-AcOH, gives the bromo acid (III), which is treated by SOCl2 and then diethylamine in ethanol. The bromoamide (IV) reacts with potassium phthalimide and is deprotected by hydrazine or methylamine to yield, after salification, title compound. 3) Lactone (I) is treated by potassium phthalimide and then SOCl2 and diethylamine in EtOH to give compound (V), treated as above. 4) Bromoamide (IV) can be treated by hexamethylenetetramine in butanol and hydrolyzed by refluxing with 15% HCl in ethanol.

参考文献中间体

【1】 Kasama, S.; et al.; Synthesis 1978, 4, 10, 304.
【2】 Patoiseau, J.-F.; Mouzin, G.; Bonnaud, B.; Cousse, H. (Pierre Fabre Medicament); Process for the preparation of (Z)-1-phenyl-1-diethylaminocarbonyl-2-aminomethyl-cyclopropane. EP 0200638; FR 2581059 .
【3】 Cousse, H.; Hascoet, P. (Pierre Fabre Medicament); Industrial process for the production of midalcipran. FR 2581060 .
【4】 Mouzin, G.; Cousse, H.; Bonnaud, B.; Morre, M.; Stenger, A. (Pierre Fabre Médicament); 1-Aryl-2-aminomethyl cyclopropane carboxyamide (Z) deivatives and their use as useful drugs in the treatment of disturbances of the central nervous system. EP 0068999; FR 2508035; JP 58004752; US 4478836 .
【5】 Briley, M.; Midalcipran Hydrochloride. Drugs Fut 1986, 11, 1, 21.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	10146	Epichlorohydrin; 2-(Chloromethyl)oxirane	106-89-8	C₃H₅ClO	详情	详情
(A)	17046	Phenylacetonitrile; 2-phenylacetonitrile; Benzyl cyanide	140-29-4	C₈H₇N	详情	详情
(F)	27890	Potassium phthalimide	1074-82-4	C₈H₄KNO₂	详情	详情
(G)	28148	1-([2-[(diethylamino)carbonyl]-2-phenylcyclopropyl]methyl)-3,5,7-triaza-1-azoniatricyclo[3.3.1.1(3,7)]decane		C₂₁H₃₂N₅O	详情	详情
(E)	28150	2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-phenylcyclopropanecarboxylic acid		C₁₉H₁₅NO₄	详情	详情
(D)	28151	2-(hydroxymethyl)-1-phenylcyclopropanecarboxylic acid		C₁₁H₁₂O₃	详情	详情
(I)	28144	1-phenyl-3-oxabicyclo[3.1.0]hexan-2-one		C₁₁H₁₀O₂	详情	详情
(II)	28145	2-(aminomethyl)-1-phenylcyclopropanecarboxylic acid		C₁₁H₁₃NO₂	详情	详情
(III)	28146	2-(bromomethyl)-1-phenylcyclopropanecarboxylic acid		C₁₁H₁₁BrO₂	详情	详情
(IV)	28147	2-(bromomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide		C₁₅H₂₀BrNO	详情	详情
(V)	28149	2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-N,N-diethyl-1-phenylcyclopropanecarboxamide		C₂₃H₂₄N₂O₃	详情	详情
(C)	28143	2-(hydroxymethyl)-1-phenylcyclopropanecarboxylic acid		C₁₁H₁₂O₃	详情	详情

合成路线2

参考文献中间体

【1】王晓琴，徐鹏，顾君琳，等.2004.盐酸米那普仑右旋异构体的合成。中国医药工业杂志，35（5）：259～260.
【2】 Bonnaud B, Cousse H, Mouzin G, et al. 1987. 1-Aryl-2-(aminomethyl) cyclopropanecarboxylic acid derivatives. A new series of potential antidepressants. J Med Chem, 30: 318～325.

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)	17046	Phenylacetonitrile; 2-phenylacetonitrile; Benzyl cyanide	140-29-4	C₈H₇N	详情	详情
(I)	17046	Phenylacetonitrile; 2-phenylacetonitrile; Benzyl cyanide	140-29-4	C₈H₇N	详情	详情
(II)	38067	(2R)-2-(Chloromethyl)oxirane; (R)-Epichlorohydrin	51594-55-9	C₃H₅ClO	详情	详情
(II)	61470	(1S,5R)-1-phenyl-3-oxabicyclo[3.1.0]hexan-2-one	63106-93-4	C₁₁H₁₀O₂	详情	详情
(III)	67285	(1R,2S)-2-(hydroxymethyl)-1-phenylcyclopropanecarbonitrile		C₁₁H₁₁NO	详情	详情
(III)	67290	(1S,2R)-N,N-diethyl-2-(hydroxymethyl)-1-phenylcyclopropanecarboxamide		C₁₅H₂₁NO₂	详情	详情
(IV)	61470	(1S,5R)-1-phenyl-3-oxabicyclo[3.1.0]hexan-2-one	63106-93-4	C₁₁H₁₀O₂	详情	详情
(IV)	67291	(1R,2S)-2-(azidomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide		C₁₅H₂₀N₄O	详情	详情
(V)	67287	(1S,2R)-2-((1,3-dioxoisoindolin-2-yl)methyl)-1-phenylcyclopropanecarboxylic acid		C₁₉H₁₅NO₄	详情	详情
(VI)	67286	(1R,2S)-2-((1,3-dioxoisoindolin-2-yl)methyl)-1-phenylcyclopropanecarbonyl chloride		C₁₉H₁₄ClNO₃	详情	详情
(VII)	67288	(1R,2S)-2-((1,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide		C₂₃H₂₄N₂O₃	详情	详情
(VIII)	67289	(1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide	92623-85-3	C₁₅H₂₂N₂O	详情	详情

合成路线3

参考文献中间体

【1】 Roggen H, Kehler J, Stensbol TB, et al. 2007.Synthesis of enantiomerically pure milnacipran analogs and inhibition of dopamine, serotonim, and norepinephrine transporters. Bioorg Med Chem, 17:2384～2387.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成

合成路线4

参考文献中间体

【1】 Roggen H, Kehler J, Stensbol TB, et al.2007.Synthesis of enantiomerically pure milnacipran analogs and inhibitions of dopamine, serotonin, and norepinephrine transporters. Bioorg Med Chem, 17:2834～2837.

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)	17046	Phenylacetonitrile; 2-phenylacetonitrile; Benzyl cyanide	140-29-4	C₈H₇N	详情	详情
(II)	61470	(1S,5R)-1-phenyl-3-oxabicyclo[3.1.0]hexan-2-one	63106-93-4	C₁₁H₁₀O₂	详情	详情
(III)	67290	(1S,2R)-N,N-diethyl-2-(hydroxymethyl)-1-phenylcyclopropanecarboxamide		C₁₅H₂₁NO₂	详情	详情

合成路线5

参考文献中间体

【1】 Lee IH, Lee JO, Moon BH, et al.2007. Preparation of cis-milnacipran hydrochloride. JP2007023005.

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)	17046	Phenylacetonitrile; 2-phenylacetonitrile; Benzyl cyanide	140-29-4	C₈H₇N	详情	详情
(II)	61470	(1S,5R)-1-phenyl-3-oxabicyclo[3.1.0]hexan-2-one	63106-93-4	C₁₁H₁₀O₂	详情	详情
(III)	67290	(1S,2R)-N,N-diethyl-2-(hydroxymethyl)-1-phenylcyclopropanecarboxamide		C₁₅H₂₁NO₂	详情	详情

合成路线6

参考文献中间体

【1】 Bonnaud B, Cousse H, Mouzin G, et al. 1987. 1-Aryl-2-(aminomethyl) cyclopropanecarboxylic acid derivatives. A new series of potential antidepressants. J Med Chem, 30: 318～325.
【2】 Shi ZH, Ning Q, Zhou WC.2005.Synthesis of trans isomers of milnacipran hydrochloride. Farming Zhuanli Shenqing Gongkai Shoumingshu. CN1699332.

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)	17046	Phenylacetonitrile; 2-phenylacetonitrile; Benzyl cyanide	140-29-4	C₈H₇N	详情	详情
(II)	67292	(1R,2R)-2-(hydroxymethyl)-1-phenylcyclopropanecarboxylic acid		C₁₁H₁₂O₃	详情	详情
(III)	61470	(1S,5R)-1-phenyl-3-oxabicyclo[3.1.0]hexan-2-one	63106-93-4	C₁₁H₁₀O₂	详情	详情
(IV)	67292	(1R,2R)-2-(hydroxymethyl)-1-phenylcyclopropanecarboxylic acid		C₁₁H₁₂O₃	详情	详情
(V)	67293	(1R,2R)-2-(bromomethyl)-1-phenylcyclopropanecarboxylic acid		C₁₁H₁₁BrO₂	详情	详情
(VI)	67294	(1R,2R)-2-(bromomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide		C₁₅H₂₀BrNO	详情	详情
(VII)	67295	(1S,2S)-2-((1,3-dioxoisoindolin-2-yl)methyl)-1-phenylcyclopropanecarboxylic acid		C₁₉H₁₅NO₄	详情	详情

合成路线7

参考文献中间体

【1】 Michael P,W WH. 2001. A new enantiselective synthesis of milnacipran and an analogue by catalytic asymmertric cyclopropanation. Adv Synth Catal, 343(5):299～302.

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)	67296	allyl 2-diazo-2-phenylacetate		C₁₁H₁₀N₂O₂	详情	详情
(II)	61470	(1S,5R)-1-phenyl-3-oxabicyclo[3.1.0]hexan-2-one	63106-93-4	C₁₁H₁₀O₂	详情	详情
(III)	67290	(1S,2R)-N,N-diethyl-2-(hydroxymethyl)-1-phenylcyclopropanecarboxamide		C₁₅H₂₁NO₂	详情	详情
(IV)	67291	(1R,2S)-2-(azidomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide		C₁₅H₂₀N₄O	详情	详情

Extended Information