CN100364966C - Process of synthesizing 1-[2-amino-1-(p-methoxylphenyl)-ethyl] cyclohexanol formate - Google Patents
Process of synthesizing 1-[2-amino-1-(p-methoxylphenyl)-ethyl] cyclohexanol formate Download PDFInfo
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- CN100364966C CN100364966C CNB2005100250883A CN200510025088A CN100364966C CN 100364966 C CN100364966 C CN 100364966C CN B2005100250883 A CNB2005100250883 A CN B2005100250883A CN 200510025088 A CN200510025088 A CN 200510025088A CN 100364966 C CN100364966 C CN 100364966C
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Abstract
The present invention discloses 1-[2-amino-1-(p-methoxylphenyl)-ethyl] cyclohexanol formate and a synthesis method. The present invention substitutes Rh-Al2O3-H2 as a catalyst for lithium aluminium hydride or aluminium hydrogen, and hydrogen gas is used for restoring 1-[cyan-(p-methoxyl phenyl)-methyl] cyclohexanol in order to obtain the crude product of 1-[2-amino-1-(p-methoxyl phenyl)-ethyl] cyclohexanol. The crude product reacts with formate to generate 1-[2-amino-1-(p-methoxyl phenyl)-ethyl] cyclohexanol formate which can be used for synthesizing effexor as a medicine treating depression, and the method simplifies production technology and raises the quality of the product.
Description
Technical field:
The present invention relates to technical field of medicine synthesis, be specifically related to a kind of 1-[2-amino-1-(p-methoxyphenyl) ethyl] hexalin formate and synthetic method.
Background technology:
1-[2-amino-1-(p-methoxyphenyl) ethyl] hexalin be the preparation thymoleptic Venlafaxines (venlafaxine) important source material, its reaction formula is:
United States Patent (USP) 4535137 has been reported a kind of 1-[2-of preparation amino-1-(p-methoxyphenyl) ethyl] method of hexalin, this method is with 1-[cyano group (p-methoxyphenyl) methyl] hexalin is that raw material prepares 1-[2-amino-1-(p-methoxyphenyl) ethyl through catalytic hydrogenation under catalyst rhodium-aluminium sesquioxide effect] hexalin.
But aforesaid method exists some defectives: 1, adopt catalyst rhodium-aluminium sesquioxide not only to cost an arm and a leg, remain in many difficulties in the recovery of catalyst rhodium-aluminium sesquioxide simultaneously.2, the reduction reaction yield is low, and only about 50%, and it is low to obtain product purity, and the further purification of reduzate also has many difficulties.Therefore, this method has been brought certain degree of difficulty to suitability for industrialized production.
Summary of the invention:
Defective, a kind of aluminium hydrogen reduction agent of design that technical problem to be solved by this invention is to overcome aforesaid method replace catalyst rhodium-aluminium sesquioxide-hydrogen reducing 1-[cyano group (p-methoxyphenyl) methyl] method of hexalin.
The present invention is based on following principle:
The present invention becomes in the reaction of amido at cyano reduction, replaces catalyst rhodium-aluminium sesquioxide-hydrogen with industrial widespread use lithium aluminium hydride or aluminium hydrogen reduction agent. reaction conditions gentleness, reaction yield height.Usually in reduction process, unavoidably there is by product to generate, and 1-[2-amino-1-(p-methoxyphenyl) ethyl] hexalin is low melting point, be difficult to purify by recrystallization method, the inventor time considers 1-[2-amino-1-(p-methoxyphenyl) ethyl in research] hexalin has alkalescence, can with the mineral acid example hydrochloric acid, sulfuric acid or organic acid such as formic acid, acetate generate and are easy to crystalline salt accordingly, wherein formate is easier purifies by recrystallization method, percent crystallization in massecuite is up to 80%, and if hydrochloride, this crystalline yield is 60-65% only.1-[2-amino-1-(p-methoxyphenyl) ethyl that makes with the inventive method] hexalin formate and formaldehyde can adopt single stage method to prepare thymoleptic Venlafaxine (venlafaxine) through the diformazan glycosylation reaction.Other salt is hydrochloride for example, need before vitriol or acetate and the formaldehyde reaction in alkali and after, with formic acid and the synthetic Venlafaxine of formaldehyde reaction, can not a step finish preparation again.
The invention provides a kind of 1-[2-amino-1-(p-methoxyphenyl) ethyl] synthetic method of hexalin formate, this method comprises the following steps:
(1) 1-[2-amino-1-(p-methoxyphenyl) ethyl] preparation of hexalin crude product
With 1-[cyano group (p-methoxyphenyl) methyl] hexalin, solvent and reductive agent place reactor, after 2-10 hour, are cooled to room temperature in the reaction of room temperature or reflux temperature, add dilute sodium hydroxide aqueous solution, after regulating pH to 10-12, branch vibration layer, organic phase is with the saturated common salt water washing, carry out drying with siccative, filter, filtrate boils off solvent, gets target product 1-[2-amino-1-(p-methoxyphenyl) ethyl] the hexalin crude product.
Described reductive agent is lithium aluminium hydride or aluminium hydrogen. said solvent is tetrahydrofuran (THF) or ether, and described siccative is sodium sulfate, sal epsom or salt of wormwood etc.
1-[cyano group (p-methoxyphenyl) methyl] hexalin and lithium aluminium hydride and aluminium hydrogen mol ratio be 1: 1-1.5.
(2) 1-[2-amino-1-(p-methoxyphenyl) ethyl] preparation of hexalin formate:
1-[2-amino-1-(p-methoxyphenyl) ethyl] the hexalin crude product is dissolved in the solvent, be warming up to backflow after, add formic acid, finish, white solid is separated out in cooling, filter, 1-[2-amino-1-(p-methoxyphenyl) ethyl] the hexalin formate.
Described solvent can be ethyl acetate, acetone, Virahol, methyl alcohol or ethanol.
1-[2-amino-1-(p-methoxyphenyl) ethyl] mol ratio of hexalin and formic acid is 1: 1-1.2.
Below will the present invention is further illustrated by embodiment.
Description of drawings:
Embodiment:
Embodiment 1
(1), with tetrahydrochysene lithium aluminium (8.36g, 0.22mol) and the tetrahydrofuran (THF) of 200ml place in the reaction flask, after the stirring and dissolving, slowly add 1-[cyano group (p-methoxyphenyl) methyl] hexalin (49g, 0.2mol), finish and be warming up to backflow, reacted 3 hours, be cooled to 0-5 ℃, drip 10% aqueous sodium hydroxide solution, regulate PH to 10-12, layering, after organic phase is washed with saturated aqueous common salt (10ml*3), add anhydrous sodium sulfate drying and spend the night, filter, filtrate is concentrated into dried, get 1-[2-amino-1-(p-methoxyphenyl) ethyl] hexalin crude product oily matter 47g, yield 94%.
(2), with 1-[2-amino-1-(p-methoxyphenyl) ethyl] hexalin crude product oily matter 47g is dissolved in the 250ml ethyl acetate, after being warming up to backflow, slowly add anhydrous formic acid 10g, white 1-[2-amino-1-(p-methoxyphenyl) ethyl is separated out in cooling] the hexalin formate, filter, filter cake is with a little washed with isopropyl alcohol, drain, advance to dry by the fire formate 42g, yield 80%, mp134-135 ℃, content＞98% (HPLC) IR (KBr) 3,380 2950 3000-2500
1H-NMR (D
2O) δ: 7.22-6.91 (m, 4H, Ar-H), 3.74 (s, 3H-OCH
3), 3.64-2.82 (m, 4H-CH
2-NH
2), 1.78 (m, 1H ,-CH-), 1.43-1.17 (m, 10H, cyclohexyl) ES:232 (M+1-18) 250 (M+1)
Embodiment 2
(1), with tetrahydrochysene lithium aluminium (8.36g, 0.22mol) and the tetrahydrofuran (THF) of 200ml place in the reaction flask, after the stirring and dissolving, reaction flask is placed ice bath, slowly add sulfuric acid (10.8g, 0.11mol), finish, after ice bath stirs 1 hour down, add 1-[cyano group (p-methoxyphenyl) methyl in batches] hexalin (49g, 0.2mol), finish, reaction is 3 hours under room temperature, is cooled to 0-5C, drip 10% aqueous sodium hydroxide solution, regulate PH to 10-12, layering is after organic phase is washed with saturated aqueous common salt (10ml*3), adding anhydrous sodium sulfate drying spends the night, filter, filtrate is concentrated into dried, gets 1-[2-amino-1-(p-methoxyphenyl) ethyl] hexalin crude product oily matter 48g, yield 97%, content 85% (HPLC).
(2), with 1-[2-amino-1-(p-methoxyphenyl) ethyl] hexalin crude product oily matter 24g is dissolved in the 100ml ethyl acetate, after being warming up to backflow, slowly add anhydrous formic acid 5g, white 1-[2-amino-1-(p-methoxyphenyl) ethyl is separated out in cooling] the hexalin formate, filter, filter cake is with a little washed with isopropyl alcohol, drain, advance to dry by the fire formate 21.4g, yield 75%, mp134-5 ℃, content＞98% (HPLC).
Embodiment 3
With tetrahydrochysene lithium aluminium (8.36g, 0.22mol) and the tetrahydrofuran (THF) of 200ml place in the reaction flask, after the stirring and dissolving, slowly adding 1-[cyano group (p-methoxyphenyl) methyl] (49g 0.2mol), finishes and is warming up to backflow hexalin, react after 3 hours, be cooled to 0-5C, drip 10% aqueous sodium hydroxide solution, regulate PH10-12, layering, organic phase adds anhydrous sodium sulfate drying and spends the night after washing with saturated aqueous common salt (10ml*3), filters, filtrate is warming up to backflow, add formic acid 10g, white 1-[2-amino-1-(p-methoxyphenyl) ethyl is separated out in cooling] the hexalin formate, filter, filter cake is with a little washed with isopropyl alcohol, drain, advance to dry by the fire formate 47.2g, yield 80%, mp134-135 ℃, the domestic unavailability of content＞98% (HPLC) rhodium-alchlor is by Trichlororhodium-alchlor catalytic hydrogenation preparation, 250,000 yuan of Trichlororhodium market price per kilograms.
Claims (3)
1. a 1-[2-amino-1-(p-methoxyphenyl) ethyl] synthetic method of hexalin formate, it is characterized in that this method comprises the following steps:
(1) 1-[2-amino-1-(p-methoxyphenyl) ethyl] preparation of hexalin crude product
With 1-[cyano group (p-methoxyphenyl) methyl] hexalin, solvent and lithium aluminium hydride place reactor, after 2-10 hour, are cooled to room temperature in the reaction of room temperature or reflux temperature, add dilute sodium hydroxide aqueous solution, after regulating PH to 10-12, branch vibration layer, organic phase is with the saturated common salt water washing, carry out drying with siccative, filter, filtrate boils off solvent, gets target product 1-[2-amino-1-(p-methoxyphenyl) ethyl] the hexalin crude product;
(2) 1-[2-amino-1-(p-methoxyphenyl) ethyl] preparation of hexalin formate:
1-[2-amino-1-(p-methoxyphenyl) ethyl] after the hexalin crude product is dissolved in and is warming up to backflow in the solvent, add formic acid, finish, white solid is separated out in cooling, filter, 1-[2-amino-1-(p-methoxyphenyl) ethyl] the hexalin formate.
2. a kind of 1-[2-amino-1-according to claim 1 (p-methoxyphenyl) ethyl] synthetic method of hexalin formate, it is characterized in that 1-[2-amino-1-(p-methoxyphenyl) ethyl] mol ratio of hexalin and reductive agent consumption is 1: 1-1.5.
3. a kind of 1-[2-amino-1-according to claim 1 (p-methoxyphenyl) ethyl] synthetic method of hexalin formate, it is characterized in that the wherein described 1-[2-amino-1-of step (2) (p-methoxyphenyl) ethyl] mol ratio of hexalin and formic acid consumption is 1: 1-1.2.
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| CN112159330A (en) * | 2020-09-28 | 2021-01-01 | 苏州第四制药厂有限公司 | Preparation method of venlafaxine hydrochloride intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002050017A1 (en) * | 2000-12-20 | 2002-06-27 | Ciba Specialty Chemicals Holding Inc. | Process for the preparation of phenethylamine derivatives |
| CN1379755A (en) * | 1999-08-09 | 2002-11-13 | 格吕伦塔尔有限公司 | Substituted 2-dialkylamino alkylbiphenyl derivatives |
| WO2003050074A1 (en) * | 2001-12-13 | 2003-06-19 | Cadila Healthcare Limited | Manufacture of venlafaxine hydrochloride and crystalline polymorphs thereof |
-
2005
- 2005-04-14 CN CNB2005100250883A patent/CN100364966C/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1379755A (en) * | 1999-08-09 | 2002-11-13 | 格吕伦塔尔有限公司 | Substituted 2-dialkylamino alkylbiphenyl derivatives |
| WO2002050017A1 (en) * | 2000-12-20 | 2002-06-27 | Ciba Specialty Chemicals Holding Inc. | Process for the preparation of phenethylamine derivatives |
| CN1481354A (en) * | 2000-12-20 | 2004-03-10 | �������⻯ѧƷ�ع�����˾ | Process for prepn. of phenethylamine derivatives |
| WO2003050074A1 (en) * | 2001-12-13 | 2003-06-19 | Cadila Healthcare Limited | Manufacture of venlafaxine hydrochloride and crystalline polymorphs thereof |
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Address after: 215433 No. 18 East Dongfang Road, petrochemical District, Taicang Port Development Zone, Jiangsu Patentee after: Aba Chemicals Corporation Address before: 215433, No. 18 Dongfang East Road, petrochemical District, Taicang Port Development Zone, Taicang, Jiangsu Patentee before: ABA Chemicals (Suzhou) Co., Ltd. |