CN1240206A - Process for preparing 1[2-(dimethyamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloridumi - Google Patents
Process for preparing 1[2-(dimethyamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloridumi Download PDFInfo
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Abstract
The present invention discloses a preparation method of antidepressant, venlafaxin-1-[2-(dimethylamino)-1-(4-methoxyphenyl) ethyl] cyclohexanol hydrochloride. The described method adopts one-step method to synthesize N, N-dimethyl-4-methoxyphenylacetamide, substitutes xylylene amine solution with dimethylamine's aqueous solution, substitutes lithium aluminium hydrogen with cheap and use-safe potassium borohydride and alchlor, and uses single solvent to make hydrochlorination, so that its preparation process is simple, easy to implement, safe and low in cost. It is a method for industrial preparation of venlafaxin.
Description
The invention belongs to thymoleptic-Wen Lafaxin (venlafaxin) bulk drug preparing technical field, relate to Wen Lafaxin (venlafaxin)-1-[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl] a kind of synthetic method of hexalin hydrochloride.
Thymoleptic-Wen Lafaxin (venlafaxin), its chemical name are 1-[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl] the hexalin hydrochloride, its structural formula is:
English Patent 2,227743 have reported a kind of 1-[2-of preparation (dimethylamino)-1-(4-p-methoxy-phenyl) ethyl] method of hexalin, this method is at first with N, N-dimethyl-4-anisole thioacetamide is a raw material, at room temperature with sec.-propyl bromination reactive magnesium, resultant again with the hexalin addition, obtain N, N-dimethyl-α-(1-hydroxy-cyclohexyl)-4-anisole thioacetamide, under the effect of catalyzer Raney's nickel, obtain target product 1-[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl then through catalytic hydrogenation] hexalin.This preparation method exists a fairly obvious defective: starting raw material N, and the preparation of N-dimethyl-4-anisole thioacetamide is difficulty quite, so the method that English Patent 2,227743 is reported has been brought certain difficulty to industrializing implementation;
United States Patent (USP) 4,535,186 reported a kind of with inflammable, explosive and expensive Li-Al hydrogen be reductive agent prepare 1-[2-(dimethylamino)-1-(phenyl) ethyl] method of hexalin, the industrialization of this method also has certain difficulty.
United States Patent (USP) 4,535,186 have reported a kind of 1-[2-of preparation (dimethylamino)-1-(4-p-methoxy-phenyl) ethyl simultaneously] method of hexalin hydrochloride, this method is with 1-[2-(dimethylamino)-1-(phenyl) ethyl] hexalin places multiple mixed solvent to carry out the salt acidifying, brought certain difficulty to operation.
The objective of the invention is to disclose a kind of with the 4-methoxyphenylacetic acid be starting raw material and with single solvent to 1-[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl] hexalin carries out the salt acidifying and prepares 1-[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl] method of hexalin hydrochloride, to overcome the defective of prior art.
Design of the present invention is such:
1. the present invention is a raw material with the 4-methoxyphenylacetic acid, carry out chlorination reaction with sulfur oxychloride, and add excessive dimethylamine agueous solution and carry out amination reaction, make N, N-dimethyl-4-anisole ethanamide, to avoid the bigger problem of industrial preparation dimethylamine benzole soln difficulty, can reclaim the 4-methoxyphenylacetic acid of hydrolysis simultaneously, help industrialized production;
2. with N, make N with the hexalin addition again behind N-dimethyl-4-anisole ethanamide and the sec.-propyl bromination reactive magnesium, N-dimethyl-α-(1-hydroxy-cyclohexyl)-4-anisole ethanamide;
3. at last by POTASSIUM BOROHYDRIDE-aluminum chloride with N, N-dimethyl-α-(1-hydroxy-cyclohexyl)-4-anisole ethanamide reduction obtains 1-[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl] hexalin, this process has replaced Li-Al hydrogen inflammable, explosive and expensive in the prior art by borane reducing agent potassium hydride KH-aluminum chloride, reducing production costs, and production process safety is easily gone;
4. 1-[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl] the salt acidifying of hexalin adopts single solvent, to replace the method for using methyl alcohol-ethyl acetate mixture in the prior art, makes preparation process more simple.
According to above-mentioned design, the present invention proposes following technical scheme:
The said 1-[2-of preparation of the present invention (dimethylamino)-1-(4-p-methoxy-phenyl) ethyl] method of hexalin hydrochloride mainly comprises the steps:
(1) chlorination of 4-methoxyphenylacetic acid and amination reaction:
4-methoxyphenylacetic acid and sulfur oxychloride are placed reactor, and reflux 2～6 hours was best with 2～4 hours, then the excessive sulfur oxychloride of pressure reducing and steaming; The dimethylamine agueous solution that adds solvent and 40% (wt%) carries out amination reaction, stirs 5～12 hours down at 10～30 ℃, and telling organic layer distills, and removes benzene, obtains intermediate product N, N-dimethyl-4-anisole ethanamide, and its reaction formula is:
The mol ratio of each reactant is: 4-methoxyphenylacetic acid: sulfur oxychloride: the dimethylamine agueous solution of 40% (wt%)
=1: (1.2～1.4): (2～4) said solvent is benzene, chloroform or hexanaphthene etc.(2) N, the Ivanov of N-dimethyl-4-anisole ethanamide reaction and with the addition reaction of hexalin:
With sec.-propyl bromination magnesium, solvent and N, N-dimethyl-4-anisole ethanamide places reactor, stirs 4～8 hours down at 10～30 ℃, and then adding pimelinketone, reacted 5～12 hours down at 40～45 ℃, the preferred reaction times is 10～12 hours, with acid for adjusting pH=1～2, filter, concentrate, add benzene and water and extract, carry out recrystallization with normal hexane-tetrahydrofuran (THF), obtain intermediate product-N, N-dimethyl-α-(1-hydroxy-cyclohexyl)-4-anisole ethanamide.
Said solvent can be organic solvents such as tetrahydrofuran (THF), glycol dimethyl ether or ether, and said acid can be adopted mineral acids such as hydrochloric acid, sulfuric acid.Its reaction formula is:
The mol ratio of participating in each material of reaction is:
N, N-dimethyl-4-anisole ethanamide: sec.-propyl bromination magnesium: pimelinketone
＝1∶(2～3)∶(2～3)。
(3) N, the reduction reaction of N-dimethyl-α-(1-hydroxy-cyclohexyl)-4-anisole ethanamide:
With N, N-dimethyl-α-(1-hydroxy-cyclohexyl)-4-anisole ethanamide, solvent, POTASSIUM BOROHYDRIDE place reactor, slowly add aluminum chloride, finish, at 10～30 ℃ of following stirring reactions 2～4 hours, pressure reducing and steaming solvent, add ethyl acetate and water and extract, and it is extremely alkaline to regulate pH with alkali, and layering obtains 1-[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl] hexalin.Its reaction formula is:
The mol ratio of participating in each material of reaction is:
N, N-dimethyl-α-(1-hydroxy-cyclohexyl)-4-anisole ethanamide: POTASSIUM BOROHYDRIDE: aluminum chloride=1: (5～7): (10～12).
Said solvent is organic solvents such as tetrahydrofuran (THF), glycol dimethyl ether or ether, and said alkali is sodium hydroxide etc.
(4.1-[2-dimethylamino)-1-(4-p-methoxy-phenyl) ethyl] the salt acidifying of hexalin:
With 1-[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl] hexalin is dissolved in the single solvent, under 20～25 ℃ condition, feed hydrogen chloride gas, and the pH to 1 of regulator solution～2, be cooled to 5～10 ℃, obtain crystallisate, i.e. target product-1-[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl] the hexalin hydrochloride.Its structural formula is:
1-[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl] ratio of hexalin and solvent is advisable with 5～7 (v/v), and said solvent is a kind of in Virahol, ethanol or the methyl alcohol.
By above-mentioned disclosed technical scheme as seen, the said method of the present invention has very significant advantage:
Adopt the synthetic N of single stage method, N-dimethyl-4-anisole ethanamide, and with dimethylamine agueous solution substituted benzene-dimethylamine solution; With cheap, and POTASSIUM BOROHYDRIDE safe in utilization and aluminum chloride replacement Li-Al hydrogen; Carry out the salt acidifying with single solvent, therefore, preparation process is comparatively simple, safety, and production cost is lower, is a kind of method that is easy to the industrialized Wen Lafaxin of preparation (venlafaxin).
Below will the present invention is further illustrated by embodiment.
Embodiment 1
(1) 0.12 mole of 4-methoxyphenylacetic acid and 0.16 mole of sulfur oxychloride are placed reactor, reflux 4 hours, the excessive sulfur oxychloride of pressure reducing and steaming then adds 0.48 mole of the dimethylamine agueous solution of benzene 100ml and 40% (wt%), 25 ℃ were stirred 12 hours, tell organic layer and distill, remove benzene, obtain intermediate product N, N-dimethyl-4-anisole ethanamide 16.6 grams, yield 72%, 43 ℃ of fusing points, spectral data is as follows: IR (KBr cm
-1) 1640NMR (CDCl
3), 7.16,6.74 (q, 4H) 3.78 (S, 3H) 3.58 (S, 2H), 2.98 (S, 6H);
(2) with N, N-dimethyl-0.1 mole of 4-anisole ethanamide and tetrahydrofuran (THF) 100ml place reactor, add 2M sec.-propyl bromination magnesium tetrahydrofuran solution 100ml, 25 ℃ were stirred 4 hours, added 0.2 mole of pimelinketone, 40 ℃ of following stirring reactions 12 hours, regulate pH=1.5 with hydrochloric acid, filter, concentrate, add benzene and water, after telling organic layer, the evaporate to dryness organic phase with normal hexane-tetrahydrofuran solution recrystallization, obtains intermediate product-N, N-dimethyl-α-(1-hydroxy-cyclohexyl)-4-anisole ethanamide 20.8 grams, yield 71.4%, 135.8 ℃ of fusing points, spectral data is as follows: NMR (CDCl
3), 7.21,6.78 (q, 4H) 5.49 (S, 1H) 3.70 (S, 2H), 3.52 (S, 1H) 2.86 (d, 6H) 1.10-1.50 (m, 10H); IR (Kbr cm
-1) 3610,1610
(3) with 0.1 mole of N, N-dimethyl-α-(1-hydroxy-cyclohexyl)-4-anisole ethanamide, 0.5 mole of POTASSIUM BOROHYDRIDE, 200ml glycol dimethyl ether place reactor, add 1 mole of aluminum chloride ethylene glycol dimethyl ether solution at 25 ℃, finish, stirring reaction 4 hours, the pressure reducing and steaming solvent, add ethyl acetate 200ml and water 200ml, and regulate pH to 11 with the sodium hydroxide of 20% (wt%), layering, the evaporate to dryness organic layer obtains 1-[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl] crude product 24.2 grams of hexalin.This crude product is dissolved in the Virahol of 150ml, under 25 ℃ temperature, feed hydrogen chloride gas, and the pH to 1 of regulator solution, be cooled to 5 ℃, obtain crystallisate, i.e. target product-1-[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl] hexalin hydrochloride 23.2 grams.Yield is 74%.Fusing point: 216 ± 0.5 ℃, spectral data is as follows: NMR (DMSO-d
6) 7.32,6.98 (and q, 4H) 3.78 (S, 3H) 3.64 (m, 2H), 3.06 (m, 1H) 2.74 (s, 6H) 1.10-1.50 (m, 10H).
Embodiment 2～3
Adopt and embodiment 1 identical operations process, with chloroform or hexanaphthene substituted benzene, the intermediate product N of acquisition, N-dimethyl-4-anisole ethanamide are respectively 15.8 grams and 16.2 grams in step 1, and yield is respectively 68% and 70%.
Embodiment 4～5
Adopt and embodiment 1 identical operations process, in step 2 respectively with glycol dimethyl ether or ether substituted tetrahydrofuran, intermediate product-the N that obtains, N-dimethyl-α-(1-hydroxy-cyclohexyl)-4-anisole ethanamide are respectively 20.5 grams and 20 grams, and yield is respectively 74% and 72.2%.
Embodiment 6
Adopt and embodiment 1 identical operations process, in step 3, replace Virahol with methyl alcohol or ethanol respectively, mark product-1-[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl that obtains] the hexalin hydrochloride is respectively 20.2 grams and 21.2 and restrains, and it is 64.4% and 67.6% that yield is respectively.
Claims (5)
1. a 1-[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl] preparation method of hexalin hydrochloride, it is characterized in that mainly comprising the steps: the chlorination and the amination reaction of (1) 4-methoxyphenylacetic acid:
4-methoxyphenylacetic acid and sulfur oxychloride reflux 2～6 hours are removed sulfur oxychloride, add molten
The dimethylamine agueous solution of agent and 40% (wt%) stirred 5-12 hour each reactant down at 10～30 ℃
Mol ratio be:
4-methoxyphenylacetic acid: sulfur oxychloride: the dimethylamine agueous solution of 40% (wt%)
＝1∶(1.2～1.4)∶(2～4)；
Said solvent is a kind of in benzene, chloroform or the hexanaphthene; (2) N, the Ivanov of N-dimethyl-4-anisole ethanamide reaction and with the addition reaction of hexalin:
Sec.-propyl bromination magnesium, solvent and N, N-dimethyl-4-anisole ethanamide is under 10～30 ℃
Reacted 4～8 hours, and then add pimelinketone, 40～45 ℃ down reaction 5～12 hours from instead
Answer collecting reaction product-N in the product, N-dimethyl-α-(1-hydroxy-cyclohexyl)-4-anisole acetyl
Amine;
Said solvent is a kind of in tetrahydrofuran (THF), glycol dimethyl ether or the ether, participates in each of reaction
The mol ratio of material is:
N, N-dimethyl-4-anisole ethanamide: sec.-propyl bromination magnesium: pimelinketone
=1: (2～3): (2～3); (3) N, the reduction reaction of N-dimethyl-α-(1-hydroxy-cyclohexyl)-4-anisole ethanamide:
N, N-dimethyl-α-(1-hydroxy-cyclohexyl)-4-anisole ethanamide, solvent, POTASSIUM BOROHYDRIDE and
Aluminum chloride reacted 2～4 hours down at 10～30 ℃, collecting reaction product 1-from reaction product
[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl] hexalin;
The mol ratio of participating in each material of reaction is: N, N-dimethyl-α-(1-hydroxy-cyclohexyl)-4-anisole ethanamide: POTASSIUM BOROHYDRIDE: aluminum chloride=1: (5～7): (10～12);
Said solvent is tetrahydrofuran (THF), glycol dimethyl ether or ether;
(4) .1-[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl] the salt acidifying of hexalin:
1-[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl] hexalin is dissolved in the solvent, 25～
Feed hydrogen chloride gas under 30 ℃ the condition, and the pH to 1 of regulator solution～2, be cooled to 5～10
℃, obtain crystallisate, i.e. target product-1-[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl] ring
The hexanol hydrochloride;
1-[2-(dimethylamino)-1-(4-p-methoxy-phenyl) ethyl] ratio of hexalin and solvent is 5～
7 (v/v), said solvent are a kind of in Virahol, ethanol or the methyl alcohol.
2. the method for claim 1 is characterized in that: N, during the reduction reaction of N-dimethyl-α-(1-hydroxy-cyclohexyl)-4-anisole ethanamide, aluminum chloride in the end slowly adds.
3. method as claimed in claim 1 or 2 is characterized in that: preferred 4-methoxyphenylacetic acid and sulfur oxychloride reflux time are 2～4 hours.
4. method as claimed in claim 1 or 2 is characterized in that: the addition reaction time of preferred hexalin is 10～12 hours.
5. the method for claim 1, it is characterized in that: preferred Muriatic solvent is a Virahol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 99113785 CN1240206A (en) | 1999-06-17 | 1999-06-17 | Process for preparing 1[2-(dimethyamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloridumi |
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|---|---|---|---|
| CN 99113785 CN1240206A (en) | 1999-06-17 | 1999-06-17 | Process for preparing 1[2-(dimethyamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloridumi |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003050074A1 (en) * | 2001-12-13 | 2003-06-19 | Cadila Healthcare Limited | Manufacture of venlafaxine hydrochloride and crystalline polymorphs thereof |
| US6696496B2 (en) | 2002-03-28 | 2004-02-24 | Synthon Bv | Low water-soluble venlafaxine salts |
| US6717015B2 (en) | 2002-03-28 | 2004-04-06 | Synthon Bv | Venlafaxine besylate |
| WO2005049560A2 (en) * | 2003-09-29 | 2005-06-02 | Sun Pharmaceutical Industries Limited | Process for the preparation of anti-depressant compound |
| WO2008013990A3 (en) * | 2006-07-26 | 2008-03-27 | Teva Pharma | Processes for the synthesis of o-desmethylvenlafaxine |
| WO2008093142A1 (en) * | 2007-01-31 | 2008-08-07 | Generics [Uk] Limited | Process for the preparation of o-desmethyl venlafaxine |
| CN101781221A (en) * | 2010-02-11 | 2010-07-21 | 上海凯米侬医药科技有限公司 | Preparation method of O-desmethylvenlafaxine |
| CN102241590A (en) * | 2011-05-17 | 2011-11-16 | 永农生物科学有限公司 | Synthetic method of spirocyclic tetronic acid compound key intermediate |
| US8063250B2 (en) | 2007-11-26 | 2011-11-22 | Teva Pharmaceutical Industries, Ltd. | Crystal forms of O-desmethylvenlafaxine fumarate |
| US8569371B2 (en) | 2010-03-29 | 2013-10-29 | Pliva Hrvatska D.O.O. | Crystal forms of O-desmethylvenlafaxine fumarate |
| CN101384544B (en) * | 2005-12-22 | 2014-01-22 | 格吕伦塔尔有限公司 | Substituted cyclohexylmethyl derivatives |
| CN109535017A (en) * | 2018-12-29 | 2019-03-29 | 合肥立方制药股份有限公司 | A kind of VENLAFAXINE HCL preparation method |
-
1999
- 1999-06-17 CN CN 99113785 patent/CN1240206A/en active Pending
Cited By (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003050074A1 (en) * | 2001-12-13 | 2003-06-19 | Cadila Healthcare Limited | Manufacture of venlafaxine hydrochloride and crystalline polymorphs thereof |
| US6696496B2 (en) | 2002-03-28 | 2004-02-24 | Synthon Bv | Low water-soluble venlafaxine salts |
| US6717015B2 (en) | 2002-03-28 | 2004-04-06 | Synthon Bv | Venlafaxine besylate |
| WO2005049560A2 (en) * | 2003-09-29 | 2005-06-02 | Sun Pharmaceutical Industries Limited | Process for the preparation of anti-depressant compound |
| WO2005049560A3 (en) * | 2003-09-29 | 2005-09-15 | Sun Pharmaceutical Ind Ltd | Process for the preparation of anti-depressant compound |
| CN101384544B (en) * | 2005-12-22 | 2014-01-22 | 格吕伦塔尔有限公司 | Substituted cyclohexylmethyl derivatives |
| US7605290B2 (en) | 2006-07-26 | 2009-10-20 | Teva Pharmaceutical Industries Ltd. | Processes for the synthesis of O-desmethylvenlafaxine |
| JP2008546850A (en) * | 2006-07-26 | 2008-12-25 | テバ ファーマシューティカル インダストリーズ リミティド | Method for synthesizing O-desmethylvenlafaxine |
| WO2008013990A3 (en) * | 2006-07-26 | 2008-03-27 | Teva Pharma | Processes for the synthesis of o-desmethylvenlafaxine |
| WO2008093142A1 (en) * | 2007-01-31 | 2008-08-07 | Generics [Uk] Limited | Process for the preparation of o-desmethyl venlafaxine |
| US8063250B2 (en) | 2007-11-26 | 2011-11-22 | Teva Pharmaceutical Industries, Ltd. | Crystal forms of O-desmethylvenlafaxine fumarate |
| CN101781221A (en) * | 2010-02-11 | 2010-07-21 | 上海凯米侬医药科技有限公司 | Preparation method of O-desmethylvenlafaxine |
| US8569371B2 (en) | 2010-03-29 | 2013-10-29 | Pliva Hrvatska D.O.O. | Crystal forms of O-desmethylvenlafaxine fumarate |
| CN102241590A (en) * | 2011-05-17 | 2011-11-16 | 永农生物科学有限公司 | Synthetic method of spirocyclic tetronic acid compound key intermediate |
| CN102241590B (en) * | 2011-05-17 | 2013-06-19 | 永农生物科学有限公司 | Synthetic method of spirocyclic tetronic acid compound key intermediate |
| CN109535017A (en) * | 2018-12-29 | 2019-03-29 | 合肥立方制药股份有限公司 | A kind of VENLAFAXINE HCL preparation method |
| CN109535017B (en) * | 2018-12-29 | 2023-08-08 | 合肥立方制药股份有限公司 | Preparation method of venlafaxine hydrochloride |
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