CN112159330A - Preparation method of venlafaxine hydrochloride intermediate - Google Patents
Preparation method of venlafaxine hydrochloride intermediate Download PDFInfo
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- CN112159330A CN112159330A CN202011037475.XA CN202011037475A CN112159330A CN 112159330 A CN112159330 A CN 112159330A CN 202011037475 A CN202011037475 A CN 202011037475A CN 112159330 A CN112159330 A CN 112159330A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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Abstract
The invention belongs to the technical field of organic synthesis, and relates to a preparation method of a venlafaxine hydrochloride intermediate, which comprises the following steps: heating, quenching, extracting, concentrating and salifying. The venlafaxine synthesized by the method has the advantages of high yield of the venlafaxine impurity C, good purity, safe reaction, simple operation, no special requirement on equipment and suitability for industrial production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, and particularly relates to a preparation method of a venlafaxine hydrochloride intermediate.
Background
The chemical name of venlafaxine impurity C is 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol hydrochloride, which is a key intermediate of venlafaxine hydrochloride. Wherein the organic moiety 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol is obtained by reducing 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol. The reduction method in the prior art mainly comprises two methods:
the first method uses metal catalyst, hydrogen gas pressure heating reduction. The catalyst mainly used is palladium carbon, Raney nickel, rhodium alumina and the like. The method has the defects that high-pressure equipment is used, hydrogen is used for reduction, and the potential safety hazard is large. The metal catalyst has high recycling difficulty, high cost, great waste and easy environmental pollution.
The second method uses lewis acid in combination with borohydride reduction. The main Lewis acid is aluminum trichloride, nickel chloride, ferric bromide and the like. The borohydride is sodium borohydride, potassium borohydride, lithium borohydride, etc. This method has a drawback in that the reaction time is long and the reaction treatment is very troublesome.
Therefore, it is necessary to develop a new preparation method to avoid the above problems.
Disclosure of Invention
The invention mainly aims to provide a preparation method of a venlafaxine hydrochloride intermediate, which can meet the industrial production requirement of the venlafaxine hydrochloride intermediate.
The invention realizes the purpose through the following technical scheme: a preparation method of venlafaxine hydrochloride intermediate comprises the following steps:
(1) heating: adding 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol, a solvent and borane or a borane complex into a reaction kettle, and heating to 25-85 ℃ to react for 2-3 h to obtain a solution A;
(2) quenching: adding acid into the solution A to carry out quenching reaction to obtain a solution B;
(3) and (3) extraction: adding inorganic base into the solution B for neutralization, and then extracting an organic phase by using an extraction liquid;
(4) concentration: evaporating the extract liquid in the organic phase to remove water to obtain a concentrated solution;
(5) salifying: adding isopropanol hydrochloride into the concentrated solution to form salt, filtering and drying to obtain a venlafaxine impurity C.
Specifically, the mass ratio of the solvent in the step (1) to the 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol is 3-50: 1.
Specifically, the solvent is one selected from tetrahydrofuran, benzene, toluene or dichloromethane.
Specifically, the molar ratio of the borane or the borane complex to the 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol is 2-10: 1.
Specifically, the borane complex is selected from one of borane dimethyl sulfide complex, borane tetrahydrofuran complex or borane N, N-diethylaniline complex.
Specifically, the quenching acid in the step (2) is hydrochloric acid, sulfuric acid, formic acid or acetic acid.
Specifically, the extract in the step (3) is selected from one of benzene, toluene, dichloromethane, ethyl acetate, diethyl ether or chloroform.
Specifically, the inorganic base in the step (3) is sodium hydroxide.
Specifically, if crystals precipitate after the concentration in the step (4), supplementing an extraction liquid to dissolve the crystals.
By adopting the technical scheme, the technical scheme of the invention has the beneficial effects that:
the venlafaxine synthesized by the method has the advantages of high yield of the venlafaxine impurity C, good purity, safe reaction, simple operation, no special requirement on equipment and suitability for industrial production.
Detailed Description
The invention relates to a preparation method of a venlafaxine hydrochloride intermediate, which comprises the following steps:
(1) heating: adding 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol, a solvent and borane or a borane complex into a reaction kettle, and heating to 25-85 ℃ to react for 2-3 h to obtain a solution A;
(2) quenching: adding acid into the solution A to carry out quenching reaction to obtain a solution B;
(3) and (3) extraction: adding inorganic base into the solution B for neutralization, and then extracting an organic phase by using an extraction liquid;
(4) concentration: evaporating the extract liquid in the organic phase to remove water to obtain a concentrated solution;
(5) salifying: adding isopropanol hydrochloride into the concentrated solution to form salt, filtering and drying to obtain a venlafaxine impurity C.
The reaction flow of the steps comprises:
the present invention will be described in further detail with reference to specific examples.
Example 1:
(1) adding 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol, 3 times of tetrahydrofuran solvent and 2 times of borane in molar number into a reaction kettle, and heating to 25 ℃ for reaction for 3 hours to obtain a solution A;
(2) adding hydrochloric acid into the solution A to carry out quenching reaction to obtain a solution B;
(3) adding sodium hydroxide into the solution B for neutralization, and then extracting an organic phase by using extraction liquid benzene;
(4) evaporating the extract liquid in the organic phase to remove water to obtain a concentrated solution;
(5) adding isopropanol hydrochloride into the concentrated solution to form salt, filtering and drying to obtain the venlafaxine impurity C (yield 95.4%, purity 98.3%).
Example 2:
(1) adding 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol, 5 times of benzene solvent and 5 times of borane dimethyl sulfide complex by mol into a reaction kettle, and heating to 40 ℃ for reaction for 2 hours to obtain a solution A;
(2) adding sulfuric acid into the solution A to carry out quenching reaction to obtain a solution B;
(3) adding sodium hydroxide into the solution B for neutralization, and then extracting an organic phase by using extract liquor toluene;
(4) evaporating the extract liquid in the organic phase to remove water to obtain a concentrated solution;
(5) adding isopropanol hydrochloride into the concentrated solution to form salt, filtering and drying to obtain the venlafaxine impurity C (yield is 96.2%, purity is 98.9%).
Example 3:
(1) adding 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol, 10 times of toluene solvent and 5 times of borane N, N-diethylaniline complex into a reaction kettle, heating to 35 ℃ and reacting for 2.5h to obtain a solution A;
(2) adding sulfuric acid into the solution A to carry out quenching reaction to obtain a solution B;
(3) adding sodium hydroxide into the solution B for neutralization, and then extracting an organic phase by using extraction liquid dichloromethane;
(4) evaporating the extract liquid in the organic phase to remove water to obtain a concentrated solution;
(5) adding isopropanol hydrochloride into the concentrated solution to form salt, filtering and drying to obtain the venlafaxine impurity C (the yield is 95.8 percent, and the purity is 98.1 percent).
Example 4:
(1) adding 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol, a dichloromethane solvent with the mass being 20 times that of the cyclohexanol, and a borane dimethyl sulfide complex with the mole number being 10 times that of the cyclohexanol into a reaction kettle, and heating to 85 ℃ to react for 2 hours to obtain a solution A;
(2) adding hydrochloric acid into the solution A to carry out quenching reaction to obtain a solution B;
(3) adding sodium hydroxide into the solution B for neutralization, and then extracting an organic phase by using extract liquor ethyl acetate;
(4) evaporating the extract liquid in the organic phase to remove water to obtain a concentrated solution;
(5) adding isopropanol hydrochloride into the concentrated solution to form salt, filtering and drying to obtain the venlafaxine impurity C (the yield is 97.5 percent, and the purity is 99.1 percent).
Example 5:
(1) adding 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol, tetrahydrofuran solvent in 40 times of mass and borane tetrahydrofuran complex in 8 times of molar number into a reaction kettle, heating to 50 ℃ and reacting for 2.5 hours to obtain solution A;
(2) adding formic acid into the solution A to carry out quenching reaction to obtain a solution B;
(3) adding sodium hydroxide into the solution B for neutralization, and then extracting an organic phase by using extraction liquid and ether;
(4) evaporating the extract liquid in the organic phase to remove water to obtain a concentrated solution;
(5) adding isopropanol hydrochloride into the concentrated solution to form salt, filtering and drying to obtain the venlafaxine impurity C (the yield is 95.9 percent, and the purity is 98.0 percent).
Example 6:
(1) adding 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol, a benzene solvent with the mass being 50 times that of the cyclohexanol and a borane N, N-diethylaniline complex with the molar number being 6 times that of the cyclohexanol into a reaction kettle, and heating to 60 ℃ to react for 3 hours to obtain a solution A;
(2) adding acetic acid into the solution A to carry out quenching reaction to obtain a solution B;
(3) adding sodium hydroxide into the solution B for neutralization, and then extracting an organic phase by using extraction liquid chloroform;
(4) evaporating the extract liquid in the organic phase to remove water to obtain a concentrated solution;
(5) adding isopropanol hydrochloride into the concentrated solution to form salt, filtering and drying to obtain the venlafaxine impurity C (yield is 96.1%, purity is 98.5%).
In conclusion, the venlafaxine synthesized by the method has high yield (more than 95 percent) of the impurity C, good purity (more than 98 percent), safe reaction, simple operation and no special requirement on equipment, and is suitable for industrial production.
In the step (3), the solution is only required to be adjusted to be neutral, so that other inorganic alkali can be used for replacing the sodium hydroxide.
And (4) if crystals are precipitated after concentration, supplementing an extraction liquid to dissolve the crystals. So that the 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol formed during heating is allowed to participate sufficiently in the salt-forming reaction with isopropanol hydrochloride.
What has been described above are merely some embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made without departing from the inventive concept thereof, and these changes and modifications can be made without departing from the spirit and scope of the invention.
Claims (9)
1. A preparation method of venlafaxine hydrochloride intermediate comprises the following steps:
(1) heating: adding 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol, a solvent and borane or a borane complex into a reaction kettle, and heating to 25-85 ℃ to react for 2-3 h to obtain a solution A;
(2) quenching: adding acid into the solution A to carry out quenching reaction to obtain a solution B;
(3) and (3) extraction: adding inorganic base into the solution B for neutralization, and then extracting an organic phase by using an extraction liquid;
(4) concentration: evaporating the extract liquid in the organic phase to remove water to obtain a concentrated solution;
(5) salifying: adding isopropanol hydrochloride into the concentrated solution to form salt, filtering and drying to obtain a venlafaxine impurity C.
2. The method of preparing a venlafaxine hydrochloride intermediate according to claim 1, wherein: the mass ratio of the solvent in the step (1) to the 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol is 3-50: 1.
3. The method of preparing a venlafaxine hydrochloride intermediate according to claim 1, wherein: the solvent is one selected from tetrahydrofuran, benzene, toluene or dichloromethane.
4. The method of preparing a venlafaxine hydrochloride intermediate according to claim 1, wherein: the molar ratio of the borane or the borane complex to the 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol is 2-10: 1.
5. The method of preparing a venlafaxine hydrochloride intermediate according to claim 1, wherein: the borane complex is selected from one of borane dimethyl sulfide complex, borane tetrahydrofuran complex or borane N, N-diethylaniline complex.
6. The method of preparing a venlafaxine hydrochloride intermediate according to claim 1, wherein: the quenching acid in the step (2) is hydrochloric acid, sulfuric acid, formic acid or acetic acid.
7. The method of preparing a venlafaxine hydrochloride intermediate according to claim 1, wherein: the extraction liquid of the step (3) is selected from one of benzene, toluene, dichloromethane, ethyl acetate, diethyl ether or chloroform.
8. The method of preparing a venlafaxine hydrochloride intermediate according to claim 1, wherein: the inorganic alkali in the step (3) is sodium hydroxide.
9. The method of preparing a venlafaxine hydrochloride intermediate according to claim 1, wherein: and (4) if crystals are precipitated after concentration, supplementing an extraction liquid to dissolve the crystals.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1847219A (en) * | 2005-04-14 | 2006-10-18 | 上海雅本化学有限公司 | Process of synthesizing 1-[2-amino-1-(p-methoxylphenyl)-ethyl] cyclohexanol formate |
| WO2007094008A2 (en) * | 2006-02-16 | 2007-08-23 | Unichem Laboratories Limited | A novel process for preparation of venlafaxine hydrochloride and its intermediates |
| CN101503365A (en) * | 2009-02-04 | 2009-08-12 | 成都樵枫科技发展有限公司 | Preparation of venlafaxine intermediate 1-[2-amino-1-(4-methoxy phenyl)ethyl] cyclohexanol |
| CN104177268A (en) * | 2014-09-22 | 2014-12-03 | 山东华生化学股份有限公司 | Preparation method of 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol |
-
2020
- 2020-09-28 CN CN202011037475.XA patent/CN112159330A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1847219A (en) * | 2005-04-14 | 2006-10-18 | 上海雅本化学有限公司 | Process of synthesizing 1-[2-amino-1-(p-methoxylphenyl)-ethyl] cyclohexanol formate |
| WO2007094008A2 (en) * | 2006-02-16 | 2007-08-23 | Unichem Laboratories Limited | A novel process for preparation of venlafaxine hydrochloride and its intermediates |
| CN101503365A (en) * | 2009-02-04 | 2009-08-12 | 成都樵枫科技发展有限公司 | Preparation of venlafaxine intermediate 1-[2-amino-1-(4-methoxy phenyl)ethyl] cyclohexanol |
| CN104177268A (en) * | 2014-09-22 | 2014-12-03 | 山东华生化学股份有限公司 | Preparation method of 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol |
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