CN112159330A - Preparation method of venlafaxine hydrochloride intermediate - Google Patents
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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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- hydrochloride intermediate
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- 229960002416 venlafaxine hydrochloride Drugs 0.000 title claims abstract description 18
- QYRYFNHXARDNFZ-UHFFFAOYSA-N venlafaxine hydrochloride Chemical compound [H+].[Cl-].C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 QYRYFNHXARDNFZ-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 17
- 238000010438 heat treatment Methods 0.000 claims abstract description 15
- 238000010791 quenching Methods 0.000 claims abstract description 15
- 230000000171 quenching effect Effects 0.000 claims abstract description 15
- 229960004688 venlafaxine Drugs 0.000 claims abstract description 15
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000012535 impurity Substances 0.000 claims abstract description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 26
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 21
- 239000007788 liquid Substances 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 239000012074 organic phase Substances 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 16
- HPKKWICRIRFOHM-UHFFFAOYSA-N 3-(1-hydroxycyclohexyl)-3-(4-methoxyphenyl)propanenitrile Chemical compound C1=CC(OC)=CC=C1C(CC#N)C1(O)CCCCC1 HPKKWICRIRFOHM-UHFFFAOYSA-N 0.000 claims description 14
- 238000000605 extraction Methods 0.000 claims description 14
- 229910000085 borane Inorganic materials 0.000 claims description 13
- AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 238000001704 evaporation Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 238000006386 neutralization reaction Methods 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 claims description 4
- KHYAFFAGZNCWPT-UHFFFAOYSA-N boron;n,n-diethylaniline Chemical compound [B].CCN(CC)C1=CC=CC=C1 KHYAFFAGZNCWPT-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 230000001502 supplementing effect Effects 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- SUQHIQRIIBKNOR-UHFFFAOYSA-N N,N-didesmethylvenlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN)C1(O)CCCCC1 SUQHIQRIIBKNOR-UHFFFAOYSA-N 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- NTKXIDDUCSFBBF-UHFFFAOYSA-N 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexan-1-ol;hydrochloride Chemical compound Cl.C1=CC(OC)=CC=C1C(CN)C1(O)CCCCC1 NTKXIDDUCSFBBF-UHFFFAOYSA-N 0.000 description 1
- ASYJSBPNAIDUHX-UHFFFAOYSA-N 2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile Chemical compound C1=CC(OC)=CC=C1C(C#N)C1(O)CCCCC1 ASYJSBPNAIDUHX-UHFFFAOYSA-N 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- FEONEKOZSGPOFN-UHFFFAOYSA-K tribromoiron Chemical compound Br[Fe](Br)Br FEONEKOZSGPOFN-UHFFFAOYSA-K 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- 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
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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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| 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 | Synthetic method of 1-[2-amino 1-(p-methoxyphenyl) 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 | Synthetic method of 1-[2-amino 1-(p-methoxyphenyl) 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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