CN111675671A - Preparation method of venlafaxine impurity E - Google Patents
Preparation method of venlafaxine impurity E Download PDFInfo
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- CN111675671A CN111675671A CN202010679913.6A CN202010679913A CN111675671A CN 111675671 A CN111675671 A CN 111675671A CN 202010679913 A CN202010679913 A CN 202010679913A CN 111675671 A CN111675671 A CN 111675671A
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- CN
- China
- Prior art keywords
- ethyl
- venlafaxine
- methoxyphenyl
- impurity
- cyclohexanol
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 229960004688 venlafaxine Drugs 0.000 title claims abstract description 22
- 239000012535 impurity Substances 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- 238000006482 condensation reaction Methods 0.000 claims abstract description 4
- 238000006722 reduction reaction Methods 0.000 claims abstract description 4
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 18
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-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 12
- SUQHIQRIIBKNOR-UHFFFAOYSA-N N,N-didesmethylvenlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN)C1(O)CCCCC1 SUQHIQRIIBKNOR-UHFFFAOYSA-N 0.000 claims description 12
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 10
- 238000010791 quenching Methods 0.000 claims description 10
- 230000000171 quenching effect Effects 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 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 8
- 235000019253 formic acid Nutrition 0.000 claims description 8
- ORAXBZFDDWPRRD-UHFFFAOYSA-N 3-(4-methoxyphenyl)propanenitrile Chemical compound COC1=CC=C(CCC#N)C=C1 ORAXBZFDDWPRRD-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- PACGLQCRGWFBJH-UHFFFAOYSA-N 2-(4-methoxyphenyl)acetonitrile Chemical compound COC1=CC=C(CC#N)C=C1 PACGLQCRGWFBJH-UHFFFAOYSA-N 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000007788 liquid Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 3
- 239000012071 phase Substances 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/02—1,2-Oxazines; Hydrogenated 1,2-oxazines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (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 venlafaxine impurity E, which comprises the following steps: (1) condensation reaction, (2) reduction reaction, and (3) cyclization reaction. The method for synthesizing venlafaxine has the advantages of fewer steps, higher product purity, safe reaction, less waste liquid, simple post-treatment, convenient operation and convenient industrial production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, and particularly relates to a preparation method of venlafaxine impurity E.
Background
Venlafaxine impurity E (Venlafaxine-4, (5RS) -5- (4-Methoxyphenyl) -3-methyl-1-oxa-3-azaspiro- [ 5.5)]undecane) is a pharmaceutical intermediate of formula C17H23N2. The substance is generally combined with hydrochloric acid to form salt for use, and according to venlafaxine impurity E in European pharmacopoeia, the synthetic route is as follows:
however, this process has the following disadvantages:
firstly, the synthesis steps are long, and 5 steps are needed for reaction;
② the purity and the yield are low;
thirdly, hydrogenation equipment is used, and high temperature and high pressure are adopted, so that the danger is high;
fourthly, dangerous reagents such as borane and the like are used, and second solvents such as toluene and the like are used;
the whole process is complex in post-treatment, generates more waste water and solid waste, and is not environment-friendly.
Therefore, it is necessary to develop a preparation method to solve the above problems.
Disclosure of Invention
The invention mainly aims to provide a preparation method of venlafaxine impurity E, which can meet the industrial production requirement of venlafaxine impurity E production.
The invention realizes the purpose through the following technical scheme: a preparation method of venlafaxine impurity E comprises the following steps:
(1) condensation reaction: dissolving 4-methoxyphenylacetonitrile in ethanol, adding a strong base to adjust the solution to be alkaline, adding cyclohexanone, reacting for 4-5 h at 15-30 ℃, adjusting the pH value to be 5-7 by using an acid, quenching, and filtering and drying the product to obtain 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol;
(2) reduction reaction: adding aluminum trichloride and sodium borohydride into tetrahydrofuran serving as a solvent, stirring for 1h, adding 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol obtained in the step (1), performing reflux reaction for 3-4 h, adding acid for quenching, extracting with ethyl acetate, and distilling an oil phase to obtain 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol;
(3) cyclization reaction: and (3) adding formic acid and formaldehyde into the 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol obtained in the step (2), reacting at 50-80 ℃ for 2-3 h, cooling, extracting with ethyl acetate, distilling the oil phase under reduced pressure, and drying to obtain a venlafaxine impurity E.
Specifically, the quenching acid in the step (1) and the quenching acid in the step (2) are hydrochloric acid, sulfuric acid, formic acid or acetic acid.
Specifically, the strong base in the step (1) is sodium hydroxide, and the mass ratio of the strong base to the 4-methoxyphenylacetonitrile is 1: 1.
specifically, the mass ratio of the cyclohexanone and the 4-methoxybenzyl acetonitrile in the step (1) is 1-3: 1.
specifically, in the step (2), the mass ratio of aluminum trichloride to 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol is 2.2-5.5: 1, the mass ratio of sodium borohydride to 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol is 2-5: 1.
specifically, in the step (3), the mass ratio of formic acid to 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol is 3-10: 1, and the mass ratio of formaldehyde to 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol is 3-10: 1.
By adopting the technical scheme, the technical scheme of the invention has the beneficial effects that:
the method for synthesizing venlafaxine has the advantages of fewer steps, higher product purity, safe reaction, less waste liquid, simple post-treatment, convenient operation and convenient industrial production.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
The invention relates to a preparation method of venlafaxine impurity E, which comprises the following steps:
(1) condensation reaction: dissolving 4-methoxybenzyl acetonitrile (A) in ethanol, adding strong base to adjust the solution to be alkaline, adding cyclohexanone, reacting for 4-5 h at 15-30 ℃, adjusting the pH value to be 5-7 by using acid, quenching, and filtering and drying the product to obtain 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol (B);
(2) reduction reaction: adding aluminum trichloride and sodium borohydride into tetrahydrofuran serving as a solvent, stirring for 1h, adding 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol (B) obtained in the step (1), performing reflux reaction for 3-4 h, adding acid for quenching, extracting with ethyl acetate, and distilling an oil phase to obtain 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol (C);
(3) cyclization reaction: and (3) adding formic acid and formaldehyde into the 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol (C) obtained in the step (2), reacting at 50-80 ℃ for 2-3 h, cooling, extracting with ethyl acetate, then carrying out reduced pressure distillation on an oil phase, and drying to obtain a venlafaxine impurity E (D).
The reaction flow of the steps comprises:
examples 1 to 5:
the specific reaction conditions and liquid phase purities of examples 1 to 5 were as follows:
as can be seen from the above table, the purity of the liquid phase is more than or equal to 99%, the steps for synthesizing venlafaxine impurity E by the method are fewer, and the purity of the product is higher. The method avoids the use of high-pressure hydrogenation equipment and chemical reagents with high risk, and has high safety. And the method has the advantages of less waste liquid, simple treatment after reaction, convenient operation and convenient industrial production.
The strong base in the step (1) is sodium hydroxide, and the mass ratio of the strong base to the 4-methoxybenzyl acetonitrile is 1: 1. the mass ratio of the cyclohexanone to the 4-methoxybenzyl acetonitrile in the step (1) is 1-3: 1. in the step (2), the mass ratio of aluminum trichloride to 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol is 2.2-5.5: 1, the mass ratio of sodium borohydride to 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol is 2-5: 1. in the step (3), the mass ratio of formic acid to 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol is 3-10: 1, and the mass ratio of formaldehyde to 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol is 3-10: 1. The core raw materials or intermediates can be fully reacted by the upper limit, and the yield is improved.
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 (6)
1. A preparation method of venlafaxine impurity E comprises the following steps:
(1) condensation reaction: dissolving 4-methoxyphenylacetonitrile in ethanol, adding a strong base to adjust the solution to be alkaline, adding cyclohexanone, reacting for 4-5 h at 15-30 ℃, adjusting the pH value to be 5-7 by using an acid, quenching, and filtering and drying the product to obtain 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol;
(2) reduction reaction: adding aluminum trichloride and sodium borohydride into tetrahydrofuran serving as a solvent, stirring for 1h, adding 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol obtained in the step (1), performing reflux reaction for 3-4 h, adding acid for quenching, extracting with ethyl acetate, and distilling an oil phase to obtain 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol;
(3) cyclization reaction: and (3) adding formic acid and formaldehyde into the 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol obtained in the step (2), reacting at 50-80 ℃ for 2-3 h, cooling, extracting with ethyl acetate, distilling the oil phase under reduced pressure, and drying to obtain a venlafaxine impurity E.
2. The method of claim 1, wherein the venlafaxine impurity E is prepared by: the quenching acid in the step (1) and the quenching acid in the step (2) are hydrochloric acid, sulfuric acid, formic acid or acetic acid.
3. The method of claim 1, wherein the venlafaxine impurity E is prepared by: the strong base in the step (1) is sodium hydroxide, and the mass ratio of the strong base to the 4-methoxybenzyl acetonitrile is 1: 1.
4. the method of claim 1, wherein the venlafaxine impurity E is prepared by: the mass ratio of the cyclohexanone to the 4-methoxybenzyl acetonitrile in the step (1) is 1-3: 1.
5. the method of claim 1, wherein the venlafaxine impurity E is prepared by: in the step (2), the mass ratio of aluminum trichloride to 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol is 2.2-5.5: 1, the mass ratio of sodium borohydride to 1- [ 2-cyano-1- (4-methoxyphenyl) ethyl ] cyclohexanol is 2-5: 1.
6. the method of claim 1, wherein the venlafaxine impurity E is prepared by: in the step (3), the mass ratio of formic acid to 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol is 3-10: 1, and the mass ratio of formaldehyde to 1- [ 2-amino-1- (4-methoxyphenyl) ethyl ] cyclohexanol is 3-10: 1.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010679913.6A CN111675671A (en) | 2020-07-15 | 2020-07-15 | Preparation method of venlafaxine impurity E |
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| CN202010679913.6A CN111675671A (en) | 2020-07-15 | 2020-07-15 | Preparation method of venlafaxine impurity E |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116354835A (en) * | 2023-03-02 | 2023-06-30 | 浙江普洛家园药业有限公司 | Preparation method of venlafaxine hydrochloride EP impurity H |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007049302A2 (en) * | 2005-10-28 | 2007-05-03 | Ind-Swift Laboratories Limited | An improved process for the preparation of pure venlafaxine |
| US20120253074A1 (en) * | 2009-12-16 | 2012-10-04 | Pharmathen S.A. | Process for the preparation of o-desmethyl-venlafaxine and salts thereof |
| CN103483210A (en) * | 2012-06-13 | 2014-01-01 | 成都弘达药业有限公司 | New compound and preparation method thereof |
-
2020
- 2020-07-15 CN CN202010679913.6A patent/CN111675671A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007049302A2 (en) * | 2005-10-28 | 2007-05-03 | Ind-Swift Laboratories Limited | An improved process for the preparation of pure venlafaxine |
| US20120253074A1 (en) * | 2009-12-16 | 2012-10-04 | Pharmathen S.A. | Process for the preparation of o-desmethyl-venlafaxine and salts thereof |
| CN103483210A (en) * | 2012-06-13 | 2014-01-01 | 成都弘达药业有限公司 | New compound and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116354835A (en) * | 2023-03-02 | 2023-06-30 | 浙江普洛家园药业有限公司 | Preparation method of venlafaxine hydrochloride EP impurity H |
| CN116354835B (en) * | 2023-03-02 | 2025-02-18 | 浙江普洛家园药业有限公司 | Preparation method of venlafaxine hydrochloride EP impurity H |
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Application publication date: 20200918 |