A preparation method of venlafaxine hydrochloride EP impurity H
Through the hydrogenation coupling reaction of hydrogenation catalyst in alcohol solvents, the process steps were successfully shortened and the purity was improved, and the problems of long process steps, difficult separation and low purity in the prior art were solved, and the efficient preparation of hydrochloric acid was achieved Effect of venlafaxine EP impurity H.
Patent Information
- Application Number
- CN202310189233.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-03-02
- Publication Date
- 2025-02-18
- Estimated Expiration
- 2043-03-02
AI Technical Summary
The prior art process has long steps, difficult to separate product, low total yield and purity, making it difficult to effectively prepare venlafaxine hydrochloride EP impurity H.
Using a hydrogenation catalyst and hydrogen in an alcohol solvent, 1-(2-amino-1-(4-methoxyphenyl)ethyl)cyclohex-1-ol and 4-methyl The reaction of oxyphenylacetonitrile gave venlafaxine hydrochloride EP impurity H.
The process steps are shortened, the separation and purification operations are simplified, and the purity and total yield of the target product are improved. It is suitable for use as impurity control materials for venlafaxine hydrochloride.
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Abstract
Description
Technical Field
[0001] The invention relates to the technical field of pharmaceutical organic synthesis, and in particular to a method for preparing venlafaxine hydrochloride EP impurity H. Background Art
[0002] Venlafaxine (Effexor) is an antidepressant in the serotonin norepinephrine reuptake inhibitor (SNRI) class of drugs. It works primarily by blocking transporters involved in the reuptake of the neurotransmitters serotonin and norepinephrine, thereby retaining more active neurotransmitters in the synapse. Venlafaxine is officially approved for the treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), social anxiety disorder, and panic disorder. As of 2014, Canadian clinical practice guidelines recommend venlafaxine as a first-line treatment for generalized anxiety, social anxiety, panic disorder, major depressive disorder (MDD), and consider it as a second-line treatment for obsessive-compulsive disorder (OCD). Venlafaxine may also be used to prevent migraines, reduce vasomotor symptoms associated with menopause13, and manage neuropathic pain (although there is only minimal evidence that this is effective).
[0003] Venlafaxine was approved for marketing in the United States in December 1993 and in Japan in December 2015. It is already available in China as a Class A drug covered by medical insurance.
[0004] The quality standard of venlafaxine hydrochloride in European Pharmacopoeia 7.0 includes impurities numbered AG, and their structural formulas are as follows:
[0005]
[0006] Yu Xufeng, Yang Kai, et al., reported the preparation method of venlafaxine hydrochloride EP impurities A / C / D / E / F / G in Chinese Journal of Pharmaceutical Industry, 2013, 44(7). However, there was no report on the synthesis method of venlafaxine hydrochloride EP impurity H.
[0007] The CAS number of Venlafaxine Hydrochloride EP Impurity H is 1329795-88-1, and the chemical structure is as follows:
[0008]
[0009] Patent CN103483210A reports a method for preparing a new impurity of venlafaxine hydrochloride. The new impurity has a similar structure to EP impurity H, but has one more methyl group than impurity H. According to the patent, EP impurity H is the previous intermediate in the preparation of the impurity. The structural formula of the impurity is as follows:
[0010]
[0011] According to the method of the patent, the synthetic route for preparing the compound of the structural formula of venlafaxine hydrochloride EP impurity H is as follows:
[0012]
[0013] p-Methoxyphenylacetonitrile is first hydrolyzed to p-methoxyphenylacetic acid under alkaline conditions, and then reduced to p-methoxyphenylethanol with sodium borohydride / boron trifluoride etherate, and then reacted with methanesulfonyl chloride to generate 2-(4-methoxy-phenyl)-ethanol methanesulfonate, and then further reacted with 1-(2-amino-1-(4-methoxyphenyl)ethyl)cyclohexan-1-ol in acetonitrile and sodium bicarbonate solution for aminolysis to obtain venlafaxine hydrochloride impurity H.
[0014] Using this method, 4 steps of reaction are required to synthesize venlafaxine hydrochloride impurity H using p-methoxyphenylacetonitrile as raw material. Summary of the invention
[0015] In order to solve the technical problems of the prior art, such as long process steps, great difficulty in product separation, low total yield and low purity, the present invention provides a method for preparing venlafaxine hydrochloride impurity H. The specific technical scheme of the present invention is:
[0016] A method for preparing venlafaxine hydrochloride EP impurity H comprises the following steps:
[0017] Under the action of a hydrogenation catalyst and hydrogen, 1-(2-amino-1-(4-methoxyphenyl)ethyl)cyclohexan-1-ol and 4-methoxyphenylacetonitrile undergo a hydrogenation coupling reaction in an alcohol solvent, and after the reaction is completed, the venlafaxine hydrochloride EP impurity H is obtained through post-treatment.
[0018] The process synthesis route is as follows:
[0019]
[0020] The possible reaction mechanism of the present invention is as follows: first, 4-methoxybenzyl cyanide is subjected to catalytic hydrogenation to generate an imine intermediate, the imine intermediate is subjected to coupling reaction with 1-(2-amino-1-(4-methoxyphenyl)ethyl)cyclohexan-1-ol and one molecule of ammonia is removed to generate an imine coupling intermediate, and then reduced in the presence of hydrogen to obtain the venlafaxine hydrochloride EP impurity H.
[0021]
[0022] The method of the present invention is used to prepare the venlafaxine hydrochloride impurity H, the process steps are short, and the separation and purification operation of the post-treatment is simple and easy, and the obtained target product has high purity.
[0023] In the present invention, the type of hydrogenation catalyst has a great influence on the reaction result. Preferably, the hydrogenation catalyst is Raney nickel, Raney cobalt, palladium carbon, platinum carbon, rhodium carbon or ruthenium carbon, and the amount of the hydrogenation catalyst is 2-10wt% of the mass of the 4-methoxybenzeneacetonitrile; most preferably, the hydrogenation catalyst is rhodium carbon, and the loading amount of the rhodium carbon is 5-10%.
[0024] Preferably, the alcohol solvent is one or more of methanol, ethanol, isopropanol, butanol and isobutanol.
[0025] Preferably, an organic acid is added as an auxiliary agent during the reaction. The addition of the auxiliary agent can promote the reaction. As a further preference, the organic acid is formic acid, acetic acid, propionic acid, methanesulfonic acid or p-toluenesulfonic acid, and the mass ratio of the organic acid to the 4-methoxybenzeneacetonitrile is 0.3 to 1.0:1.
[0026] Preferably, the reaction temperature of the hydrogenation coupling reaction is 20 to 80° C., and the reaction time is 2 to 40 hours.
[0027] Preferably, the pressure range of the hydrogen is 0.1 to 3.0 MPa, more preferably 0.5 to 1.0 MPa.
[0028] Preferably, the molar ratio of the 1-(2-amino-1-(4-methoxyphenyl)ethyl)cyclohexan-1-ol to 4-methoxyphenylacetonitrile is 1.1 to 1.3:1.
[0029] Preferably, the post-processing process is as follows:
[0030] The hydrogenation catalyst is removed by cooling and filtering, the filtrate is adjusted to pH 10-11 by adding alkali, and concentrated under reduced pressure, and the concentrate is subjected to column chromatography to obtain the venlafaxine hydrochloride EP impurity H. As a further preferred embodiment, the alkali is sodium hydroxide.
[0031] Compared with the prior art, the present invention has the following advantages:
[0032] The method of the invention is used to prepare the venlafaxine hydrochloride EP impurity H, which has a short synthesis route, a high total yield, and fewer operation steps. The prepared impurity has high purity and is suitable for being used as an impurity reference substance of venlafaxine hydrochloride. DETAILED DESCRIPTION
[0034] Figure 1 This is the 'H NMR spectrum of the venlafaxine hydrochloride EP impurity H obtained in Example 5;
[0035] Figure 2 The impurity H of venlafaxine hydrochloride EP obtained in Example 5 13 CNMR spectrum;
[0036] Figure 3 This is the mass spectrum of the venlafaxine hydrochloride EP impurity H obtained in Example 5. DETAILED DESCRIPTION
[0037] The present invention will be further described below in conjunction with the embodiments.
[0038] Example 1
[0039] Venlafaxine hydrochloride EP impurity H was prepared by the following steps:
[0040] (1) Addition reduction reaction:
[0041] 4.2 g of 1-(2-amino-1-(4-methoxyphenyl)ethyl)cyclohexan-1-ol (FW249, 16.8 mmol), 2.0 g of 4-methoxyphenylacetonitrile (FW147, 13.6 mmol), 0.2 g of Raney nickel, 20 ml of methanol, and 0.8 g of glacial acetic acid were placed in a 50 mL autoclave, and the autoclave was sealed. The autoclave was filled with hydrogen for three times, hydrogenated to 1.0 MPa, heated to 50°C, and stirred for reaction for 24 hours.
[0042] (2) Post-purification treatment:
[0043] The mixture was cooled and filtered to remove Raney nickel. Sodium hydroxide was added to the filtrate to adjust the pH to 10-11 and the mixture was concentrated under reduced pressure. The residue was purified by a 200-mesh silica gel column, and a mixed solution of ethyl acetate and n-hexane in a volume ratio of 1:8 was used as the eluent. The higher purity fraction was collected and concentrated to dryness under reduced pressure to obtain 3.3 g (FW383.5, 8.6 mmol) of venlafaxine hydrochloride EP impurity H, with a purity of 97.1% (HPLC) and a yield of 63.3%.
[0044] Example 2
[0045] Venlafaxine hydrochloride EP impurity H was prepared by the following steps:
[0046] (1) Addition reduction reaction:
[0047] 4.2 g of 1-(2-amino-1-(4-methoxyphenyl)ethyl)cyclohexan-1-ol (FW249, 16.8 mmol), 2.0 g of 4-methoxyphenylacetonitrile (FW147, 13.6 mmol), 0.2 g of Raney cobalt, 20 ml of methanol, and 0.8 g of glacial acetic acid were placed in a 50 ml autoclave, and the autoclave was sealed. The reaction was replaced with hydrogen three times, hydrogenation was added to 1.0 MPa, and the temperature was raised to 50°C and stirred for reaction for 24 hours.
[0048] (2) Post-purification treatment:
[0049] Cool and filter to remove the Raney cobalt, add sodium hydroxide to the filtrate to adjust the pH to 10-11, and concentrate under reduced pressure. The residue is purified by a 200-mesh silica gel column, and the eluent is a mixed solution of ethyl acetate and n-hexane in a volume ratio of 1:8. Collect the higher purity fraction, and concentrate to dryness under reduced pressure to obtain 3.5 g (FW383.5, 9.1 mmol) of venlafaxine hydrochloride EP impurity H, with a purity of 97.6% (HPLC) and a yield of 66.9%.
[0050] Example 3
[0051] Venlafaxine hydrochloride EP impurity H was prepared by the following steps:
[0052] (1) Addition reduction reaction:
[0053] In a 50 ml autoclave, 4.2 g of 1-(2-amino-1-(4-methoxyphenyl)ethyl)cyclohexan-1-ol (FW249, 16.8 mmol), 2.0 g of 4-methoxyphenylacetonitrile (FW147, 13.6 mmol), 0.2 g of 10% palladium on carbon, 20 ml of methanol, and 0.8 g of glacial acetic acid were placed. The autoclave was sealed, and hydrogen was charged and replaced three times, hydrogenated to 1.0 MPa, and heated to 50°C for 24 hours with stirring.
[0054] (2) Post-purification treatment:
[0055] The temperature was lowered and filtered to remove palladium carbon. Sodium hydroxide was added to the filtrate to adjust the pH to 10-11, and the mixture was concentrated under reduced pressure. The residue was purified by a 200-mesh silica gel column, and the eluent was a mixed solution of ethyl acetate and n-hexane in a volume ratio of 1:8. The higher purity fraction was collected and concentrated to dryness under reduced pressure to obtain 3.9 g (FW383.5, 10.2 mmol) of venlafaxine hydrochloride EP impurity H, with a purity of 98.3% (HPLC) and a yield of 75.3%.
[0056] Example 4
[0057] Venlafaxine hydrochloride EP impurity H was prepared by the following steps:
[0058] (1) Addition reduction reaction:
[0059] 4.2 g of 1-(2-amino-1-(4-methoxyphenyl)ethyl)cyclohexan-1-ol (FW249, 16.8 mmol), 2.0 g of 4-methoxyphenylacetonitrile (FW147, 13.6 mmol), 0.2 g of 10% ruthenium carbon, 20 ml of methanol, and 0.8 g of glacial acetic acid were placed in a 50 ml autoclave, and the autoclave was sealed. The reaction was carried out by hydrogenation three times, hydrogenation was added to 1.0 MPa, and the temperature was raised to 50°C and stirred for reaction for 24 hours.
[0060] (2) Post-purification treatment:
[0061] The ruthenium carbon was removed by cooling and filtering, and the filtrate was added with sodium hydroxide to adjust the pH to 10-11, and concentrated under reduced pressure. The residue was purified by a 200-mesh silica gel column, and the eluent was a mixed solution of ethyl acetate and n-hexane in a volume ratio of 1:8. The higher purity fraction was collected and concentrated to dryness under reduced pressure to obtain 4.1 g (FW383.5, 10.7 mmol) of venlafaxine hydrochloride EP impurity H, with a purity of 98.5% (HPLC) and a yield of 78.7%.
[0062] Example 5
[0063] Venlafaxine hydrochloride EP impurity H was prepared by the following steps:
[0064] (1) Addition reduction reaction:
[0065] 4.2 g of 1-(2-amino-1-(4-methoxyphenyl)ethyl)cyclohexan-1-ol (FW249, 16.8 mmol), 2.0 g of 4-methoxyphenylacetonitrile (FW147, 13.6 mmol), 0.2 g of 10% rhodium on carbon, 20 ml of isopropanol, and 0.8 g of glacial acetic acid were placed in a 50 ml autoclave, and the autoclave was sealed. The autoclave was filled with hydrogen three times to 1.0 MPa, and the temperature was raised to 50°C and stirred for reaction for 24 hours.
[0066] (2) Post-purification treatment:
[0067] The temperature was lowered and filtered to remove the rhodium carbon. Sodium hydroxide was added to the filtrate to adjust the pH to 10-11, and the mixture was concentrated under reduced pressure. The residue was purified by a 200-mesh silica gel column, and the eluent was a mixed solution of ethyl acetate and n-hexane in a volume ratio of 1:8. The higher purity fraction was collected and concentrated to dryness under reduced pressure to obtain 4.2 g (FW383.5, 10.9 mmol) of venlafaxine hydrochloride EP impurity H, with a purity of 98.6% (HPLC) and a yield of 80.1%. The characterization spectrum of the product is shown in Figures 1 to 3 .
[0068] Example 6
[0069] Venlafaxine hydrochloride EP impurity H was prepared by the following steps:
[0070] (1) Addition reduction reaction:
[0071] 4.2 g of 1-(2-amino-1-(4-methoxyphenyl)ethyl)cyclohexan-1-ol (FW249, 16.8 mmol), 2.0 g of 4-methoxyphenylacetonitrile (FW147, 13.6 mmol), 0.2 g of 10% rhodium carbon, 20 ml of isopropanol, and 0.8 g of glacial acetic acid were placed in a 50 ml autoclave, and the autoclave was sealed. The reaction was replaced with hydrogen three times, hydrogenation was added to 0.5 MPa, and the temperature was raised to 50°C and stirred for reaction for 24 hours.
[0072] (2) Post-purification treatment:
[0073] The temperature was lowered and filtered to remove the rhodium carbon. Sodium hydroxide was added to the filtrate to adjust the pH to 10-11, and the mixture was concentrated under reduced pressure. The residue was purified by a 200-mesh silica gel column, and the eluent was a mixed solution of ethyl acetate and n-hexane in a volume ratio of 1:8. The higher purity fraction was collected and concentrated to dryness under reduced pressure to obtain 4.0 g (FW383.5, 10.5 mmol) of venlafaxine hydrochloride EP impurity H, with a purity of 98.3% (HPLC) and a yield of 77.2%.
[0074] Example 7
[0075] Venlafaxine hydrochloride EP impurity H was prepared by the following steps:
[0076] (1) Addition reduction reaction:
[0077] 4.2 g of 1-(2-amino-1-(4-methoxyphenyl)ethyl)cyclohexan-1-ol (FW249, 16.8 mmol), 2.0 g of 4-methoxyphenylacetonitrile (FW147, 13.6 mmol), 0.2 g of 10% rhodium on carbon, 20 ml of isopropanol, and 0.8 g of glacial acetic acid were placed in a 50 ml autoclave, and the autoclave was sealed. The reaction was replaced with hydrogen three times, hydrogenated to 1.0 MPa, and heated to 60°C for 24 hours with stirring.
[0078] (2) Post-purification treatment:
[0079] The temperature was lowered and filtered to remove the rhodium carbon. Sodium hydroxide was added to the filtrate to adjust the pH to 10-11, and the mixture was concentrated under reduced pressure. The residue was purified by a 200-mesh silica gel column, and the eluent was a mixed solution of ethyl acetate and n-hexane in a volume ratio of 1:8. The higher purity fraction was collected and concentrated to dryness under reduced pressure to obtain 3.9 g (FW383.5, 10.2 mmol) of venlafaxine hydrochloride EP impurity H, with a purity of 98.1% (HPLC) and a yield of 75.0%.
[0080] The raw materials and equipment used in the present invention, unless otherwise specified, are all commonly used raw materials and equipment in the art; the methods used in the present invention, unless otherwise specified, are all conventional methods in the art.
[0081] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any way. Any simple modification, change and equivalent transformation made to the above embodiment based on the technical essence of the present invention still falls within the protection scope of the technical solution of the present invention.
Claims
1. A method for preparing venlafaxine hydrochloride EP impurity H, characterized in that: The following steps are involved: Under the action of a hydrogenation catalyst and hydrogen, 1-(2-amino-1-(4-methoxyphenyl)ethyl)cyclohexan-1-ol and 4-methoxyphenylacetonitrile undergo a hydrogenation coupling reaction in an alcohol solvent, and after the reaction is completed, the venlafaxine hydrochloride EP impurity H is obtained through post-treatment.
2. The preparation method according to claim 1, characterized in that The hydrogenation catalyst is Raney nickel, Raney cobalt, palladium carbon, platinum carbon, rhodium carbon or ruthenium carbon, and the amount of the hydrogenation catalyst is 2-10wt% of the mass of the 4-methoxybenzeneacetonitrile.
3. The preparation method according to claim 1, characterized in that: The alcohol solvent is one or more of methanol, ethanol, isopropanol, butanol and isobutanol.
4. The preparation method according to claim 1, characterized in that: An organic acid is also added as an auxiliary agent during the reaction.
5. The preparation method according to claim 4, characterized in that: The organic acid is formic acid, acetic acid, propionic acid, methanesulfonic acid or p-toluenesulfonic acid, and the mass ratio of the organic acid to the 4-methoxybenzeneacetonitrile is 0.3 to 1.0:
1.
6. The preparation method according to claim 1, characterized in that: The temperature of the hydrogenation coupling reaction is 20 to 80° C., and the reaction time is 2 to 40 hours.
7. The preparation method according to claim 1, characterized in that: The pressure range of the hydrogen is 0.1-3.0 MPa.
8. The preparation method according to claim 1, characterized in that: The molar ratio of the 1-(2-amino-1-(4-methoxyphenyl)ethyl)cyclohexan-1-ol to 4-methoxyphenylacetonitrile is 1.1-1.3:
1.
9. The preparation method according to claim 1, characterized in that: The post-processing process is as follows: The hydrogenation catalyst is removed by cooling and filtering, the filtrate is adjusted to pH 10-11 by adding alkali, and concentrated under reduced pressure. The concentrate is subjected to column chromatography to obtain the venlafaxine hydrochloride EP impurity H.
10. The preparation method according to claim 9, characterized in that: The alkali is sodium hydroxide.
Citation Information
Patent Citations
New compound and preparation method thereof
CN103483210A
Preparation method of venlafaxine impurity E
CN111675671A