CN116354835A - Preparation method of venlafaxine hydrochloride EP impurity H - Google Patents
Preparation method of venlafaxine hydrochloride EP impurity H Download PDFInfo
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- CN116354835A CN116354835A CN202310189233.XA CN202310189233A CN116354835A CN 116354835 A CN116354835 A CN 116354835A CN 202310189233 A CN202310189233 A CN 202310189233A CN 116354835 A CN116354835 A CN 116354835A
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- venlafaxine hydrochloride
- methoxyphenylacetonitrile
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- 229960002416 venlafaxine hydrochloride Drugs 0.000 title claims abstract description 41
- 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 41
- OUCSEDFVYPBLLF-KAYWLYCHSA-N 5-(4-fluorophenyl)-1-[2-[(2r,4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-n,4-diphenyl-2-propan-2-ylpyrrole-3-carboxamide Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@H]2OC(=O)C[C@H](O)C2)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 OUCSEDFVYPBLLF-KAYWLYCHSA-N 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- PACGLQCRGWFBJH-UHFFFAOYSA-N 2-(4-methoxyphenyl)acetonitrile Chemical compound COC1=CC=C(CC#N)C=C1 PACGLQCRGWFBJH-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 16
- -1 2-amino-1 (4-methoxyphenyl) ethyl Chemical group 0.000 claims abstract description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 239000001257 hydrogen Substances 0.000 claims abstract description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 11
- 238000011282 treatment Methods 0.000 claims abstract description 9
- 238000005859 coupling reaction Methods 0.000 claims abstract description 8
- 230000009471 action Effects 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 13
- RPNNPZHFJPXFQS-UHFFFAOYSA-N methane;rhodium Chemical compound C.[Rh] RPNNPZHFJPXFQS-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 8
- 150000007524 organic acids Chemical class 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 239000007868 Raney catalyst Substances 0.000 claims description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical group [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 4
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 4
- 229910017052 cobalt Inorganic materials 0.000 claims description 4
- 239000010941 cobalt Substances 0.000 claims description 4
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- 239000012752 auxiliary agent Substances 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- NCPHGZWGGANCAY-UHFFFAOYSA-N methane;ruthenium Chemical compound C.[Ru] NCPHGZWGGANCAY-UHFFFAOYSA-N 0.000 claims description 3
- 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 2
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims 1
- 229940098779 methanesulfonic acid Drugs 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000000926 separation method Methods 0.000 abstract description 3
- 238000011403 purification operation Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000012535 impurity Substances 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 229960000583 acetic acid Drugs 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 239000012362 glacial acetic acid Substances 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000011259 mixed solution Substances 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 229960004688 venlafaxine Drugs 0.000 description 5
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 5
- 150000002466 imines Chemical class 0.000 description 4
- 208000024714 major depressive disease Diseases 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 208000011688 Generalised anxiety disease Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 208000029364 generalized anxiety disease Diseases 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 208000019906 panic disease Diseases 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- ORTPEEDBOZIXNC-UHFFFAOYSA-N 2-(4-methoxyphenyl)ethyl methanesulfonate Chemical compound COC1=CC=C(CCOS(C)(=O)=O)C=C1 ORTPEEDBOZIXNC-UHFFFAOYSA-N 0.000 description 1
- IUUULXXWNYKJSL-UHFFFAOYSA-N 4-methoxy-alpha-methylbenzyl alcohol Chemical compound COC1=CC=C(C(C)O)C=C1 IUUULXXWNYKJSL-UHFFFAOYSA-N 0.000 description 1
- NRPFNQUDKRYCNX-UHFFFAOYSA-N 4-methoxyphenylacetic acid Chemical compound COC1=CC=C(CC(O)=O)C=C1 NRPFNQUDKRYCNX-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 102100038736 Histone H3.3C Human genes 0.000 description 1
- 101001031505 Homo sapiens Histone H3.3C Proteins 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 206010041250 Social phobia Diseases 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 208000037870 generalized anxiety Diseases 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000009245 menopause Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 229940127221 norepinephrine reuptake inhibitor Drugs 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000011519 second-line treatment Methods 0.000 description 1
- 239000003775 serotonin noradrenalin reuptake inhibitor Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 230000001457 vasomotor Effects 0.000 description 1
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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
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of medicine organic synthesis, and discloses a preparation method of venlafaxine hydrochloride EP impurity H, which comprises the following steps: 1- (2-amino-1 (4-methoxyphenyl) ethyl) cyclohex-1-ol and 4-methoxyphenylacetonitrile are taken as raw materials, and hydrogenation coupling reaction is carried out under the action of a hydrogenation catalyst and hydrogen to prepare the venlafaxine hydrochloride EP impurity H. The raw materials of the whole synthesis route are easy to obtain, the conversion rate is high, the separation and purification operation of the post-treatment is simple and easy to implement, and the prepared product has higher purity.
Description
Technical Field
The invention relates to the technical field of medicine organic synthesis, in particular to a preparation method of venlafaxine hydrochloride EP impurity H.
Background
Venlafaxine (affexor) is an antidepressant in the 5-hydroxytryptamine norepinephrine reuptake inhibitor (SNRI) class of drugs. Its role is primarily to retain more active neurotransmitters in the synapse by blocking the transport proteins involved in the reuptake of the neurotransmitters 5-hydroxytryptamine and norepinephrine. Venlafaxine is formally approved for the treatment of Major Depressive Disorder (MDD), generalized Anxiety Disorder (GAD), social anxiety disorder, and panic disorder. Canadian clinical practice guidelines, as of 2014, suggest venlafaxine as a first line treatment regimen for the treatment of generalized anxiety, social anxiety, panic disorder, major Depressive Disorder (MDD), and consider it as a second line treatment regimen (OCD) for the treatment of obsessive-compulsive disorder. Venlafaxine may also be used to prevent migraine, alleviate vasomotor symptoms 13 associated with menopause and manage neuropathic pain (although little evidence suggests that this is effective).
Venlafaxine was marketed in U.S. under 12 months 1993 and in japan under 2015 under 12 months. The medicine class A is marketed in China.
The quality standard of the venlafaxine hydrochloride of European pharmacopoeia 7.0 is listed with the impurity with the number of A-G, and the structural formula is as follows respectively:
xufeng, yang Kai, etc., in journal of the Chinese medical industry, 2013,44 (7), a process for the preparation of venlafaxine hydrochloride EP impurity A/C/D/E/F/G has been reported. However, there are only few reports on the synthesis of venlafaxine hydrochloride, EP impurity H.
The CAS number of the venlafaxine hydrochloride EP impurity H is 1329795-88-1, and the chemical structural formula is as follows:
patent CN103483210a reports a process for the preparation of venlafaxine hydrochloride, a new impurity which is structurally similar to EP impurity H, one methyl more than impurity H. According to this patent, EP impurity H is the previous intermediate for the preparation of this impurity. The structural formula of the impurity is as follows:
according to the method of the patent, the synthetic route for preparing venlafaxine hydrochloride EP impurity H is as follows:
the p-methoxyphenylacetonitrile is firstly hydrolyzed into p-methoxyphenylacetic acid under alkaline conditions, then reduced into p-methoxyphenylethanol by sodium borohydride/boron trifluoride diethyl ether, then reacted with methylsulfonyl chloride to generate 2- (4-methoxy-phenyl) -ethanol methane sulfonate, and further subjected to ammonolysis reaction with 1- (2-amino-1- (4-methoxyphenyl) ethyl) cyclohex-1-ol in acetonitrile and sodium bicarbonate solution to obtain venlafaxine hydrochloride Xin Zazhi H.
By using the method, the p-methoxyphenylacetonitrile is taken as a raw material, and 4 steps of reactions are needed to synthesize the venlafaxine hydrochloride Xin Zazhi H.
Disclosure of Invention
The invention provides a preparation method of a Venlafaxine hydrochloride Xin Zazhi H for solving the technical problems of long process steps, high product separation difficulty and low total yield and purity in the prior art. The specific technical scheme of the invention is as follows:
a method for preparing venlafaxine hydrochloride EP impurity H, which comprises the following steps:
under the action of a hydrogenation catalyst and hydrogen, carrying out hydrogenation coupling reaction on 1- (2-amino-1- (4-methoxyphenyl) ethyl) cyclohexane-1-alcohol and 4-methoxyphenylacetonitrile in an alcohol solvent, and carrying out post-treatment after the reaction is finished to obtain the venlafaxine hydrochloride EP impurity H.
The synthetic route of the process is as follows:
the possible reaction mechanisms of the present invention are as follows: firstly, 4-methoxyphenylacetonitrile 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) cyclohex-1-ol, one molecule of ammonia is removed to generate an imine coupling intermediate, and then the imine coupling intermediate is reduced in the presence of hydrogen to obtain the venlafaxine hydrochloride EP impurity H.
The method for preparing the venlafaxine hydrochloride Xin Zazhi H has short process steps, and the post-treatment separation and purification operation is simple and easy to implement, and the prepared target product has higher purity.
In the invention, the type of hydrogenation catalyst has a great influence on the reaction result, and preferably, the hydrogenation catalyst is Raney nickel, raney cobalt, palladium carbon, platinum carbon, rhodium carbon or ruthenium carbon, and the dosage of the hydrogenation catalyst is 2-10wt% of the mass of the 4-methoxy benzyl cyanide; most preferably, the hydrogenation catalyst is rhodium carbon, and the loading of the rhodium carbon is 5-10%.
Preferably, the alcohol solvent is one or more of methanol, ethanol, isopropanol, butanol and isobutanol.
Preferably, organic acid is also added as an auxiliary agent during the reaction. The addition of the auxiliary agent can promote the reaction, and as a further preferable mode, the organic acid is formic acid, acetic acid, propionic acid, methyl sulfonic acid or p-toluenesulfonic acid, and the mass ratio of the organic acid to the 4-methoxyphenylacetonitrile is 0.3-1.0:1.
Preferably, the reaction temperature of the hydrogenation coupling reaction is 20-80 ℃ and the reaction time is 2-40 hours.
The pressure of the hydrogen gas is preferably in the range of 0.1 to 3.0MPa, more preferably 0.5 to 1.0MPa.
Preferably, the molar ratio of the 1- (2-amino-1- (4-methoxyphenyl) ethyl) cyclohex-1-ol to the 4-methoxyphenylacetonitrile is 1.1 to 1.3:1.
preferably, the post-treatment process is as follows:
cooling, filtering to remove the hydrogenation catalyst, adding alkali into the filtrate to adjust the pH value to 10-11, concentrating under reduced pressure, and carrying out column chromatography on the concentrated solution to obtain the venlafaxine hydrochloride EP impurity H. As a further preferred, the base is sodium hydroxide.
Compared with the prior art, the invention has the following advantages:
the method for preparing the venlafaxine hydrochloride EP impurity H has the advantages of short synthesis route, high total yield, few operation steps, high purity of the prepared impurity and suitability for serving as an impurity reference substance of the venlafaxine hydrochloride.
Detailed Description
FIG. 1 is a `H NMR spectrum of venlafaxine hydrochloride EP impurity H obtained in example 5;
FIG. 2 shows the venlafaxine hydrochloride as impurity H obtained in example 5 13 CNMR profile;
FIG. 3 is a mass spectrum of venlafaxine hydrochloride EP impurity H obtained in example 5.
Detailed Description
The invention is further described below with reference to examples.
Example 1
Venlafaxine hydrochloride EP impurity H was prepared by the following steps:
(1) And (3) addition reduction reaction:
into a 50mL autoclave, 4.2g of 1- (2-amino-1- (4-methoxyphenyl) ethyl) cyclohex-1-ol (FW 249, 16.8 mmol), 2.0g of 4-methoxyphenylacetonitrile (FW 147, 13.6 mmol), 0.2g of Raney nickel, 20mL of methanol, 0.8g of glacial acetic acid were charged, and the autoclave was sealed. Charging hydrogen for three times, hydrogenating to 1.0MPa, heating to 50 ℃ and stirring for reaction for 24 hours.
(2) Purifying and post-treating:
cooling, filtering to remove Raney nickel, adding sodium hydroxide into the filtrate to adjust pH to 10-11, and concentrating under reduced pressure. The residue was purified by passing through 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 fractions were collected and concentrated to dryness under reduced pressure to give venlafaxine hydrochloride as an EP impurity H3.3 g (FW 383.5,8.6 mmol), 97.1% purity (HPLC) in 63.3% yield.
Example 2
Venlafaxine hydrochloride EP impurity H was prepared by the following steps:
(1) And (3) addition reduction reaction:
into a 50ml autoclave, 4.2g of 1- (2-amino-1- (4-methoxyphenyl) ethyl) cyclohex-1-ol (FW 249, 16.8 mmol), 2.0g of 4-methoxyphenylacetonitrile (FW 147, 13.6 mmol), 0.2g of Raney cobalt, 20ml of methanol, 0.8g of glacial acetic acid were charged, and the autoclave was sealed. Charging hydrogen for three times, hydrogenating to 1.0MPa, heating to 50 ℃ and stirring for reaction for 24 hours.
(2) Purifying and post-treating:
cooling, filtering to remove Raney cobalt, adding sodium hydroxide into the filtrate to adjust pH to 10-11, and concentrating under reduced pressure. The residue was purified by passing through 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 fractions were collected and concentrated to dryness under reduced pressure to give venlafaxine hydrochloride as an EP impurity H3.5 g (FW 383.5,9.1 mmol), 97.6% purity (HPLC) in 66.9% yield.
Example 3
Venlafaxine hydrochloride EP impurity H was prepared by the following steps:
(1) And (3) addition reduction reaction:
into a 50ml autoclave, 4.2g of 1- (2-amino-1- (4-methoxyphenyl) ethyl) cyclohex-1-ol (FW 249, 16.8 mmol), 2.0g of 4-methoxyphenylacetonitrile (FW 147, 13.6 mmol), 0.2g of 10% palladium on charcoal, 20ml of methanol, 0.8g of glacial acetic acid were charged, and the autoclave was sealed. Charging hydrogen for three times, hydrogenating to 1.0MPa, heating to 50 ℃ and stirring for reaction for 24 hours.
(2) Purifying and post-treating:
cooling, filtering to remove palladium carbon, adding sodium hydroxide into the filtrate to adjust pH to 10-11, and concentrating under reduced pressure. The residue was purified by passing through 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 fractions were collected and concentrated to dryness under reduced pressure to give venlafaxine hydrochloride as an EP impurity H3.9 g (FW 383.5, 10.2 mmol), 98.3% purity (HPLC) in 75.3% yield.
Example 4
Venlafaxine hydrochloride EP impurity H was prepared by the following steps:
(1) And (3) addition reduction reaction:
into a 50ml autoclave, 4.2g of 1- (2-amino-1- (4-methoxyphenyl) ethyl) cyclohex-1-ol (FW 249, 16.8 mmol), 2.0g of 4-methoxyphenylacetonitrile (FW 147, 13.6 mmol), 0.2g of 10% ruthenium char, 20ml of methanol, 0.8g of glacial acetic acid were charged, and the autoclave was sealed. Charging hydrogen for three times, hydrogenating to 1.0MPa, heating to 50 ℃ and stirring for reaction for 24 hours.
(2) Purifying and post-treating:
cooling, filtering to remove ruthenium carbon, adding sodium hydroxide into the filtrate to adjust pH to 10-11, and concentrating under reduced pressure. The residue was purified by passing through 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 fractions were collected and concentrated to dryness under reduced pressure to give venlafaxine hydrochloride as an EP impurity H4.1 g (FW 383.5, 10.7 mmol), 98.5% purity (HPLC) in 78.7% yield.
Example 5
Venlafaxine hydrochloride EP impurity H was prepared by the following steps:
(1) And (3) addition reduction reaction:
into a 50ml autoclave, 4.2g of 1- (2-amino-1- (4-methoxyphenyl) ethyl) cyclohex-1-ol (FW 249, 16.8 mmol), 2.0g of 4-methoxyphenylacetonitrile (FW 147, 13.6 mmol), 0.2g of 10% rhodium charcoal, 20ml of isopropyl alcohol, 0.8g of glacial acetic acid were charged, and the autoclave was sealed. Charging hydrogen for three times, hydrogenating to 1.0MPa, heating to 50 ℃ and stirring for reaction for 24 hours.
(2) Purifying and post-treating:
cooling, filtering to remove rhodium carbon, adding sodium hydroxide into the filtrate to adjust pH to 10-11, and concentrating under reduced pressure. The residue was purified by passing through 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 fractions were collected and concentrated to dryness under reduced pressure to give venlafaxine hydrochloride as an EP impurity H4.2 g (FW 383.5, 10.9 mmol), 98.6% purity (HPLC) in 80.1% yield. The characterization map of the product is shown in figures 1-3.
Example 6
Venlafaxine hydrochloride EP impurity H was prepared by the following steps:
(1) And (3) addition reduction reaction:
into a 50ml autoclave, 4.2g of 1- (2-amino-1- (4-methoxyphenyl) ethyl) cyclohex-1-ol (FW 249, 16.8 mmol), 2.0g of 4-methoxyphenylacetonitrile (FW 147, 13.6 mmol), 0.2g of 10% rhodium charcoal, 20ml of isopropyl alcohol, 0.8g of glacial acetic acid were charged, and the autoclave was sealed. Charging hydrogen for three times, hydrogenating to 0.5MPa, heating to 50 ℃ and stirring for reaction for 24 hours.
(2) Purifying and post-treating:
cooling, filtering to remove rhodium carbon, adding sodium hydroxide into the filtrate to adjust pH to 10-11, and concentrating under reduced pressure. The residue was purified by passing through 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 fractions were collected and concentrated to dryness under reduced pressure to give venlafaxine hydrochloride as an EP impurity H4.0 g (FW 383.5, 10.5 mmol), 98.3% purity (HPLC) in 77.2% yield.
Example 7
Venlafaxine hydrochloride EP impurity H was prepared by the following steps:
(1) And (3) addition reduction reaction:
into a 50ml autoclave, 4.2g of 1- (2-amino-1- (4-methoxyphenyl) ethyl) cyclohex-1-ol (FW 249, 16.8 mmol), 2.0g of 4-methoxyphenylacetonitrile (FW 147, 13.6 mmol), 0.2g of 10% rhodium charcoal, 20ml of isopropyl alcohol, 0.8g of glacial acetic acid were charged, and the autoclave was sealed. Charging hydrogen for three times, hydrogenating to 1.0MPa, heating to 60 ℃ and stirring for reaction for 24 hours.
(2) Purifying and post-treating:
cooling, filtering to remove rhodium carbon, adding sodium hydroxide into the filtrate to adjust pH to 10-11, and concentrating under reduced pressure. The residue was purified by passing through 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 fractions were collected and concentrated to dryness under reduced pressure to give venlafaxine hydrochloride as an EP impurity H3.9 g (FW 383.5, 10.2 mmol), 98.1% purity (HPLC) in 75.0% yield.
The raw materials and equipment used in the invention are common raw materials and equipment in the field unless specified otherwise; the methods used in the present invention are conventional in the art unless otherwise specified.
The foregoing description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and any simple modification, variation and equivalent transformation of the above embodiment according to the technical substance of the present invention still fall within the scope of the technical solution of the present invention.
Claims (10)
1. The preparation method of the venlafaxine hydrochloride EP impurity H is characterized by comprising the following steps of:
under the action of a hydrogenation catalyst and hydrogen, carrying out hydrogenation coupling reaction on 1- (2-amino-1- (4-methoxyphenyl) ethyl) cyclohexane-1-alcohol and 4-methoxyphenylacetonitrile in an alcohol solvent, and carrying out post-treatment after the reaction is finished to obtain the venlafaxine hydrochloride EP impurity H.
2. The preparation method according to claim 1, wherein 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-methoxyphenylacetonitrile.
3. The method of claim 1, wherein the alcoholic solvent is one or more of methanol, ethanol, isopropanol, butanol, and isobutanol.
4. The process according to claim 1, wherein an organic acid is added as an auxiliary agent during the reaction.
5. The method according to claim 4, wherein 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-methoxyphenylacetonitrile is 0.3-1.0:1.
6. The process according to claim 1, wherein the hydrogenation coupling reaction is carried out at a temperature of 20 to 80℃for a period of 2 to 40 hours.
7. The method of claim 1, wherein the hydrogen gas has a pressure in the range of 0.1 to 3.0MPa.
8. The process according to claim 1, wherein the molar ratio of 1- (2-amino-1- (4-methoxyphenyl) ethyl) cyclohex-1-ol to 4-methoxyphenylacetonitrile is from 1.1 to 1.3:1.
9. the method of claim 1, wherein the post-treatment process is as follows:
cooling, filtering to remove the hydrogenation catalyst, adding alkali into the filtrate to adjust the pH value to 10-11, concentrating under reduced pressure, and carrying out column chromatography on the concentrated solution to obtain the venlafaxine hydrochloride EP impurity H.
10. The method of claim 9, wherein the base is sodium hydroxide.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103483210A (en) * | 2012-06-13 | 2014-01-01 | 成都弘达药业有限公司 | New compound and preparation method thereof |
| CN111675671A (en) * | 2020-07-15 | 2020-09-18 | 苏州第四制药厂有限公司 | Preparation method of venlafaxine impurity E |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103483210A (en) * | 2012-06-13 | 2014-01-01 | 成都弘达药业有限公司 | New compound and preparation method thereof |
| CN111675671A (en) * | 2020-07-15 | 2020-09-18 | 苏州第四制药厂有限公司 | Preparation method of venlafaxine impurity E |
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| Title |
|---|
| HIRAM RANGEL: "Structural features of N-benzylated-b-amino acid methyl esters essential for enantiodifferentiation by lipase B from Candida antarctica in hydrolytic reactions", 《TETRAHEDRON: ASYMMETRY》, 31 December 2015 (2015-12-31), pages 325 * |
| KRISZTINA LÉVAY ETAL: "Heterogeneous Catalytic Hydrogenation of 3‑Phenylpropionitrile over Palladium on Carbon", 《ACS OMEGA》, 31 December 2020 (2020-12-31), pages 5487 * |
| SAITO, YUKI: "Continuous-Flow Synthesis of (R)-Tamsulosin Utilizing Sequential Heterogeneous Catalysis", 《ANGEWANDTE CHEMIE, INTERNATIONAL EDITION》, 31 December 2022 (2022-12-31), pages 1 - 6 * |
| SUMEET K. SHARMA ETAL: "Pt/C catalysed direct reductive amination of nitriles with primary amines in a continuous flow multichannel microreactor", 《CATAL. SCI. TECHNOL》, 31 December 2013 (2013-12-31), pages 85 * |
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