CN104478803A - Preparation method of varenicline intermediate and nitroreduction impurity thereof - Google Patents
Preparation method of varenicline intermediate and nitroreduction impurity thereof Download PDFInfo
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- CN104478803A CN104478803A CN201410799025.2A CN201410799025A CN104478803A CN 104478803 A CN104478803 A CN 104478803A CN 201410799025 A CN201410799025 A CN 201410799025A CN 104478803 A CN104478803 A CN 104478803A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
Abstract
The invention discloses a preparation method of a varenicline intermediate and nitroreduction impurity thereof. The preparation method of the varenicline intermediate and nitroreduction impurity thereof comprises the following steps: nitrifying 2,3,4,5-tetrahydro-3-(trifluoroacetyl)-1,5-methano-1H-3-benazepine, hydrogenating Pd/C, and selectively reducing nitryl, thus obtaining a target compound shown in a formula (I). The preparation method of the varenicline intermediate and nitroreduction impurity thereof has the advantages that no pollution is produced to the environment, column chromatography operation is avoided, and yield and purity of a product are improved. The formula (I) is described in the specification.
Description
Technical field
The present invention relates to field of medicine and chemical technology, be specifically related to the preparation method of varenicline intermediate and nitroreduction impurity thereof.
Background technology
Varenicline (Varenicline), commodity are by name freely abundant (Chantix (FDA), Champix (EMA)), are selectivity α
4β
2nAChR hypotype partial agonist, for helping adult's smoking cessation.Developed by Pfizer company and go on the market, first 2006 days were ratified by FDA, and in August, 2008 obtains the SFDA approval of import.
Aspect, market, the main market of varenicline tartrate is in the U.S., and after within 2008, reaching 8.5 hundred million dollars, global marketing climax, sales volume declines all to some extent, and within 2011, global marketing volume reaches 7.6 hundred million dollars, increases 0.05% than 2010 years; China's sales volume of 2011 is 0.0035 hundred million dollars, decreases 49.3% than 2010.
In the synthesis technique of varenicline, " nitro " to be produced on 7 by the impurity of selective reduction (its production process is as follows), in order to be conducive to the control of pharmaceutical production from now on and quality, we are studied the synthetic method of this compound.Find through By consulting literatures, mainly H is applied to the selective reduction of dinitrobenzene
2s/NH
4oH, has been come by the equivalent controlling reagent.But consider the toxic of hydrogen sulfide and the pollution level to air, add that the equivalent of hydrogen sulfide is difficult to control, hydrogen sulfide is when quantity not sufficient, and reaction not exclusively; Excessive a little, continue reaction at once, produce the product of diamino, and the product obtained needs column chromatography purification, so in order to reduce the pollution of air and avoid the operation of column chromatography purification as far as possible, we abandon this method, find better method.
Summary of the invention
The invention reside in the preparation method that a kind of varenicline intermediate is provided, comprise: trifluoromethanesulfonic acid, methylene dichloride are added in reaction flask, dropping concentrated nitric acid stirs, and temperature control dropping compound (II) afterwards room temperature reaction obtains midbody compound (III) in 5 ~ 8 hours
Another object of the present invention is also the method for the nitroreduction impurity providing the varenicline shown in a kind of formula (I), comprises and formula (III) compound is obtained target product through Pd/C hydrogenation selectivity reduction nitro,
Preferably, described preparation method, comprising:
Add in reaction flask by formula III compound, organic solvent and Pd/C, room temperature reaction, hydrogen exchange at least three times, monitoring reaction is complete, filters, dry formula (I) compound.
Preferably, described Pd/C is selected from the Pd/C that water content is 20%, 30%, 40%, 50%, 60% and 70%, more preferably the Pd/C of 60%.
Preferably, described organic solvent is selected from methyl alcohol, ethanol or Virahol, more preferably methyl alcohol.
Preferably, hydrogen donor is selected from ammonium formiate or hydrogen, more preferably hydrogen.
Preferably, described formula (III) compound is obtained by aforesaid method.
Formula I is the impurity of varenicline nitroreduction, selective reduction nitro is carried out first on the basis of intermediate formula (III) compound, and achieve efficient, that high-quality obtains required impurity object, for pharmaceutical production from now on and quality control play an important role.
Through constantly attempting, contriver's Late Cambrian preparation technology of the present invention better can carry out selective reduction to dinitrobenzene, and the product yield obtained is high, and purity is high, decreases the purification process of column chromatography.
Embodiment
Below will the present invention will be further described by specific embodiment.Should be appreciated that, those skilled in the art, based on content disclosed herein, can carry out variously not departing from various amendment in spirit and scope of the invention and improvement to the present invention.They should all drop in the scope of patent protection of claim definition of the application.In addition, should be appreciated that, embodiment provided herein only for illustration of object of the present invention, and should not be construed as restriction of the present invention.
Embodiment 1: the preparation of varenicline intermediate
Trifluoromethanesulfonic acid (1.23g), methylene dichloride (10ml) are added in reaction flask, drip concentrated nitric acid (0.25g) to stir,-50 ~-60 DEG C drip compound (II) (1g) room temperature reaction 6 hours afterwards, TLC monitoring reaction is complete, add water, dichloromethane extraction three times, organic phase is washed, drying, evaporate to dryness obtains compound (III) (1g); TLC point plate is single-point, TLC condition (developping agent normal hexane: ethyl acetate=1:1, Rf=0.3), and detect through HPLC, product purity is 97%.
Embodiment 2: the preparation of selectivity nitroreduction impurity
Compound (III) (1g), methyl alcohol (10mL) and Pd/C (0.1g) (water content is 60%) are added in reaction flask, hydrogen exchange three times, room temperature reaction, TLC monitoring reaction is complete, filter, evaporate to dryness obtains compound (I); Off-white color solid, yield 90.5%.TLC point plate is single-point, TLC condition (developping agent normal hexane: ethyl acetate=1:1, Rf=0.2), and detect through HPLC, product purity is 98%.MS-ESI(m/z):[M+H]
+316.22。
Embodiment 3:
Compound (III) (1g), methyl alcohol (10mL) and Pd/C (0.1g) (water content is 50%) are added in reaction flask, hydrogen exchange three times, room temperature reaction, TLC monitoring reaction is complete, filter, evaporate to dryness obtains compound (I); Off-white color solid, yield 85.5%.TLC point plate is single-point, TLC condition (developping agent normal hexane: ethyl acetate=1:1, Rf=0.2), and detect through HPLC, product purity is 93%.MS-ESI(m/z):[M+H]
+316.22。
Embodiment 4:
Compound (III) (1g), methyl alcohol (10mL) and Pd/C (0.1g) (water content is 40%) are added in reaction flask, hydrogen exchange three times, room temperature reaction, TLC monitoring reaction is complete, filter, evaporate to dryness obtains compound (I); Off-white color solid, yield 79.3%.TLC point plate is single-point, TLC condition (developping agent normal hexane: ethyl acetate=1:1, Rf=0.2), and detect through HPLC, product purity is 90.2%.MS-ESI(m/z):[M+H]
+316.22。
Embodiment 5:
Compound (III) (1g), methyl alcohol (10mL) and Pd/C (0.1g) (water content is 30%) are added in reaction flask, hydrogen exchange three times, room temperature reaction, TLC monitoring reaction is complete, filter, evaporate to dryness obtains compound (I); Off-white color solid, yield 75.3%.TLC point plate is single-point, TLC condition (developping agent normal hexane: ethyl acetate=1:1, Rf=0.2), and detect through HPLC, product purity is 85.2%.MS-ESI(m/z):[M+H]
+316.22。
Embodiment 6:
Compound (III) (1g), methyl alcohol (10mL) and Pd/C (0.1g) (water content is 20%) are added in reaction flask, hydrogen exchange three times, room temperature reaction, TLC monitoring reaction is complete, filter, evaporate to dryness obtains compound (I); Off-white color solid, yield 70.5%.TLC point plate is single-point, TLC condition (developping agent normal hexane: ethyl acetate=1:1, Rf=0.2), and detect through HPLC, product purity is 80.1%.MS-ESI(m/z):[M+H]
+316.22。
Embodiment 7:
Compound (III) (1g), methyl alcohol (10mL) and Pd/C (0.1g) (water content is 70%) are added in reaction flask, hydrogen exchange three times, room temperature reaction, TLC monitoring reaction is complete, filter, evaporate to dryness obtains compound (I); Off-white color solid, yield 83.5%.TLC point plate is single-point, TLC condition (developping agent normal hexane: ethyl acetate=1:1, Rf=0.2), and detect through HPLC, product purity is 85.8%.MS-ESI(m/z):[M+H]
+316.22。
Embodiment 8:
Compound (III) (1g), ethanol (10mL) and Pd/C (0.1g) (water content is 60%) are added in reaction flask, hydrogen exchange three times, room temperature reaction, TLC monitoring reaction is complete, filter, evaporate to dryness obtains compound (I); Off-white color solid, yield 90%.TLC point plate is single-point, TLC condition (developping agent normal hexane: ethyl acetate=1:1, Rf=0.2), and detect through HPLC, product purity is 92%.MS-ESI(m/z):[M+H]
+316.22。
Embodiment 9:
Compound (III) (1g), Virahol (10mL) and Pd/C (0.1g) (water content is 60%) are added in reaction flask, hydrogen exchange three times, room temperature reaction, TLC monitoring reaction is complete, filter, evaporate to dryness obtains compound (I); Off-white color solid, yield 89.2%.TLC point plate is single-point, TLC condition (developping agent normal hexane: ethyl acetate=1:1, Rf=0.2), and detect through HPLC, product purity is 90.7%.MS-ESI(m/z):[M+H]
+316.22。
Embodiment 10:
Compound (III) (1g), methyl alcohol (10mL) and ammonium formiate (0.36g) are added in reaction flask, hydrogen exchange three times, room temperature reaction, TLC monitoring reaction is complete, filter, evaporate to dryness obtains compound (I); Off-white color solid, yield 82.6%.TLC point plate is two points, TLC condition (developping agent normal hexane: ethyl acetate=1:1, Rf=0.2), and detect through HPLC, product purity is 76.1%.MS-ESI(m/z):[M+H]
+316.22。
Claims (7)
1. the preparation method of varenicline intermediate shown in formula (III), comprise and trifluoromethanesulfonic acid, methylene dichloride are added in reaction flask, dropping concentrated nitric acid stirs, and temperature control dropping compound (II) afterwards room temperature reaction obtains midbody compound (III) in 5 ~ 8 hours
2. the preparation method of varenicline impurity 2,3,4,5-tetrahydrochysene-7-amino-8-nitro-3-(trifluoroacetyl group)-1,5-first bridge-1-hydrogen-3-benzazepine shown in formula (I), comprising:
Formula (III) compound is obtained target product through Pd/C hydrogenation selectivity reduction nitro,
3. preparation method according to claim 2, is characterized in that, comprising:
Add in reaction flask by formula III compound, organic solvent and Pd/C, hydrogen exchange at least three times, room temperature reaction, monitoring reaction is complete, filters, dry formula (I) compound.
4. preparation method according to claim 3, is characterized in that, described Pd/C is selected from the Pd/C that water content is 20%, 30%, 40%, 50%, 60% and 70%, preferably the Pd/C of 60%.
5. preparation method according to claim 3, is characterized in that, described organic solvent is selected from methyl alcohol, ethanol or Virahol, particular methanol.
6. preparation method according to claim 3, is characterized in that, hydrogen donor is selected from ammonium formiate or hydrogen, preferred hydrogen.
7. according to the preparation method shown in claim 2, it is characterized in that, described formula (III) compound is obtained by the method for claim 1.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021259396A3 (en) * | 2021-08-20 | 2022-06-30 | 威智医药有限公司 | Nitrosamine impurity, varenicline pharmaceutical composition capable of reducing generation of nitrosamine impurities and preparation and use thereof |
| CN115466214A (en) * | 2022-09-06 | 2022-12-13 | 上海皓元生物医药科技有限公司 | Preparation method of varenicline intermediate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1321107C (en) * | 2001-04-20 | 2007-06-13 | 辉瑞产品公司 | Process for the preparatino of 1,3-substituted indenes and aryl-fused azapolycyclic compounds |
| US20070224690A1 (en) * | 2006-03-27 | 2007-09-27 | Pfizer Inc | Varenicline standards and impurity controls |
| WO2009111623A2 (en) * | 2008-03-06 | 2009-09-11 | Dr. Reddy's Laboratories Ltd. | Amorphous varenicline tartrate |
| CN101535310A (en) * | 2006-11-09 | 2009-09-16 | 辉瑞产品公司 | Polymorphs of nicotinic intermediates |
-
2014
- 2014-12-19 CN CN201410799025.2A patent/CN104478803A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1321107C (en) * | 2001-04-20 | 2007-06-13 | 辉瑞产品公司 | Process for the preparatino of 1,3-substituted indenes and aryl-fused azapolycyclic compounds |
| US20070224690A1 (en) * | 2006-03-27 | 2007-09-27 | Pfizer Inc | Varenicline standards and impurity controls |
| CN101535310A (en) * | 2006-11-09 | 2009-09-16 | 辉瑞产品公司 | Polymorphs of nicotinic intermediates |
| WO2009111623A2 (en) * | 2008-03-06 | 2009-09-11 | Dr. Reddy's Laboratories Ltd. | Amorphous varenicline tartrate |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021259396A3 (en) * | 2021-08-20 | 2022-06-30 | 威智医药有限公司 | Nitrosamine impurity, varenicline pharmaceutical composition capable of reducing generation of nitrosamine impurities and preparation and use thereof |
| CN115466214A (en) * | 2022-09-06 | 2022-12-13 | 上海皓元生物医药科技有限公司 | Preparation method of varenicline intermediate |
| CN115466214B (en) * | 2022-09-06 | 2024-03-26 | 上海皓元生物医药科技有限公司 | Preparation method of valicarb intermediate |
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Effective date of registration: 20170519 Address after: 222200 Guanyun City, Jiangsu province Lingang Industrial Zone, the south side of the weft Road, eight Applicant after: Lianyungang Hengyun Pharmaceutical Co. Ltd. Address before: 222200 Jiangsu city of Lianyungang province Guanyun County Harbor Industrial Zone weft seven road No. 1 Applicant before: LIANYUNGANG HENGYUN MEDICAL TECHNOLOGY CO., LTD. |
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Application publication date: 20150401 |