CN106543061A - The preparation method of 3 alcohol of N benzhydryl ring fourths heterocycle - Google Patents
The preparation method of 3 alcohol of N benzhydryl ring fourths heterocycle Download PDFInfo
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- CN106543061A CN106543061A CN201610913537.6A CN201610913537A CN106543061A CN 106543061 A CN106543061 A CN 106543061A CN 201610913537 A CN201610913537 A CN 201610913537A CN 106543061 A CN106543061 A CN 106543061A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
Abstract
The present invention relates to a kind of preparation method of 3 alcohol of azelnidipine intermediate N benzhydryl ring fourth heterocycle, the method is improved to traditional handicraft, technique after improvement is by adding alkali in reaction system, reaction time is by traditional more than 48 hours, shorten to less than 16 hours, the reaction time is substantially reduced, energy consumption is reduced；Effective adjustment and appropriate post processing of complex reaction temperature, yield can be stablized 83% ~ 88%, and product purity is higher than 99.9%, is a route for being especially suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of preparation process amelioration of Azelnidipine key intermediate N- benzhydryls ring fourth heterocycle -3- alcohol
Method, belongs to pharmaceutical technology field.
Background technology
Azelnidipine is the dihydropyridines of Japanese Sankyo Co., Ltd and UBE Industries Ltd.'s joint development
Calcium ion antagonist, its hypotensive effect relaxes, persistently, and few to cardiac stimulation, has protective effect to heart, is adapted to heart failure type
Hyperpietic uses.
The preparation of Azelnidipine bulk drug needs to use key intermediate N- benzhydryl ring fourth heterocycle -3- alcohol（Formula III）,
The related manufacturing processes of report mainly adopt benzhydrylamine with epoxychloropropane for raw material at present, and detailed process can be divided into two classes：
（One）One kettle way
WO2011148888 adds compound I and compound II equimolar amounts in methyl alcohol, under the conditions of argon gas protection and lucifuge
It is stirred at room temperature 3 days, then flows back 3 days.Jing process after intermediate III, yield 83%, purity is unknown；Chinese patent
CN101402598 adopts same method, and yield is 63%；WO9743255 adopts the same manner, is first stirred at room temperature 3 days, then returns
Stream 2 days, the total recovery for obtaining intermediate III are 52.4%.This several report yield differences are larger, through repeating to test, stable yield
53% or so.
Bioorganic & Medicinal Chemistry Letters, 21(20), 6031-6035;2011 use instead
Ethanol is solvent, first room temperature reaction 3 days, then is flowed back 3 days, yield 51%.
Chinese patent application CN102453023 is stirred at room temperature 2 days with methyl alcohol as solvent, then is flowed back 2 days, separates out first
The hydrochloride of intermediate III, mother liquor continue backflow and obtain second batch solid in 18 hours.Two batches merging treatment, obtains intermediate III
Mass yield is 85%, is converted to molar yield for 65%.
《Chinese pharmaceutical chemistry magazine》, 20（3）, 192-194 in the same way, react 10 hours at 45 DEG C by elder generation, then
Backflow 12 hours, obtains the hydrochloride of first intermediate III, and mother liquor continues backflow 12 hours, and merging treatment obtains intermediate
III, yield 67.9%, purity is unknown.Reacted although with mother liquor is reclaimed again, improve yield, but total yield is not still high,
And increasing operational sequence, production efficiency is further reduced.
WO2003106462 adds compound I and compound II, 95 DEG C of temperature control to react 72 hours, obtain with DMF as solvent
The yield of intermediate III is 74%, and purity is unknown.
（Two）The method of fractional steps
Organic Letters, 16(10), 2744-2747;2014 with isopropanol as solvent, adds compound I and chemical combination
Thing II, 30 DEG C of reactions generate intermediate state IV in nearly 1 day, do not purify, then concentrate again, use acetonitrile instead for solvent, addition sodium acid carbonate
Back flow reaction 30 hours.It is post-treated to obtain intermediate III, yield 83%, purity is unknown.
Organic Process Research &Development, 14(4), 931-935;2010 using same
Mode, compound I and compound II generate intermediate state IV in 30 hours in 30 DEG C of reactions, do not purify, and concentrated rear acetonitrile is molten
Agent, adds triethylamine back flow reaction 100-105 hour, post-treated to obtain intermediate III, yield 80%, purity 99.3%.
WO2013014448 adds compound I and compound II first in room temperature reaction is overnight obtained with methyl alcohol as solvent
Between state IV, yield 73%；Again with ethanol as solvent, diisopropylethylamine is added, back flow reaction overnight, always receive by yield 75%, two steps
Rate 54.75%, purity is unknown.
《Chinese Journal of Pharmaceuticals》, 43 (11), 885-887；2012 with methyl alcohol as solvent, adds compound I and compound II
First react at 25 DEG C 66 hours, concentration, does not add triethylamine to flow back 9 hours, yield 71.1%, purity 95.5%.
In sum, technique made above has that the reaction time is long, and yield is low, and yield is unstable, of poor quality, production effect
The low problem of rate.
The content of the invention
It is an object of the invention to provide the improved preparation of Azelnidipine key intermediate N- benzhydryl ring fourth heterocycle -3- alcohol
Technique, solves that product yield in the middle production procedure is low and ropy problem.
The technical scheme is that a kind of preparation method of N- benzhydryls ring fourth heterocycle -3- alcohol, it is characterised in that will
During equimolar benzhydrylamine and epoxychloropropane add solvent C 1～C4 alcohol, alkali is added, heating response is anti-to benzhydrylamine
Should finish, post processing can obtain the intermediate, wherein, heating response is little less than 16 to the time that benzhydrylamine reaction is finished
When.
According to the present invention, C1～C4 alcohol is selected from methyl alcohol, ethanol, normal propyl alcohol, isopropanol, n-butanol, sec-butyl alcohol, isobutyl
The many factors such as alcohol or the tert-butyl alcohol, combined reaction effect, material price and solvent recovery, preferred alcohol, isopropanol.
According to the present invention, found by studying, highly basic such as NaOH, KOH, various by-product impurities can be increased, react institute
Alkali is weak base to middle highly basic, preferred sodium carbonate, sodium acid carbonate..
, according to the invention it is preferred to, when C1～C4 alcohol is selected from methyl alcohol, ethanol, isopropanol or the tert-butyl alcohol, heating response body
Be to backflow, and maintain the reflux for state to benzhydrylamine reaction finish.
, according to the invention it is preferred to, when C1～C4 alcohol it is non-selected from methyl alcohol, ethanol, isopropanol or the tert-butyl alcohol when, heating response
When, not higher than 95 DEG C, preferred 90-95 DEG C of system temperature.
According to the present invention, the post processing includes first being acidified, and rear alkali dissociates process.
According to the present invention, more specifically, a kind of preparation method of N- benzhydryls ring fourth heterocycle -3- alcohol, including it is following
Operation, equimolar benzhydrylamine and epoxychloropropane are added in solvent C 1～C4 alcohol, alkali is added, and heating response is to hexichol
Methylamine reaction is finished（The generally reaction time is 8-16 hours, and HPLC detection benzhydrylamine contents are less than 1.0%, you can think reaction
Finish）, filtering, filtrate concentration, raffinate adds ethyl acetate dissolving, then is passed through hydrogen chloride gas or adds concentrated hydrochloric acid, adjusts pH
For 3 ~ 4, solid is leached, then solid is alkalized in water free, you can obtain target product.
The invention has the beneficial effects as follows the technique after improving is by alkali is added in reaction system, the reaction time is by traditional
More than 48 hours, shorten to less than 16 hours, substantially reduce the reaction time, reduce energy consumption；Complex reaction temperature has
Effect adjustment and appropriate post processing, yield can be stablized 83% ~ 88%, and product purity is higher than 99.9%, is one and is especially suitable for work
The route that industry metaplasia is produced.
Specific embodiment：
Content, is described further with reference to specific embodiment for a better understanding of the present invention, but the present invention is not only limited to
This.
Embodiment 1
By 183g benzhydrylamines and 92.5g epoxychloropropane, about 400ml isopropanols are added, is stirred, is added 63g carbonic acid
Sodium, is heated to reflux 12 hours, and HPLC monitoring reactions are complete.Filter, isopropanol washing filter cake, filtrate reclaim isopropanol, and raffinate adds
Enter ethyl acetate dissolving, it is 3 ~ 4 to add concentrated hydrochloric acid to adjust pH, separates out a large amount of solids, filtration washing filter cake.Filter cake is added to the water,
Slowly dropping liquid aqueous slkali again, it is 10 ~ 11 to adjust pH, filters out solid, dry white solid product III 210.9g, yield
88.2%, purity 99.98%.
Implement row 2
By 183g benzhydrylamines and 92.5g epoxychloropropane, about 400ml methyl alcohol is added, is stirred, is added 63g sodium carbonate,
It is heated to reflux 16 hours, HPLC monitoring reactions are complete.Filter, methyl alcohol washing filter cake, filtrate reclaim methyl alcohol, and raffinate adds acetic acid second
Ester dissolves, and it is 3 ~ 4 to add concentrated hydrochloric acid to adjust pH, separates out a large amount of solids, filtration washing filter cake.Filter cake is added to the water, then slowly drips
Liquid feeding aqueous slkali, it is 10 ~ 11 to adjust pH, filters out solid, and dry white solid product III 198.7g, yield 83.1% are pure
Degree 99.91%.
Implement row 3
By 183g benzhydrylamines and 92.5g epoxychloropropane, about 400ml isopropanols are added, is stirred, is added 100 g carbon
Sour hydrogen sodium, is heated to reflux 16 hours, and HPLC monitoring reactions are complete.Filter, isopropanol washing filter cake, filtrate reclaims isopropanol, residual
Liquid adds ethyl acetate dissolving, and it is 3 ~ 4 to add concentrated hydrochloric acid to adjust pH, separates out a large amount of solids, filtration washing filter cake.Filter cake adds water
In, then slowly dropping liquid aqueous slkali, it is 10 ~ 11 to adjust pH, filters out solid, dry white solid product III 204g, is received
Rate 85.4%, purity 99.96%.
Implement row 4
By 183g benzhydrylamines and 92.5g epoxychloropropane, about 400ml n-butanols are added, is stirred, is added 63g carbonic acid
Sodium, heats 95 DEG C and reacts 8 hours, and HPLC monitoring reactions are complete.Filter, n-butanol washing filter cake, filtrate reclaim n-butanol, raffinate
Ethyl acetate dissolving is added, it is 3 ~ 4 to be passed through hydrogen chloride gas and adjust pH, separates out a large amount of solids, filtration washing filter cake.Filter cake is added
In water, then slowly dropping liquid aqueous slkali, it is 10 ~ 11 to adjust pH, filters out solid, dry white solid product III
209.6g, yield 87.7%, purity 99.95%.
Implement row 5
By 183g benzhydrylamines and 92.5g epoxychloropropane, about 400ml normal propyl alcohols are added, is stirred, is added 100g carbonic acid
Hydrogen sodium, heats 90 DEG C and reacts 10 hours, and HPLC monitoring reactions are complete.Filter, normal propyl alcohol washing filter cake, filtrate reclaim normal propyl alcohol,
Raffinate adds ethyl acetate dissolving, and it is 3 ~ 4 to add concentrated hydrochloric acid to adjust pH, separates out a large amount of solids, filtration washing filter cake.Filter cake is added
In water, then slowly dropping liquid aqueous slkali, it is 10 ~ 11 to adjust pH, filters out solid, dry white solid product III
202.5g, yield 84.7%, purity 99.94%.
Claims (6)
1. a kind of preparation method of N- benzhydryls ring fourth heterocycle -3- alcohol, it is characterised in that by equimolar benzhydrylamine and ring
During oxygen chloropropane adds solvent C 1～C4 alcohol, alkali is added, heating response is finished to benzhydrylamine reaction, and post processing is obtained
The intermediate, wherein, heating response was less than 16 hours to the time that benzhydrylamine reaction is finished.
2. preparation method according to claim 1, it is characterised in that C1～C4 alcohol preferred alcohol, isopropanol.
3. preparation method according to claim 1, it is characterised in that the alkali is weak base to middle highly basic, preferred sodium carbonate,
Sodium acid carbonate.
4. preparation method according to claim 1, it is characterised in that C1～C4 alcohol is selected from methyl alcohol, ethanol, isopropanol or uncle
During butanol, heating response system to flow back, and maintain the reflux for state to benzhydrylamine reaction finish.
5. preparation method according to claim 1, it is characterised in that C1～C4 alcohol it is non-selected from methyl alcohol, ethanol, isopropanol or
During the tert-butyl alcohol, during heating response, not higher than 95 DEG C, preferred 90-95 DEG C of system temperature.
6. preparation method according to claim 1, it is characterised in that the post processing includes first being acidified, and rear alkali dissociated
Journey.
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| CN201610913537.6A CN106543061B (en) | 2016-10-20 | 2016-10-20 | The preparation method of N- benzhydryl ring fourth heterocycle -3- alcohol |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103509003A (en) * | 2012-06-27 | 2014-01-15 | 威海威太医药技术开发有限公司 | Preparation method of azelnidipine |
| CN104356040A (en) * | 2014-09-17 | 2015-02-18 | 爱斯特（成都）生物制药有限公司 | Preparation method of 1-benzhydryl-3-hydroxylazetidine hydrochloride |
| CN105949102A (en) * | 2016-06-20 | 2016-09-21 | 许昌豪丰化学科技有限公司 | Production method of azelnidipine intermediate |
-
2016
- 2016-10-20 CN CN201610913537.6A patent/CN106543061B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103509003A (en) * | 2012-06-27 | 2014-01-15 | 威海威太医药技术开发有限公司 | Preparation method of azelnidipine |
| CN104356040A (en) * | 2014-09-17 | 2015-02-18 | 爱斯特（成都）生物制药有限公司 | Preparation method of 1-benzhydryl-3-hydroxylazetidine hydrochloride |
| CN105949102A (en) * | 2016-06-20 | 2016-09-21 | 许昌豪丰化学科技有限公司 | Production method of azelnidipine intermediate |
Non-Patent Citations (2)
| Title |
|---|
| 米春来 等: "阿折地平的合成", 《中药医药工业杂志》 * |
| 赵燕 等: "3-氯-2-羟丙基脲的合成", 《精细化工》 * |
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Effective date of registration: 20191104 Address after: 264205 Guangzhou East Road South and an East Road East, Wendeng economic and Technological Development Zone, Weihai City, Shandong Province Co-patentee after: WEIHAI DISU PHARMACEUTICAL Co.,Ltd. Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Co-patentee after: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Address before: 264205 Shandong city of Weihai province by the district Gushan Town No. 18 South Road, No. 19 North Road, No. 3 East Road, the west five Co-patentee before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Patentee before: WEIHAI DISU PHARMACEUTICAL Co.,Ltd. |
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Effective date of registration: 20220407 Address after: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Address before: 264205 Wendeng economic and Technological Development Zone, Weihai City, Shandong Province Patentee before: Dijia Pharmaceutical Group Co.,Ltd. Patentee before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Effective date of registration: 20220407 Address after: 264205 Wendeng economic and Technological Development Zone, Weihai City, Shandong Province Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Patentee after: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Address before: 264205 Wendeng economic and Technological Development Zone, Weihai City, Shandong Province Patentee before: Dijia Pharmaceutical Group Co.,Ltd. Patentee before: WEIHAI DISU PHARMACEUTICAL Co.,Ltd. Patentee before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. |
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Address after: No. 268, Tianrun Road, Wendeng Economic and Technological Development Zone, Weihai City, Shandong Province, 264200 Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Address before: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Patentee before: Dijia Pharmaceutical Group Co.,Ltd. |
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