CN106543061B - The preparation method of N- benzhydryl ring fourth heterocycle -3- alcohol - Google Patents
The preparation method of N- benzhydryl ring fourth heterocycle -3- alcohol Download PDFInfo
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- CN106543061B CN106543061B CN201610913537.6A CN201610913537A CN106543061B CN 106543061 B CN106543061 B CN 106543061B CN 201610913537 A CN201610913537 A CN 201610913537A CN 106543061 B CN106543061 B CN 106543061B
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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
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Abstract
The present invention relates to a kind of preparation methods of azelnidipine intermediate N- benzhydryl ring fourth heterocycle -3- alcohol, this method improves traditional handicraft, improved technique is by being added alkali in reaction system, reaction time is greater than 48 hours by traditional, it shortens to and is no more than 16 hours, the reaction time is substantially reduced, energy consumption is reduced；Effective adjustment of complex reaction temperature and appropriate post-processing, yield can be stablized 83% ~ 88%, and it is the route for being very suitable to industrialized production that product purity, which is higher than 99.9%,.
Description
Technical field
The present invention relates to a kind of preparation process ameliorations of Azelnidipine key intermediate N- benzhydryl ring fourth heterocycle -3- alcohol
Method belongs to pharmaceutical technology field.
Background technique
Azelnidipine is the dihydropyridines of Japanese Sankyo Co., Ltd and UBE Industries Ltd.'s joint development
Calcium ion antagonist, antihypertensive effect mitigate, persistently, and few to cardiac stimulation, have protective effect to heart, are suitble to heart failure type
Hypertensive patient uses.
The preparation of Azelnidipine bulk pharmaceutical chemicals needs to use key intermediate N- benzhydryl ring fourth heterocycle -3- alcohol (formula III),
The related manufacturing processes reported at present mainly use benzhydrylamine and epoxychloropropane for raw material, and detailed process can be divided into two classes:
(1) one kettle way
Compound I and compound II equimolar amounts are added in methanol WO2011148888, protect and be protected from light item in argon gas
It is stirred at room temperature 3 days, then flows back 3 days under part.Intermediate III is obtained after processing, and yield 83%, purity is unknown；Chinese patent
CN101402598 uses same method, yield 63%；WO9743255 uses the same manner, is first stirred at room temperature 3 days, then return
Stream 2 days, the total recovery for obtaining intermediate III is 52.4%.This several report yield differences are larger, test by repeating, stable yield
53% or so.
Bioorganic & Medicinal Chemistry Letters, 21(20), 6031-6035;2011 use instead
Ethyl alcohol is solvent, is first reacted at room temperature 3 days, then flow back 3 days, yield 51%.
Chinese patent application CN102453023 is stirred at room temperature 2 days using methanol as solvent, then flows back 2 days, first is precipitated
The hydrochloride of intermediate III, mother liquor continue reflux 18 hours to obtain second batch solid.Two batches merging treatment, obtains intermediate III
Mass yield is 85%, and being converted to molar yield is 65%.
" Chinese journal of Medicinal Chemistry ", 20(3), 192-194 in the same way, first reacts 10 hours at 45 DEG C, then
Reflux 12 hours obtains the hydrochloride of first intermediate III, and mother liquor continues reflux 12 hours, and merging treatment obtains intermediate
III, yield 67.9%, purity is unknown.It is reacted again although with recycling mother liquor, improves yield, but total yield is not still high,
And increasing operational sequence, production efficiency further decreases.
Compound I and compound II is added using DMF as solvent in WO2003106462, and 95 DEG C of temperature control are reacted 72 hours, obtains
The yield of intermediate III is 74%, and purity is unknown.
(2) method of fractional steps
Organic Letters, 16(10), 2744-2747;2014 using isopropanol as solvent, be added compound I and
Compound II, nearly 1 day generation intermediate state IV of 30 DEG C of reactions, does not purify, is then concentrated again, and using acetonitrile instead is solvent, and carbonic acid is added
Hydrogen sodium back flow reaction 30 hours.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 are not purified in 30 DEG C of reactions, 30 hours generation intermediate state IV, and it is molten that acetonitrile is used after concentrated
Agent is added triethylamine back flow reaction 100-105 hours, post-treated to obtain intermediate III, yield 80%, purity 99.3%.
It is first in room temperature reaction obtains overnight that compound I and compound II is added using methanol as solvent in WO2013014448
Between state IV, yield 73%；Again using ethyl alcohol as solvent, diisopropylethylamine is added, back flow reaction is overnight, and yield 75%, two steps are always received
Rate 54.75%, purity is unknown.
" Chinese Journal of Pharmaceuticals ", 43 (11), 885-887；2012 using methanol as solvent, and compound I and chemical combination is added
Object II is first reacted at 25 DEG C 66 hours, and concentration, is not added triethylamine and flows back 9 hours, yield 71.1%, purity 95.5%.
In conclusion technique made above is long there is the reaction time, yield is low, and yield is unstable, of poor quality, production effect
The low problem of rate.
Summary of the invention
The object of the present invention is to provide the improved preparations of Azelnidipine key intermediate N- benzhydryl ring fourth heterocycle -3- alcohol
Technique solves the problems, such as that product yield is low and ropy in the intermediate production procedure.
The technical scheme is that a kind of preparation method of N- benzhydryl ring fourth heterocycle -3- alcohol, which is characterized in that will
Equimolar benzhydrylamine and epoxychloropropane are added in 1~C4 of solvent C alcohol, add alkali, and heating reaction is anti-to benzhydrylamine
It should finish, the intermediate can be obtained in post-processing, wherein it is small that the time of heating reaction to benzhydrylamine end of reaction is no more than 16
When.
According to the present invention, C1~C4 alcohol is selected from methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, sec-butyl alcohol, isobutyl
Alcohol or the tert-butyl alcohol, many factors such as combined reaction effect, material price and solvent recovery, preferred alcohol, isopropanol.
According to the present invention, by the study found that highly basic such as NaOH, KOH, will increase various by-product impurities, reaction institute
Alkali is weak base to middle highly basic, preferably sodium carbonate, sodium bicarbonate.
, according to the invention it is preferred to, when C1~C4 alcohol is selected from methanol, ethyl alcohol, isopropanol or the tert-butyl alcohol, heat reactant
System extremely flows back, and maintains the reflux for state to benzhydrylamine end of reaction.
, according to the invention it is preferred to, when C1~C4 alcohol is non-is selected from methanol, ethyl alcohol, isopropanol or the tert-butyl alcohol, heating reaction
When, system temperature is not higher than 95 DEG C, preferably 90-95 DEG C.
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- benzhydryl ring fourth heterocycle -3- alcohol, including it is following
Equimolar benzhydrylamine and epoxychloropropane are added in 1~C4 of solvent C alcohol process, add alkali, heating reaction to hexichol
(the usual reaction time is 8-16 hours to methylamine end of reaction, and HPLC detects benzhydrylamine content and is lower than 1.0%, i.e., it is believed that reaction
Finish), filtering, filtrate concentration, ethyl acetate dissolution is added in raffinate, then is passed through hydrogen chloride gas or concentrated hydrochloric acid is added, and adjusts pH
It is 3 ~ 4, filters out solid, then solid is alkalized in water and is dissociated, target product can be obtained.
The beneficial effects of the invention are as follows improved techniques by the way that alkali is added in reaction system, the reaction time is by traditional
Greater than 48 hours, shortens to no more 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 very suitable to work
The route that industry metaplasia produces.
Specific embodiment:
Content for a better understanding of the present invention is described further combined with specific embodiments below, but the present invention not only office
It is limited to this.
Embodiment 1
By 183g benzhydrylamine and 92.5g epoxychloropropane, about 400ml isopropanol is added, stirs evenly, adds 63g
Sodium carbonate is heated to reflux 12 hours, and HPLC monitors fully reacting.Filtering, isopropanol wash filter cake, and filtrate recycles isopropanol, residual
Ethyl acetate dissolution is added in liquid, and it is 3 ~ 4 that concentrated hydrochloric acid, which is added, and adjusts pH, and a large amount of solids, filtration washing filter cake is precipitated.Water is added in filter cake
In, then slowly dropping liquid aqueous slkali, adjusting pH is 10 ~ 11, filters out solid, dry white solid product III 210.9g,
Yield 88.2%, purity 99.98%.
Implementation column 2
By 183g benzhydrylamine and 92.5g epoxychloropropane, about 400ml methanol is added, stirs evenly, adds 63g carbon
Sour sodium is heated to reflux 16 hours, and HPLC monitors fully reacting.Filtering, methanol wash filter cake, and filtrate recycles methanol, and raffinate is added
Ethyl acetate dissolution, it is 3 ~ 4 that concentrated hydrochloric acid, which is added, and adjusts pH, and a large amount of solids, filtration washing filter cake is precipitated.Filter cake is added to the water, then
Slowly dropping liquid aqueous slkali, adjusting pH is 10 ~ 11, filters out solid, dry white solid product III 198.7g, yield
83.1%, purity 99.91%.
Implementation column 3
By 183g benzhydrylamine and 92.5g epoxychloropropane, about 400ml isopropanol is added, stirs evenly, adds 100
G sodium bicarbonate is heated to reflux 16 hours, and HPLC monitors fully reacting.Filtering, isopropanol wash filter cake, and filtrate recycles isopropanol,
Ethyl acetate dissolution is added in raffinate, and it is 3 ~ 4 that concentrated hydrochloric acid, which is added, and adjusts pH, and a large amount of solids, filtration washing filter cake is precipitated.Filter cake is added
In water, then slowly dropping liquid aqueous slkali, adjusting pH is 10 ~ 11, filters out solid, dry white solid product III 204g,
Yield 85.4%, purity 99.96%.
Implementation column 4
By 183g benzhydrylamine and 92.5g epoxychloropropane, about 400ml n-butanol is added, stirs evenly, adds 63g
Sodium carbonate heats 95 DEG C and reacts 8 hours, and HPLC monitors fully reacting.Filtering, n-butanol wash filter cake, and filtrate recycles n-butanol,
Ethyl acetate dissolution is added in raffinate, and being passed through hydrogen chloride gas and adjusting pH is 3 ~ 4, and a large amount of solids, filtration washing filter cake is precipitated.Filter cake
It is added to the water, then slowly dropping liquid aqueous slkali, adjusting pH is 10 ~ 11, filters out solid, dry white solid product III
209.6g, yield 87.7%, purity 99.95%.
Implementation column 5
By 183g benzhydrylamine and 92.5g epoxychloropropane, about 400ml normal propyl alcohol is added, stirs evenly, adds 100g
Sodium bicarbonate heats 90 DEG C and reacts 10 hours, and HPLC monitors fully reacting.Filtering, normal propyl alcohol wash filter cake, filtrate recycling positive third
Ethyl acetate dissolution is added in alcohol, raffinate, and it is 3 ~ 4 that concentrated hydrochloric acid, which is added, and adjusts pH, and a large amount of solids, filtration washing filter cake is precipitated.Filter cake
It is added to the water, then slowly dropping liquid aqueous slkali, adjusting pH is 10 ~ 11, filters out solid, dry white solid product III
202.5g, yield 84.7%, purity 99.94%.
Claims (6)
1. the preparation method of N- benzhydryl ring fourth heterocycle -3- alcohol described in a kind of formula III, which is characterized in that by equimolar two
Benzene methanamine and epoxychloropropane are added in 1~C4 of solvent C alcohol, add alkali, and heating reaction to benzhydrylamine end of reaction is rear to locate
The intermediate can be obtained in reason, wherein the time of heating reaction to benzhydrylamine end of reaction is no more than 16 hours, the alkali choosing
From sodium carbonate, sodium bicarbonate,
。
2. the preparation method of N- benzhydryl ring fourth heterocycle -3- alcohol according to claim 1, which is characterized in that the C1~
C4 alcohol is selected from ethyl alcohol, isopropanol.
3. the preparation method of N- benzhydryl ring fourth heterocycle -3- alcohol according to claim 1, which is characterized in that the C1~
When C4 alcohol is selected from methanol, ethyl alcohol, isopropanol or the tert-butyl alcohol, heating reaction system to reflux, and state is maintained the reflux for hexichol first
Amine end of reaction.
4. the preparation method of N- benzhydryl ring fourth heterocycle -3- alcohol according to claim 1, which is characterized in that the C1~
C4 alcohol is non-selected from methanol, ethyl alcohol, isopropanol or when the tert-butyl alcohol, and when heating reaction, system temperature is not higher than 95 DEG C.
5. the preparation method of N- benzhydryl ring fourth heterocycle -3- alcohol according to claim 1, which is characterized in that place after described
Reason includes first acidification, the free process of rear alkali.
6. the preparation method of N- benzhydryl ring fourth heterocycle -3- alcohol according to claim 1, which is characterized in that the C1~
C4 alcohol is non-selected from methanol, ethyl alcohol, isopropanol or when the tert-butyl alcohol, and when heating reaction, system temperature is 90~95 DEG C.
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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 |
|---|
| 3-氯-2-羟丙基脲的合成;赵燕 等;《精细化工》;20060430;第23卷(第4期);第393-396页 |
| 阿折地平的合成;米春来 等;《中药医药工业杂志》;20121231;第43卷(第11期);第885-887页 |
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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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