CN109721587A - A kind of method and its application preparing phthalyl Amlodipine - Google Patents
A kind of method and its application preparing phthalyl Amlodipine Download PDFInfo
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- CN109721587A CN109721587A CN201811653516.0A CN201811653516A CN109721587A CN 109721587 A CN109721587 A CN 109721587A CN 201811653516 A CN201811653516 A CN 201811653516A CN 109721587 A CN109721587 A CN 109721587A
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Abstract
The invention discloses a kind of method for preparing phthalyl Amlodipine, under molecular sieve catalyst effect react to obtain compound shown in structural formula II with N- bromo-succinimide as structural formula I compound represented dihydropyridine；Compound shown in compound shown in compound ii and structural formula III makees solvent in benzene toluene ketone compounds, and inorganic carbonate makees catalyst, and organic compounds containing nitrogen does co-catalyst, and heating reflux reaction obtains compound shown in structural formula IV；The compound as shown in structural formula IV makees catalyst in four (triphenyl phosphorus) palladiums, inorganic carbonate, and benzene makees solvent, reacts to obtain phthalyl Amlodipine with 2- chlorophenylboronic acid；Preparation method reaction step of the present invention is succinct, only need three steps, reaction condition is mild, post-reaction treatment is convenient, product purity is high, obtain the Amlodipine imines of different crystal forms by a variety of recrystallization methods the present invention also provides a kind of, meet the different market demands, ensure that drug safety and efficiently.
Description
Technical field
A kind of method preparing phthalyl Amlodipine of the invention, belongs to synthesis technical field.
Background technique
The membrane phospholipid of phthalyl Amlodipine and biomembrane has the affinity of height, can be gathered in vascular cell film
Lipid layer depths can slowly lasting expand to the receptor of calcium channel calculate, be a kind of excellent calcium ion antagonist.Simultaneously
Can also make NO generate enzyme activity recovery it is normal, also have the effects that anti-cell film oxidation, be applied to treat hypertension, angina pectoris,
The diseases such as heart failure, are widely used, and have good market prospects, and the requirement to purity and crystal form is stringenter.
Its synthetic method mainly has at present:
1. Korean Patent (patent No. 86-1921)
The reaction step is succinct, but its reaction yield is low, is unable to satisfy the demand currently produced.
2. United States Patent (USP) (6784297B2), United States Patent (USP) (6653481B2)
The synthetic route feature: route is longer, and technique is cumbersome, and ultimate yield is low.
Summary of the invention
The present invention provides a kind of methods for preparing phthalyl Amlodipine.The prior synthesizing method cyclization avoided
It is more at step, the shortcomings that low yield.
In order to overcome the above problem, the technical scheme adopted by the invention is that it is such, it is a kind of to prepare phthalyl
The method of Amlodipine, includes the following steps:
1) by structural formula I compound represented dihydropyridine and N- bromo-succinimide under molecular sieve catalyst effect
Reaction obtains compound shown in structural formula II；
2) compound shown in the structural formula II obtained as step 1) reacts to obtain structural formula with III compound represented of structural formula
Compound shown in IV；
3) it reacts compound shown in the structural formula IV 2) obtained to obtain chemical combination shown in structural formula V with 2- chlorophenylboronic acid
Object phthalyl Amlodipine；
Entire reaction structure formula is as follows:
Preferably, the method for preparing phthalyl Amlodipine, specifically comprises the following steps:
1) by structural formula I compound represented dihydropyridine under molecular sieve catalyst, with methylene chloride, ethyl acetate,
Benzene, one or more of toluene are used as solvent, obtain shown in structural formula II with N- bromo-succinimide heating reflux reaction
Compound；
2) step 1) compound shown in II compound represented of structural formula and structural formula III is obtained to make in ketone compounds
Solvent, inorganic carbonate make catalyst, and organic compounds containing nitrogen makees co-catalyst, and heating reflux reaction obtains shown in structural formula IV
Compound；
3) compound shown in structural formula IV that step 2) obtains is made into catalyst in four (triphenyl phosphorus) palladiums, inorganic carbonate
Make alkali, benzene makees solvent, obtains compound phthalyl ammonia shown in structural formula V with 2- chlorophenylboronic acid heating reflux reaction
Flordipine；
Preferably, in step 1): molecular sieve catalyst is aluminium sial silicon 3A molecular sieve, a kind of or several in aluminium silicon 5A molecular sieve
Kind；Dihydropyridine, molecular sieve catalyst, NBS, solvent molar ratio be 1:0.1~1:1~3:2~6；Reaction time be 1~
12h, reaction temperature are 30~100 DEG C.
Preferably, in step 2), ketone compounds are methyl ethyl ketone, methyl iso-butyl ketone (MIBK), 4-methyl-2 pentanone, cyclohexanone
One or more of；Inorganic carbonate is one or more of sodium carbonate, potassium carbonate, zinc carbonate；Organic compounds containing nitrogen
For one or more of N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, four butyl bromation amine, pyridine；Structural formula II
Compound represented, III compound represented of structural formula, ketone compounds, catalyst, co-catalyst molar ratio be 1:1~
1.3:1~6:0.5~2:0.1~0.5, reaction time are 1~12h, and reaction temperature is 30~150 DEG C.
Preferably, in step 3), inorganic carbonate is one or more of sodium carbonate, potassium carbonate, zinc carbonate；Structural formula
IV compound represented, four (triphenyl phosphorus) palladiums, inorganic carbonate, 2- chlorophenylboronic acid, benzene molar ratio be 1:0.1~0.5:
0.1~0.5:1~1.5:1~6, the reaction time be 1~12h, 50~100 DEG C of reaction temperature.
The present invention also provides a kind of methods for preparing different crystal forms phthalyl Amlodipine, will be above-mentioned obtained
Phthalyl Amlodipine is in water, methylene chloride, methanol, ethyl alcohol, ethyl acetate, n-hexane, hexamethylene, N, N- dimethyl
One or more of formamide, DMAC N,N' dimethyl acetamide, -2 pentanone of 4- methyl, methylisobutylketone mix in recrystallization solvent
Recrystallization, wherein the mass ratio of Amlodipine imines and recrystallization solvent is 1:1~10.
Preferably, the present invention be recrystallized to give fusing point be 138~140 DEG C, 147~149 DEG C, 152~153 DEG C of the not isomorphous
The Amlodipine imines of type.
The utility model has the advantages that
1, the present invention is using dihydropyridine as raw material, the shortcomings that prior synthesizing method ring synthesis step avoided is more, low yield.
2, the entire synthesis technology of the present invention only has three steps, and technique is brief, and yield is high, and wastewater flow rate is small, more environmentally friendly.
3, the Amlodipine imines of different crystal forms is obtained by a variety of recrystallization methods the present invention also provides a kind of, met not
With the market demand, ensure that drug safety and efficiently.
Figure of description
Fig. 1 is the X-ray map of phthalyl Amlodipine crystal form A；
Fig. 2 is the X-ray map of phthalyl Amlodipine crystal form B；
Fig. 3 is the X-ray map of phthalyl Amlodipine crystal form C.
Specific embodiment
In order to deepen the understanding of the present invention, below in conjunction with embodiment and attached drawing, the invention will be further described, should
The examples are only for explaining the invention, is not intended to limit the scope of the present invention..
The preparation of 1 phthalyl Amlodipine of embodiment
1) 50g dihydropyridine, sial 3A molecular sieve 4g, N- bromo-succinimide are added in 1000ml round-bottomed flask
(NBS) 70g, stirring, 80 DEG C are heated to reflux, and react 6h；After reaction, it stirs, is cooled to room temperature, is stirred in ice-water bath cold
But 1h, filtering, 50 DEG C of vacuum drying 12h of filter cake obtain 74g faint yellow solid powder (compound shown in structural formula II), thick to produce
Rate 90%, purity 98.375%.
2) faint yellow solid powder (compound shown in structural formula II) 74g, N- ethoxy are added in 1000ml round-bottomed flask
Phthalimide 37.4g, potassium carbonate 13g, n,N-Dimethylformamide 1.3g, methyl ethyl ketone 300g, stirring, 80 DEG C are heated to reflux, instead
Answer 8h；After reaction, 40 DEG C are cooled to, 200g water is added, stirs 1h, filtering, 50 DEG C of vacuum drying 12h of filter cake are obtained
87.7g white solid powder (compound shown in structural formula III), thick yield 95%, purity 97.932%.
3) white solid powder (compound shown in structural formula III) is added in 1000ml round-bottomed flask) 87.7g, 2- chlorphenyl
Boric acid 28.4g, four (triphenyl phosphorus) palladium 19g, potassium carbonate 13g, benzene 360g, stirring, 80 DEG C are heated to reflux, and react 8h；Reaction knot
200g water is added in Shu Hou, stirs 1h, filtering, and 50 DEG C of vacuum drying 12h of filter cake obtain 81.7g faint yellow solid powder (adjacent benzene
Diformyl Amlodipine), thick yield 92%, purity 98.547%.
Faint yellow solid (phthalyl Amlodipine) fusing point is obtained prepared by measurement, it is 151.7 DEG C of incipient melting, molten eventually
152.6℃。
The preparation of 2 phthalyl Amlodipine crystal form A of embodiment
Faint yellow solid powder 50g, ethyl acetate 400g prepared by embodiment 1 are added in 1000ml round-bottomed flask to stir
It mixes, is heated to 60 DEG C or more solid dissolutions, stop heating, stirring is down to room temperature to temperature, 50g ethyl alcohol is added dropwise, stirs 2h, mistake
Filter, 50 DEG C of vacuum drying 12h of filter cake obtain 49.6g faint yellow solid powder (phthalyl Amlodipine crystal form A), slightly
Yield 99.2%, purity 99.758%.Phthalyl Amlodipine crystal form A is measured, 138.1 DEG C of incipient melting, melts 138.7 eventually
℃。
The X ray picture spectrum peak of phthalyl Amlodipine crystal form A as shown in Figure 1: 5.7,1107；8.7,10103；
11.1 5312；11.3 2912；13.4 759；15.2 463；15.6 786；17.6 1633；18.0 561；19.5 490；
20.2 498；21.8 589；22.1 1159；22.6 923；24.5 849；25.5 839；26.1 1482；26.3 1167；
27.4 569；27.7 1772.
The preparation of 3 phthalyl Amlodipine crystal form B of embodiment
It is added in 1000ml round-bottomed flask by above-mentioned faint yellow solid powder 49.6g, n,N-Dimethylformamide is added
250g, stirring, is heated to 60 DEG C or more and dissolves, and stirs 30min, stops heating, and 20g water is added dropwise, and stirs 2h, and solid is analysed completely
Out, it filters, 50 DEG C of vacuum drying 12h of filter cake obtain 49.4g faint yellow solid powder (phthalyl Amlodipine crystal form
B), thick yield 99.6%, purity 99.862%.Phthalyl Amlodipine crystal form B fusing point is measured, it is 147.2 DEG C of incipient melting, whole
Melt 148.8 DEG C of
The X ray picture spectrum peak of Amlodipine imines is as shown in Figure 2: 7.0,5001；8.5,945；8.7,483；10.1,
274；11.1 622；11.9 3099；12.2 405；14.0 2107；14.3 691；14.6 371；16.3 310；16.9,
1398；17.2 1656；18.4 406；20.5 905；22.0 1891；22.7 482；23.1 515；24.1 868；24.2,
1097；24.6 588；25.5 719；25.7 804；27.1 655；27.7 954；28.1 1151.
The preparation of 4 phthalyl Amlodipine crystal form C of embodiment
It is added in 1000ml round-bottomed flask by above-mentioned faint yellow solid powder 49.4g, methylene chloride 100g, stirring is added
30min is completely dissolved, and 100g n-hexane is added dropwise, and ice-water bath stirs 2h, and solid is precipitated completely, is filtered, 50 DEG C of filter cake vacuum drying
12h obtains 49.3g faint yellow solid powder (phthalyl Amlodipine crystal form C), thick yield 99.8%, purity
99.901%.Phthalyl Amlodipine crystal form C fusing point is measured, it is 151.9 DEG C of incipient melting, 152.4 DEG C molten eventually.
The X ray picture spectrum peak of phthalyl Amlodipine crystal form C is as shown in Figure 3: 5.7,322；6.7,495；
7.0,2562；8.5,515；8.8,4013；10.0 318；11.1 2316；11.9 1517；12.3 798；13.5 473；
14.0 1021；14.3 953；14.6 575；15.7 593；16.3 358；16.9 516；17.3 845；17.7 485；
18.5 381；20.6 745；21.9 1263；22.8 711；23.2 916；24.3 833；24.6 1170；25.5 701；
26.2 716；26.4 622；27.8 814；28.1 635.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Within mind and principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of method for preparing phthalyl Amlodipine, which comprises the steps of:
1) it is reacted under molecular sieve catalyst effect by structural formula I compound represented dihydropyridine with N- bromo-succinimide
Obtain compound shown in structural formula II；
2) compound shown in the structural formula II obtained as step 1) reacts to obtain IV institute of structural formula with III compound represented of structural formula
Show compound；
3) it reacts compound shown in structural formula IV that step 2) obtains to obtain chemical combination shown in structural formula V with 2- chlorophenylboronic acid
Object phthalyl Amlodipine；
2. a kind of method for preparing phthalyl Amlodipine according to claim 1, which is characterized in that specific packet
Include following steps:
1) by structural formula I compound represented dihydropyridine under molecular sieve catalyst, with methylene chloride, ethyl acetate, benzene, first
One or more of benzene is used as solvent, obtains chemical combination shown in structural formula II with N- bromo-succinimide heating reflux reaction
Object；
2) step 1) is obtained into compound shown in II compound represented of structural formula and structural formula III and makees solvent in ketone compounds,
Inorganic carbonate makees catalyst, and organic compounds containing nitrogen makees co-catalyst, and heating reflux reaction obtains chemical combination shown in structural formula IV
Object；
3) compound shown in structural formula IV that step 2) obtains is made into catalyst in four (triphenyl phosphorus) palladiums and inorganic carbonate, benzene
Make solvent, obtains compound phthalyl Amlodipine shown in structural formula V with 2- chlorophenylboronic acid heating reflux reaction.
3. a kind of method for preparing phthalyl Amlodipine according to claim 2, which is characterized in that step 1)
Middle molecular sieve catalyst is aluminium si molecular sieves.
4. a kind of method for preparing phthalyl Amlodipine according to claim 3, which is characterized in that step 1)
Middle dihydropyridine, molecular sieve catalyst, NBS, solvent molar ratio be 1:0.1~1:1~3:2~6, the reaction time be 1~
12h, reaction temperature are 30~100 DEG C.
5. a kind of method for preparing phthalyl Amlodipine according to claim 1, it is characterised in that: step 2)
In, ketone compounds are one or more of methyl ethyl ketone, methyl iso-butyl ketone (MIBK), 4-methyl-2 pentanone, cyclohexanone；Inorganic carbon
Hydrochlorate is one or more of sodium carbonate, potassium carbonate, zinc carbonate；Organic compounds containing nitrogen be N,N-dimethylformamide, N,
One or more of N- dimethyl acetamide, four butyl bromation amine, pyridine.
6. a kind of method for preparing phthalyl Amlodipine according to claim 5, which is characterized in that step 2)
In, II compound represented of structural formula, III compound represented of structural formula, ketone compounds, catalyst, co-catalyst mole
Than for 1:1~1.3:1~6:0.5~2:0.1~0.5, the reaction time is 1~12h, reaction temperature is 30~150 DEG C.
7. a kind of method for preparing phthalyl Amlodipine according to claim 1, it is characterised in that: step 3)
In, inorganic carbonate is one or more of sodium carbonate, potassium carbonate, zinc carbonate.
8. a kind of method for preparing phthalyl Amlodipine according to claim 7, it is characterised in that: structural formula
IV compound represented, four (triphenyl phosphorus) palladiums, inorganic carbonate, 2- chlorophenylboronic acid, benzene molar ratio be 1:0.1~0.5:
0.1~0.5:1~1.5:1~6, the reaction time be 1~12h, 50~100 DEG C of reaction temperature.
9. a kind of method for preparing different crystal forms phthalyl Amlodipine, it is characterised in that: claim 1-8 is any
The obtained phthalyl Amlodipine of claim water, methylene chloride, methanol, ethyl alcohol, ethyl acetate, n-hexane,
One of hexamethylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, -2 pentanone of 4- methyl, methylisobutylketone are several
It is recrystallized in kind mixing recrystallization solvent, wherein the mass ratio of Amlodipine imines and recrystallization solvent is 1:1~10.
10. a kind of method for preparing different crystal forms phthalyl Amlodipine according to claim 9, feature exist
In: be recrystallized to give fusing point be 138~140 DEG C, 147~149 DEG C, the Amlodipine imines of 152~153 DEG C of different crystal forms.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114516774A (en) * | 2021-02-08 | 2022-05-20 | 中国科学院成都生物研究所 | Preparation method of chiral bromo-1, 4-dihydropyridine compound |
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| CN102070611A (en) * | 2010-12-28 | 2011-05-25 | 山东新华制药股份有限公司 | Preparation method of amlodipine intermediate |
| CN106749187A (en) * | 2016-12-29 | 2017-05-31 | 千辉药业（安徽）有限责任公司 | A kind of synthetic method of phthalyl Amlodipine |
| CN108358833A (en) * | 2018-03-15 | 2018-08-03 | 上海峰林生物科技有限公司 | A kind of synthesis technology of amlodipine maleate |
| CN108456160A (en) * | 2018-03-15 | 2018-08-28 | 上海峰林生物科技有限公司 | A kind of synthesis technology of Amlodipine Besylate Tablet |
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2018
- 2018-12-29 CN CN201811653516.0A patent/CN109721587B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102070611A (en) * | 2010-12-28 | 2011-05-25 | 山东新华制药股份有限公司 | Preparation method of amlodipine intermediate |
| CN106749187A (en) * | 2016-12-29 | 2017-05-31 | 千辉药业（安徽）有限责任公司 | A kind of synthetic method of phthalyl Amlodipine |
| CN108358833A (en) * | 2018-03-15 | 2018-08-03 | 上海峰林生物科技有限公司 | A kind of synthesis technology of amlodipine maleate |
| CN108456160A (en) * | 2018-03-15 | 2018-08-28 | 上海峰林生物科技有限公司 | A kind of synthesis technology of Amlodipine Besylate Tablet |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114516774A (en) * | 2021-02-08 | 2022-05-20 | 中国科学院成都生物研究所 | Preparation method of chiral bromo-1, 4-dihydropyridine compound |
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