CN101544597B - Method for preparing amlodipine - Google Patents
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- CN101544597B CN101544597B CN200910136780A CN200910136780A CN101544597B CN 101544597 B CN101544597 B CN 101544597B CN 200910136780 A CN200910136780 A CN 200910136780A CN 200910136780 A CN200910136780 A CN 200910136780A CN 101544597 B CN101544597 B CN 101544597B
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Abstract
The present invention relates to a method for preparing a novel S-(-)-amlodipine, and especially to a novel method for preparing S-(-)-amlodipine through the resolution of racemic amlodipine. The N,N-dimethylformamide (DMF) is used as a dissolvent. The L-(+)-tartaric acid is used as a resolving agent. Not only can the excellent resolving effect be obtained, but also the cost is low and safety is excellent.
Description
Technical field
The present invention relates to a kind of preparation method of new S-(-)-amlodipine, relate in particular to a kind of new passing through and split the method that racemic amlodipine prepares S-(-)-amlodipine, belong to field of medicine and chemical technology.
Background technology
Amlodipine is a kind of calcium ion antagonist, clinically is used to treat hypertension and stable angina pectoris.According to Arrowsmiith, J.E.; Etal.J.Med.chem (1956) 29; 1696-1702 report, its pharmacologically active staple is S-(-)-amlodipine, its calcium ion antagonistic activity approximately is 1000 times of R-(+)-amlodipine, 2 times of raceme; Young, J.W., WO93/10779 report use S-(-)-amlodipine and can reduce spinoffs such as acro-edema, headache, dizziness with respect to using racemic amlodipine.Therefore adopt S-(-)-amlodipine treatment hypertension and stable angina pectoris to have good market outlook.
The amlodipine chemical structural formula is following:
A chiral carbon atom is arranged in the molecular structure, therefore two kinds of optical isomers, i.e. R-(+)-amlodipine and S-(-)-amlodipine are arranged.
The method of having reported at present for preparing the amlodipine enantiomorph mainly is to split racemic amlodipine.The WO95/25722 patent of Pfizer provides one to be resolving agent with D or L-tartrate, and DMSO 99.8MIN. is a solvent, directly splits the method that amlodipine obtains the amlodipine enantiomorph; Its weak point is that solvent DMSO 99.8MIN. boiling point is high; Be 189 ℃, be prone to cause solvent to be difficult for the problem that reclaims in process of production, and because DMSO 99.8MIN. can produce violent disproportionation reaction in the heating recovery process; Cause blast, industrial production is dangerous big.
It is resolving agent with D or L-tartrate that the WO03/035623 patent of Sepracor company has been described a kind of, is solvent with the DMAC N,N; Directly split the method for amlodipine raceme, but 164-166 ℃ of DMAC N,N (DMAC) boiling point; High difficult recovery of boiling point; And DMAC is two kind solvents, and toxicity is big, is prone to cause serious pollution in the production process.
The Chinese patent 200310119335.7 of Ouyi Pharmaceutical Industry Co., Ltd., Shijiazhuang Pharmaceutical Group adopts racemic amlodipine and L-(+)-tartrate are dissolved in the organic solvent that contains 2-butanone, and reaction produces the deposition of S-(-)-amlodipine L-(+)-tartrate; Through filtration or centrifugal after; Adopt lower alcohol solvent to carry out recrystallization again, obtain above-mentioned solid, add methylene dichloride then; With the sodium hydroxide solution neutralization, obtain S-(-)-amlodipine.The employed 2-butanone of this method, large usage quantity reaches 20 times (volume/weight) of racemic amlodipine; Because the 2-butanone boiling point is 80 ℃, boiling point is low, though easy recovery; But the removal process loss is big; Cause that to reclaim yield not high, under the situation of large usage quantity, not only wasted but also contaminate environment, and be dissipated in airborne solvent and set off an explosion easily.
The one Chinese patent application 200610170655.9 of application such as clock Nan Ping, disclosing one is solvent with the THF, is resolving agent with D-tartrate, splits the method that racemic amlodipine prepares S-(-)-amlodipine.Because the boiling point of THF has only 66 ℃, and is volatile, inflammable and explosive; Though easy recovery, the removal process loss is big, causes the recovery yield not high; Under the situation of large usage quantity, not only wasted but also contaminate environment, and be dissipated in airborne solvent and set off an explosion easily.In addition, enantiomeric purity can only reach 99.2% under this method best-case, and numerical value is on the low side.
The Chinese patent 03821593.4 of Hanlim Pharmaceutical Co., Ltd. discloses the method that is prepared as follows S-(-)-amlodipine:
1. method for preparing S-(-)-amlodipine, it comprises the steps:
(i) make (R, S)-amlodipine reacts with L-(+) tartrate in methyl-sulphoxide (DMSO);
The (ii) gained throw out of filtration step (i);
(iii) make S-(-)-amlodipine-half-L-tartrate-DMSO-solvolyte deposition through in step filtrating (ii), adding methylene dichloride;
(iv) optional through adding alcohol in S-(-)-amlodipine-half-L-tartrate-DMSO-solvolyte that (iii) obtains to step to form S-(-)-amlodipine-half-L-tartrate-monohydrate; With
(S-(-)-amlodipine that v) (iii) obtains in step with alkaline purification-half-L-tartrate-DMSO-solvolyte or S-(-)-amlodipine-half-L-tartrate-monohydrate that (iv) obtains in step, wherein said alkali is sodium hydrogencarbonate.
Owing to still used DMSO; There are aforementioned difficult recovery, explosive shortcoming, and find in the actually operating, after in step filtrating (ii), adding methylene dichloride; Obtain a kind of very heavy-gravity deposition; Be difficult to filter and separates, and filtrating is the mixed solvent of methylene dichloride and DMSO, be difficult to recovery more.The ultimate yield 69% that this method splits; With adopting D-tartrate is that the WO95/25722 ultimate yield 67% of the Pfizer of resolving agent is compared; Do not have considerable change; Operation bothers many on the contrary, and splits that enantiomeric purity can only reach 97.9% under the best-case of back, and to compare obvious numerical value on the low side with 99.5% of the WO95/25722 of Pfizer.
The one Chinese patent application 200510028964.8 of Yangzijiang Pharmaceutical Group, Shanghai Haini Pharmaceutical Co., Ltd discloses a kind of method for splitting of amlodipine.As chiral reagent, N-Methyl pyrrolidone is as chiral auxiliary(reagent) with tartrate for this method.The boiling point of N-Methyl pyrrolidone is difficult to reclaim up to 203 ℃.N-Methyl pyrrolidone toxicity is bigger, and skin is had slight hormesis, and chronic effect can cause the cns dysfunction, causes the pathology of respiratory organs, kidney, vascular system.
The one Chinese patent application 200580040627.9 of SK CHEMICALS is used isopropanol solvent and as optically active O of chiral reagent, O '-dibenzoyl tartaric acid.Its method comprises that (a) is through making (R; S)-amlodipine and optically active O; O '-dibenzoyl tartaric acid is reacted in isopropanol solvent; Obtain (R)-or (S)-and amlodipine dibenzoyl tartaric acid salt or its solvolyte and (b) with alkaline purification (R)-or (S)-Amlodipine, obtain optically active amlodipine thus.Optically active O, the price of O '-dibenzoyl tartaric acid is far above D-tartrate and L-tartrate, and cost is too high.In addition, enantiomeric purity can only reach 99.2% under the best-case of fractionation back, and numerical value is on the low side.
The Chinese patent 200610076935.3 of Zhongqi Pharmaceutical Technology (Shijiazhuang) Co. Ltd. of Shiyao Group, the resolving agent of use are L or D-tartrate, and solvent is the first and second basic sulfoxides or the mixed solvent that contains the first and second basic sulfoxides.
The first and second basic sulfoxides are not that common solvent is gone up in industry, do not have industrial source, in this patent, prepare through hydrogen peroxide oxidation through the first and second basic thioethers, obtain being easy to blast in the process of product in the reaction mixture distillation.
Summary of the invention:
For overcoming the defective of prior art, seek the method for a kind of better S-of preparation (-)-amlodipine, the inventor has carried out lot of test; Be surprised to find that; Use N, dinethylformamide (DMF) is made solvent, the agent that splits of L-(+)-tartrate; Not only can reach excellent fractionation effect, and overcome the defective of prior art.
S-of the present invention (-)-amlodipine preparation method comprises the steps:
(1), the preparation of S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte
R, S-(-)-amlodipine adding envelope-bulk to weight ratio is 2～4 times N, dinethylformamide (DMF), 30～60 ℃ of stirring and dissolving; Stir and in 0.5～1 hour, to drip down with starting raw material R, S-amlodipine meter mol ratio is the solution that L-(+)-tartrate of 1: 0.166～0.25 is dissolved in DMF, 30～60 ℃ of insulated and stirred 0.5～5 hour, and room temperature continues stirred overnight then; Have a large amount of solids to separate out, filter, filter cake is drained after washing with a small amount of DMF; Aftertreatment: solid adds DMF, stirs 0.5～5 hour stirred overnight at room temperature under 30～60 ℃ of water bath condition; Filter, filter cake is drained after washing with a small amount of DMF; Drying is weighed, and gets S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte.
(2), the preparation of S-(-)-amlodipine
By S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte alkalization preparation S-(-)-amlodipine.
We discover; In the preparation of above-mentioned (1) step S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte; To what split the influential effect maximum is R in the starting raw material, the mol ratio of S-amlodipine and resolution reagent L-(+)-tartrate meter, available mol ratio 1: 0.166～0.25; Preferred 1: 0.166～0.21, most preferably 1: 0.166; Next is a temperature, and usable temp is 30～60 ℃, preferred 50 ℃.
Therefore, (1) step is preferably according to following method:
R, S-amlodipine adding envelope-bulk to weight ratio are 2 times N, dinethylformamide (DMF), 30～60 ℃ of stirring and dissolving; Stir in 1 hour, drip with starting raw material down in R, S-amlodipine meter mol ratio is the solution that L-(+)-tartrate of 1: 0.166～0.21 is dissolved in DMF, 30～60 ℃ of insulated and stirred 1 hour, room temperature continues stirred overnight then; Have a large amount of solids to separate out, filter, filter cake is drained after washing with a small amount of DMF; Aftertreatment: solid adds with starting raw material R, and S-amlodipine meter envelope-bulk to weight ratio is 3 times DMF, stirs 1 hour stirred overnight at room temperature under 30～60 ℃ of water bath condition; Filter, filter cake is drained drying after washing with a small amount of DMF; Weigh, get S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte, ee value 99.4-99.9%.
Further preferred, above-mentioned (1) goes on foot used L-(+)-tartaric consumption with starting raw material R, and the mol ratio of S-amlodipine meter is 1: 0.166, and reaction and post-processing temperature are 30-60 ℃, ee value 99.7-99.9%; On this basis most preferably: L-(+)-tartaric consumption is with starting raw material R, and the mol ratio of S-amlodipine meter is 1: 0.166, and reaction and post-processing temperature are 50 ℃, ee value 99.9%.
The preparation of above-mentioned (2), S-(-)-amlodipine can be carried out with reference to the general operation of S-(-)-amlodipine salinization in the disclosed prior art, and for example the S-(-) in the aforementioned background art-amlodipine splits relevant operating process in the patent.Also can be according to following operation:
Get S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte, add the 1mol/L aqueous sodium hydroxide solution of 10 times of envelope-bulk to weight ratios, stirring at room 1 hour.The dichloromethane extraction twice that adds 10 times of envelope-bulk to weight ratios then merges organic phase, with the water washing of 10 times of envelope-bulk to weight ratios.Organic phase is used dried over sodium sulfate, filters, and concentrates, and obtains oily matter.The normal hexane that adds 5 times of envelope-bulk to weight ratios, stirring and crystallizing filtered after 1 hour, got S-(-)-amlodipine.
Concrete operations are general to be described below:
1, the preparation of S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte
R, S-amlodipine 50g (0.12mol), (be that envelope-bulk to weight ratio is 2～4, the preferred volume weight ratio is 2 to add DMF100～200ml; Be 100ml), 30～60 ℃ of (preferred 50 ℃) stirring and dissolving stir down in 0.5～1 hour (preferred 1 hour) and drip L-(+)-tartrate 3～4.5g (0.02mol～0.03mol is with R in the starting raw material; S-amlodipine meter mol ratio is 1: 0.166～0.25, preferred 1: 0.166) be dissolved in the solution of DMF 80～120ml (preferred 80ml), 30～60 ℃ of (preferred 50 ℃) insulated and stirred 0.5～5 hour (preferred 1 hour); Room temperature continues stirred overnight then, has a large amount of solids to separate out, and filters; Filter cake is drained after washing with a small amount of DMF, and solid adds DMF 150ml; Stir 0.5～5 hour (preferred 1 hour) under 30～60 ℃ of (preferred 50 ℃) water bath condition, stirred overnight at room temperature is filtered; Filter cake is drained drying after washing with a small amount of DMF; Weigh, get S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte 21.6g～32.8g, yield: 63.5%～96.4%.The ee pH-value determination pH is 94.4-99.9% as a result.
2, the preparation of S-(-)-amlodipine
By S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte alkalization preparation S-(-)-amlodipine; Can carry out with reference to the general operation of S-(-)-amlodipine salinization in the disclosed prior art; For example the S-(-) in the aforementioned background art-amlodipine splits relevant operating process in the patent, also can be according to following operation:
S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte 10g adds 1mol/L aqueous sodium hydroxide solution 100ml, stirring at room 1 hour.Add 100ml dichloromethane extraction twice, merge organic phase, use the 100ml water washing.Organic phase is used dried over sodium sulfate, filters, and concentrates, and obtains oily matter.Add the 50ml normal hexane, stirring and crystallizing was filtered after 1 hour, got the off-white color solid, and vacuum-drying gets 6.7g, yield 91.3%.
The ee pH-value determination pH of S-(-)-amlodipine that finally obtains according to the method described above is 94.7-99.9% as a result.
The advantage of this method:
1, make solvent with respect to DMSO, because DMSO is in the process of solvent recuperation, 90 ℃ disproportionation reaction can take place, and has the danger of blast, thus cause pollution in the industry easily to environment, and DMF reclaims easily, not dangerous.
2, with respect to THF, 2-butanone, Virahol, DMF is far better in security, mainly is that boiling point is high slightly, more difficult blast.
3, with respect to methyl-sulfinyl-ethane; Do not go up common solvent because the first and second basic sulfoxides are not industry, do not have industrial source, in this patent, prepare through hydrogen peroxide oxidation through the first and second basic thioethers; Obtain being easy to blast in the process of product in the reaction mixture distillation.And methyl-sulfinyl-ethane is the same with DMSO, also exists to be prone to take place disproportionation reaction in the concentration process, has the danger of blast.
4, with respect to O, O '-dibenzoyl tartaric acid, the tartrate cost is low.
5, with respect to N-Methyl pyrrolidone, toxicity is littler, and solvent stability is better.
Add methylene chloride during 6, with respect to fractionation, it is easier than mixed solvent that single solvent reclaims.
7, S-(-)-amlodipine enantiomeric purity of obtaining of present method is very high, and the scheme ee value after preferred can reach 99.7-99.9%.
In addition, the present invention also provides a kind of new compound, and promptly S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte can be used as the raw material for preparing S-(-)-amlodipine.Its structural formula is following:
Molecular formula: C
20H
25ClN
2O
50.5C
4H
6O
6C
3H
7NO
The ee value is 99.9% o'clock (sample source is embodiment 9), and fusing point: 128～130 ℃, results of elemental analyses is following:
| C | H | N | |
| Theoretical value | 53.91％ | 6.63％ | 7.54％ |
| Measured value | 53.79％ | 6.66％ | 7.61％ |
The main fragment peak of mass spectrum (FAB): 409 (C
20H
25ClN
2O
5+ 1), 294 (C
14H
19N
2O
5), 238 (C
12H
17N
2O
3)
1HNMR(CD
3OD)：7.10～7.42(m，4H)，5.29(s，1H)，4.54～4.66(dd，2H)，4.38(s，1H)，3.93～3.99(m，2H)，3.61～3.63(m，2H)，3.55(s，3H)，3.45(s，DMF)，3.14～3.16(m，2H)，2.21(s，3H)，1.14～1.17(t，3H)。
We study the back and find; In the process of S-(-)-amlodipine preparation; The optical purity of product, just the ee value overwhelming majority of product depends on the ee value of midbody S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte, alkalization preparation S-(-)-amlodipine is very little to the contribution that improves the ee value; Therefore as long as the ee value of midbody S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte is higher, just can guarantee the optical purity of product S-(-)-amlodipine.
Embodiment:
Embodiment 1
1., the preparation of S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte
R, S-amlodipine 50g (0.12mol) adds DMF150ml, 30 ℃ of stirring and dissolving; Stir the solution that is added dropwise to L-(+)-tartrate 9g (0.06mol) (mol ratio is 1: 0.5)/DMF 240ml down, after being added dropwise to complete, 30 ℃ of insulated and stirred 5 hours, stirred overnight at room temperature; Have a large amount of solids to separate out, filter, filter cake is drained after washing with a small amount of DMF; Solid adds DMF 150ml, stirs 1 hour under 30 ℃ of water bath condition, and room temperature continues stirred overnight, filters; Filter cake with a small amount of DMF washing after, drain, drying, weigh S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte 42.2g.Yield: 124.1% (by S-(-)-amlodipine, down together).Fusing point: 123～128 ℃, ee pH-value determination pH result 74.6%.
2., the preparation of S-(-)-amlodipine
With above-mentioned S-(-)-amlodipine-half L-(+) for preparing-tartrate-DMF solvolyte 10g, add 1mol/L aqueous sodium hydroxide solution 100ml, stirring at room 1 hour.Add 100ml dichloromethane extraction twice, merge organic phase, use the 100ml water washing.Organic phase is used dried over sodium sulfate, filters, and concentrates, and obtains oily matter.Add the 50ml normal hexane, stirring and crystallizing was filtered after 1 hour, got the off-white color solid, and vacuum-drying gets 6.8g.Yield 92.0%.Ee pH-value determination pH result 74.7%.
The above results shows, put down in writing in the WO95/25722 patent according to Pfizer ratio (mol ratio is 1: 0.5) add L-(+)-tartrate, split poor.
Embodiment 2
1., the preparation of S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte
R, S-amlodipine 50g (0.12mol) adds DMF150ml, 30 ℃ of stirring and dissolving; Stir the solution that is added dropwise to L-(+)-tartrate 4.5g (0.03mol) (mol ratio is 1: 0.25)/DMF 120ml down, after being added dropwise to complete, 30 ℃ of insulated and stirred 5 hours, stirred overnight at room temperature; Have a large amount of solids to separate out, filter, filter cake is drained after washing with a small amount of DMF; Solid adds DMF 150ml, stirs 1 hour under 30 ℃ of water bath condition, and room temperature continues stirred overnight, filters; Filter cake with a small amount of DMF washing after, drain, drying, weigh S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte 32.8g.Yield: 96.4%.Fusing point: 125～129 ℃, ee pH-value determination pH result 94.4%.
2., the preparation of S-(-)-amlodipine
Method is with embodiment 1, and vacuum-drying gets 6.7g.Yield 91.3%.Ee pH-value determination pH result 94.7%.
Embodiment 3
1., the preparation of S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte
R, S-amlodipine 50g (0.12mol) adds DMF150ml, and 40 ℃ of stirring and dissolving stir the solution that is added dropwise to L-(+)-tartrate 4.5g (0.03mol) (mol ratio is 1: 0.25)/DMF 120ml down; After being added dropwise to complete, 40 ℃ of insulated and stirred 3 hours, stirred overnight at room temperature has a large amount of solids to separate out, and filters; Filter cake is drained after washing with a small amount of DMF, and solid adds DMF 150ml, stirs 1 hour under 40 ℃ of water bath condition, and room temperature continues stirred overnight; Filter, filter cake is drained drying after washing with a small amount of DMF; Weigh 32g, (yield: 94.1%), fusing point: 126～129 ℃, the ee pH-value determination pH is 95.9%. as a result
2., the preparation of S-(-)-amlodipine
Method gets 6.8g with embodiment 1.(yield 92.6%).Ee pH-value determination pH result 96.0%.
Embodiment 4,
1., the preparation of S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte
R, S-amlodipine 50g (0.12mol) adds DMF100ml, 50 ℃ of stirring and dissolving; Stir the solution that is added dropwise to L-(+)-tartrate 4.5g (0.03mol) (mol ratio is 1: 0.25)/DMF 120ml down, after being added dropwise to complete, 50 ℃ of insulated and stirred 1 hour, stirred overnight at room temperature; Have a large amount of solids to separate out, filter, filter cake is drained after washing with a small amount of DMF; Solid adds DMF 150ml, stirs 1 hour under 50 ℃ of water bath condition, and room temperature continues stirred overnight, filters; Filter cake with a small amount of DMF washing after, drain, drying, weigh 31.5g.Yield: 92.6%.Fusing point: 127～130 ℃ of ee pH-value determination pH results 97.8%.
2., the preparation of S-(-)-amlodipine
Method gets 6.8g with embodiment 1.(yield 92.6%).Ee pH-value determination pH result 97.9%.
Embodiment 5,
1., the preparation of S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte
R, S-amlodipine 50g (0.12mol) adds DMF100ml, 60 ℃ of stirring and dissolving; Stir the solution that is added dropwise to L-(+)-tartrate 4.5g (0.03mol) (mol ratio is 1: 0.25)/DMF 120ml down, after being added dropwise to complete, 60 ℃ of insulated and stirred 1 hour, stirred overnight at room temperature; Have a large amount of solids to separate out, filter, filter cake is drained after washing with a small amount of DMF; Solid adds DMF 150ml, stirs 1 hour under 60 ℃ of water bath condition, and room temperature continues stirred overnight, filters; Filter cake with a small amount of DMF washing after, drain, drying, weigh 31.3g.Yield: 92.1%.Fusing point: 127～130 ℃, ee pH-value determination pH result 97.4%.
2., the preparation of S-(-)-amlodipine
Method gets 6.4g with embodiment 1.(yield 87.2%).Ee pH-value determination pH result 97.3%.
Embodiment 6,
1., the preparation of S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte
R, S-amlodipine 50g (0.12mol) adds DMF100ml, 50 ℃ of stirring and dissolving; Stir the solution that is added dropwise to L-(+)-tartrate 3.75g (0.025mol) (mol ratio is 1: 0.21)/DMF 100ml down, after being added dropwise to complete, 50 ℃ of insulated and stirred 1 hour, stirred overnight at room temperature; Have a large amount of solids to separate out, filter, filter cake is drained after washing with a small amount of DMF; Solid adds DMF 150ml, stirs 1 hour under 50 ℃ of water bath condition, and room temperature continues stirred overnight, filters; Filter cake with a small amount of DMF washing after, drain, drying, weigh 26.4g.Yield: 77.6%, fusing point: 127～130 ℃, ee pH-value determination pH result 99.4%.
2., the preparation of S-(-)-amlodipine
Method gets 6.7g with embodiment 1.(yield 91.3%).Ee pH-value determination pH result 99.7%.
Embodiment 7,
1., the preparation of S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte
R, S-amlodipine 50g (0.12mol) adds DMF100ml, 30 ℃ of stirring and dissolving; Stir and to be added dropwise to L-(+)-tartrate 3g (0.02mol) (mol ratio is 1: 0.166)/add the solution of DMF 80ml down, after being added dropwise to complete, 30 ℃ of insulated and stirred 1 hour, stirred overnight at room temperature; Have a large amount of solids to separate out, filter, filter cake is drained after washing with a small amount of DMF; Solid adds DMF 150ml, stirs 1 hour under 30 ℃ of water bath condition, and room temperature continues stirred overnight, filters; Filter cake with a small amount of DMF washing after, drain, drying, weigh 21.6g.Yield: 63.5%.Fusing point: 128～130 ℃, ee pH-value determination pH result 99.7%.
2., the preparation of S-(-)-amlodipine
Method gets 6.8g with embodiment 1.(yield 92.6%).Ee pH-value determination pH result 99.7%.
Embodiment 8,
1., the preparation of S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte
R, S-amlodipine 50g (0.12mol) adds DMF100ml, 40 ℃ of stirring and dissolving; Stir and to be added dropwise to L-(+)-tartrate 3g (0.02mol) (mol ratio is 1: 0.166)/add the solution of DMF 80ml down, after being added dropwise to complete, 40 ℃ of insulated and stirred 1 hour, stirred overnight at room temperature; Have a large amount of solids to separate out, filter, filter cake is drained after washing with a small amount of DMF; Solid adds DMF 150ml, stirs 1 hour under 40 ℃ of water bath condition, and room temperature continues stirred overnight, filters; Filter cake with a small amount of DMF washing after, drain, drying, weigh 21.7g.Yield: 63.8%, fusing point: 127～129 ℃ of ee pH-value determination pH results 99.7%.
2., the preparation of S-(-)-amlodipine
Method gets 6.8g with embodiment 1.(yield 92.6%).Ee pH-value determination pH result 99.8%.
Embodiment 9,
1., the preparation of S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte
R, S-amlodipine 50g (0.12mol) adds DMF100ml, 50 ℃ of stirring and dissolving; Stir and to be added dropwise to L-(+)-tartrate 3g (0.02mol) (mol ratio is 1: 0.166)/add the solution of DMF 80ml down, after being added dropwise to complete, 50 ℃ of insulated and stirred 1 hour, stirred overnight at room temperature; Have a large amount of solids to separate out, filter, filter cake is drained after washing with a small amount of DMF; Solid adds DMF 150ml, stirs 1 hour under 50 ℃ of water bath condition, and room temperature continues stirred overnight, filters; Filter cake with a small amount of DMF washing after, drain, drying, weigh 21.6g.Yield: 63.5%, fusing point: 128～130 ℃, ee pH-value determination pH result 99.9%.
Results of elemental analyses is following:
| C | H | N | |
| Theoretical value | 53.91％ | 6.63％ | 7.54％ |
| Measured value | 53.79％ | 6.66％ | 7.61％ |
The main fragment peak of mass spectrum (FAB): 409 (C
20H
25ClN
2O
5+ 1), 294 (C
14H
19N
2O
5), 238 (C
12H
17N
2O
3)
1HNMR(CD
3OD)：7.10～7.42(m，4H)，5.29(s，1H)，4.54～4.66(dd，2H)，4.38(s，1H)，3.93～3.99(m，2H)，3.61～3.63(m，2H)，3.55(s，3H)，3.45(s，DMF)，3.14～3.16(m，2H)，2.21(s，3H)，1.14～1.17(t，3H)。
2., the preparation of S-(-)-amlodipine
Method gets 6.8g with embodiment 1.(yield 92.6%).Ee pH-value determination pH result 99.9%.
Claims (6)
1. a S-(-)-amlodipine preparation method is characterized in that comprising the steps:
(1), the preparation of S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte
R, S-amlodipine adding envelope-bulk to weight ratio are 2～4 times N, dinethylformamide (DMF), 30～60 ℃ of stirring and dissolving; Stir and in 0.5～1 hour, to drip down with starting raw material R, S-amlodipine meter mol ratio is the solution that L-(+)-tartrate of 1: 0.166～0.25 is dissolved in DMF, 30～60 ℃ of insulated and stirred 0.5～5 hour, and room temperature continues stirred overnight then; Have a large amount of solids to separate out, filter, filter cake is drained after washing with a small amount of DMF; Aftertreatment: solid adds DMF, stirs 0.5～5 hour stirred overnight at room temperature under 30～60 ℃ of water bath condition; Filter, filter cake is drained after washing with a small amount of DMF; Drying is weighed, and gets S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte;
(2), the preparation of S-(-)-amlodipine
By S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte alkalization preparation S-(-)-amlodipine.
2. according to the described S-of claim 1 (-)-amlodipine preparation method, the preparation that it is characterized in that said S-(-)-amlodipine is according to following method:
Get S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte, add the 1mol/L aqueous sodium hydroxide solution of 10 times of envelope-bulk to weight ratios, stirring at room 1 hour; The dichloromethane extraction twice that adds 10 times of envelope-bulk to weight ratios then merges organic phase, with the water washing of 10 times of envelope-bulk to weight ratios; Organic phase is used dried over sodium sulfate, filters, and concentrates, and obtains oily matter; The normal hexane that adds 5 times of envelope-bulk to weight ratios, stirring and crystallizing filtered after 1 hour, got S-(-)-amlodipine.
3. according to the described S-of claim 1 (-)-amlodipine preparation method, the preparation that it is characterized in that said S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte is according to following method:
R, S-amlodipine adding envelope-bulk to weight ratio are 2 times N, dinethylformamide (DMF), 30～60 ℃ of stirring and dissolving; Stir and in 1 hour, to drip down with starting raw material R, S-amlodipine meter mol ratio is the solution that L-(+)-tartrate of 1: 0.166～0.21 is dissolved in DMF, 30～60 ℃ of insulated and stirred 1 hour, and room temperature continues stirred overnight then; Have a large amount of solids to separate out, filter, filter cake is drained after washing with a small amount of DMF; Aftertreatment: solid adds with starting raw material R, and S-amlodipine meter envelope-bulk to weight ratio is 3 times DMF, stirs 1 hour stirred overnight at room temperature under 30～60 ℃ of water bath condition; Filter, filter cake is drained after washing with a small amount of DMF; Drying is weighed, and gets S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte.
4. according to the described S-of claim 3 (-)-amlodipine preparation method; It is characterized in that in the preparation of said S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte; Said L-(+)-tartaric consumption is with starting raw material R, and S-amlodipine meter mol ratio is 1: 0.166.
5. according to the described S-of claim 4 (-)-amlodipine preparation method, it is characterized in that in the preparation of said S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte that reaction and post-processing temperature are 50 ℃.
6. the solid form of a S-as claimed in claim 1 (-)-amlodipine-half L-(+)-tartrate-DMF solvolyte is characterized in that 128～130 ℃ of fusing points, and the ee value is 99.9%, and adopts following method preparation:
R, S-amlodipine 50g adds DMF 100ml, and 50 ℃ of stirring and dissolving are added dropwise to L-(+)-tartrate 3g under stirring and add the solution of DMF80ml; After being added dropwise to complete, 50 ℃ of insulated and stirred 1 hour, stirred overnight at room temperature has a large amount of solids to separate out, and filters; Filter cake is drained after washing with a small amount of DMF, and solid adds DMF 150ml, stirs 1 hour under 50 ℃ of water bath condition, and room temperature continues stirred overnight; Filter, filter cake is drained after washing with a small amount of DMF, drying, weigh 21.6g;
The solid form of said S-(-)-amlodipine-half L-(+)-tartrate-DMF solvolyte has following physical parameter:
Ultimate analysis:
The main fragment peak of mass spectrum (FAB): 409 (C
20H
25ClN
2O
5+ 1), 294 (C
14H
19N
2O
5), 238 (C
12H
17N
2O
3);
1HNMR(CD
3OD)：7.10～7.42(m，4H)，5.29(s，1H)，4.54～4.66(dd，2H)，4.38(s，1H)，3.93～3.99(m，2H)，3.61～3.63(m，2H)，3.55(s，3H)，3.45(s，DMF)，3.14～3.16(m，2H)，2.21(s，3H)，1.14～1.17(t，3H)。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1608051A (en) * | 2001-10-24 | 2005-04-20 | 塞普拉科有限公司 | Method of resolving amlodipine racemate |
| CN101209991A (en) * | 2006-12-27 | 2008-07-02 | 钟南平 | Method for preparing S-(-)-amlodipine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1608051A (en) * | 2001-10-24 | 2005-04-20 | 塞普拉科有限公司 | Method of resolving amlodipine racemate |
| CN101209991A (en) * | 2006-12-27 | 2008-07-02 | 钟南平 | Method for preparing S-(-)-amlodipine |
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Application publication date: 20090930 Assignee: Beijing Tianheng Drug Research Institute, Nanyang Tianheng Pharmacy Factory Assignor: Beijing Tianheng Medicine Inst. Contract record no.: 2015410000041 Denomination of invention: Method for preparing S- (-) amlodipine Granted publication date: 20120905 License type: Exclusive License Record date: 20150515 |
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