CN101759631A - Method for preparing butyrate clevidipine - Google Patents
Method for preparing butyrate clevidipine Download PDFInfo
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- CN101759631A CN101759631A CN200910214376A CN200910214376A CN101759631A CN 101759631 A CN101759631 A CN 101759631A CN 200910214376 A CN200910214376 A CN 200910214376A CN 200910214376 A CN200910214376 A CN 200910214376A CN 101759631 A CN101759631 A CN 101759631A
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- butyrate clevidipine
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- clevidipine
- key intermediate
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- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 title claims abstract description 40
- KPBZROQVTHLCDU-GOSISDBHSA-N clevidipine Chemical compound CCCC(=O)OCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@H]1C1=CC=CC(Cl)=C1Cl KPBZROQVTHLCDU-GOSISDBHSA-N 0.000 title claims abstract description 36
- 229960003597 clevidipine Drugs 0.000 title claims abstract description 33
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 title claims abstract description 28
- 238000000034 method Methods 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 238000003445 Hantzsch reaction Methods 0.000 claims abstract description 8
- -1 acetoacetate propionitrile ester Chemical class 0.000 claims abstract description 8
- BDPZFQLKFUONAG-UHFFFAOYSA-N chloromethyl butanoate Chemical compound CCCC(=O)OCCl BDPZFQLKFUONAG-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 238000005580 one pot reaction Methods 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 238000002360 preparation method Methods 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 7
- PDBKEJXQZUIZAY-UHFFFAOYSA-N 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylic acid Chemical compound OC(=O)C1=C(C)NC(C)=CC1C1=CC=CC(Cl)=C1Cl PDBKEJXQZUIZAY-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 150000004702 methyl esters Chemical class 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000000746 purification Methods 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000013375 chromatographic separation Methods 0.000 abstract description 3
- LLMLNAVBOAMOEE-UHFFFAOYSA-N 2,3-dichlorobenzaldehyde Chemical compound ClC1=CC=CC(C=O)=C1Cl LLMLNAVBOAMOEE-UHFFFAOYSA-N 0.000 abstract description 2
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000012043 crude product Substances 0.000 abstract 2
- 230000036632 reaction speed Effects 0.000 abstract 1
- 238000004237 preparative chromatography Methods 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000002220 antihypertensive agent Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 4
- 229940127088 antihypertensive drug Drugs 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 244000309464 bull Species 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 239000003317 industrial substance Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical group CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- KPBZROQVTHLCDU-UHFFFAOYSA-N clevidipine Chemical compound CCCC(=O)OCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC(Cl)=C1Cl KPBZROQVTHLCDU-UHFFFAOYSA-N 0.000 description 1
- 229960003621 clevidipine butyrate Drugs 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 231100000584 environmental toxicity Toxicity 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229910000474 mercury oxide Inorganic materials 0.000 description 1
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for preparing butyrate clevidipine. The method comprises that 2, 3-dichlorobenzaldehyde, acetoacetate propionitrile ester and 3-amino-2-methyl crotonate are mixed and one-pot Hantzsch reaction is conducted, base catalyst is added to remove 2-cyanoethyl to obtain key intermediate, the key intermediate reacts with n-butyric acid chloromethyl ester to obtain butyrate clevidipine crude product, and the crude product is recrystallized to obtain high-purity butyrate clevidipine. Raw material 3-amino-2-methyl crotonate can be prepared by using low-price methyl acetoacetate. Raw material acetoacetate propionitrile ester can be prepared by using diketene. The synthesis of all raw materials requires no chromatographic separation for purification. The intermediate is synthesized through one-pot Hantzsch reaction, the reaction speed is fast, the condition is mild, the technological reliability is high and the purity of the intermediate is high. The conditions for the reaction of the key intermediate and the n-butyric acid chloromethyl ester can be easily controlled, the operation is simple and convenient, the cost is low, the post treatment requires no chromatographic separation for purification, the purity of the obtained butyrate clevidipine is above 99.5 percent and the mass production can be realized.
Description
Technical field
The present invention relates to the preparation method of a kind of novel antihypertensive medicament butyrate clevidipine (Clevidipine butyrate).
Background technology
Hypertension is one of modal cardiovascular disorder in the world, and multiple therapy methods is arranged, and wherein the antihypertensive drugs result of treatment is better, and use range is the widest.
Antihypertensive drug has a variety of, comprises diuretic hypotensive agent, nervus centralis and sympathetic inhibitor, adrenergic receptor blocker, calcium ion antagonist etc.
Butyrate clevidipine be the 4th generation dihydropyridine calcium ion channel blocking medicine, can selectivity suppress the extracellular flow of calcium ions of vascular smooth muscle, thereby make blood vessel lax, blood pressure reduces.Its structure is shown below.It is the antihypertensive drugs of external first used for intravenous injection over past ten years, is adapted at inapplicable or does not wish to use under the situation of oral preparations and carry out hypertensive treatment, aspect the acute elevation of blood pressure treatment application is arranged also after heart operation.Butyrate clevidipine is rapid-action, and effect is eliminated also fast, but ascending-dose controlling blood pressure accurately.With present many intravenous injections through kidney and (or) antihypertensive drug of hepatic metabolism is different, its metabolism in blood and tissue, thereby do not accumulate in vivo.
Patent and the document that relates to butyrate clevidipine has (WO2009/140527, WO2009/121031, WO2008/109343, WO2008/106659, WO2005/000217, WO2004/110375, WO2004/096217, WO2004/089416, WO2000/31035, WO1995/13066, WO1995/12578), mainly still is the prescription of preparation.About the synthetic following patent and the article (WO2000/31035, WO1995/13066, WO1995/12578, Chinese Journal of Pharmaceuticals, 2009,40,791 etc.) of mainly containing of butyrate clevidipine bulk drug, the synthetic method of report respectively has its relative merits.
Patent WO1995/12578 has mentioned the route of many synthetic butyric acid Clevidipines; but only introduced in the case study on implementation of its patent from (±)-4-(2 '; 3 '-dichlorophenyl)-2; 6-dimethyl-1; 4-dihydropyridine-5-carboxylic acid methyl-3-formic acid (intermediate II) sets out, by the route (being shown below) of esterification synthetic butyric acid Clevidipine, this reaction needed nitrogen protection; product will pass through the preparative chromatography separation and purification, is unfavorable for suitability for industrialized production.The reaction and the separation case synthetic and other synthetic route of intermediate II are all not mentioned.
Patent WO1995/13066 has also reported from intermediate II synthetic butyric acid Clevidipine, the reaction needed nitrogen protection, and product also will pass through the preparative chromatography separation and purification.Synthesizing of not mentioned intermediate II.
Patent WO2000/31035 has reported from (±)-4-(2 ', 3 '-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-5-carboxylic acid methyl-3-carboxylic acid propionitrile ester (intermediate compound IV) the synthetic butyric acid Clevidipine that sets out, and product can pass through recrystallization purifying.But the preparation of not mentioned intermediate compound IV, and second step esterification use acetonitrile solvent, environmental toxicity is bigger.
Synthetic report (Chem.Pharm.Bull.1994,42,1579 that several pieces of intermediate compound IV are also arranged in addition; Chem.Pharm.Bull.1993,41,1049; Chem.Pharm.Bull.1993,41,108; JP 07126251 etc.).Intermediate compound IV can also can be passed through three kinds of raw material stepwise synthesis (Method 2) by one steps of three kinds of raw materials directly synthetic (Method 1), and weak point is all will use the preparative chromatography separation and purification, is not suitable for a large amount of preparing products.
In sum, the butyrate clevidipine building-up reactions is wayward at present, and impurity is more, and product needs to be unfavorable for large-scale commercial production by the preparative chromatography separation and purification more.
Summary of the invention
The objective of the invention is to overcome the deficiency that prior art exists, provide a kind of and can improve yield and quality product, reduce cost, easy and simple to handle, the preparation method of suitable industrial butyrate clevidipine.
A kind of preparation method of butyrate clevidipine, comprise the steps: 2, the 3-dichlorobenzaldehyde, etheric acid propionitrile ester, one pot of Hantzsch reaction is carried out in 3-amino-2-butylene acid methyl esters mixing, adding alkaline catalysts then removes the 2-cyanoethyl and makes key intermediate II (±)-4-(2 ', 3 '-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-5-carboxylic acid methyl-3-formic acid, key intermediate II reacts with the butanic acid chloromethyl ester again, reaction solution obtains the thick product of butyrate clevidipine after with ethyl acetate and water treatment, and thick product is again through ethyl acetate/petroleum ether, isopropanol or isopropyl ether/acetone recrystallization obtain high purity butyric acid Clevidipine III.
In the preparation method of above-mentioned butyrate clevidipine, the solvent of described Hantzsch reaction is a Virahol, temperature of reaction is 20-180 ℃, and the reaction times is 2-24h, adds alkaline catalysts subsequently and removes the 2-cyanoethyl, use the washed with dichloromethane water, water slowly adds phosphoric acid, obtains key intermediate (±)-4-(2 ', 3 '-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-5-carboxylic acid methyl-3-formic acid.
In the preparation method of above-mentioned butyrate clevidipine, described one pot of Hantzsch reaction also adds catalyzer, and described catalyzer is organic bases or mineral alkali.Organic bases is preferably triethylamine or pyridine; Described mineral alkali is preferably NaOH, KOH, CsOH, KHCO
3, NaHCO
3, K
2CO
3, Na
2CO
3Or Cs
2CO
3
In the preparation method of above-mentioned butyrate clevidipine, it is Bu that the used alkaline catalysts of 2-cyanoethyl protecting group is taken off in hydrolysis
4NF, Na
2S, Ca (OH)
2, NaOH, KOH, Ba (OH)
2, Mg (OH)
2Or Sr (OH)
2
In the preparation method of above-mentioned butyrate clevidipine, being reflected under the alkaline condition of described key intermediate and butanic acid chloromethyl ester carried out.
Compared with prior art, the present invention has following advantage:
1. raw material 3-amino-2-butylene acid methyl esters can be easy to preparation by cheap industrial chemicals methyl acetoacetate; raw material etheric acid propionitrile ester can be by industrial chemicals ketene dimer or 5-ethanoyl-2; 2-dimethyl-1,3-dioxane-4,6-diketone are easy to preparation.Related raw material is synthetic all to need not the preparative chromatography separation and purification.
2. the reaction of intermediate and butanic acid chloromethyl ester uses DMF to be solvent, N in patent in the past or the document
2Protect following 80 ℃ of reaction 18h, product butyrate clevidipine (III) need just can obtain meeting the bulk drug of preparation production requirement through the preparative chromatography separation and purification.Adopt chromatographic separation can't be applied to industrialized production.The present invention does not have N
2Protection; reaction solution obtains thick product I II after with ethyl acetate and water treatment; III need not to use the preparative chromatography purifying through ethyl acetate/petroleum ether (also can be isopropanol, isopropyl ether/acetone) recrystallization again, can obtain qualified product, and purity is greater than 99.5%.This law technological process is simple, and cost is low, is fit to industrial production.
Embodiment
Be described in detail the present invention with the following examples, but it not a limitation of the present invention.
Embodiment 1:(±)-4-(2 ', 3 '-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-5-carboxylic acid methyl-3-formic acid (II)
In round-bottomed flask, add 2,3 dichloro benzaldehyde (175g, 1mol), etheric acid propionitrile ester (160g, 1.03mol) and 3-amino-(115g, 1mol), Virahol is made solvent to 2-butylene acid methyl esters, 50 ℃ of reactions 12 hours.Decompression removes the solvent postcooling to room temperature, adds the ethanol/water mixing solutions of sodium hydroxide, adds 1L water again behind the stirring 5h, uses the washed with dichloromethane water.Water slowly adds 300mL phosphoric acid, has yellow mercury oxide to generate, and suction filtration gets solid 273.2g, productive rate 77%.IR(KBr，cm
-1)：3344，2950，1656，1477，1229，779.
1H?NMR(DMSO，ppm)：δ＝11.59(s，1H)，8.81(s，1H)，7.38-7.21(m，3H)，5.30(s，1H)，3.48(s，3H)，2.23(s，3H)，2.22(s，3H)；
13C?NMR(DMSO，ppm)：δ＝168.46，167.27，149.09，145.82，144.89，131.35，129.61，129.51，128.02，127.92，102.34，101.03，50.39，38.35，18.07，18.04。
Embodiment 2:(±)-4-(2 ', 3 '-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid methyl (butyryl acyloxy methyl) ester (III)
In round-bottomed flask, add (±)-4-(2 ', 3 '-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-5-carboxylic acid methyl-3-formic acid (171.0g, 0.48mol), anhydrous sodium carbonate (101.8g, 0.96mol) and 3L DMF, add again the butanic acid chloromethyl ester (61.8mL, 0.49mol), 60 ℃ of stirring reaction 12h.With the reaction solution cool to room temperature, add 2L ethyl acetate and 1L water, isolate organic phase, remove solvent after the drying and can get yellow solid.With ethyl acetate/petroleum ether recrystallization repeatedly, white (slightly glassy yellow) solid 97.5g, productive rate about 45%.Mp.136.4℃-138.9℃。Specific rotation:
(c＝5，MeOH)。The HPLC purity assay is 99.8%.IR(KBr，cm
-1)：3333，3224，2966，1732，1711，1642，1618，1494，1272，1054，734.
1HNMR(CDCl
3，ppm)：δ＝7.22-6.96(m，3H)，6.48(s，1H)，5.65(dd，2H，J＝5.5Hz，J＝16.1Hz)，5.38(s，1H)，3.52(s，1H)，2.21-2.15(m，8H)，1.56-1.48(m，2H)，0.82(t，J＝7.4Hz，3H)；
13C?NMR(CDCl
3，ppm)：δ＝172.25，167.72，165.82，147.56，147.10，144.22，132.69，130.90，129.64，128.16，126.94，103.61，101.56，78.53，50.79，38.30，35.67，19.44，18.85，17.88，13.35。
Claims (7)
1. the preparation method of a butyrate clevidipine, it is characterized in that comprising the steps: with 2, the 3-dichlorobenzaldehyde, etheric acid propionitrile ester, one pot of Hantzsch reaction is carried out in 3-amino-2-butylene acid methyl esters mixing, adding alkaline catalysts then removes the 2-cyanoethyl and makes key intermediate (±)-4-(2 ', 3 '-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-5-carboxylic acid methyl-3-formic acid, key intermediate reacts with the butanic acid chloromethyl ester again, reaction solution obtains the thick product of butyrate clevidipine after with ethyl acetate and water treatment, and thick product obtains high purity butyric acid Clevidipine through recrystallization again.
2. according to the preparation method of the described butyrate clevidipine of claim 1, it is characterized in that the used solvent of described recrystallization is ethyl acetate/petroleum ether, isopropanol or isopropyl ether/acetone.
3. according to the preparation method of the described butyrate clevidipine of claim 1, the solvent that it is characterized in that described Hantzsch reaction is a Virahol, temperature of reaction is 20-180 ℃, and the reaction times is 2-24h, adds alkaline catalysts subsequently and removes the 2-cyanoethyl, use the washed with dichloromethane water, water slowly adds phosphoric acid, obtains key intermediate (±)-4-(2 ', 3 '-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-5-carboxylic acid methyl-3-formic acid.
4. according to the preparation method of the described butyrate clevidipine of claim 1, it is characterized in that the catalyzer that one pot of Hantzsch reaction adds is organic bases or mineral alkali.
5. according to the preparation method of the described butyrate clevidipine of claim 1, it is characterized in that it is triethylamine or pyridine that one pot of Hantzsch reacts used organic bases; Used mineral alkali is NaOH, KOH, CsOH, KHCO
3, NaHCO
3, K
2CO
3, Na
2CO
3Or Cs
2CO
3
6. according to the preparation method of the described butyrate clevidipine of claim 1, it is characterized in that it is Bu that hydrolysis removes the used alkaline catalysts of 2-cyanoethyl protecting group
4NF, Na
2S, Ca (OH)
2, NaOH, KOH, Ba (OH)
2, Mg (OH)
2Or Sr (OH)
2
7. according to the preparation method of the described butyrate clevidipine of claim 1, it is characterized in that being reflected under the alkaline condition of key intermediate and butanic acid chloromethyl ester carry out.
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ID=42491031
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Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102000027A (en) * | 2010-11-23 | 2011-04-06 | 北京中海康医药科技发展有限公司 | Clevidipine butyrate medium-length chain fat emulsion and preparation method thereof |
| CN102285901A (en) * | 2011-07-14 | 2011-12-21 | 四川大学 | Method for preparing 3-oxo-butyric acid-2-cyanoacetate and homologs thereof |
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| CN103373956A (en) * | 2012-04-23 | 2013-10-30 | 黑龙江省格润药业有限责任公司 | Method for preparing clevidipine butyrate |
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| CN103450076A (en) * | 2013-09-13 | 2013-12-18 | 朱从敏 | Method for preparing clevidipine butyrate |
| CN105092769A (en) * | 2015-01-15 | 2015-11-25 | 上海馨平医药科技发展有限公司 | Method for simultaneously detecting clevidipine butyrate and related substances |
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| CN102000027A (en) * | 2010-11-23 | 2011-04-06 | 北京中海康医药科技发展有限公司 | Clevidipine butyrate medium-length chain fat emulsion and preparation method thereof |
| CN102531998A (en) * | 2010-12-09 | 2012-07-04 | 天津药物研究院 | Alpha-type polymorphic clevidipine butyrate crystal and preparation method, application and pharmaceutical composition thereof |
| CN102827068A (en) * | 2011-06-17 | 2012-12-19 | 张锐豪 | Preparation method of 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydro-5-methoxy-carbonyl-3-pyridinecarboxylic acid |
| CN102285901A (en) * | 2011-07-14 | 2011-12-21 | 四川大学 | Method for preparing 3-oxo-butyric acid-2-cyanoacetate and homologs thereof |
| CN102432527A (en) * | 2011-11-04 | 2012-05-02 | 浙江九旭药业有限公司 | Method for preparing clevidipine butyrate |
| CN102516160A (en) * | 2011-12-16 | 2012-06-27 | 北京赛科药业有限责任公司 | Synthesis process for high-purity lercanidipine hydrochloride |
| CN103242220B (en) * | 2012-02-08 | 2016-03-09 | 上海医药工业研究院 | The preparation method of butyrate clevidipine |
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| CN103373956B (en) * | 2012-04-23 | 2015-07-01 | 黑龙江省格润药业有限责任公司 | Method for preparing clevidipine butyrate |
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| CN103382175B (en) * | 2012-05-04 | 2016-02-24 | 上海医药工业研究院 | A kind of preparation method of cleviprex crystal form II |
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| CN103420899B (en) * | 2012-05-25 | 2016-01-27 | 四川科伦药物研究有限公司 | A kind of purification process of butyrate clevidipine |
| CN103420899A (en) * | 2012-05-25 | 2013-12-04 | 四川科伦药物研究有限公司 | Purification method of clevidipine butyrate |
| CN103012249A (en) * | 2013-01-06 | 2013-04-03 | 武汉科福新药有限责任公司 | Preparation method of clevidipine butyrate |
| CN103086956B (en) * | 2013-01-17 | 2015-11-04 | 北京嘉林药业股份有限公司 | A kind of purification process of clevidipine butyrate intermediate |
| CN103086956A (en) * | 2013-01-17 | 2013-05-08 | 北京嘉林药业股份有限公司 | Purification method of clevidipine butyrate intermediate |
| CN103073485A (en) * | 2013-01-17 | 2013-05-01 | 北京嘉林药业股份有限公司 | Preparation method for clevidipine butyrate |
| CN103130711A (en) * | 2013-03-19 | 2013-06-05 | 董慧芳 | Preparation method of clevidipine butyrate |
| CN103450076A (en) * | 2013-09-13 | 2013-12-18 | 朱从敏 | Method for preparing clevidipine butyrate |
| CN105092769A (en) * | 2015-01-15 | 2015-11-25 | 上海馨平医药科技发展有限公司 | Method for simultaneously detecting clevidipine butyrate and related substances |
| CN105198797A (en) * | 2015-11-12 | 2015-12-30 | 华仁药业股份有限公司 | Purification method of clevidipine butyrate |
| CN108840819A (en) * | 2018-04-02 | 2018-11-20 | 常州瑞明药业有限公司 | A kind of preparation method of felodipine |
| CN108840819B (en) * | 2018-04-02 | 2021-07-30 | 常州瑞明药业有限公司 | Preparation method of felodipine |
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