CN104072404A - Preparation method of clevidipine butyrate - Google Patents
Preparation method of clevidipine butyrate Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 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 title abstract description 8
- 229960003621 clevidipine butyrate Drugs 0.000 title abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 66
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 22
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims abstract description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- 150000001875 compounds Chemical class 0.000 claims description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 24
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 24
- 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 claims description 24
- 229960003597 clevidipine Drugs 0.000 claims description 24
- 239000012043 crude product Substances 0.000 claims description 22
- 239000007787 solid Substances 0.000 claims description 17
- 239000012044 organic layer Substances 0.000 claims description 16
- 239000000047 product Substances 0.000 claims description 13
- 238000010992 reflux Methods 0.000 claims description 13
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims description 12
- 239000010410 layer Substances 0.000 claims description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 11
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 229960005215 dichloroacetic acid Drugs 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 4
- 235000011152 sodium sulphate Nutrition 0.000 claims description 4
- 238000001514 detection method Methods 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 235000007715 potassium iodide Nutrition 0.000 claims description 3
- 229960004839 potassium iodide Drugs 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims description 2
- 238000007086 side reaction Methods 0.000 abstract description 9
- 238000009833 condensation Methods 0.000 abstract description 6
- 230000005494 condensation Effects 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 5
- JKUYRAMKJLMYLO-UHFFFAOYSA-N tert-butyl 3-oxobutanoate Chemical class CC(=O)CC(=O)OC(C)(C)C JKUYRAMKJLMYLO-UHFFFAOYSA-N 0.000 abstract description 3
- 238000011160 research Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 229940106681 chloroacetic acid Drugs 0.000 abstract 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 230000036632 reaction speed Effects 0.000 abstract 1
- 230000035484 reaction time Effects 0.000 abstract 1
- 235000011054 acetic acid Nutrition 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- 238000004519 manufacturing process Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 5
- BDPZFQLKFUONAG-UHFFFAOYSA-N chloromethyl butanoate Chemical compound CCCC(=O)OCCl BDPZFQLKFUONAG-UHFFFAOYSA-N 0.000 description 4
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- LLMLNAVBOAMOEE-UHFFFAOYSA-N 2,3-dichlorobenzaldehyde Chemical compound ClC1=CC=CC(C=O)=C1Cl LLMLNAVBOAMOEE-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 229940010811 cleviprex Drugs 0.000 description 3
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 3
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 description 3
- WSGYTJNNHPZFKR-UHFFFAOYSA-N 3-hydroxypropanenitrile Chemical compound OCCC#N WSGYTJNNHPZFKR-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 229940127088 antihypertensive drug Drugs 0.000 description 2
- -1 benzylidene methyl Chemical group 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 238000009423 ventilation Methods 0.000 description 2
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- NOEPPQGBTHAHDG-UHFFFAOYSA-N CC(N(C)C(C)=C(C1C(C=CC=C2Cl)=C2Cl)C(OCCC#N)=O)=C1C(O)=O Chemical compound CC(N(C)C(C)=C(C1C(C=CC=C2Cl)=C2Cl)C(OCCC#N)=O)=C1C(O)=O NOEPPQGBTHAHDG-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- OPFKMLLBILXFRV-UHFFFAOYSA-N acetic acid piperazine Chemical compound C(C)(=O)O.N1CCNCC1.N1CCNCC1 OPFKMLLBILXFRV-UHFFFAOYSA-N 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- XKORCTIIRYKLLG-ONEGZZNKSA-N methyl (e)-3-aminobut-2-enoate Chemical compound COC(=O)\C=C(/C)N XKORCTIIRYKLLG-ONEGZZNKSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of clevidipine butyrate, belonging to the field of chemical synthesis. In the method disclosed by the invention, piperazine and acetic acid are added as catalysts in the first step of condensation process; researches show that the reaction lasts for 40 hours and the yield is 30-75% without adding piperazine and acetic acid as catalysts while the reaction time is shortened to 10-30 hours and the yield reaches 90-100% with the catalysts; with the catalysts, the reaction of aldehyde with two tert-butyl acetoacetates is avoided, so that side reaction is avoided. Moreover, in the method disclosed by the invention, chloroacetic acid is added in the fourth step of reaction, thus the reaction speed is obviously increased, and few side reactions occur; otherwise, without chloroacetic acid, the reaction is very slow or does not happen. According to the preparation method of clevidipine butyrate, disclosed by the invention, the reaction conditions are mild, and the reaction is stable; meanwhile, the time for the whole preparation flow can be greatly shortened, and the product yield is increased, thereby meeting the need for large-scale industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of compound, particularly a kind of preparation method of butyrate clevidipine, the invention belongs to the field of chemical synthesis.
Background technology
Butyrate clevidipine (Cleviprex butyrate, 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-dinicotinic acid methyl (1-butyryl acyloxy) methyl esters) be the novel fugitive dihydropyridine calcium channel antagonist of the third generation by the development of AstraZeneca company of Britain, in August, 2008 is first at U.S.'s listing, trade(brand)name Cleviprex.The molecular formula of butyrate clevidipine is C21H23Cl2NO6, and CAS accession number is 167221-71-8, and molecular structure is as follows:
In August, 2008, butyrate clevidipine emulsion used for intravenous injection (the clevidipine butyrate of U.S. FDA approval The Medicines Company company, Cleviprex) listing, for reducing unsuitable oral administration or the invalid hypertension of oral administration.This medicine is the first intravenous injection antihypertensive drug of U.S. FDA approval over 10 years.
By the retrieval to the synthetic document of domestic and international butyrate clevidipine, find about existing open in preparation method's prior art of butyrate clevidipine, but all some defects of existence more or less to such an extent as to can not meet the needs of large-scale commercial production of these methods.
Butyrate clevidipine has following several synthetic schemes at present:
One, route one
This route is first with 2,3-dichlorobenzaldehyde, amino methyl crotonate, etheric acid-2-methylthio group ethyl ester are starting raw material, carry out cyclized condensation reaction, after products therefrom and iodomethane reaction again in sodium hydroxide solution Water Under solution, obtain 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-dipicolinic acid monomethyl ester, then sodium bicarbonate exist under with butyric acid chloromethyl ester generation esterification, obtain target compound (Yakhak Hoechi, 1989,33 (4): 219-325).
In this route, methyl iodide is expensive, and etheric acid-2-methylthio group ethyl ester is difficult to obtain, and is unfavorable for suitability for industrialized production.
Two, route two
Cao Xiuzhi etc. (CN101602710A) are taking 2,3 dichloro benzaldehyde, methyl acetoacetate and strong aqua as raw material, and in methyl alcohol, directly closed loop condensation obtains 4-(2,3-dichlorophenyl)-Isosorbide-5-Nitrae-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid dimethyl ester, selective hydrolysis obtains 4-(2,3-dichlorophenyl)-Isosorbide-5-Nitrae-dihydro-2,6-dimethyl-3,5-dipicolinic acid monomethyl ester, then react with butyric acid chloromethyl ester, target compound obtained.
Reaction equation is as follows:
This route, in the time of selective hydrolysis, can not be hydrolyzed substantially, and the yield of the monocarboxylic acid obtaining is extremely low, more all can not get, and has no foreign literature report except Chinese document.We repeat this experiment, substantially can determine that this route can not be applied to lab scale and large production.
Three, route three
Sun Junhua etc. (US6350877) people has reported taking ketene dimer and 3-hydroxypropionitrile as starting raw material, at triethylamine, in vinyl acetic monomer, obtain etheric acid cyanogen ethyl ester through open loop addition, obtain the amino β-crotonic acid cyanogen of 3-ethyl ester with ammonium acetate generation amination reaction again, then with 2, the condensation of 3-dichlorin benzylidene methyl acetoacetate closed loop obtain 2-cyanoethyl methyl-4-(2 ', 3 '-dichlorophenyl)-1, 4-dihydro-2, 6-dimethyl-3, 5-pyridine dicarboxylate, through potassium hydroxide hydrolysis again with acetic acid neutralize 4-(2 ', 3 '-dichlorophenyl)-1, 4-dihydro-2, 6-dimethyl-3, 5-dipicolinic acid monomethyl ester, finally react with butanic acid chloromethyl ester, product purification obtains target product after processing.
Reaction equation is as follows:
This route process is longer, complex operation, and 2,3-dichlorin benzylidene methyl acetoacetate is difficult to obtain, and ketene dimer has irritating smell, very high to environment ventilation requirement while production in a large number, is difficult to suitability for industrialized production.
Four, route four
The people such as Zhang Jing (CN 101759631A, WO 1995/12578) report taking ketene dimer and 3-hydroxypropionitrile as starting raw material, under the effect of triethylamine, make etheric acid nitrile ethyl ester, again with 2,3-dichlorobenzaldehyde, METHYL 3 AMINO CROTONATE are through the condensation of Hantzsch closed loop, then with the hydrolysis of sodium sulphite selective hydrolysis selection at normal temperatures row, eliminate and obtain monocarboxylic acid by β, 4-(2,3-dichlorophenyl)-Isosorbide-5-Nitrae-dihydro-2,6-dimethyl-3,5-dipicolinic acid monomethyl ester, then react and make antihypertensive drug Clevidipine with butanic acid chloromethyl ester.
Reaction equation is as follows:
The overall productive rate of this route is better, and selective hydrolysis is eliminated and obtained monocarboxylic acid by β, has equally the shortcoming of route three: ketene dimer has irritating smell, very high to environment ventilation requirement while production in a large number, is difficult to suitability for industrialized production.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of improving one's methods of butyrate clevidipine of preparing, the method reaction conditions gentleness, avoid the generation of side reaction, can greatly shorten the required time of whole preparation flow simultaneously, therefore, method of the present invention can meet the needs of large-scale commercial production.
In order to achieve the above object, the technique means that the present invention adopts is:
The preparation method of a kind of butyrate clevidipine of the present invention, is characterized in that comprising the following steps:
(1) equimolar Compound I and Compound I I are added in the trimethyl carbinol, according to molar percentage meter, to the piperazine and the acetic acid that add respectively Compound I or Compound I I molar weight 5%-10% in the reaction solution obtaining, backflow 20-45 hour, concentrated, obtain light yellow oil, with methylene dichloride dissolving, wash collected organic layer 1-3 time, dried over sodium sulfate, obtains the crude product of intermediate III;
(2) in intermediate III, add methylene dichloride, then in the reaction solution obtaining, add formic acid or trifluoroacetic acid, at 0-55 DEG C, stir 3-7 hour, react complete, carry out concentrating under reduced pressure, in the product after concentrated, add methylene dichloride to dissolve, then wash with water 1-3 time, collected organic layer, then with saturated sodium bicarbonate washing 1-3 time, collect water layer, use again washed with dichloromethane 1-3 time, collect water layer, water layer phosphoric acid acidifying, obtain off-white color solid, i.e. intermediate compound IV;
(3) in intermediate compound IV, add compound V, then in the reaction solution obtaining, add saleratus, potassiumiodide and acetonitrile, reflux 1-5 hour, after TLC detection reaction, is poured into water reaction solution, use dichloromethane extraction 1-3 time, collected organic layer, the light yellow oil of concentrated organic layer, obtains intermediate VI;
(4) in the intermediate VI obtaining, add compound VI I, then in reaction solution, add Mono Chloro Acetic Acid and Virahol, stopped reaction after reflux 30-60 hour, be cooled to room temperature, add water, stir 1-3 hour, there is solid to separate out, filter, obtain faint yellow solid, be butyrate clevidipine crude product;
(5) product purification
The butyrate clevidipine crude product that step (4) is obtained is dissolved in ethyl acetate, and reflux progressively adds the sherwood oil of 60-90 DEG C, is cooled to room temperature, separates out off-white color solid, filters, and to obtain final product.
In the present invention, preferred, in step (1), the mol ratio of piperazine and acetic acid is 1:1-2.
In the present invention, preferred, in step (4), described Mono Chloro Acetic Acid is Monochloro Acetic Acid or dichloro acetic acid.
Compared to prior art, usefulness of the present invention is:
1, in the method for the invention, in the condensation course of the first step, add piperazine and acetic acid as catalyzer, this catalyzer gentleness, different ratios by piperazine and acetic acid mix, can regulate the acid-basicity of whole system, be beneficial to reaction temperature and, steadily and carry out fast.Research shows, reacts 40 hours in the situation that not adding piperazine and acetic acid as catalyzer, and yield is 30-75%, and adds after catalyzer, and reaction shortens to 10-30 hour, and yield reaches 90-100%; In addition, add after this catalyzer and do not see aldehyde with 2 tert-butyl acetoacetates reactions, avoided the generation of side reaction;
2, in the method for the invention, add Mono Chloro Acetic Acid in four-step reaction, Mono Chloro Acetic Acid acidity is moderate, make reaction can under a good pH environment, carry out, thereby reaction temperature and, speed of response is obviously accelerated, side reaction is few, does not add on the contrary Mono Chloro Acetic Acid and reacts very slowly or not and react.
In a word, the preparation method of a kind of butyrate clevidipine of the present invention, its reaction conditions gentleness, reacting balance, has avoided the generation of side reaction, can greatly shorten the required time of whole preparation flow simultaneously, improve the yield of product, can meet the needs of large-scale commercial production.
Brief description of the drawings
Fig. 1 is nucleus magnetic resonance (NMR) collection of illustrative plates of intermediate III;
Fig. 2 is nucleus magnetic resonance (NMR) collection of illustrative plates of intermediate compound IV;
Fig. 3 is nucleus magnetic resonance (NMR) collection of illustrative plates of intermediate VI;
Fig. 4 is nucleus magnetic resonance (NMR) collection of illustrative plates of butyrate clevidipine crude product.
Embodiment
Further describe the present invention below in conjunction with specific embodiment, advantage and disadvantage of the present invention will be more clear along with description.But these embodiment are only exemplary, scope of the present invention are not formed to any restriction.It will be understood by those skilled in the art that lower without departing from the spirit and scope of the present invention and can the details of technical solution of the present invention and form be modified or be replaced, but these amendments and replacement all fall within the scope of protection of the present invention.
The preparation of embodiment 1 intermediate III
The Compound I I of the Compound I of 11mmol and 11mmol is added in the 100ml trimethyl carbinol, according to molar percentage meter, to the piperazine and the acetic acid that add respectively Compound I or Compound I I molar weight 5% (molar percentage) in the reaction solution obtaining, reflux 35 hours, concentrated, obtain light yellow oil, with the dissolving of 100ml methylene dichloride, 50ml washing 2 times, collected organic layer, by dried over sodium sulfate, obtain the crude product of intermediate III, yield 100%; HNMR as shown in Figure 1.
The preparation of embodiment 2 intermediate III
The Compound I I of the Compound I of 11mmol and 11mmol is added in the 100ml trimethyl carbinol, according to molar percentage meter, to the acetic acid that adds respectively the piperazine and 10% (molar percentage) of Compound I or Compound I I molar weight 5% (molar percentage) in the reaction solution obtaining, reflux 35 hours, concentrated, obtain light yellow oil, with the dissolving of 100ml methylene dichloride, 50ml washing 2 times, collected organic layer, by dried over sodium sulfate, obtain the crude product of intermediate III, yield 100%.
The preparation of embodiment 3 intermediate compound IV
In 3.46 grams of (about 11mmol) intermediate III that prepare to embodiment 1 or 2, add 100ml methylene dichloride, then in the reaction solution obtaining, add formic acid 30ml, at 50 DEG C, stir 5 hours, react complete, carry out concentrating under reduced pressure, add the methylene dichloride of 50ml to dissolve, then add 50ml water washing 2 times, collected organic layer, organic layer is again with 50ml saturated sodium bicarbonate washing 2 times, collect water layer (saturated sodium bicarbonate washs the alkali lye after 2 times), use again 50ml washed with dichloromethane 2 times, collect water layer, water layer phosphoric acid acidifying, obtain off-white color solid, be 2.21 grams of intermediate compound IV, yield 85.32%.HNMR as shown in Figure 2.
The preparation of embodiment 4 intermediate compound IV
In 3.46 grams of (about 11mmol) intermediate III that prepare to embodiment 1 or 2, add 100ml methylene dichloride, then in the reaction solution obtaining, add trifluoroacetic acid 5ml, at 0 DEG C, stir 5 hours, react complete, carry out concentrating under reduced pressure, add the methylene dichloride of 50ml to dissolve, then add 50ml water washing 2 times, collected organic layer, organic layer is again with 50ml saturated sodium bicarbonate washing 2 times, collect water layer (saturated sodium bicarbonate washs the alkali lye after 2 times), use again 50ml washed with dichloromethane 2 times, collect water layer, water layer phosphoric acid acidifying, obtain off-white color solid, be 2.06 grams of intermediate compound IV, yield 79.53%.
The preparation of embodiment 5 intermediate VI
In the 10mmol intermediate compound IV preparing to embodiment 3 or 4, add the compound V of 11mmol, then in the reaction solution obtaining, add saleratus 15mmol, potassiumiodide 1mmol and acetonitrile 50ml, reflux 3 hours, after TLC detection reaction, reaction solution is poured in 100ml water, use 100ml dichloromethane extraction 3 times, collected organic layer, the light yellow oil of concentrated organic layer, obtain intermediate VI, yield 96.25%; As shown in Figure 3, Fig. 3 A is proton nmr spectra to NMR, and Fig. 3 B is carbon-13 nmr spectra.
The preparation of embodiment 6 butyrate clevidipine crude products
In the 10mmol intermediate VI obtaining to embodiment 5, add 10mmol compound VI I, then in reaction solution, add 0.5mmol dichloro acetic acid and 50ml Virahol, reflux is stopped reaction after 48 hours, is cooled to room temperature, add water 100ml, stir 2 hours, have a large amount of solids to separate out, filter, obtain faint yellow solid, be butyrate clevidipine crude product, it is 96.72% that crude product HPLC detects purity, yield 96.45%.HNMR as shown in Figure 4.
The preparation of embodiment 7 butyrate clevidipine crude products
In the 10mmol intermediate VI obtaining to embodiment 5, add 10mmol compound VI I, then in reaction solution, add 1mmol Monochloro Acetic Acid and 50ml Virahol, reflux is stopped reaction after 30 hours, is cooled to room temperature, add water 100ml, stir 2 hours, have a large amount of solids to separate out, filter, obtain faint yellow solid, be butyrate clevidipine crude product, it is 96.72% that crude product HPLC detects purity, yield 96.17%.
Embodiment 8 product purifications
The 100g butyrate clevidipine crude product that embodiment 6 or 7 is obtained is dissolved in 250ml ethyl acetate, and reflux progressively adds the sherwood oil 500ml of 75 DEG C, be cooled to room temperature, separate out off-white color solid, filter, obtain 81.33 grams of products, yield 81.33%, HPLC purity 99.75%.
Experimental example 1 piperazine and acetic acid is the promoter action to reaction as catalyzer
For show piperazine and acetic acid as catalyzer to reaction promoter action, the present invention has carried out following contrast experiment:
1, method
Experimental group: adopt the method for the embodiment of the present invention 1, add respectively the piperazine of Compound I or Compound I I molar weight 5% (molar percentage) and acetic acid piperazine and acetic acid (mol ratio 1:1) as catalyzer in the condensation course of the first step;
Control group: method is identical with experimental group, but do not add piperazine and acetic acid.
2, result
Result of study shows, reacts 40 hours in the control group that does not add piperazine and acetic acid as catalyzer, and product yield is 30-75%, and adds after catalyzer, and reaction shortens to 10-30 hour, and product yield can reach 90-100%; In addition, do not add in the control group product of catalyzer and side reaction product detected, and in the experimental group that adds catalyzer, do not see the by products of aldehyde with 2 tert-butyl acetoacetates reactions, therefore, effectively avoided the generation of side reaction.
Experimental example 2 Mono Chloro Acetic Acids are for the promoter action of reaction
In order to show the promoter action of Mono Chloro Acetic Acid to reaction, the present invention has carried out following contrast experiment:
Method is set up the initial stage, the present invention has adopted respectively following acid to verify the promoter action to reaction, has respectively acetic acid (pKa=4.74), formic acid (pKa=3.74), Monochloro Acetic Acid (pKa=2.86), dichloro acetic acid (pKa=1.30).Experiment is divided into unit and carries out:
1, acetic acid group
Method: add 10mmol compound VI I in the 10mmol intermediate VI obtaining to embodiment 5, then in reaction solution, add 1mmol acetic acid and 50ml Virahol, reflux is stopped reaction after 48 hours, is cooled to room temperature, adds water 100ml, stir 2 hours, there are a large amount of solids to separate out, filter, obtain faint yellow solid, be butyrate clevidipine crude product, it is 35.68% that crude product HPLC detects purity.
2, formic acid group
Method, with acetic acid group, just replaces with formic acid by acetic acid, and it is 44.78% that the crude product HPLC obtaining detects purity.
3, Monochloro Acetic Acid group
Method, with acetic acid group, just replaces with Monochloro Acetic Acid by acetic acid, and it is 96.72% that the crude product HPLC obtaining detects purity, yield 93.17%
4, dichloro acetic acid group
Method, with acetic acid group, just replaces with dichloro acetic acid by acetic acid, and it is 94.14% that the crude product HPLC obtaining detects purity, yield 96.45%.
5, blank group
Method, with acetic acid group, does not just add any acid as catalyst, and it is 10.32% that the crude product HPLC obtaining detects purity.
Result:
Can find out by above-mentioned simultaneous test, add Mono Chloro Acetic Acid, acid moderate, reaction can be carried out under a good pH environment, thus reaction temperature and, speed of response is obviously accelerated, side reaction is few, acid adding is not reacted very slowly or not and is reacted on the contrary.
Claims (3)
1. a preparation method for butyrate clevidipine, is characterized in that comprising the following steps:
(1) equimolar Compound I and Compound I I are added in the trimethyl carbinol, according to molar percentage meter, to the piperazine and the acetic acid that add respectively Compound I or Compound I I molar weight 5%-10% in the reaction solution obtaining, backflow 20-45 hour, concentrated, obtain light yellow oil, with methylene dichloride dissolving, wash collected organic layer 1-3 time, by dried over sodium sulfate, obtain the crude product of intermediate III;
(2) in intermediate III, add methylene dichloride, then in the reaction solution obtaining, add formic acid or trifluoroacetic acid, at 0-55 DEG C, stir 3-7 hour, react complete, carry out concentrating under reduced pressure, in the product after concentrated, add methylene dichloride to dissolve, then wash with water 1-3 time, collected organic layer, then with saturated sodium bicarbonate washing 1-3 time, collect water layer, use again washed with dichloromethane 1-3 time, collect water layer, water layer phosphoric acid acidifying, obtain off-white color solid, i.e. intermediate compound IV;
(3) in intermediate compound IV, add compound V, then in the reaction solution obtaining, add saleratus, potassiumiodide and acetonitrile, reflux 1-5 hour, after TLC detection reaction, is poured into water reaction solution, use dichloromethane extraction 1-3 time, collected organic layer, the light yellow oil of concentrated organic layer, obtains intermediate VI;
(4) in the intermediate VI obtaining, add compound VI I, then in reaction solution, add Mono Chloro Acetic Acid and Virahol, stopped reaction after reflux 30-60 hour, be cooled to room temperature, add water, stir 1-3 hour, there is solid to separate out, filter, obtain faint yellow solid, be butyrate clevidipine crude product;
(5) product purification
The butyrate clevidipine crude product that step (4) is obtained is dissolved in ethyl acetate, and reflux progressively adds the sherwood oil of 60-90 DEG C, is cooled to room temperature, separates out off-white color solid, filters, and to obtain final product.
2. the method for claim 1, is characterized in that, in step (1), the mol ratio of piperazine and acetic acid is 1:1-2.
3. the method for claim 1, is characterized in that, in step (4), described Mono Chloro Acetic Acid is Monochloro Acetic Acid or dichloro acetic acid.
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