CN115504975A - Preparation method of Alvatripopa maleate intermediate - Google Patents
Preparation method of Alvatripopa maleate intermediate Download PDFInfo
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- CN115504975A CN115504975A CN202211273383.0A CN202211273383A CN115504975A CN 115504975 A CN115504975 A CN 115504975A CN 202211273383 A CN202211273383 A CN 202211273383A CN 115504975 A CN115504975 A CN 115504975A
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 title claims description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 229940125904 compound 1 Drugs 0.000 claims abstract description 23
- 239000002904 solvent Substances 0.000 claims abstract description 23
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- 238000002425 crystallisation Methods 0.000 claims abstract description 15
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- 239000003960 organic solvent Substances 0.000 claims abstract description 12
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- 229960001770 atorvastatin calcium Drugs 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- -1 5,6-dichloro-N- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-yl) -1,3-thiazol-2-yl Chemical group 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims description 11
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims description 11
- 229960005370 atorvastatin Drugs 0.000 claims description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000011976 maleic acid Substances 0.000 claims description 8
- OFZJKCQENFPZBH-UHFFFAOYSA-N 1-[3-chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)-1,3-thiazol-2-yl]carbamoyl]pyridin-2-yl]piperidine-4-carboxylic acid Chemical compound C1CC(C(=O)O)CCN1C1=NC=C(C(=O)NC=2SC(=C(C=3SC=C(Cl)C=3)N=2)N2CCN(CC2)C2CCCCC2)C=C1Cl OFZJKCQENFPZBH-UHFFFAOYSA-N 0.000 claims description 6
- RUJPPJYDHHAEEK-UHFFFAOYSA-N ethyl piperidine-4-carboxylate Chemical compound CCOC(=O)C1CCNCC1 RUJPPJYDHHAEEK-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000002699 waste material Substances 0.000 abstract description 4
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- 239000000543 intermediate Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 11
- 238000001914 filtration Methods 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 5
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- MISPBGHDNZYFNM-BTJKTKAUSA-N (z)-but-2-enedioic acid;1-[3-chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)-1,3-thiazol-2-yl]carbamoyl]pyridin-2-yl]piperidine-4-carboxylic acid Chemical compound OC(=O)\C=C/C(O)=O.C1CC(C(=O)O)CCN1C1=NC=C(C(=O)NC=2SC(=C(C=3SC=C(Cl)C=3)N=2)N2CCN(CC2)C2CCCCC2)C=C1Cl MISPBGHDNZYFNM-BTJKTKAUSA-N 0.000 description 2
- AJPKQSSFYHPYMH-UHFFFAOYSA-N 2,6-dichloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=C(Cl)N=C1Cl AJPKQSSFYHPYMH-UHFFFAOYSA-N 0.000 description 2
- DUVRDRIDUGKOHS-UHFFFAOYSA-N 2-chloro-1-thiophen-3-ylethanone Chemical compound ClCC(=O)C=1C=CSC=1 DUVRDRIDUGKOHS-UHFFFAOYSA-N 0.000 description 2
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
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- 206010043554 thrombocytopenia Diseases 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- DHBCPZKZOIVYER-UHFFFAOYSA-N C(=O)O.C(C)C1CCNCC1 Chemical compound C(=O)O.C(C)C1CCNCC1 DHBCPZKZOIVYER-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- SRJOCJYGOFTFLH-UHFFFAOYSA-M piperidine-4-carboxylate Chemical compound [O-]C(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-M 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000011172 small scale experimental method Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 229940126460 thrombopoietin receptor agonist Drugs 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/145—Maleic acid
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a preparation method of an atorvastatin calcium maleate intermediate, wherein the intermediate 2 and 4-ethyl piperidinecarboxylate are mixed in an organic solvent, heated and reacted, after the reaction is finished, a crystallization solvent is added into a reaction system, and the mixture is crystallized and filtered to obtain a compound 1; mixing the compound 1 and sodium hydroxide in a solvent, heating for hydrolysis, and adding acid to adjust the pH value after the reaction is finished to obtain a compound 2. The invention greatly reduces the production cost and the production waste, and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of medicines, in particular to a preparation method of an atorvastatin asperpa maleate intermediate.
Background
Avatrompag maleate (avatrompag maleate), which is a thrombopoietin receptor agonist, was first developed by ansettai pharmaceutical group in japan, several of which were granted, and finally, new drug development was completed by akarrx pharmaceutical company, a subsidiary of the us Dova pharmaceutical company, and a new drug marketing application was proposed to the us Food and Drug Administration (FDA), which was approved to market 5 and 21 months in 2018 under the trade name Doptelet, for adult Chronic Liver Disease (CLD) patients suffering from thrombocytopenia and scheduled to undergo medical or dental surgery. The 16-day Rexingx medicine release notice in 4/2020 is called that the Alvatripopa tablets (imported) are approved by the national drug administration, and is suitable for treating adult patients with chronic liver disease related thrombocytopenia who are subjected to selective diagnostic operation or operation.
The chemical name of the Alvatripopa maleate is as follows: 1- [ 3-chloro-5- [ [ [4- (4-chloro-2-thienyl) -5- (4-cyclohexyl-1-piperazinyl) -2-thiazolyl ] amino ] carbonyl ] -2-pyridinyl ] -4-piperidinecarboxylic acid maleate.
The first one is a synthetic route represented by WO2003062233 and WO2004029049, 4-chloroacetylthiophene is used as a starting material, the intermediate 1 is obtained by processes such as bromination and the like, the intermediate reacts with dichloronicotinic acid, the intermediate reacts with 4-ethyl piperidinecarboxylate to obtain a compound 1, and the compound 1 is hydrolyzed and salified to obtain the maleic acid avariaappa. The basic route is as follows:
the second is a synthetic route represented by CN111620863 and RU2709496, 4-chloroacetyl thiophene is also used as a starting material, the intermediate 1 is obtained by processes such as bromination and the like, the intermediate reacts with a compound prepared from dichloronicotinic acid and 4-ethyl piperidinecarboxylate to obtain a compound 1, and then the compound 1 is hydrolyzed and salified to obtain the Alvatripopar maleate. The basic route is as follows:
both routes involve two intermediate compounds 1 and 2, and the process adopted for preparing the compound 1 in the report is to evaporate the solvent after the reaction is finished and then purify the compound by utilizing a column chromatography mode; after the reaction of the compound 2 is finished, hydrochloric acid is used for regulating acid to obtain atorvastatin calcium hydrochloride, then alkali regulation, extraction, salt formation and other operations are carried out to obtain maleic acid atorvastatin calcium, and analysis shows that the reported preparation process has the defects of complex operation, high cost, high pollution and the like, and is difficult to realize industrialization and the like.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a preparation method of an atorvastatin asperppa intermediate, which greatly reduces the production cost and the production waste and is suitable for industrial production.
The technical scheme adopted by the invention is as follows:
the invention provides a preparation method of an atorvastatin calcium maleate intermediate, which comprises the steps of mixing an intermediate 2 and 4-ethyl piperidinecarboxylate in an organic solvent, heating for reaction, adding a crystallization solvent after the reaction is finished, crystallizing at room temperature, and filtering to obtain a compound 1;
the intermediate 2 is 5,6-dichloro-N- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-yl) -1,3-thiazol-2-yl) pyridine-3-carbamoyl, which has the structural formula:
the compound 1 is ethyl-1- (3-chloro-5- ((4- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1,3-thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylic acid having the structural formula:
further, intermediate 2: 4-Piperidinecarboxylic acid ethyl ester: the mass ratio of the organic solvent is 1:0.3 to 0.38:7. preferably, the organic solvent is one of N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, tetrahydrofuran or ethyl acetate; more preferably, the organic solvent is N, N-dimethylformamide; the heating temperature range in the heating reaction is 39-80 ℃, and preferably, the heating temperature range in the heating reaction is 65 ℃. The reaction time for the heating reaction was 3 hours.
Preferably, the crystallization solvent is one of methanol, ethanol, ethyl acetate, isopropanol or n-hexane. More preferably, the crystallization solvent is isopropanol.
Further, the mass ratio of the intermediate 2 to the crystallization solvent is 1.
Further, the compound 1 and sodium hydroxide are mixed in a solvent, then heated and hydrolyzed, after the reaction is finished for 2 hours, acid is added to adjust the pH value, and the crystallization is carried out at room temperature, so as to obtain a compound 2.
The compound 2 is 1- (3-chloro-5- ((4- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1,3-thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylic acid, the structural formula of which is:
further, compound 1 is mixed with sodium hydroxide in a solvent, wherein the solvent is composed of an organic solvent and water in a mass ratio of 3:1, and the organic solvent in the solvent is one of ethanol, methanol or isopropanol. Further, the mass ratio of the compound 1, sodium hydroxide, solvent and acid is 1:0.12 to 0.23:8:0.68.
preferably, the compound 1 is mixed with sodium hydroxide in a solvent, and then heated for hydrolysis, wherein the temperature of the heating for hydrolysis is 30-80 ℃; more preferably, the temperature of the heated hydrolysis is 50 ℃, and the acid is preferably maleic acid.
Preferably, the mass ratio of the reaction charge for preparing the compound 2 is as follows: ethyl-1- (3-chloro-5- ((4- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1,3-thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylic acid: sodium hydroxide: acid =1:0.12:8:0.68.
in the present invention, the room temperature is 25-30 ℃.
The invention has the beneficial effects that:
the invention overcomes the defects of complex operation, large pollution and unsuitability for industrialization in the prior art, greatly reduces the production cost, reduces the production waste and is suitable for industrialized production.
Drawings
FIG. 1 is a typical HPLC profile of Compound 1.
FIG. 2 is a typical HPLC profile for Compound 2.
FIG. 3 is a representation of Compound 1 1 HNMR map.
FIG. 4 is a representation of Compound 2 1 HNMR map.
Detailed Description
To further illustrate the technical means and effects of the present invention adopted to achieve the predetermined objects, the following detailed description of the embodiments, structures, characteristics and effects according to the present invention will be made with reference to the accompanying drawings and preferred embodiments.
The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application, and it is obvious that the described embodiments are only a part of the embodiments of the present application, and not all of the embodiments. The following description of at least one exemplary embodiment is merely illustrative in nature and is in no way intended to limit the application, its application, or uses. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
The relative arrangement of the components and steps, the numerical expressions, and numerical values set forth in these embodiments do not limit the scope of the present application unless specifically stated otherwise. Meanwhile, it should be understood that the sizes of the respective portions shown in the drawings are not drawn in an actual proportional relationship for the convenience of description. Techniques, methods, and apparatus known to those of ordinary skill in the relevant art may not be discussed in detail but are intended to be part of the specification where appropriate. In all examples shown and discussed herein, any particular value should be construed as merely illustrative, and not limiting. Thus, other examples of the exemplary embodiments may have different values. It should be noted that: like reference numbers and letters refer to like items in the following figures, and thus, once an item is defined in one figure, it need not be discussed further in subsequent figures.
The invention provides a preparation method of a compound 1, wherein the chemical name of the compound 1 is as follows: ethyl1- (3-chloro-5- { [4- (4-chlorothiophen-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1,3-thiazole-2-yl ] carbomoyl } pyridine-2-yl) piperidine-4-carboxylate;
ethyl-1- (3-chloro-5- ((4- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1,3-thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylic acid
The structural formula is as follows:
the chemical name of the compound 2 is as follows: 1- (3-chloro-5- ((4- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1,3-thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylic acid
The structural formula is as follows:
the reaction equation of the invention is as follows:
example 1
5,6-dichloro-N- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-yl) -1,3-thiazol-2-yl) pyridine-3-carboxamide 500g and N, N-dimethylformamide 3.5L were weighed into a reactor, stirring was turned on, ethyl 4-piperidinecarboxylate 170g was added, the temperature was raised to 80 ℃ and the system was cleared. The reaction was complete after 3 hours of stirring. 5L of isopropanol was added, and the mixture was stirred at room temperature to crystallize. Filtration afforded ethyl-1- (3-chloro-5- ((4- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1,3-thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylic acid 520.8g in 85.6% yield.
A typical HPLC profile of the obtained Compound 1 is shown in FIG. 1, and a typical HPLC profile of the obtained Compound 1 1 The HNMR map is shown in FIG. 3.
Example 2
Weighing 5,6-dichloro-N- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-yl) -1,3-thiazol-2-yl) pyridine-3-carbamoyl 400g and 2.8L of dimethyl sulfoxide, adding into a reactor, starting stirring, adding 140g of 4-ethyl piperidinecarboxylate, heating to 65 ℃, and dissolving to clear. Stirring to complete the reaction. 4L of methanol was added, and the mixture was stirred at room temperature to crystallize. Filtration and methanol elution gave ethyl-1- (3-chloro-5- ((4- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1,3-thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylic acid 320.9g in 65.9% yield.
Example 3
5,6-dichloro-N- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-yl) -1,3-thiazol-2-yl) pyridine-3-carboxamide, 450g, and 3.2L methylene chloride were weighed into a reactor, and stirring was turned on, 150g of 4-piperidinecarboxylic acid ethyl ester was added, the temperature was raised to 39 ℃ and the solution was clear. Stirring to complete the reaction. Ethyl acetate (4.5L) was added thereto, and the mixture was stirred at room temperature to crystallize. Filtration and elution with ethyl acetate gave ethyl-1- (3-chloro-5- ((4- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1,3-thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylic acid 380.6g in 69.5% yield.
Example 4
Weighing 5,6-dichloro-N- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-yl) -1,3-thiazol-2-yl) pyridine-3-carbamoyl 400g and tetrahydrofuran 2.8L, adding to a reactor, stirring, adding 4-piperidinecarboxylic acid ethyl ester 150g, heating to 50 ℃, and dissolving to clear. The reaction was complete after 3 hours of stirring. Adding n-hexane 4L, stirring at room temperature, and crystallizing. Filtration and elution with n-hexane gave ethyl-1- (3-chloro-5- ((4- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1,3-thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylic acid 410.5g in 84.4% yield.
Example 5
5,6-dichloro-N- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-yl) -1,3-thiazol-2-yl) pyridine-3-carboxamide and 2.1L ethyl acetate were weighed into a reactor, stirring was turned on, 90g of 4-piperidinecarboxylic acid ethyl ester was added, the temperature was raised to 65 ℃ and the solution was clear. Stirring to completely counteract the noise. 3L of ethanol is added, and the mixture is stirred at room temperature for crystallization. Filtration and ethanol elution gave ethyl-1- (3-chloro-5- ((4- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1,3-thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylic acid 256.7g in 70.3% yield.
When the compound 1 is prepared, 5,6-dichloro-N- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazine-yl) -1,3-thiazole-2-yl) pyridine-3-carbamyl and 4-ethyl piperidine formate are heated in a proper organic solvent (N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, tetrahydrofuran or ethyl acetate) to directly react, a catalyst is not required to be added in the middle of the reaction, the reaction can be thorough, after the reaction is completed, complicated purification treatment is not required, a proper solvent (methanol, ethanol, ethyl acetate, isopropanol or N-hexane) is added to crystallize, and a target product with the purity of over 99% can be obtained, and the quality requirement of the target product as a pharmaceutical intermediate is met. The invention innovatively adopts less operation, not only can effectively control the product quality, but also can solve the problems of high energy consumption and large pollution in the prior art, and is suitable for industrial production.
The invention also provides a preparation method of the compound 2, wherein the chemical name of the compound 2 is as follows: 1- (3-chloro-5- ((4- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1,3-thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylic acid
The structural formula is as follows:
the reaction equation of the invention is as follows:
example 6
Typical HPLC profile of the obtained Compound 2 is shown in FIG. 2, and typical HPLC profile of the obtained Compound 2 1 The HNMR map is shown in FIG. 4.
Example 7
Ethyl-1- (3-chloro-5- ((4- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1,3-thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylic acid 500g, sodium hydroxide 88.5g, water 1.0L, methanol 3.0L were weighed into a reactor, stirred, and reacted at 30 ℃ for 2 hours to completion. 342.5g of maleic acid is weighed and added into the reaction system, solid is separated out, the temperature is changed to room temperature, and the mixture is stirred for crystallization. Filtration and drying gave 422.3g of 1- (3-chloro-5- ((4- (4-chlorothien-2-yl) -5- (4-cyclohexylqylpiperazin-1-yl) -1,3-thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylic acid in 84.5% yield.
Example 8
Ethyl-1- (3-chloro-5- ((4- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1,3-thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylic acid 435g, sodium hydroxide 102.7g, water 0.8L, isopropanol 2.6L were weighed into a reactor, stirred, and reacted at 80 ℃ for 2 hours to completion. 298g of maleic acid is weighed and added into the reaction system, solid is separated out, the temperature is changed to room temperature, and the mixture is stirred for crystallization. Filtration and drying gave 361.1g of 1- (3-chloro-5- ((4- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1,3-thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylic acid in 83.1% yield.
In the embodiment of the invention, the filtration is conventional suction filtration or centrifugal separation.
When the compound 2 is prepared, after hydrolysis is finished, the obtained hydrolysis product is not prepared into hydrochloride by using common hydrochloric acid and the like according to a conventional method, the pH value is innovatively adjusted by using maleic acid, the purity of the obtained product exceeds 99%, and the quality requirement of the product serving as a pharmaceutical intermediate is met. Thus, not only is the corrosion of equipment caused by using hydrochloric acid reduced, but also the operation for subsequent maleate formation is reduced. The operation steps in the prior art are reduced, the generation of waste water and waste residues is reduced, and the method is more environment-friendly and suitable for industrial production.
At present, the technical scheme of the invention has been subjected to pilot plant test, namely a small-scale experiment before large-scale mass production of products; after the pilot test is finished, the investigation for the use of the user is carried out in a small range, and the investigation result shows that the satisfaction degree of the user is higher; the preparation of products for formal production for industrialization (including intellectual property risk early warning research) has been set forth.
The above-described embodiments are preferred examples of the present invention and are not exhaustive of the possible implementations of the present invention. Various modifications to the invention which do not depart from the spirit and substance of the invention should be construed as being included within the scope thereof.
Claims (10)
1. A preparation method of an atorvastatin intermediate is characterized in that an intermediate 2 and 4-ethyl piperidinecarboxylate are mixed in an organic solvent, heated and reacted, a crystallization solvent is added after the reaction is completed, crystallization is carried out at room temperature, and the mixture is filtered to obtain a compound 1;
the intermediate 2 is 5,6-dichloro-N- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-yl) -1,3-thiazol-2-yl) pyridine-3-carbamoyl, which has the structural formula:
the compound 1 is ethyl-1- (3-chloro-5- ((4- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1,3-thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylic acid having the structural formula:
2. the method for preparing the intermediate of atorvastatin asperpa maleate according to claim 1, wherein the ratio of intermediate 2: 4-Piperidinecarboxylic acid ethyl ester: the mass ratio of the organic solvent is 1:0.3 to 0.38:7.
3. the method for preparing the atorvastatin intermediate as claimed in claim 1, wherein the organic solvent is one of N, N-dimethylformamide, dimethylsulfoxide, dichloromethane, tetrahydrofuran or ethyl acetate; the heating temperature range in the heating reaction is 39-80 ℃, and the heating reaction time is 3 hours.
4. The method for preparing the atorvastatin intermediate as claimed in claim 1, wherein the crystallization solvent is one of methanol, ethanol, ethyl acetate, isopropanol or n-hexane.
5. The method for preparing the atorvastatin intermediate as claimed in claim 1, wherein the mass ratio of the intermediate 2 to the crystallization solvent is 1.
6. The preparation method of the intermediate of atorvastatin calcium maleate according to claim 1, wherein the compound 1 and sodium hydroxide are mixed in a solvent, then heated and hydrolyzed, after the reaction is completed for 2 hours, acid is added to adjust the pH value, and the crystallization is performed at room temperature to obtain a compound 2;
the compound 2 is 1- (3-chloro-5- ((4- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazine-1-yl) -1,3-thiazol-2-yl) carbamoyl) pyridin-2-yl) piperidine-4-carboxylic acid, and the structural formula of the compound is as follows:
7. the method for preparing the atorvastatin intermediate as claimed in claim 6, wherein the compound 1 is mixed with sodium hydroxide in a solvent, the solvent is composed of 3:1 by mass and water, and the organic solvent in the solvent is one of ethanol, methanol or isopropanol.
8. The method for preparing the atorvastatin intermediate as claimed in claim 6, wherein the mass ratio of the compound 1 to the sodium hydroxide to the solvent to the acid is 1:0.12 to 0.23:8:0.68.
9. the method for preparing the atorvastatin intermediate as claimed in claim 6, wherein the temperature for the hydrolysis by heating is 30-80 ℃.
10. The method for preparing the atorvastatin intermediate as claimed in claim 6, wherein the acid is maleic acid.
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| WO2004029049A1 (en) * | 2002-09-30 | 2004-04-08 | Yamanouchi Pharmaceutical Co., Ltd. | Novel salt of 2-acylaminothiazole derivative |
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| WO2004029049A1 (en) * | 2002-09-30 | 2004-04-08 | Yamanouchi Pharmaceutical Co., Ltd. | Novel salt of 2-acylaminothiazole derivative |
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