CN109970763B - Preparation method of DGAT1 inhibitor - Google Patents
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a novel preparation method of DGAT1 inhibitor 4-amino-6- (3, 5-dimethyl-4- (3-methyl-1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) phenyl) -7, 8-dihydropyrimidine [5,4-f ] [1,4] oxazepine-5 (6H) -one-hydrochloride. 3, 5-dimethyl-4- (3-methyl-1- (2,2,2 trifluoroethyl) -1H-pyrazol-4-yl) aniline-hydrochloride is used as a starting material and is subjected to condensation reaction with chloroethyl chloroformate to generate an intermediate 1; the intermediate 1 is alkylated in alcohol and alkali solution and then hydrolyzed to generate an intermediate 2; the intermediate 2 and 4, 6-dichloropyrimidine-5-acyl chloride are subjected to condensation reaction to generate an intermediate 3; after alkylation of the intermediate 3, intramolecular ring closure reaction is carried out to generate an intermediate 4; the intermediate 4 is aminated in dioxane solution of ammonia to generate an intermediate 5; and (5) forming salt in acetone solution of hydrochloric acid to obtain the finished product. All reaction intermediates of the invention are solid and are easy to purify.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a novel preparation method of DGAT1 inhibitor 4-amino-6- (3, 5-dimethyl-4- (3-methyl-1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) phenyl) -7, 8-dihydropyrimidine [5,4-f ] [1,4] oxazepine-5 (6H) -one-hydrochloride.
Background
DGAT1 inhibitor is a diacylglycerol acyltransferase, and its indications include Familial Chylomicronemia Syndrome (FCS), diabetes, obesity, hyperlipoproteinemia or hypertriglyceridemia. The gene defect and inhibition of DGAT1 can prevent obesity caused by high fat diet and increase the sensitivity of body to insulin without side effect.
The DGAT1 inhibitor has the structural formula:
the present DGAT1 inhibitor compound has patent application No. 201310371069.0, and specifically has two preparation methods,
route 1
Route 1 has the following drawbacks: in the route, the intermediate 9 needs to be separated and purified by a column to remove isomers, so that the difficulty is high, the yield is low, and the process amplification is not facilitated; the intermediates 3 to 5 need to be recrystallized by methanol to obtain a product with higher purity, but the yield is lower; the final step of the Suzuki reaction treatment needs a method of pulping for multiple times to obtain a high-purity product, the yield is reduced, and the removal of the heavy metal Pd is difficult to reach the limit.
Route 2:
route 2 has the following drawbacks: the steps are long, and the intermediates of the steps are oily substances; the polarity is small, the purification is not suitable, and the quality control difficulty of the intermediate is high; disubstituted by-products are easily generated in the first step and cannot be removed in post-treatment; intermediate 13 still needs to be separated and purified by column to remove isomers.
Therefore, the existing preparation process has many defects, so that a new method for preparing the DGAT1 inhibitor is urgently needed.
Disclosure of Invention
The invention aims to provide a novel preparation method of DGAT1 inhibitor 4-amino-6- (3, 5-dimethyl-4- (3-methyl-1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) phenyl) -7, 8-dihydropyrimidine [5,4-f ] [1,4] oxazepin-5 (6H) -one-hydrochloride.
In order to achieve the purpose, the invention adopts the technical scheme that:
a preparation method of DGAT1 inhibitor comprises the steps of carrying out condensation reaction on 3, 5-dimethyl-4- (3-methyl-1- (2,2,2 trifluoroethyl) -1H-pyrazol-4-yl) aniline-hydrochloride serving as a starting material and chloroethyl chloroformate to generate an intermediate 1; the intermediate 1 is alkylated in alcohol and alkali solution and then hydrolyzed to generate an intermediate 2; the intermediate 2 and 4, 6-dichloropyrimidine-5-acyl chloride are subjected to condensation reaction to generate an intermediate 3; after alkylation of the intermediate 3, intramolecular ring closure reaction is carried out to generate an intermediate 4; the intermediate 4 is aminated in dioxane solution of ammonia to generate an intermediate 5; and (5) forming salt in acetone solution of hydrochloric acid to obtain the finished product.
The synthetic route is as follows:
carrying out condensation reaction on the starting material 3, 5-dimethyl-4- (3-methyl-1- (2,2,2 trifluoroethyl) -1H-pyrazol-4-yl) aniline-hydrochloride (the starting material is dissolved by a solvent) and chloroethyl chloroformate at the temperature of-10-0 ℃ in the presence of an acid-binding agent to obtain a generated intermediate 1; wherein the molar ratio of the 3, 5-dimethyl-4- (3-methyl-1- (2,2,2 trifluoroethyl) -1H-pyrazol-4-yl) aniline-hydrochloride, the chloroethyl chloroformate to the acid-binding agent is 1:1.2: 1.5-1: 2: 3.
The acid-binding agent is pyridine, 4-dimethylaminopyridine, triethylamine or N, N-diisopropylethylamine.
Heating the intermediate 1 in an alkali-containing alcohol solution to reflux, and performing hydrolysis reaction to obtain an intermediate 2; wherein the molar ratio of the intermediate 1 to the alkali is 1: 2-1: 8.
The alkali is NaOH or KOH; the alcohol is methanol or ethanol.
Adding an acid binding agent, an intermediate 2 and 4, 6-dichloropyrimidine-5-acyl chloride at the low temperature of-10-0 ℃ for condensation reaction to generate an intermediate 3; wherein the molar ratio of the intermediate 2, 4, 6-dichloropyrimidine-5-acyl chloride to the acid-binding agent is 1:1: 2-1: 1.2: 4.
The 4, 6-dichloropyrimidine-5-acyl chloride is dropwise added into a reaction system in batches under the stirring condition; the acid-binding agent is triethylamine, 4-dimethylaminopyridine or N, N-diisopropylethylamine.
Under an alkaline condition, heating the intermediate 3 in an acetonitrile solution to 80-85 ℃ for reflux, and performing intramolecular cyclization reaction to generate an intermediate 4; wherein the molar ratio of the intermediate 3 to the alkali is 1: 2-1: 5; the base is triethylamine, pyridine, or 4-dimethylamino pyridine, such as N, N-diisopropylethylamine.
The above-mentionedIntermediate 4 addition to saturated NH3Stirring for 15-20 h at 20-30 ℃ in a dioxane system, and carrying out an amination reaction to generate an intermediate 5; wherein NH is saturated3The dosage of the dioxane solution system is 8-12 times of the volume of the intermediate 4.
Dissolving the intermediate 5 in acetone, dropwise adding an acetone solution containing hydrochloric acid, stirring at normal temperature, and filtering to obtain a finished product; wherein the molar ratio of the intermediate 5 to the hydrochloric acid is 1: 1-1: 1.2, and the volume ratio of the hydrochloric acid to the acetone in the dropwise added hydrochloric acid/acetone solution is 1:1.
Compared with the existing synthesis technology, the route has the following advantages:
1) all reaction intermediates are solid and are easy to purify; 2) the post-treatment of the process is all conventional operations such as pulping, recrystallization and the like, so that the post-treatment process of column chromatography is avoided, and the process is more suitable for process amplification; 3) the Suzuki reaction in the existing preparation method 1 is the last step of reaction, so that the heavy metal palladium in the product can reach the standard after being purified for many times.
Detailed Description
The above-mentioned aspects of the present invention will be further illustrated by the following examples.
The method of the invention is a method for preparing DGAT1 by using 5-dimethyl-4- (3-methyl-1- (2,2,2 trifluoroethyl) -1H-pyrazol-4-yl) aniline-hydrochloride as a starting material through 6 steps of reactions, and has the advantages of easy operation, easy purification and suitability for industrial large-scale production.
The starting material 3, 5-dimethyl-4- (3-methyl-1- (2,2,2 trifluoroethyl) -1 h-pyrazol-4-yl) aniline-hydrochloride used in the present invention was prepared by the following method:
under the alkaline condition, the 3-methyl-4- (4,4,5, 5-tetramethyl- [1,3,2] dioxolan-2-yl) -1- (2,2, 2-trifluoro-ethyl) -1H-pyrazole reacts with 4-bromo-3, 5-dimethyl-aniline under the catalysis of palladium tetratriphenylphosphine, the reaction system is extracted and pulped to obtain a crude product of the 3, 5-dimethyl-4- (3-methyl-1- (2,2, 2-trifluoroethyl) -1H-pyrazole-4-yl) aniline, the crude product is pulped and purified after being salified with hydrogen chloride gas to obtain the 3, 5-dimethyl-4- (3-methyl-1- (2,2,2 trifluoroethyl) -1 h-pyrazol-4-yl) aniline-hydrochloride.
Example 1
Step 1: condensation step, Synthesis of intermediate 1
950g of the starting materials 3, 5-dimethyl-4- (3-methyl-1- (2,2,2 trifluoroethyl) -1 h-pyrazol-4-yl) aniline-hydrochloride and 9.5L of dichloromethane were charged into a 50L reaction vessel, 630g of pyridine was added, the temperature of the reaction vessel was adjusted to-5 ℃, 472g of chloroethyl chloroformate was added dropwise to the reaction vessel, and stirred for 2 hours.
After the reaction, water was added for extraction, and the organic phase was concentrated in vacuo to give 1.09kg of intermediate 1 with a yield of 98%.
Step 2: cyclization and hydrolysis step, Synthesis of intermediate 2
1.09kg of intermediate 1 and 11L of methanol were charged into a 30L reactor, a solution of sodium hydroxide (408.9g) in water (2.2L) was added, the temperature of the reactor was adjusted to 80 ℃ and stirred at this temperature for 16 hours.
After the reaction was completed, the system was concentrated to dryness, the obtained solid was slurried with water and filtered, and the filter cake was air dried to obtain 859g of intermediate 2 with a yield of 94%.
And step 3: condensation step, Synthesis of intermediate 3
855g of the intermediate 2 and 8.55L of dichloromethane are added into a 50L reaction kettle, 744g of triethylamine is added, the temperature is reduced to minus 5 ℃, a dichloromethane (740mL) solution containing 4, 6-dichloropyrimidine-5-acyl chloride (368g) is dripped into the reaction kettle, stirring is carried out for 1 hour, a dichloromethane (440mL) solution containing 4, 6-dichloropyrimidine-5-acyl chloride (221g) is dripped, stirring is carried out for 1 to 1.5 hours, a dichloromethane (300mL) solution containing 4, 6-dichloropyrimidine-5-acyl chloride (147g) is dripped, after dripping is finished, the reaction solution is continuously stirred for 1 hour at minus 5 ℃.
After the reaction is completed, 6L of 1N HCl is added for quenching, water is added for extraction, the organic phase is concentrated to be dry under the pressure, the obtained crude product is added with methyl tert-butyl ether for pulping and then is filtered, and 962g of intermediate 3 is obtained after the filter cake is dried by air blowing, and the yield is 73%.
And 4, step 4: cyclization step, Synthesis of intermediate 4
958g of intermediate 3 and 19L of acetonitrile were charged into a 30L reactor, 546g of triethylamine was added, the temperature was raised to 80 ℃ and stirring was carried out for 16 hours.
After the reaction is completed, dichloromethane is added for extraction, the water phase is extracted twice by dichloromethane, the organic phases are combined and concentrated under reduced pressure to be dry, the obtained crude product is added with methyl tert-butyl ether for pulping and then filtered, and 660g of intermediate 4 is obtained after the filter cake is dried by air blowing, and the yield is 74%.
And 5: amination step, Synthesis of intermediate 5
Ammonia gas was bubbled through 6.52L dioxane for 0.5 h to saturation, then added to a 10L three necked round bottom reaction flask, 652g intermediate 4 was added and the reaction stirred at 25 ℃ for 16 h.
After the reaction is completed, the system is decompressed and concentrated to be dry, the obtained solid is added with water and is pulped and then filtered, and 615g of intermediate 5 is obtained after the filter cake is dried by air blast, and the yield is 99%.
Step 6: salt-forming process, synthesis of final product
605g of intermediate 5 were dissolved in 12L of dichloromethane. Filtering, and concentrating the filtrate at 45 deg.C under reduced pressure to dryness. The concentrate was dissolved in 10.5L of acetone. A solution of concentrated hydrochloric acid (0.115L) in acetone (0.115L) was added dropwise at 25 ℃ and stirred for 24 hours.
Filtering and collecting filter cakes. The filter cake was vacuum dried at 45 ℃ for 48 hours under reduced pressure to give 600g of the final product in 92% yield.
Example 2
Step 1: condensation step, Synthesis of intermediate 1
1.5kg of the starting materials 3, 5-dimethyl-4- (3-methyl-1- (2,2,2 trifluoroethyl) -1 h-pyrazol-4-yl) aniline-hydrochloride and 15L of dichloromethane were charged into a 50L reactor, 667g of pyridine was added, the temperature of the reactor was adjusted to-8 ℃, 1.2kg of chloroethyl chloroformate was dropped into the reactor, and stirred for 2 hours.
After the reaction, water was added for extraction, and the organic phase was concentrated in vacuo to give 1.63kg of intermediate 1 with a yield of 99%.
Step 2: cyclization and hydrolysis step, Synthesis of intermediate 2
1.6kg of intermediate 1 and 16L of methanol were charged into a 30L reactor, a solution of sodium hydroxide (985g) in water (3.2L) was added, the temperature of the reactor was adjusted to 80 ℃ and stirred at this temperature for 16 hours.
After the reaction was completed, the system was concentrated to dryness, the obtained solid was slurried with water and filtered, and the filter cake was air-dried to obtain 1.3kg of intermediate 2 with a yield of 96.5%.
And step 3: condensation step, Synthesis of intermediate 3
Adding 1.2kg of the intermediate 2 and 12L of dichloromethane into a 50L reaction kettle, adding 1.48kg of triethylamine, cooling to-6 ℃, dropwise adding a dichloromethane (930mL) solution containing 4, 6-dichloropyrimidine-5-acyl chloride (465g), stirring for 1 hour, dropwise adding a dichloromethane (558mL) solution containing 4, 6-dichloropyrimidine-5-acyl chloride (279g), stirring for 1-1.5 hours, dropwise adding a dichloromethane (372mL) solution containing 4, 6-dichloropyrimidine-5-acyl chloride (186g), and after the dropwise adding is finished, continuously stirring the reaction solution for 1 hour at-5 ℃.
After the reaction is completed, 8.5L of 1N HCl is added for quenching, water is added for extraction, the organic phase is concentrated to be dry under pressure, the obtained crude product is added with methyl tert-butyl ether for pulping and then is filtered, and the filter cake is dried by air blast to obtain 1.36kg of intermediate 3 with the yield of 74.2 percent.
And 4, step 4: cyclization step, Synthesis of intermediate 4
1.3kg of intermediate 3 and 26L of acetonitrile were added to a 50L reactor, 1.1kg of triethylamine was added, the temperature was raised to 80 ℃ and stirred for 16 hours.
After the reaction is completed, dichloromethane is added for extraction, the water phase is extracted twice by dichloromethane, the organic phases are combined and concentrated under reduced pressure to be dry, the obtained crude product is added with methyl tert-butyl ether for pulping and then filtered, and 920g of intermediate 4 is obtained after the filter cake is dried by air blowing, and the yield is 76.3%.
And 5: amination step, Synthesis of intermediate 5
Ammonia gas was purged into 12L dioxane for 0.5 hour to saturation, and then the mixture was charged into a 30L reaction vessel, 900g of intermediate 4 was added, and the reaction solution was stirred at 25 ℃ for 16 hours.
After the reaction is completed, the system is decompressed and concentrated to be dry, the obtained solid is added with water and is pulped and then filtered, and 846g of intermediate 5 is obtained after the filter cake is dried by air blasting, and the yield is 98.2%.
Step 6: salt-forming process, synthesis of final product
840g of intermediate 5 were dissolved in 16L of dichloromethane. Filtering, and concentrating the filtrate at 45 deg.C under reduced pressure to dryness. The concentrate was dissolved in 14.5L of acetone. A solution of concentrated hydrochloric acid (0.18L) in acetone (0.18L) was added dropwise at 25 ℃ and stirred for 24 hours.
Filtering and collecting filter cakes. The filter cake was vacuum dried at 45 ℃ for 48 hours under reduced pressure to yield 854g of final product in 94% yield.
While the method of the present invention has been described in detail by way of the preferred embodiments, it is not limited thereto, but is for the purpose of facilitating understanding of the present invention, and it will be apparent to those skilled in the art that various modifications may be made without departing from the principle of the present invention, and the modifications are within the scope of the appended claims.
Claims (10)
1. A process for the preparation of a DGAT1 inhibitor, characterized in that: 3, 5-dimethyl-4- (3-methyl-1- (2,2,2 trifluoroethyl) -1H-pyrazol-4-yl) aniline-hydrochloride is used as a starting material and is subjected to condensation reaction with chloroethyl chloroformate to generate an intermediate 1; the intermediate 1 is alkylated in alcohol and alkali solution and then hydrolyzed to generate an intermediate 2; the intermediate 2 and 4, 6-dichloropyrimidine-5-acyl chloride are subjected to condensation reaction to generate an intermediate 3; after alkylation of the intermediate 3, intramolecular ring closure reaction is carried out to generate an intermediate 4; the intermediate 4 is aminated in dioxane solution of ammonia to generate an intermediate 5; the intermediate 5 is salted in acetone solution of hydrochloric acid to obtain a finished product;
the synthetic route is as follows:
2. a process for the preparation of a DGAT1 inhibitor according to claim 1, wherein: carrying out condensation reaction on the starting material 3, 5-dimethyl-4- (3-methyl-1- (2,2,2 trifluoroethyl) -1H-pyrazol-4-yl) aniline-hydrochloride and chloroethyl chloroformate at the temperature of-10-0 ℃ in the presence of an acid-binding agent to obtain an intermediate 1; wherein the molar ratio of the 3, 5-dimethyl-4- (3-methyl-1- (2,2,2 trifluoroethyl) -1H-pyrazol-4-yl) aniline-hydrochloride, the chloroethyl chloroformate to the acid-binding agent is 1:1.2: 1.5-1: 2: 3.
3. A process for the preparation of a DGAT1 inhibitor according to claim 2, wherein: the acid-binding agent is pyridine, 4-dimethylaminopyridine, triethylamine or N, N-diisopropylethylamine.
4. A process for the preparation of a DGAT1 inhibitor according to claim 1, wherein: heating the intermediate 1 in an alkali-containing alcohol solution to reflux, and performing hydrolysis reaction to obtain an intermediate 2; wherein the molar ratio of the intermediate 1 to the alkali is 1: 2-1: 8.
5. The process for preparing a DGAT1 inhibitor according to claim 4, wherein: the alkali is NaOH or KOH; the alcohol is methanol or ethanol.
6. A process for the preparation of a DGAT1 inhibitor according to claim 1, wherein: adding an acid binding agent, an intermediate 2 and 4, 6-dichloropyrimidine-5-acyl chloride at the low temperature of-10-0 ℃ for condensation reaction to generate an intermediate 3; wherein the molar ratio of the intermediate 2, 4, 6-dichloropyrimidine-5-acyl chloride to the acid-binding agent is 1:1: 2-1: 1.2: 4.
7. The process for preparing a DGAT1 inhibitor according to claim 6, wherein: the 4, 6-dichloropyrimidine-5-acyl chloride is dropwise added into a reaction system in batches under the stirring condition; the acid-binding agent is triethylamine, 4-dimethylaminopyridine or N, N-diisopropylethylamine.
8. A process for the preparation of a DGAT1 inhibitor according to claim 1, wherein: under an alkaline condition, heating the intermediate 3 in an acetonitrile solution to 80-85 ℃ for reflux, and performing intramolecular cyclization reaction to generate an intermediate 4; wherein the molar ratio of the intermediate 3 to the alkali is 1: 2-1: 5; the base is triethylamine, pyridine, 4-dimethylaminopyridine or N, N-diisopropylethylamine.
9. A process for the preparation of a DGAT1 inhibitor according to claim 1, wherein: the intermediate 4 is added to saturated NH3Stirring for 15-20 h at 20-30 ℃ in a dioxane system, and carrying out an amination reaction to generate an intermediate 5; wherein NH is saturated3The dosage of the dioxane solution system is 8-12 times of the volume of the intermediate 4.
10. A process for the preparation of a DGAT1 inhibitor according to claim 1, wherein: dissolving the intermediate 5 in acetone, dropwise adding an acetone solution containing hydrochloric acid, stirring at normal temperature, and filtering to obtain a finished product; wherein the molar ratio of the intermediate 5 to the hydrochloric acid is 1: 1-1: 1.2, and the volume ratio of the hydrochloric acid to the acetone in the dropwise added hydrochloric acid/acetone solution is 1:1.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010086820A1 (en) * | 2009-02-02 | 2010-08-05 | Pfizer Inc. | 4-amino-5-oxo-7, 8-dihydropyrimido [5,4-f] [1,4] oxazepin-6 (5h) -yl) phenyl derivatives, pharmaceutical compositions and uses thereof |
| CN104418866A (en) * | 2013-08-23 | 2015-03-18 | 南京明德新药研发股份有限公司 | DGAT1 inhibitor, and preparation method and application thereof |
| CN104496795A (en) * | 2014-12-12 | 2015-04-08 | 重庆博腾制药科技股份有限公司 | Method for preparing DGAT-1 inhibitor intermediate |
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- 2017-12-27 CN CN201711443173.0A patent/CN109970763B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010086820A1 (en) * | 2009-02-02 | 2010-08-05 | Pfizer Inc. | 4-amino-5-oxo-7, 8-dihydropyrimido [5,4-f] [1,4] oxazepin-6 (5h) -yl) phenyl derivatives, pharmaceutical compositions and uses thereof |
| CN104418866A (en) * | 2013-08-23 | 2015-03-18 | 南京明德新药研发股份有限公司 | DGAT1 inhibitor, and preparation method and application thereof |
| EP3042907A1 (en) * | 2013-08-23 | 2016-07-13 | Medshine Discovery Inc. | Dgat1 inhibitor and preparation method and use thereof |
| CN104496795A (en) * | 2014-12-12 | 2015-04-08 | 重庆博腾制药科技股份有限公司 | Method for preparing DGAT-1 inhibitor intermediate |
Non-Patent Citations (1)
| Title |
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| Discovery of diamide compounds as diacylglycerol acyltransferase 1(DGAT1) inhibitors;Katsumasa Nakajima et al.;《Bioorganic & Medicinal Chemistry Letters》;20161231;1-4 * |
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