CN114105889B - Preparation method and application of key intermediate of DPP-IV inhibitor - Google Patents
Preparation method and application of key intermediate of DPP-IV inhibitor Download PDFInfo
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- CN114105889B CN114105889B CN202111543991.4A CN202111543991A CN114105889B CN 114105889 B CN114105889 B CN 114105889B CN 202111543991 A CN202111543991 A CN 202111543991A CN 114105889 B CN114105889 B CN 114105889B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
- C07D239/62—Barbituric acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention provides a preparation method and application of a key intermediate of a DPP-IV inhibitor, and belongs to the technical fields of organic synthesis and compound preparation. The invention takes 1-methyltrimyrimidinone as a raw material, and reacts with 2-cyano-5-fluorobenzyl bromide in a proper solvent through base catalysis to prepare a key intermediate 2- (6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidine-1-ylmethyl) -4-fluorobenzonitrile of DPP-IV inhibitor, and the intermediate is subjected to chlorination to prepare the target 2- (6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidine-1-ylmethyl) -4-fluorobenzonitrile. The trelagliptin free alkali prepared from the intermediate has high purity, can meet the requirement of single impurity below 0.1%, can be salified to prepare trelagliptin succinate without refining, and has good practical application value.
Description
Technical Field
The invention belongs to the technical field of organic synthesis and compound preparation, and particularly relates to a preparation method and application of a key intermediate of a DPP-IV inhibitor.
Background
The information disclosed in the background of the invention is only for enhancement of understanding of the general background of the invention and is not necessarily to be taken as an admission or any form of suggestion that this information forms the prior art already known to a person of ordinary skill in the art.
Trelagliptin (CAS number 865759-25-7), a novel DPP-IV inhibitor developed by the Wuta-tsai pharmaceutical company, was marketed in Japan in 2015 and controls blood glucose levels by selectively and consistently inhibiting DPP-IV. DPP-IV is an enzyme capable of triggering inactivation of incretins (glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which play an important role in blood glucose regulation, inhibiting DPP-IV, and increasing blood glucose level-dependent insulin secretion, thereby controlling blood glucose levels, is administered once a week, is convenient to use, thereby improving patient compliance, and has few adverse effects, thus being a novel, potential drug for treating type II diabetes.
In the existing preparation method of the trelagliptin, a key intermediate 2- (6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidine-1-ylmethyl) -4-fluorobenzonitrile of the trelagliptin is generally synthesized firstly, and then the trelagliptin is prepared by aminolysis reaction with (R) -3-aminopiperidine. The prior key intermediates for synthesis are usually 4-fluoro-2-halomethylbenzonitrile and 3-methyl-6-chlorouracil as starting materials, however, the inventor discovers that the 3-methyl-6-chlorouracil has high raw material cost, harsh reaction conditions and low yield, and is unfavorable for large-scale industrial production.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a preparation method and application of a key intermediate of a DPP-IV inhibitor. The invention takes 1-methyltrimyrimidinone as a raw material, and reacts with 2-cyano-5-fluorobenzyl bromide in a proper solvent through base catalysis to prepare a key intermediate 2- (6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidine-1-ylmethyl) -4-fluorobenzonitrile of DPP-IV inhibitor, and the intermediate is subjected to chlorination to prepare the target 2- (6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidine-1-ylmethyl) -4-fluorobenzonitrile. The trelagliptin free alkali prepared from the intermediate has high purity, can meet the requirement of single impurity below 0.1%, can be salified to prepare trelagliptin succinate without refining, and has good practical application value.
In a first aspect of the present invention, a preparation method of a key intermediate of a DPP-IV inhibitor is provided, wherein the key intermediate of the DPP-IV inhibitor is 2- (6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidin-1-ylmethyl) -4-fluorobenzonitrile, and the synthetic route is as follows:
specifically, the preparation method comprises the following steps: 1-methyltrisyrimidinone is used as a raw material and reacts with 2-cyano-5-fluorobenzyl bromide in an organic solvent through base catalysis.
In a second aspect of the invention, there is provided the use of a preparation process and/or a key intermediate of a DPP-IV inhibitor obtained by the above preparation process for the preparation of troglitazone free base.
In a third aspect of the present invention, there is provided a process for preparing a trelagliptin free base, said process comprising: the DPP-IV inhibitor key intermediate is reacted with chloro compound to obtain the DPP-IV inhibitor.
The beneficial technical effects of one or more of the technical schemes are as follows:
according to the technical scheme, 1-methyltrimyrimidinone is used as a raw material, and is reacted with 2-cyano-5-fluorobenzyl bromide in a proper solvent through base catalysis to prepare a key intermediate 2- (6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidin-1-ylmethyl) -4-fluorobenzonitrile of DPP-IV inhibitor, and the intermediate is subjected to chlorination to prepare a target 2- (6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidin-1-ylmethyl) -4-fluorobenzonitrile.
The preparation method provided by the technical scheme is concise, convenient to operate, low in preparation cost and more suitable for the requirement of large-scale production. The trelagliptin prepared from the intermediate has low cost and high purity, accords with the economic and environment-friendly chemical synthesis concept better, and has good practical application value.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 is a high performance liquid chromatogram of the trelagliptin free base prepared in example 1 of the present invention;
FIG. 2 is a high performance liquid chromatogram of the trelagliptin free base prepared in example 3 of the present invention.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
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 invention. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
The invention will now be further illustrated with reference to specific examples, which are given for the purpose of illustration only and are not intended to be limiting in any way. If experimental details are not specified in the examples, it is usually the case that the conditions are conventional or recommended by the reagent company; reagents, consumables, etc. used in the examples described below are commercially available unless otherwise specified.
As described above, the key intermediates 2- (6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidin-1-ylmethyl) -4-fluorobenzonitrile of trelagliptin are usually synthesized in the existing synthesis method, and then subjected to aminolysis with (R) -3-aminopiperidine to prepare trelagliptin, however, the key intermediates are usually 4-fluoro-2-halomethylbenzonitrile and 3-methyl-6-chlorouracil as starting materials, however, the 3-methyl-6-chlorouracil has high raw material cost, severe reaction conditions and low yield, and is unfavorable for large-scale industrial production.
In view of this, in an exemplary embodiment of the present invention, a process for preparing a key intermediate of a DPP-IV inhibitor is provided, wherein the key intermediate of the DPP-IV inhibitor is 2- (6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidin-1-ylmethyl) -4-fluorobenzonitrile, and the synthetic route is as follows:
in yet another embodiment of the present invention, the preparation method includes: 1-methyltrisyrimidinone is used as a raw material and reacts with 2-cyano-5-fluorobenzyl bromide in an organic solvent through base catalysis.
The molar ratio of the 1-methyltrimyrimidinone to the 2-cyano-5-fluorobenzyl bromide is 1-5:1, further 1-3:1, and most preferably 1.5:1.
The organic solvent comprises toluene and xylene, preferably toluene;
basic catalysts used in the base catalyzed process include, but are not limited to, N-diisopropylethylamine and triethylamine, preferably N, N-diisopropylethylamine; the addition amount of the basic catalyst is 1-3 times, preferably 2 times, the mole number of the 2-cyano-5-fluorobenzyl bromide;
in the reaction process, the reaction temperature is controlled to be 80-130 ℃, preferably 110-120 ℃; the reaction time is generally 4 hours, and then the DPP-IV inhibitor key intermediate 2- (6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidine-1-ylmethyl) -4-fluorobenzonitrile is obtained after cooling and crystallization.
In a further embodiment of the present invention, there is provided the use of the preparation process and/or the key intermediate of a DPP-IV inhibitor obtained by the preparation process as described above for the preparation of trelagliptin free base.
In yet another embodiment of the present invention, there is provided a process for preparing trelagliptin free base, said process comprising: the DPP-IV inhibitor key intermediate is reacted with chloro compound to obtain the DPP-IV inhibitor. The reaction route is as follows:
wherein the chloride comprises phosphorus oxychloride and thionyl chloride, preferably phosphorus oxychloride.
The molar ratio of the key intermediate of the DPP-IV inhibitor to the chloro compound is 1:2-10, preferably 1:4-5.
In a further embodiment of the present invention, the method is specifically:
mixing the key intermediate of the DPP-IV inhibitor with the chloro compound, stirring, cooling to below 0 ℃, adding water, heating to 80-90 ℃ for reaction for 4-8 hours, removing residual chloro compound, extracting residues, and concentrating under reduced pressure to obtain the Trelagliptin free alkali.
The extraction method can be specifically carried out by using 10% sodium carbonate solution and methylene chloride for 2-3 times, preferably 2 times. The trelagliptin free base further prepared from the key intermediate has high purity, can meet the requirement of single impurity below 0.1%, and can be salified to prepare trelagliptin succinate without refining.
The invention is further illustrated by the following examples, which are not to be construed as limiting the invention. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The following examples are test methods in which specific conditions are noted, and are generally conducted under conventional conditions.
Example 1: preparation of 2- (6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidin-1-ylmethyl) -4-fluorobenzonitrile
7g of 1-methyltrimyrimidinone and 30ml of toluene were added to a reaction flask, stirring was started, and then 7g of 8.5g of N, N-diisopropylethylamine, 2-cyano-5-fluorobenzyl bromide were added in this order. Heated to about 110 ℃ and reacted for 4 hours. Cooling to 0-5 ℃ for crystallization for 1 hour, filtering, washing a filter cake with purified water, and drying in vacuum at 50 ℃ for 8 hours to obtain 8.5g of intermediate with the yield of 94.42 percent.
Mixing 5g of intermediate with 12g of phosphorus oxychloride, stirring, cooling to below 0 ℃, adding 1ml of water, slowly heating to 80 ℃ for reaction for 6 hours, decompressing, evaporating phosphorus oxychloride, slowly adding 100ml of 10% sodium carbonate solution into the residue, extracting with 100ml of dichloromethane twice, decompressing and concentrating to obtain 4.6g of white trelagliptin free base. Yield: 86.22%. The purity of the high performance liquid chromatography is 98.588 percent. The liquid phase diagram is shown in figure 1.
Example 2: preparation of 2- (6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidin-1-ylmethyl) -4-fluorobenzonitrile
20.5g of 1-methyltrimyrimidinone and 100ml of toluene were added to a reaction flask, stirring was started, and then 20g of N, N-diisopropylethylamine, 2-cyano-5-fluorobenzyl bromide were added in sequence. Heated to 120℃and reacted for 4 hours. Cooling to 0-5 ℃ for crystallization for 1 hour, filtering, washing a filter cake with purified water, and drying in vacuum at 50 ℃ for 8 hours to obtain 24.6g of intermediate with the yield of 95.65 percent.
Mixing 15g of intermediate with 37g of phosphorus oxychloride, stirring, cooling to below 0 ℃, adding 2ml of water, slowly heating to 85 ℃ for reaction for 6 hours, decompressing and steaming to remove the phosphorus oxychloride, slowly adding 250ml of 10% sodium carbonate solution into the residue, extracting with 250ml of dichloromethane twice, decompressing and concentrating to obtain 14.1g of white trelagliptin free base. Yield: 88.10%.
Example 3: preparation of Trelagliptin free base
9.0g of (R) -3-aminopiperidine dihydrochloride (8.5 g) 2- (6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidin-1-ylmethyl) -4-fluorobenzonitrile prepared by the method described above and 100ml of ethanol were added to a reaction flask, stirring was turned on, and the temperature was raised to 80℃for 2 hours. Cooling to 0-5 deg.c for crystallization for 1 hr, filtering, and vacuum drying at about 50 deg.c for 6 hr to obtain trelagliptin free alkali 9.5g. The yield thereof was found to be 86.74%. The purity of the high performance liquid chromatography is determined as follows: 99.927%. The liquid phase diagram is shown in figure 2.
The invention is not a matter of the known technology.
The above embodiments are provided to illustrate the technical concept and features of the present invention and are intended to enable those skilled in the art to understand the content of the present invention and implement the same, and are not intended to limit the scope of the present invention. All equivalent changes or modifications made in accordance with the spirit of the present invention should be construed to be included in the scope of the present invention.
Claims (3)
1. A preparation method of a key intermediate of a DPP-IV inhibitor is characterized in that 20.5g of 1-methyltrimyrimidinone and 100ml of toluene are added into a reaction bottle, stirring is started, and then 24.3g of N, N-diisopropylethylamine and 20g of 2-cyano-5-fluorobenzyl bromide are sequentially added; heating to 120 ℃ for reaction for 4 hours; cooling to 0-5 ℃ for crystallization for 1 hour, filtering, washing a filter cake with purified water, and drying in vacuum at 50 ℃ for 8 hours to obtain an intermediate;
15g of intermediate is taken, mixed with 37g of phosphorus oxychloride, stirred and cooled to below 0 ℃, 2ml of water is added, the temperature is slowly raised to 85 ℃ for reaction for 6 hours, 10% sodium carbonate solution 250ml is slowly added into the residue after decompression and evaporation, and the mixture is extracted twice with 250ml of dichloromethane and concentrated under decompression to prepare 2- (6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidine-1-ylmethyl) -4-fluorobenzonitrile.
2. Use of the process according to claim 1 for the preparation of trelagliptin free base.
3. A process for preparing trelagliptin free base, said process comprising: the preparation method of claim 1, 9.0g of 2- (6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidin-1-ylmethyl) -4-fluorobenzonitrile, (R) -3-aminopiperidine dihydrochloride 8.5g, triethylamine 2g and ethanol 100ml are added into a reaction flask, stirring is started, and the temperature is raised to 80 ℃ for reaction for 2 hours; cooling to 0-5 ℃ for crystallization for 1 hour, filtering, and drying in vacuum at about 50 ℃ for 6 hours to obtain the trelagliptin free alkali.
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| CA2622642C (en) * | 2005-09-16 | 2013-12-31 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
| TW200838536A (en) * | 2006-11-29 | 2008-10-01 | Takeda Pharmaceutical | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
| AU2010228902A1 (en) * | 2009-03-26 | 2011-10-06 | Mapi Pharma Limited | Process for the preparation of alogliptin |
| CN107698560A (en) * | 2017-11-17 | 2018-02-16 | 石家庄度恩医药科技有限公司 | One koji Ge Lieting preparation method |
| CN112480013A (en) * | 2020-12-08 | 2021-03-12 | 湖南千金湘江药业股份有限公司 | 3, 4-dihydropyrimidine benzonitrile derivative, and preparation method and application thereof |
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