CN104961726A - Preparation method of trelagliptin - Google Patents
Preparation method of trelagliptin Download PDFInfo
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- CN104961726A CN104961726A CN201510347134.5A CN201510347134A CN104961726A CN 104961726 A CN104961726 A CN 104961726A CN 201510347134 A CN201510347134 A CN 201510347134A CN 104961726 A CN104961726 A CN 104961726A
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- 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 belongs to the field of chemical synthesis of medicines, and particularly relates to a preparation method of trelagliptin. A synthesis path of the trelagliptin is shown in the specification. The trelagliptin which is protected by Boc is synthesized by (R)-3-Boc-aminopiperidines, the trelagliptin is obtained through hydrolysis deprotection, by-products produced by reaction on amidogen can be avoided, the synthesis path is novel, technological conditions are reasonable, the type and the content of impurities in the trelagliptin can be controlled effectively, a technology is easy to operate, and the yield is high. Moreover, the preparation method of the trelagliptin is suitable to be produced industrially and has high application value, high social benefit and high economic benefit.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis field, the specifically preparation method of a kind of bent Ge Lieting.
Background technology
Diabetes mainly contain two types, called after I type and II type, and wherein type II diabetes accounts for 90% of all diabetes in the whole world, and the feature of type II diabetes is insulopathic and consequent insulin resistant.DPP IV (DPP-IV) belongs to the S9b peptidase families of proteolytic enzyme, it is active by the incretin controlling glucagon-like peptide 1 (GLP-1) and glucose-dependent-insulinotropic polypeptide (GIP), plays a key effect in stable in maintenance glucose.Bent Ge Lieting (Trelagliptin), chemistry 2-by name [6-(3-amino-piperadine-1-base]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl] the fluoro-benzonitrile of-4-, it is the long-acting DPP-4 inhibitor of one of Japanese Wu Tian company exploitation, once, alternative, persistence suppresses DPP-4 to Per-Hop behavior, controls glucose level.
The structural formula of bent Ge Lieting is as follows:
Patent CN1926128A, CN101360723A etc. disclose the preparation method of bent Ge Lieting, and synthetic route is as follows:
3-methyl-6-chlorouracil and 2-cyanogen-5-fluorine bromobenzyl carry out alkylated reaction in the basic conditions and obtain 2-(the chloro-3-methyl-2 of 6-, 4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl) the fluoro-benzonitrile of-4-, then obtain bent Ge Lieting (I) with the condensation of (R)-3-amino piperidine dihydrochloride.In this route, the selectivity of (R)-3-amino piperidine is not high, easily produces by product, and cause magazins' layout difficulty, aftertreatment is loaded down with trivial details, produces serious influence to quality product.
Summary of the invention
In view of this, not high in order to solve the selectivity existed in above-mentioned bent Ge Lieting preparation, easily produce the shortcomings such as by product, the invention provides a kind of new preparation method, this preparation technology is easy, and raw material is easy to get, and yield is high, and selectivity is high, is applicable to suitability for industrialized production.
Synthetic route of the present invention is as follows:
Prepare a method of bent Ge Lieting, comprise the following steps:
1) with 3-methyl-6-chlorouracil (II) for raw material, under solvent and alkaline condition, carry out alkylated reaction with 2-cyanogen-5-fluorine bromobenzyl (III) obtain 2-(the chloro-3-methyl-2 of 6-, 4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl) the fluoro-benzonitrile of-4-(IV);
2) by step 1) 2-(the chloro-3-methyl-2 of 6-that obtains, 4-dioxo-3, 4-dihydro-2H-pyrimidine-1-ylmethyl) the fluoro-benzonitrile of-4-is dissolved in organic solvent, under alkaline condition and phase transfer catalysis condition, (Boc group here refers to tertiary butyl oxycarbonyl with (R)-3-Boc-amino piperidine (V), also can be 3 amino piperidines protected through other protecting group) there is nucleophilic substitution reaction, obtain (R)-tertiary butyl-1-(3-(the fluoro-benzyl of 2-isocyanide-5-)-1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidine-4-base) piperidines-3-aminocarbamic acid ester (VI),
3) by step 2) (R)-tertiary butyl-1-(3-(the fluoro-benzyl of 2-isocyanide-5-)-1-methyl-2 of obtaining; 6-dioxo-1; 2; 3; 6-tetrahydropyrimidine-4-base) piperidines-3-aminocarbamic acid ester is dissolved in organic solvent; slough protecting group through acid hydrolysis, obtain bent Ge Lieting (I).
Wherein, step 1) in the mass ratio that feeds intake of 3-methyl-6-chlorouracil and 2-cyanogen-5-fluorine bromobenzyl be 1:1-1:3, preferred 1:1-1:2, more preferably 1:1.1-1:1.5.
Step 2) middle 2-(the chloro-3-methyl-2 of 6-, 4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl) mass ratio that feeds intake of the fluoro-benzonitrile of-4-and (R)-3-Boc-amino piperidine is 1:1-1:3, preferred 1:1-1:2, more preferably 1:1.1-1:1.5.
Method of the present invention, it is characterized in that step 1) in the alkaline reagents of alkylated reaction be one in triethylamine, salt of wormwood, sodium bicarbonate, diethylamine, solvent is the mixture of one or more in ethyl acetate, toluene, tetrahydrofuran (THF), DMF (DMF), dimethyl sulfoxide (DMSO) (DMSO).
Method of the present invention, it is characterized in that step 2) in alkaline reagents be one in sodium ethylate, sodium methylate, potassium tert.-butoxide, sodium hydroxide, potassium hydroxide, salt of wormwood, solvent is ethyl acetate, toluene, tetrahydrofuran (THF), N, the mixture of one or more in dinethylformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), phase-transfer catalyst is quaternary ammonium compound, comprises Tetrabutyl amonium bromide, tetrabutylammonium chloride, cetyl trimethylammonium bromide etc.
Method of the present invention, it is characterized in that step 3) in solvent be ethyl acetate, toluene, tetrahydrofuran (THF), N, the mixture of one or more in dinethylformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), ethanol, Virahol, water, acid is the one in trifluoroacetic acid, hydrochloric acid, acetic acid.
Method of the present invention, is characterized in that step 1) to step 3) in temperature of reaction between room temperature and the reflux temperature of solvent.
The present invention adopts the bent Ge Lieting of (R)-3-Boc-amino piperidine anamorphic zone Boc protection; bent Ge Lieting is obtained again through hydrolysis deprotection; can avoid amino reacts and the by product produced; synthetic route is novel, and processing condition are reasonable, effectively can control the dopant species in bent Ge Lieting and content; technological operation is simple; yield is high, is suitable for suitability for industrialized production, has larger implementary value and economic results in society.
Accompanying drawing explanation
Fig. 1 is embodiment 1 compounds Ⅳ nucleus magnetic hydrogen spectrum.
Fig. 2 is embodiment 3 compound VI nucleus magnetic hydrogen spectrum.
Fig. 3 is embodiment 5 chemical compounds I nucleus magnetic hydrogen spectrum.
Embodiment
Set forth the present invention further below in conjunction with specific embodiment, should be understood that following examples are only not used in for illustration of the present invention and limit the scope of the invention.
Material required in the embodiment of the present invention, reagent all can be buied in market.
(1) preparation of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl) the fluoro-benzonitrile of-4-(IV)
Embodiment 1
3-methyl-6-chlorouracil 6.42g and 2-cyanogen-5-fluorine bromobenzyl 10.27g is dissolved in 40ml ethyl acetate, adds triethylamine 8.4ml, stir and be warming up to 80 DEG C, react 2 hours.Be down to room temperature, recycling design, extract by water and ethyl acetate, organic layer saturated common salt water washing, with anhydrous sodium sulfate drying, recycling design.Resistates, through purification by column chromatography, obtains 9.54g product, yield 81.2%, purity 99.7%.
1h NMR (500MHz, CDCl
3) δ: 7.75 (dd, J
1=5.5Hz, J
2=8.5Hz, 1H), 7.16-7.12 (m, 1H), 7.45 (t, J=7.5Hz, 1H), 6.95 (dd, J
1=2.5Hz, J
2=9.0Hz, 1H), 6.04 (s, 1H), 5.49 (s, 2H), 3.39 (s, 3H). (nucleus magnetic hydrogen spectrum is shown in accompanying drawing 1)
Embodiment 2
3-methyl-6-chlorouracil 32.1g and 2-cyanogen-5-fluorine bromobenzyl 47.1g is dissolved in 200ml DMF (DMF), adds triethylamine 56ml, stir and be warming up to 100 DEG C, react 2 hours.Be down to room temperature, add water and ethyl acetate extraction, organic layer saturated common salt water washing, with anhydrous sodium sulfate drying, recycling design.Resistates, through purification by column chromatography, obtains product 49.3g, yield 83.9%, purity 99.6%.
(2) preparation of (R)-tertiary butyl-1-(3-(the fluoro-benzyl of 2-isocyanide-5-)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base) piperidines-3-aminocarbamic acid ester (VI)
Embodiment 3
By 2-(the chloro-3-methyl-2 of 6-, 4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl) the fluoro-benzonitrile 58.7g of-4-and (R)-3-Boc-amino piperidine 48g be dissolved in 500ml toluene, add salt of wormwood 55g and Tetrabutyl amonium bromide 1.0g, vigorous stirring is also warming up to 100 DEG C, reacts 24 hours.Be down to room temperature, recycling design, add water and ethyl acetate extraction, organic layer saturated common salt water washing, anhydrous sodium sulfate drying, recycling design obtains crude product, off-white color solid 84.2g is obtained, yield 92.0%, purity 99.3% with ethyl acetate and sherwood oil recrystallization.
1h NMR (500MHz, CDCl
3): 7.70 (dd, J
1=5.5Hz, J
2=8.5Hz, 1H), 7.10-7.06 (m, 1H), 6.91 (d, J=8.5Hz, 1H), 5.30 (dd, J
1=16.5Hz, J
2=28.0Hz, 2H), 4.49 (s, 1H), 3.74-3.70 (m, 1H), 3.30 (s, 3H), 3.22-2.50 (m, 4H), 1.91-1.60 (m, 4H), 1.39 (s, 9H), 1.27-1.23 (m, 1H). (nucleus magnetic hydrogen spectrum is shown in accompanying drawing 2)
Embodiment 4
By 2-(chloro-3 methyl-2 of 6-, 4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl)-benzonitrile 7.34g and (R)-3-Boc-amino piperidine 5.5g be dissolved in 40ml ethanol, add cetyl trimethylammonium bromide 0.2g and salt of wormwood 6.9g, stir and be warming up to backflow, reacting 30 hours.Be down to room temperature, recycling design, with water and dichloromethane extraction, organic layer saturated common salt water washing, anhydrous sodium sulfate drying, recycling design obtains crude product, obtains off-white color solid 10.6g, yield 92.7%, purity 99.4% with ethyl acetate and sherwood oil recrystallization.
(3) preparation of bent Ge Lieting (I)
Embodiment 5
By (R)-benzyl formate-1-(3-(2-isocyanide benzyl)-1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidine-4-base) piperidines-3-aminocarbamic acid ester 9.15g is dissolved in 20ml tetrahydrofuran (THF), add trifluoroacetic acid 10ml, stirring at room temperature 2 hours, recycling design, extract by water and ethyl acetate, water layer adds sodium bicarbonate and is adjusted to alkalescence, use dichloromethane extraction again, organic layer saturated common salt water washing, with anhydrous sodium sulfate drying, recycling design, obtain bent Ge Lieting crude product, crude product ethanol 30ml heats, be down to room temperature again, stirring is spent the night, filter, obtain bent Ge Lieting 8.13g, yield 85.5%, purity 99.6%.
1h NMR (500MHz, CD
3oD) δ: 7.85 (dd, J
1=5.5Hz, J
2=8.5Hz, 1H), 7.26-7.22 (m, 1H), 7.14 (dd, J
1=2.5Hz, J
2=9.0Hz, 1H), 5.44 (s, 1H), 5.30 (s, 2H), 3.26 (s, 3H), 3.22-3.19 (m, 1H), 3.06-3.04 (m, 1H), 2.89-2.84 (m, 1H), 2.68-2.64 (m, 1H), 2.50-2.45 (m, 1H), 1.99-1.95 (m, 1H), 1.80-1.76 (m, 1H), 1.67-1.58 (m, 1H), 1.31-1.26 (m, 1H). (nucleus magnetic hydrogen spectrum is shown in accompanying drawing 3).
Claims (10)
1. a preparation method of bent Ge Lieting, is characterized in that: comprise the following steps:
1) with 3-methyl-6-chlorouracil for raw material, under solvent and alkaline condition, carry out alkylated reaction with 2-cyanogen-5-fluorine bromobenzyl obtain 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl) the fluoro-benzonitrile of-4-;
2) by step 1) 2-(the chloro-3-methyl-2 of 6-that obtains, 4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl) the fluoro-benzonitrile of-4-is dissolved in organic solvent, under alkaline condition and phase transfer catalysis condition, with (R)-3-Boc-amino piperidine generation nucleophilic substitution reaction, obtain (R)-tertiary butyl-1-(3-(the fluoro-benzyl of 2-isocyanide-5-)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base) piperidines-3-aminocarbamic acid ester;
3) by step 2) (R)-tertiary butyl-1-(3-(the fluoro-benzyl of 2-isocyanide-5-)-1-methyl-2 of obtaining; 6-dioxo-1; 2; 3; 6-tetrahydropyrimidine-4-base) piperidines-3-aminocarbamic acid ester is dissolved in organic solvent; slough protecting group through acid hydrolysis, obtain bent Ge Lieting.
2. the method for claim 1, is characterized in that: step 1) in the mass ratio that feeds intake of 3-methyl-6-chlorouracil and 2-cyanogen-5-fluorine bromobenzyl be 1:1-1:3; Step 2) in the mass ratio that feeds intake of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl) the fluoro-benzonitrile of-4-and (R)-3-Boc-amino piperidine be 1:1-1:3.
3. method as claimed in claim 2, is characterized in that: step 1) in the mass ratio that feeds intake of 3-methyl-6-chlorouracil and 2-cyanogen-5-fluorine bromobenzyl be 1:1-1:2; Step 2) in the mass ratio that feeds intake of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl) the fluoro-benzonitrile of-4-and (R)-3-Boc-amino piperidine be 1:1-1:2.
4. the method for claim 1, is characterized in that: step 1) in the alkaline condition of alkylated reaction be one in triethylamine, salt of wormwood, sodium bicarbonate, diethylamine; Solvent is the mixture of one or more in ethyl acetate, toluene, tetrahydrofuran (THF), DMF (DMF), dimethyl sulfoxide (DMSO) (DMSO).
5. method as claimed in claim 4, is characterized in that: step 1) in the alkaline condition of alkylated reaction be triethylamine; Solvent is DMF (DMF).
6. the method for claim 1, is characterized in that: step 2) in alkaline reagents be one in sodium ethylate, sodium methylate, potassium tert.-butoxide, sodium hydroxide, potassium hydroxide, salt of wormwood; Solvent is the mixture of one or more in ethyl acetate, ethanol, toluene, tetrahydrofuran (THF), DMF (DMF), dimethyl sulfoxide (DMSO) (DMSO); Phase-transfer catalyst is quaternary ammonium compound, comprises Tetrabutyl amonium bromide, tetrabutylammonium chloride, cetyl trimethylammonium bromide etc.
7. method as claimed in claim 6, is characterized in that: step 2) in alkaline reagents be salt of wormwood; Solvent is toluene or ethanol; Phase-transfer catalyst is Tetrabutyl amonium bromide or cetyl trimethylammonium bromide etc.
8. the method for claim 1, it is characterized in that: step 3) in solvent be the mixture of one or more in ethyl acetate, toluene, tetrahydrofuran (THF), DMF (DMF), dimethyl sulfoxide (DMSO) (DMSO), ethanol, Virahol, water; Acid is the one in trifluoroacetic acid, hydrochloric acid, acetic acid.
9. method as claimed in claim 8, is characterized in that: step 3) in solvent be tetrahydrofuran (THF); Acid is trifluoroacetic acid.
10. the method for claim 1, is characterized in that: step 1) to step 3) in temperature of reaction between room temperature and the reflux temperature of solvent.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105646447A (en) * | 2015-12-25 | 2016-06-08 | 北京康立生医药技术开发有限公司 | Synthesis method of dipeptidyl peptidase inhibitor |
| CN105669645A (en) * | 2016-02-18 | 2016-06-15 | 南京正大天晴制药有限公司 | Trelagliptin and preparation method of succinate thereof |
| CN106008459A (en) * | 2016-08-05 | 2016-10-12 | 平原县四环药业有限公司 | Trelagliptin preparation method |
| CN107219307A (en) * | 2016-03-22 | 2017-09-29 | 中美华世通生物医药科技（武汉）有限公司 | The method that enantiomter impurity in song Ge Lieting bulk drugs and its preparation is determined using HPLC |
| CN107540656A (en) * | 2016-06-29 | 2018-01-05 | 常州市第四制药厂有限公司 | A kind of preparation method of SYR-322 |
| CN107778281A (en) * | 2016-08-26 | 2018-03-09 | 扬子江药业集团江苏紫龙药业有限公司 | One koji Ge Lieting process for purification |
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| CN101360723A (en) * | 2005-09-16 | 2009-02-04 | 武田药品工业株式会社 | Process for the preparation of pyrimidinedione derivatives |
| CN102361557A (en) * | 2009-03-26 | 2012-02-22 | Mapi医药公司 | Process for the preparation of alogliptin |
| CN103819450A (en) * | 2014-01-25 | 2014-05-28 | 浙江永宁药业股份有限公司 | Novel method for preparing alogliptin benzoate |
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| CN1926128A (en) * | 2004-03-15 | 2007-03-07 | 武田药品工业株式会社 | Dipeptidyl peptidase inhibitors |
| CN101360723A (en) * | 2005-09-16 | 2009-02-04 | 武田药品工业株式会社 | Process for the preparation of pyrimidinedione derivatives |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105646447A (en) * | 2015-12-25 | 2016-06-08 | 北京康立生医药技术开发有限公司 | Synthesis method of dipeptidyl peptidase inhibitor |
| CN105669645A (en) * | 2016-02-18 | 2016-06-15 | 南京正大天晴制药有限公司 | Trelagliptin and preparation method of succinate thereof |
| CN105669645B (en) * | 2016-02-18 | 2019-12-31 | 南京正大天晴制药有限公司 | Preparation method of trelagliptin and succinate thereof |
| CN107219307A (en) * | 2016-03-22 | 2017-09-29 | 中美华世通生物医药科技（武汉）有限公司 | The method that enantiomter impurity in song Ge Lieting bulk drugs and its preparation is determined using HPLC |
| CN107540656A (en) * | 2016-06-29 | 2018-01-05 | 常州市第四制药厂有限公司 | A kind of preparation method of SYR-322 |
| CN107540656B (en) * | 2016-06-29 | 2021-03-02 | 常州市第四制药厂有限公司 | Preparation method of alogliptin benzoate |
| CN106008459A (en) * | 2016-08-05 | 2016-10-12 | 平原县四环药业有限公司 | Trelagliptin preparation method |
| CN106008459B (en) * | 2016-08-05 | 2018-07-13 | 山东四环药业股份有限公司 | The preparation method of one koji Ge Lieting |
| CN107778281A (en) * | 2016-08-26 | 2018-03-09 | 扬子江药业集团江苏紫龙药业有限公司 | One koji Ge Lieting process for purification |
| CN107778281B (en) * | 2016-08-26 | 2020-06-30 | 扬子江药业集团江苏紫龙药业有限公司 | Refining method of trelagliptin |
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Application publication date: 20151007 |