CN103951589A - Synthesis method of anagliptin intermediate 2-amino-2-methylpropylamine tert-butyl ester - Google Patents
Synthesis method of anagliptin intermediate 2-amino-2-methylpropylamine tert-butyl ester Download PDFInfo
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- CN103951589A CN103951589A CN201410191609.1A CN201410191609A CN103951589A CN 103951589 A CN103951589 A CN 103951589A CN 201410191609 A CN201410191609 A CN 201410191609A CN 103951589 A CN103951589 A CN 103951589A
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Abstract
The invention discloses a synthesis method of an anagliptin intermediate 2-amino-2-methylpropylamine tert-butyl ester, belonging to the technical field of medicines. The synthetic route is characterized by using 2-amino-2-methylpropionitrile as a starting material, generating an intermediate A through reduction reaction and amidating the intermediate A in an alkaline solution to generate 2-amino-2-methylpropylamine tert-butyl ester. The preparation method can achieve synthesis of the anagliptin key intermediate 2-amino-2-methylpropylamine tert-butyl ester only through two-step conventional reactions, has the advantages of short synthetic route, low cost, mild reaction conditions and environment friendliness, has little harm to operating personnel, is little in pollution and is suitable for large-scale industrial production.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of synthetic method of my Ge Lieting intermediate 2-amino-2-methyl propylamine tert-butyl ester.
Background technology
I Ge Lieting (anagliptin) is DPP-IV inhibitor, is to be developed by Wu Tian company, and in June, 2010 first in Japan's listing, listing formulation is 25mg, 12.5mg and 6.25mg tablet.In human plasma in vitro study, find, this product is 10nmol/L to the inhibiting IC50 value of DPP-IV.Normal adults single oral this product 25mg, after 24 hours in blood the inhibiting rate of DPP-IV up to 81%, thereby active GLP-I and GIP circulation composition are raise 2 to 3 times.I Ge Lieting is the newtype drug for the treatment of diabetes, and this medicine has three main fragments: 2-methyl-pyrazolo [1,5-A] pyrimidine-6-carboxylic acid, (2S)-N-chloracetyl-2-cyano group Pyrrolidine, the 2-amino-2-methyl propylamine tert-butyl ester.
The 2-amino-2-methyl propylamine tert-butyl ester is as the important intermediate of I Ge Lieting, through retrieval, there is bibliographical information with 2,2-dimethyl cyclopropylamine (CAS:2658-24-4) (JournaloftheAmericanChemicalSociety, 1948,70,184) and 2,2-dimethyl-5-oxyethyl group imidazoles (CAS:4879-95-2) (JournaloftheAmericanChemical Society, 1985,107,2931) be the synthetic 2-amino-2-methyl propylamine of raw material, synthetic method is as follows:
Synthetic method 1:
Synthetic method 2:
But all there is following shortcoming in above-mentioned two kinds of synthetic methods:
(1) starting raw material 2,2-dimethyl cyclopropylamine and 2,2-dimethyl-5-oxyethyl group imidazoles itself need polystep reaction synthetic, and expensive raw material price is difficult on market obtain;
(2) the route complexity of synthetic 2-amino-2-methyl propylamine, building-up process condition harshness, length consuming time;
(3) yield of products obtained therefrom is low, is unfavorable for batch production scale operation.
Summary of the invention
The object of the invention is to overcome the shortcoming of prior art, a kind of synthetic method of my Ge Lieting intermediate 2-amino-2-methyl propylamine tert-butyl ester is provided, the method has advantages of that synthetic route is brief, yield is high, reaction conditions is gentle, environmental protection, cost are low, is suitable for batch production scale operation.
Object of the present invention is achieved through the following technical solutions: the synthetic method of my Ge Lieting intermediate 2-amino-2-methyl propylamine tert-butyl ester, and synthetic route is:
Taking 2-amino-2-methyl propionitrile as starting raw material, generate the amidation in basic solution of intermediate A, intermediate A by reduction reaction and generate the 2-amino-2-methyl propylamine tert-butyl ester:
S1. reduction reaction: 2-amino-2-methyl propionitrile is added in solvent orange 2 A, then add reductive agent react 1～100h or add catalyzer to lead to hydrogen exchange at 25～100 DEG C, generate intermediate A; Wherein, the weight ratio of described 2-amino-2-methyl propionitrile, solvent orange 2 A, reductive agent is 1:1～20:0.05～4;
Particularly: S1 can have following 2 kinds of methods:
Method one: in three-necked bottle, 2-amino-2-methyl propionitrile hydrochloride is suspended in solvent orange 2 A, in 30 minutes, slowly drip reductive agent, add rear intensification and stir, after its reaction completes, cool to room temperature, slowly drip distilled water and decompose unnecessary reductive agent, with sodium hydroxide solution adjusting pH to 8～9, add ethyl acetate, separatory, the organic phase merging is concentrated after anhydrous sodium sulfate drying, makes intermediate A;
Method two: in reactor, catalyzer, 2-amino-2-methyl propionitrile hydrochloride are suspended in solvent orange 2 A, air 3 times in logical hydrogen exchange reactor, after completing, pressurization heats up and stirs, then cool to room temperature, filters, and organic phase is concentrated, makes intermediate A;
S2. amidate action: synthetic intermediate A, protective material, acid binding agent are added in solvent B, react 1～100h at 25～100 DEG C, the synthetic product 2-amino-2-methyl propylamine tert-butyl ester; Wherein, the weight ratio of described intermediate A, protective material, solvent B is 1:1～6:2～20;
Particularly: in three-necked bottle, intermediate A, acid binding agent are dissolved in solvent B, add protective material; add rear stirring at room temperature, then temperature reaction, the completely rear cool to room temperature of question response; boil off solvent B, resistates makes the 2-amino-2-methyl propylamine tert-butyl ester through aftertreatment.
Post-treating method is: it is 9 that resistates is regulated to pH with sodium hydroxide solution, and water is with after dichloromethane extraction, and organic phase anhydrous sodium sulfate drying, must solid be the 2-amino-2-methyl propylamine tert-butyl ester after concentrating.
Further, described solvent orange 2 A is any one of toluene, tetrahydrofuran (THF), methylene dichloride, chloroform, dioxane, ethyl acetate, methyl alcohol or ethanol.
Further, described reductive agent is one or more mixing of red aluminium, Raney's nickel, borine, Lithium Aluminium Hydride, lithium borohydride, sodium borohydride, three tert.-butoxy lithium aluminum hydrides, aluminum hydride.
Further, described catalyzer is one or more mixing of Raney's nickel, palladium carbon, palladium, palladium hydroxide.
Further, described protective material is any one of tertiary butyloxycarbonyl acid anhydrides, tertiary butyloxycarbonyl acyl chlorides or tertbutyloxycarbonyl phenyl ester.
Further, described solvent B is toluene, tetrahydrofuran (THF), methylene dichloride, chloroform, dioxane, ethyl acetate, methyl alcohol, ethanol or H
2any one of O.
Further, described acid binding agent is triethylamine, Diisopropylamine, diisopropylethylamine, N, any one of N-diethyl methylamine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, potassium hydroxide or sodium hydroxide.
The present invention has the following advantages: the present invention, taking 2-amino-2-methyl propionitrile as starting raw material, obtains product by reduction reaction, amidate action.Preparation method of the present invention only just can realize synthesizing of my Ge Lieting key intermediate 2-amino-2-methyl propylamine tert-butyl ester by two step popular responses, have advantages of that synthetic route is brief, cost is low, reaction conditions is gentle, environmental protection, injury to operator is little, it is little to pollute, and is suitable for batch production scale operation.
Embodiment
Below in conjunction with embodiment, the present invention will be further described, and protection scope of the present invention is not limited to the following stated.
The synthetic method of my Ge Lieting intermediate 2-amino-2-methyl propylamine tert-butyl ester, synthetic route is: taking 2-amino-2-methyl propionitrile as starting raw material, generate the amidation in basic solution of intermediate A, intermediate A generate the 2-amino-2-methyl propylamine tert-butyl ester by reduction reaction.
Embodiment 1: the synthetic method of my Ge Lieting intermediate 2-amino-2-methyl propylamine tert-butyl ester, specifically comprises the following steps:
S1. in three-necked bottle, 2-amino-2-methyl propionitrile hydrochloride is suspended in toluene, in 30 minutes, slowly drip aluminum hydride, after adding, be warming up to 100 DEG C and stir 1h, after its reaction completes, cool to room temperature, slowly drip distilled water and decompose unnecessary aluminum hydride, with sodium hydroxide solution adjusting pH to 8, add ethyl acetate, separatory, the organic phase merging is concentrated after anhydrous sodium sulfate drying, makes intermediate A; Wherein, the weight ratio of 2-amino-2-methyl propionitrile, toluene, aluminum hydride is 1:1:0.05;
S2. in three-necked bottle, intermediate A, triethylamine are dissolved in toluene, add tertiary butyloxycarbonyl acid anhydrides, add rear stirring at room temperature, then heat up 100 DEG C and stir 1h, the completely rear cool to room temperature of question response, boil off toluene, it is 9 that resistates regulates pH with sodium hydroxide solution, and water is with after dichloromethane extraction, organic phase anhydrous sodium sulfate drying, is the 2-amino-2-methyl propylamine tert-butyl ester after concentrating.Wherein, the weight ratio of described intermediate A, tertiary butyloxycarbonyl acid anhydrides, toluene is 1:1:2.
Embodiment 2: the synthetic method of my Ge Lieting intermediate 2-amino-2-methyl propylamine tert-butyl ester, specifically comprises the following steps:
S1. in three-necked bottle, 2-amino-2-methyl propionitrile hydrochloride is suspended in tetrahydrofuran (THF), in 30 minutes, slowly drip borine, after adding, be warming up to 25 DEG C and stir 100h, after its reaction completes, cool to room temperature, slowly drip distilled water and decompose unnecessary borine, with sodium hydroxide solution adjusting pH to 9, add ethyl acetate, separatory, the organic phase merging is concentrated after anhydrous sodium sulfate drying, makes intermediate A; Wherein, the weight ratio of 2-amino-2-methyl propionitrile, tetrahydrofuran (THF), borine is 1:20:4;
S2. in three-necked bottle, intermediate A, triethylamine are dissolved in tetrahydrofuran (THF), then add tertiary butyloxycarbonyl acyl chlorides; add rear stirring at room temperature; then be warming up to 25 DEG C and stir 100h, the completely rear cool to room temperature of question response, concentrated; it is 9 that resistates regulates pH with sodium hydroxide solution; water is with after dichloromethane extraction, and organic phase anhydrous sodium sulfate drying, must solid be the 2-amino-2-methyl propylamine tert-butyl ester after concentrating; wherein, the weight ratio of described intermediate A, protective material, tetrahydrofuran (THF) is 1:6:20.
Embodiment 3: the synthetic method of my Ge Lieting intermediate 2-amino-2-methyl propylamine tert-butyl ester, specifically comprises the following steps:
S1. in reactor, Raney's nickel, 2-amino-2-methyl propionitrile hydrochloride are suspended in methyl alcohol, air 3 times in logical hydrogen exchange reactor, after completing, pressurization is warming up to 40 DEG C and stirs 24h, then cool to room temperature, filters, and organic phase is concentrated, makes intermediate A; Wherein, the weight ratio of 2-amino-2-methyl propionitrile, methylene dichloride, Raney's nickel is 1:8:1.2;
S2. in three-necked bottle, intermediate A, Diisopropylamine are dissolved in methylene dichloride, add tertbutyloxycarbonyl phenyl ester, add rear stirring at room temperature, then be warming up to 45 DEG C and stir 8h, the completely rear cool to room temperature of question response, regulating pH with sodium hydroxide solution is 9, water is with after dichloromethane extraction, organic phase anhydrous sodium sulfate drying, concentrate and be the 2-amino-2-methyl propylamine tert-butyl ester, wherein, the weight ratio of described intermediate A, tertbutyloxycarbonyl phenyl ester, methylene dichloride is 1:1.2:10.
Embodiment 4: the synthetic method of my Ge Lieting intermediate 2-amino-2-methyl propylamine tert-butyl ester, specifically comprises the following steps:
S1. in reactor, palladium carbon, 2-amino-2-methyl propionitrile hydrochloride are suspended in chloroform, air 3 times in logical hydrogen exchange reactor, after completing, pressurization is warming up to 60 DEG C and stirs 50h, then cool to room temperature, filters, and organic phase is concentrated, makes intermediate A; Wherein, the weight ratio of 2-amino-2-methyl propionitrile, chloroform, palladium carbon is 1:12:3;
S2. in three-necked bottle, intermediate A, Diisopropylamine are dissolved in chloroform, then add tertiary butyloxycarbonyl acyl chlorides, add rear stirring at room temperature, then be warming up to 60 DEG C and stir 80h, the completely rear cool to room temperature of question response, concentrated, it is 9 that resistates regulates pH with sodium hydroxide solution, water is with after dichloromethane extraction, and organic phase anhydrous sodium sulfate drying, must solid be the 2-amino-2-methyl propylamine tert-butyl ester after concentrating, wherein, the weight ratio of described intermediate A, tertiary butyloxycarbonyl acyl chlorides, chloroform is 1:4:18.
Embodiment 5: the synthetic method of my Ge Lieting intermediate 2-amino-2-methyl propylamine tert-butyl ester, specifically comprises the following steps:
S1. in the three-necked bottle of 1000ml, 36.15g2-amino-2-methyl propionitrile hydrochloride is suspended in 200ml dioxane, in 30 minutes, slowly drip the dioxane solution 400ml of Lithium Aluminium Hydride, after adding, stir 10h at 45 DEG C, after having reacted, cool to room temperature, slowly drips 100ml distilled water and decomposes unnecessary Lithium Aluminium Hydride, with 1M sodium hydroxide solution adjusting pH to 8, add 400ml ethyl acetate, separatory, the organic phase of merging is after anhydrous sodium sulfate drying, concentrate to obtain intermediate A 19.5g, productive rate: 73.8%;
S2. in the three-necked bottle of 1000ml, by 18g intermediate A, 45ml1M diisopropylethylamine is dissolved in 300ml dioxane, add 20g tertiary butyloxycarbonyl acid anhydrides, add rear stirring at room temperature 30 minutes, be then warmed up to 50 DEG C of reactions 4 hours, cool to room temperature, concentrated, it is 9 that resistates regulates pH with sodium hydroxide solution, and water is with after dichloromethane extraction, organic phase anhydrous sodium sulfate drying, after concentrated, obtain 2-amino-2-methyl propylamine tert-butyl ester 24g, yield 86%, liquid phase purity 98.5%.
Embodiment 6: the synthetic method of my Ge Lieting intermediate 2-amino-2-methyl propylamine tert-butyl ester, specifically comprises the following steps:
S1. in the reactor of 500ml, by 3g palladium, 2g palladium hydroxide, 36.15g2-amino-2-methyl propionitrile hydrochloride is suspended in 200ml methyl alcohol, and air 3 times in logical hydrogen exchange reactor, after completing, be pressurized to 20atm, stir 24h at 90 DEG C, cool to room temperature, filters, after organic phase is concentrated, obtain intermediate A 22.6g, yield: 85.6%;
S2. in the three-necked bottle of 100ml, 3.0g intermediate A, 45ml1M saleratus are dissolved in 100ml dehydrated alcohol, add 26.4g tertiary butyloxycarbonyl acid phenenyl ester, add rear stirring at room temperature 30 minutes, then be warmed up to 70 DEG C of reactions 10 hours, cool to room temperature, boil off dehydrated alcohol, it is 9 that resistates regulates pH with 1M sodium hydroxide solution, methylene dichloride 200ml extraction for water, after anhydrous sodium sulfate drying, concentrates to obtain generation 2-amino-2-methyl propylamine tert-butyl ester 4.0g, yield 56.8%, liquid phase purity 92%.
Embodiment 7: the synthetic method of my Ge Lieting intermediate 2-amino-2-methyl propylamine tert-butyl ester, specifically comprises the following steps:
S1. in the three-necked bottle of 1000ml, 3.62g2-amino-2-methyl propionitrile hydrochloride is suspended in 100ml ethyl acetate, in 30 minutes, slowly add 3.40g sodium borohydride in batches, after adding, stir 10h at 45 DEG C, after having reacted, cool to room temperature, slowly drips the hydrochloric acid of 15ml1M, with 1M sodium hydroxide solution adjusting pH to 9, add 200ml ethyl acetate, separatory, the organic phase of merging is after anhydrous sodium sulfate drying, after organic phase is concentrated, obtain intermediate A 1.65g, productive rate: 62.5%; S2. in the three-necked bottle of 1000ml, 18g intermediate A, 45ml1M dissolution of sodium hydroxide, in 300ml distilled water, are added to 20g tertiary butyloxycarbonyl acid anhydrides, add rear stirring at room temperature 1 hour, then be warmed up to 40 DEG C of reactions 24 hours, cool to room temperature, adds 200ml ethyl acetate, separatory, the organic phase merging is after anhydrous sodium sulfate drying, concentrate to obtain 2-amino-2-methyl propylamine tert-butyl ester 18g, yield 64.5%, liquid phase purity 98%.
Claims (7)
1. the synthetic method of my Ge Lieting intermediate 2-amino-2-methyl propylamine tert-butyl ester, is characterized in that, synthetic route is:
Taking 2-amino-2-methyl propionitrile as starting raw material, generate the amidation in basic solution of intermediate A, intermediate A by reduction reaction and generate the 2-amino-2-methyl propylamine tert-butyl ester:
S1. reduction reaction: 2-amino-2-methyl propionitrile is added in solvent orange 2 A, then add reductive agent react 1～100h or add catalyzer to lead to hydrogen exchange at 25～100 DEG C, generate intermediate A; Wherein, the weight ratio of described 2-amino-2-methyl propionitrile, solvent orange 2 A, reductive agent is 1:1～20:0.05～4;
S2. amidate action: synthetic intermediate A, acid binding agent, protective material are added in solvent B, react 1～100h at 25～100 DEG C, the synthetic product 2-amino-2-methyl propylamine tert-butyl ester; Wherein, the weight ratio of described intermediate A, protective material, solvent B is 1:1～6:2～20.
2. the synthetic method of my Ge Lieting intermediate 2-amino-2-methyl propylamine tert-butyl ester as claimed in claim 1, it is characterized in that, described solvent orange 2 A is any one of toluene, tetrahydrofuran (THF), methylene dichloride, chloroform, dioxane, ethyl acetate, methyl alcohol or ethanol.
3. the synthetic method of my Ge Lieting intermediate 2-amino-2-methyl propylamine tert-butyl ester as claimed in claim 1, it is characterized in that, described reductive agent is one or more mixing of red aluminium, Raney's nickel, borine, Lithium Aluminium Hydride, lithium borohydride, sodium borohydride, three tert.-butoxy lithium aluminum hydrides, aluminum hydride.
4. the synthetic method of my Ge Lieting intermediate 2-amino-2-methyl propylamine tert-butyl ester as claimed in claim 1, is characterized in that, described catalyzer is one or more mixing of Raney's nickel, palladium carbon, palladium, palladium hydroxide.
5. the synthetic method of my Ge Lieting intermediate 2-amino-2-methyl propylamine tert-butyl ester as claimed in claim 1, is characterized in that, described protective material is any one of tertiary butyloxycarbonyl acid anhydrides, tertiary butyloxycarbonyl acyl chlorides or tertbutyloxycarbonyl phenyl ester.
6. the synthetic method of my Ge Lieting intermediate 2-amino-2-methyl propylamine tert-butyl ester as claimed in claim 1, is characterized in that, described solvent B is toluene, tetrahydrofuran (THF), methylene dichloride, chloroform, dioxane, ethyl acetate, methyl alcohol, ethanol or H
2any one of O.
7. the synthetic method of my Ge Lieting intermediate 2-amino-2-methyl propylamine tert-butyl ester as claimed in claim 1, it is characterized in that, described acid binding agent is triethylamine, Diisopropylamine, diisopropylethylamine, N, any one of N-diethyl methylamine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, potassium hydroxide or sodium hydroxide.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105585505A (en) * | 2015-12-25 | 2016-05-18 | 辽宁本源制药有限公司 | Novel preparation method of anagliptin intermediate 1,2-diamido-2-methylpropane |
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| CN102656151A (en) * | 2009-09-04 | 2012-09-05 | 扎里卡斯药品有限公司 | Substituted heterocyclic derivatives for the treatment of pain and epilepsy |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102656151A (en) * | 2009-09-04 | 2012-09-05 | 扎里卡斯药品有限公司 | Substituted heterocyclic derivatives for the treatment of pain and epilepsy |
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| FELIX FREIRE ET AL.: "Macrocyclic Design Strategies for Small, Stable Parallel β-Sheet Scaffolds", 《JOURNAL OF THE AMERICAN SOCIETY》, vol. 131, 20 May 2009 (2009-05-20), pages 7970 - 7972 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105585505A (en) * | 2015-12-25 | 2016-05-18 | 辽宁本源制药有限公司 | Novel preparation method of anagliptin intermediate 1,2-diamido-2-methylpropane |
| CN105585505B (en) * | 2015-12-25 | 2017-10-31 | 辽宁本源制药有限公司 | A kind of new preparation method of the methylpropane of 1,2 diaminourea of An Naigelieting intermediates 2 |
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