CN105315189A - (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid-1(1,1-dimethylethyl)ester preparation method - Google Patents
(5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid-1(1,1-dimethylethyl)ester preparation method Download PDFInfo
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- CN105315189A CN105315189A CN201410234339.8A CN201410234339A CN105315189A CN 105315189 A CN105315189 A CN 105315189A CN 201410234339 A CN201410234339 A CN 201410234339A CN 105315189 A CN105315189 A CN 105315189A
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Abstract
The present invention discloses a (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid-1(1,1-dimethylethyl)ester preparation method, wherein is 4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid[1-(1,1-dimethylethyl), 5-ethyl]ester is adopted as a raw material, sodium isopropoxide is adopted as an alkali reagent, and the raw material, the alkali reagent and formamide are subjected to a reaction in a solvent so as to obtain the target product. According to the present invention, the reaction conditions in the prior art are further optimized so as to improve the yield and easily achieve industrial production.
Description
Technical field
The present invention relates to preparation method's technical field of (5S)-5-aminocarboxyl-4,5-dihydro-1H-pyrroles-1-carboxylic acid-1 (1,1-dimethyl ethyl) ester.
Background technology
(5S)-5-aminocarboxyl-4,5-dihydro-1H-pyrroles-1-carboxylic acid-1 (1,1-dimethyl ethyl) ester is intermediate for the production of inhibitors of dipeptidyl IV, embodiment 32 in patent CN1791401 specification sheets, 33 preparation object product (5S)-5-aminocarboxyls-4,5-dihydro-1H-pyrroles-1-carboxylic acid-1 (1,1-dimethyl ethyl) ester (CAS709031-38-9).Embodiment 32 is with 4,5-dihydro-1H-pyrroles-1,5-dicarboxylic acid [1-(1,1-dimethyl ethyl), 5-ethyl] ester is that raw material is through saponification, acidifying, salify, dry acquisition intermediate product, in embodiment 33, intermediate product and methylsulfonyl chloride are reacted and form leavings group, pass into ammonia (drying) again, introduce amino, form acid amides.These two kinds of methods are all at least through two step synthesis object products, and productive rate is 82.8%.Disclosed two kinds of method operating process are loaded down with trivial details, and solvent usage quantity is large; Reaction conditions is comparatively harsh, becomes in acid amides one step at intermediate, needs dried feed, solvent THF, ammonia, and needs the low temperature of-25 DEG C; Reaction reagent employs poisonous, easily poison processed, and be difficult to the N that the methylsulfonyl chloride of purchase and the ammonia of irritant smell and price are more expensive, N-diisopropyl ethyl amine (DIPEA), this will increase production cost greatly.Also similar one-step synthesis method object product is taked in patent US2006035954, but productive rate is lower, be only 47.7%, in this patent Example 1, use methanol as solvent, methane amide, sodium methylate makes reaction reagent, with ammonium chloride solution dilute reaction solution after reaction terminates, add toluene and water, be separated organic layer, washing, concentrated after dry.This patent is compared with CN1791401, easy in operation, but reaction yield is well below the latter's 82.8%.
Summary of the invention
Object of the present invention is exactly the above-mentioned defect solving prior art, there is provided a kind of not only easy handling and high (the 5S)-5-aminocarboxyl-4 being suitable for suitability for industrialized production of yield, 5-dihydro-1H-pyrroles-1-carboxylic acid-1 (1,1-dimethyl ethyl) ester preparation method.
For reaching above-mentioned purpose, the technical scheme that the present invention takes is as follows:
(5S)-5-aminocarboxyl-4,5-dihydro-1H-pyrroles-1-carboxylic acid-1 (1,1-dimethyl ethyl) preparation method of ester, the method is with 4,5-dihydro-1H-pyrroles-1,5-dicarboxylic acid [1-(1,1-dimethyl ethyl), 5-ethyl] ester is raw material, sodium isopropylate is alkaline reagents, obtains object product in a solvent with formamide
The preparation method of above-mentioned (5S)-5-aminocarboxyl-4,5-dihydro-1H-pyrroles-1-carboxylic acid-1 (1,1-dimethyl ethyl) ester, reaction at room temperature.Reaction solvent used can be anhydrous diethyl ether, ethyl propionate, methyl-formiate, ethyl formate or p-Xylol etc., preferred anhydrous diethyl ether or p-Xylol.
Further, above-mentioned (5S)-5-aminocarboxyl-4,5-dihydro-1H-pyrroles-1-carboxylic acid-1 (1,1-dimethyl ethyl) preparation method of ester, operation steps is: in reaction vessel, first drop into raw material 4,5-dihydro-1H-pyrroles-1,5-dicarboxylic acid [1-(1,1-dimethyl ethyl), 5-ethyl] ester, then add reaction solvent and and methane amide, stir, keep temperature-5-5 DEG C in reaction vessel, add sodium isopropylate in batches.
Further, above-mentioned (5S)-5-aminocarboxyl-4,5-dihydro-1H-pyrroles-1-carboxylic acid-1 (1,1-dimethyl ethyl) preparation method of ester, post-processing step is: poured into by reaction solution in frozen water and stir fully, be separated organic layer, again with reaction solvent aqueous layer extracted, merge organic layer, wash organic layer with water, concentrated under last vacuum condition, obtain yellow oil (5S)-5-aminocarboxyl-4,5-dihydro-1H-pyrroles-1-carboxylic acid-1 (1,1-dimethyl ethyl) ester.
The present invention adopts single stage method, with methane amide, sodium isopropylate is reaction reagent, reacts under room temperature, through extraction, be separated, extraction obtains object product (5S)-5-aminocarboxyl-4,5-dihydro-1H-pyrroles-1-carboxylic acid-1 (1,1-dimethyl ethyl) ester again, improve productive rate, be beneficial to suitability for industrialized production.Specifically:
1) the original rate 47.7% in single step reaction method in patent US2006035954 is brought up to more than 90% by choosing suitable reaction reagent, solvent etc. by the present invention.
2) simplify operation sequence one-step synthesis and replace existing two-step reaction.Without the need to carrying out saponification, the process of acidifying, it also avoid raw material, tetrahydrofuran (THF), and the drying treatment of ammonia is reacted under room temperature condition, without the need to the cold condition of-25 DEG C
3) reduce the three wastes, reduce cost.Avoid using poisonous, easily poison processed, unstable and be difficult to the reaction reagent methylsulfonyl chloride bought, and the more expensive DIPEA of price and there is the ammonia of irritating smell; Solvent usage quantity greatly reduces.
4) solvent used in reaction industrially by heavily steaming, can be recycled.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but does not therefore limit the present invention among described scope of embodiments.
Experiment material involved in following content and reagent are then commercially available product if not otherwise specified.Present method makes solvent with anhydrous diethyl ether or p-Xylol, methane amide, and sodium isopropylate is that the synthesis of reagent single step reaction obtains object product (5S)-5-aminocarboxyl-4,5-dihydro-1H-pyrroles-1-carboxylic acid-1 (1,1-dimethyl ethyl) ester
Reaction raw materials: 4,5-dihydro-1H-pyrroles-1,5-dicarboxylic acid [1-(1,1-dimethyl ethyl), 5-ethyl] ester (30g)
Methane amide: 56g (10 times of equivalents)
Sodium isopropylate: 33.7g (3.3 times)
Anhydrous diethyl ether: 600mL
Get 1000mL four-hole boiling flask, add raw material 4,5-dihydro-1H-pyrroles-1,5-dicarboxylic acid [1-(1,1-dimethyl ethyl), 5-ethyl] ester (30g), then add anhydrous diethyl ether (600mL) and methane amide (56g), stir 10min.In ice-water bath, add sodium isopropylate (33.7g) in batches, prevent reaction from heating up too fast.Remove ice-water bath, react two hours under room temperature condition, normal hexane: ethyl acetate (4:1) is developping agent monitoring, and raw material reaction is complete.
Reaction solution is poured in the frozen water of cooling in advance (1500mL), stir fully, be separated organic layer, then with 300mL × 2 anhydrous diethyl ether aqueous layer extracted, merge organic layer.Again with 400mL water washing organic layer.Under vacuum condition, concentrated, obtain yellow oil (5S)-5-aminocarboxyl-4,5-dihydro-1H-pyrroles-1-carboxylic acid-1 (1,1-dimethyl ethyl) ester, [M+Na
+] 235,26.4g, 93%.
Embodiment 2
Reaction raw materials: 4,5-dihydro-1H-pyrroles-1,5-dicarboxylic acid [1-(1,1-dimethyl ethyl), 5-ethyl] ester (30g)
Methane amide: 56g (10 times of equivalents)
Sodium isopropylate: 33.7g (3.3 times)
P-Xylol: 600mL
Get 1000mL four-hole boiling flask, add raw material 4,5-dihydro-1H-pyrroles-1,5-dicarboxylic acid [1-(1,1-dimethyl ethyl), 5-ethyl] ester (30g), then add p-Xylol (600mL) and methane amide (56g), stir 10min.In ice-water bath, add sodium isopropylate (33.7g) in batches, prevent reaction from heating up too fast.Remove ice-water bath, react two hours under room temperature condition, normal hexane: ethyl acetate (4:1) is developping agent monitoring, and raw material reaction is complete.
Reaction solution is poured in the frozen water of cooling in advance (1500mL), stir fully, be separated organic layer, then with 300mL × 2 p-Xylol aqueous layer extracted, merge organic layer.Again with 400mL water washing organic layer.Under vacuum condition, concentrated, obtain yellow oil (5S)-5-aminocarboxyl-4,5-dihydro-1H-pyrroles-1-carboxylic acid-1 (1,1-dimethyl ethyl) ester, [M+Na
+] 235,23.75g, 90%.
The present invention adopts the method for similar US2006035954, but chooses different solvents and reaction reagent, and Optimizing operation step and different post-treating methods, be increased to more than 90% by productive rate.
Claims (5)
1. (5S)-5-aminocarboxyl-4,5-dihydro-1H-pyrroles-1-carboxylic acid-1 (1,1-dimethyl ethyl) preparation method of ester, the method is with 4,5-dihydro-1H-pyrroles-1,5-dicarboxylic acid [1-(1,1-dimethyl ethyl), 5-ethyl] ester is raw material, sodium isopropylate is alkaline reagents, obtains object product in a solvent with formamide
2. (5S)-5-aminocarboxyl-4 as claimed in claim 1,5-dihydro-1H-pyrroles-1-carboxylic acid-1 (1,1-dimethyl ethyl) preparation method of ester, it is characterized in that, reaction solvent is anhydrous diethyl ether, ethyl propionate, methyl-formiate, ethyl formate or p-Xylol.
3. the preparation method of (5S)-5-aminocarboxyl-4,5-dihydro-1H-pyrroles-1-carboxylic acid-1 (1,1-dimethyl ethyl) ester as claimed in claim 2, it is characterized in that, reaction solvent is anhydrous diethyl ether or p-Xylol.
4. (5S)-5-aminocarboxyl-4 as claimed in claim 2,5-dihydro-1H-pyrroles-1-carboxylic acid-1 (1,1-dimethyl ethyl) preparation method of ester, it is characterized in that, the operation steps of the method is: in reaction vessel, first drop into raw material 4,5-dihydro-1H-pyrroles-1,5-dicarboxylic acid [1-(1,1-dimethyl ethyl), 5-ethyl] ester, then add reaction solvent and and methane amide, stir, keep temperature-5-5 DEG C in reaction vessel, add sodium isopropylate in batches.
5. (5S)-5-aminocarboxyl-4 as claimed in claim 2,5-dihydro-1H-pyrroles-1-carboxylic acid-1 (1,1-dimethyl ethyl) preparation method of ester, it is characterized in that, post-processing step is: poured into by reaction solution in frozen water and stir fully, be separated organic layer, again with reaction solvent aqueous layer extracted, merge organic layer, wash organic layer with water, concentrated under last vacuum condition, obtain yellow oil (5S)-5-aminocarboxyl-4,5-dihydro-1H-pyrroles-1-carboxylic acid-1 (1,1-dimethyl ethyl) ester.
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Citations (6)
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|---|---|---|---|---|
| WO2005106011A2 (en) * | 2004-04-14 | 2005-11-10 | Bristol-Myers Squibb Company | Process for preparing dipeptidyl iv inhibitors and intermediates therefor |
| WO2005108594A1 (en) * | 2004-05-04 | 2005-11-17 | Bristol-Myers Squibb Company | Enzymatic ammonolysis process for the preparation of intermediates for dpp iv inhibitors |
| WO2006020664A2 (en) * | 2004-08-11 | 2006-02-23 | Bristol-Myers Squibb Company | Ammonolysis process for the preparation of intermediates for dpp iv inhibitors |
| CN1791401A (en) * | 2002-12-09 | 2006-06-21 | 布里斯托尔-迈尔斯斯奎布公司 | Methods and compounds for producing dipeptidyl peptidase IV inhibitors and intermediates thereof |
| WO2013111158A2 (en) * | 2012-01-03 | 2013-08-01 | Msn Laboratories Limited | Process for the preparation of dpp-iv inhibitor |
| WO2013175395A2 (en) * | 2012-05-21 | 2013-11-28 | Dr. Reddys Laboratories Limited | Improved process for preparation of saxagliptin and its salts |
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2014
- 2014-05-29 CN CN201410234339.8A patent/CN105315189A/en active Pending
Patent Citations (6)
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| CN1791401A (en) * | 2002-12-09 | 2006-06-21 | 布里斯托尔-迈尔斯斯奎布公司 | Methods and compounds for producing dipeptidyl peptidase IV inhibitors and intermediates thereof |
| WO2005106011A2 (en) * | 2004-04-14 | 2005-11-10 | Bristol-Myers Squibb Company | Process for preparing dipeptidyl iv inhibitors and intermediates therefor |
| WO2005108594A1 (en) * | 2004-05-04 | 2005-11-17 | Bristol-Myers Squibb Company | Enzymatic ammonolysis process for the preparation of intermediates for dpp iv inhibitors |
| WO2006020664A2 (en) * | 2004-08-11 | 2006-02-23 | Bristol-Myers Squibb Company | Ammonolysis process for the preparation of intermediates for dpp iv inhibitors |
| WO2013111158A2 (en) * | 2012-01-03 | 2013-08-01 | Msn Laboratories Limited | Process for the preparation of dpp-iv inhibitor |
| WO2013175395A2 (en) * | 2012-05-21 | 2013-11-28 | Dr. Reddys Laboratories Limited | Improved process for preparation of saxagliptin and its salts |
Non-Patent Citations (3)
| Title |
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| IQBAL GILL等: "Biocatalytic ammonolysis of (5S)-4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)-5-ethyl ester:Preparation of an intermediate to the dipeptidyl peptidase IV inhibitor Saxagliptin", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| JIZHE DONG等: "Synthesis and biological evaluation of all eight stereoisomers of DPP-IV inhibitor saxagliptin", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
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