CN113045480A - Preparation method of epimer of saxagliptin heterocyclic intermediate - Google Patents
Preparation method of epimer of saxagliptin heterocyclic intermediate Download PDFInfo
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- CN113045480A CN113045480A CN201911377225.8A CN201911377225A CN113045480A CN 113045480 A CN113045480 A CN 113045480A CN 201911377225 A CN201911377225 A CN 201911377225A CN 113045480 A CN113045480 A CN 113045480A
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- azabicyclo
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- 229960004937 saxagliptin Drugs 0.000 title claims abstract description 15
- 108010033693 saxagliptin Proteins 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims description 13
- 238000000034 method Methods 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- MCEWPPMUTVLMJG-VAYJURFESA-N (1S,3R,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide Chemical compound [C@H]12N[C@H](C[C@@H]2C1)C(=O)N MCEWPPMUTVLMJG-VAYJURFESA-N 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 14
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical group CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 11
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 3
- 238000010511 deprotection reaction Methods 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 238000004537 pulping Methods 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 claims 1
- MCEWPPMUTVLMJG-YUPRTTJUSA-N (1s,3s,5s)-2-azabicyclo[3.1.0]hexane-3-carboxamide Chemical compound N1[C@H](C(=O)N)C[C@@H]2C[C@@H]21 MCEWPPMUTVLMJG-YUPRTTJUSA-N 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 125000006239 protecting group Chemical group 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 238000006243 chemical reaction Methods 0.000 description 29
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- -1 (1S,3R,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide methane Chemical compound 0.000 description 9
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 6
- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 3
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 3
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- JFUDIEFZSNQJBS-SHLRHQAISA-N (1s,3s,5s)-2-azabicyclo[3.1.0]hexane-3-carboxamide;hydrochloride Chemical compound Cl.N1[C@H](C(=O)N)C[C@@H]2C[C@@H]21 JFUDIEFZSNQJBS-SHLRHQAISA-N 0.000 description 2
- WPIYZQBALIBMAA-SHLRHQAISA-N (1s,3s,5s)-2-azabicyclo[3.1.0]hexane-3-carboxamide;methanesulfonic acid Chemical compound CS(O)(=O)=O.N1[C@H](C(=O)N)C[C@@H]2C[C@@H]21 WPIYZQBALIBMAA-SHLRHQAISA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- QGJUIPDUBHWZPV-UYSAFFCTSA-N (1s,3r,5s)-2-[(2s)-2-amino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-UYSAFFCTSA-N 0.000 description 1
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- QYJOOVQLTTVTJY-RXMQYKEDSA-N ethyl (2r)-5-oxopyrrolidine-2-carboxylate Chemical compound CCOC(=O)[C@H]1CCC(=O)N1 QYJOOVQLTTVTJY-RXMQYKEDSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a method for preparing an epimer (1S,3R,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide of a saxagliptin heterocyclic intermediate and a salt thereof. The method comprises the steps of racemizing (1S,3S,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide or salt thereof under alkaline conditions, protecting with Boc, purifying, and removing protecting groups to form salts to obtain a target product. Compared with the prior art, the method for preparing the epimer (1S,3R,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide of the saxagliptin heterocyclic intermediate and the salt thereof, disclosed by the invention, has the advantages of simplicity in operation, high yield and suitability for industrial production.
Description
The technical field is as follows:
the invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of an epimer (1S,3R,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide of a saxagliptin heterocyclic intermediate and a salt thereof.
Background art:
saxagliptin is a highly efficient dipeptidyl peptidase-4 (DPP-4) selective and competitive inhibitor developed by Bristol-Myers Squibb company and Astra Zeneca company in combination, and is mainly used for treating type II diabetes. The main action mechanism of the medicine is that glucagon-like peptide-1 (GLP-1) hydrolysis is reduced and insulin release is increased to reduce blood sugar by reversible, competitive and selective inhibition of dipeptidyl peptidase-4. The medicine has obvious effect of reducing blood sugar, small toxic and side effects and high safety. The chemical name of saxagliptin is (1S,3S,5S) -2- [ (2S) -2-amino-2- (3-hydroxytricyclo [3.3.1.13,7]Decan-1-yl) acetyl]-2-azabicyclo [3.1.0]Hexane-3-nitrile, the structure is shown as compound VI.
(1S,3S,5S) -2-azabicyclo [3.1.0]Hexane-3-carboxamide (compound II) is an important intermediate required for the synthesis of saxagliptin, containing three chiral centers. (1S,3R,5S) -2-azabicyclo [3.1.0]Hexane-3-carboxamide (Compound I) is an epimer of Compound II, a substance which must be used for analyzing and detecting the purity of Compound II, and a substance involved in the synthesis of Saxagliptin (1S,3R,5S) -2- [ (2S) -2-amino-2- (3-hydroxytricyclo [3.3.1.13,7]Decan-1-yl) acetyl]-2-azabicyclo [3.1.0]Hexane-3-carbonitrile (Compound VII) as an important starting material. However, the literature reports that the preparation method of the compound I is very few, and therefore, the preparation method thereof needs to be studied.
The Bioorganic & Medicinal Chemistry,22(2014): 1383-1393 discloses a process for the preparation of the mesylate salt of the epimeric compound I of the heterocyclic intermediate of saxagliptin, the route being shown in Scheme 1.
The method uses D-pyroglutamic acid ethyl ester as a raw material, obtains a target product through six steps of reaction, has complex operation process, needs to be carried out at low temperature in multiple steps of reaction, and has low total route yield of about 5 percent.
The invention content is as follows:
the invention aims to provide a method for preparing an epimer (1S,3R,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide of a saxagliptin heterocyclic intermediate and a salt thereof, which has simple operation and high yield aiming at the defects of the prior art.
The invention provides a preparation method of an epimer (1S,3R,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide methane of a saxagliptin heterocyclic intermediate and a salt thereof, which is characterized by comprising the following steps of:
racemizing a compound II or a salt thereof under the alkaline condition to obtain a mixture of a compound I and a compound III;
step (b), the mixture obtained in the step (a) is protected by Boc to obtain a mixture of a compound IV and a compound V;
step (c), purifying the mixture obtained in step (b) to obtain a compound IV;
and (d) deprotecting the compound IV obtained in the step (c) to form a salt to obtain an epimeric compound I of the saxagliptin heterocyclic intermediate and a salt thereof.
Further, in step (a), compound II or a salt thereof is selected as a starting material, wherein the salt of compound II is selected from hydrochloride and methanesulfonate, preferably methanesulfonate.
Further, the basic condition is selected from potassium tert-butoxide, sodium hydroxide, potassium hydroxide, preferably potassium tert-butoxide.
Furthermore, the compound II is racemized at 20-30 ℃, preferably 25 ℃.
Furthermore, the compound II undergoes a derotation reaction at 20-30 ℃ for 10-28 h, preferably 24 h.
Further, the protecting group reagent in step (b) is Boc anhydride.
Further, the purification method in step (c) is solvent pulping, column chromatography or crystallization, and preferably solvent pulping purification.
Furthermore, the solvent is selected from any one of n-heptane, petroleum ether, ethyl acetate, tetrahydrofuran, acetone, acetonitrile and dichloromethane or a mixed solvent thereof, and the mixed solvent of n-heptane and ethyl acetate is preferred.
Furthermore, the volume ratio of the n-heptane to the ethyl acetate is 1: 3-3: 1, preferably 1: 3.
Further, hydrochloric acid, methanesulfonic acid, sulfuric acid and trifluoroacetic acid are selected as deprotection reagents in the deprotection process in the step (d).
The invention has the following beneficial effects: the invention adopts alkaline condition racemization to prepare the epimer (1S,3R,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide of saxagliptin heterocyclic intermediate and the salt thereof, the total yield of the route is more than 50 percent, and the ee value of the final product can reach more than 99 percent. Compared with the prior art, the method has the advantages of greatly improving the yield and the purity and being suitable for industrial production.
Drawings
FIG. 1 chiral HPLC of example 1 product
FIG. 2 chiral HPLC of example 2 product
Detailed Description
The technical content of the present invention is further described below with reference to specific examples for better understanding of the content of the present invention, but the scope of the present invention is not limited thereto.
EXAMPLE 1 preparation of (1S,3R,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide
Under the protection of nitrogen, 7mL of tert-butyl alcohol, 7mL of tetrahydrofuran, 1.0g of (1S,3S,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide and 0.1g of potassium tert-butoxide are sequentially added into a 25mL three-mouth reaction bottle and stirred, the temperature is controlled at 20 ℃ to react for 24 hours, so as to obtain a mixed reaction solution of a compound I and a compound III, and the reaction solution is directly fed into the next step.
1.28g of Boc anhydride was added to the reaction solution obtained in the previous step, the reaction was stirred at 25 ℃ for 2h and HPLC followed until the reaction was complete. The reaction mixture was concentrated to dryness, extracted with dichloromethane, and the organic phase was concentrated to dryness after separation, and 20mL of a mixed solvent (n-heptane: ethyl acetate: 1:3) was added to the residue, stirred for 15min, filtered, and dried to obtain 1.43g of a white solid with an ee value of 98.0%.
The solid obtained above was added to 5mL of isopropanol at room temperature, adjusted to pH 8 with sodium hydroxide solution, extracted with dichloromethane, concentrated and dried under vacuum to give 0.73g of (1S,3R,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide with a purity of 99.5% and an ee value of 100%.
EXAMPLE 2 preparation of (1S,3R,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide methanesulfonate
Under the protection of nitrogen, 2L of tert-butyl alcohol, 2L of tetrahydrofuran, 1.0kg of (1S,3S,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide methane sulfonate and 100g of potassium hydroxide are sequentially added into a 10L three-mouth reaction bottle and stirred, the temperature is controlled at 25 ℃ to react for 24 hours, mixed reaction liquid of a compound I and a compound III is obtained, and the reaction liquid is directly fed into the next step.
1.28kg of Boc anhydride was added to the reaction solution obtained in the previous step, the reaction was stirred at 25 ℃ for 2h and HPLC followed until the reaction was complete. The reaction mixture was concentrated to dryness, extracted with dichloromethane, the organic phase was concentrated to dryness after separation, and 10L of a mixed solvent (n-heptane: ethyl acetate: 1:2) was added to the residue, stirred for 15min, filtered, and dried to obtain 0.72Kg of a white solid with an ee value of 98.0%.
Adding the solid obtained at room temperature into 2.5L of isopropanol, and then adding 0.42Kg of methanesulfonic acid; heating to 60 ℃ for reaction for 3h, adding 3L of ethyl acetate, stirring for 10min, filtering, and washing a filter cake by using 1L of ethyl acetate. Vacuum oven-dried to give 0.68kg of (1S,3R,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide methanesulfonate, purity: 99.5%, and an ee value of 99.7%.
EXAMPLE 3 preparation of (1S,3R,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide hydrochloride
Under the protection of nitrogen, 7mL of tert-butyl alcohol, 7mL of tetrahydrofuran, 1.0g of (1S,3S,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide hydrochloride and 0.1g of sodium tert-butoxide are sequentially added into a 25mL three-mouth reaction bottle and stirred, the temperature is controlled at 20 ℃ to react for 24 hours, and mixed reaction liquid of a compound I and a compound III is obtained and is directly put into the next step.
1.28g of Boc anhydride was added to the reaction solution obtained in the previous step, the reaction was stirred at 25 ℃ for 2h and HPLC followed until the reaction was complete. The reaction mixture was concentrated to dryness, extracted with dichloromethane, the organic phase was concentrated to dryness after separation, purified by column chromatography (n-heptane: ethyl acetate 1:1), concentrated and dried to give 1.02g of a white solid with an ee value of 97.0%.
The solid obtained above was added to 5mL of isopropanol at room temperature, followed by addition of 0.42g of hydrochloric acid; heating to 70 ℃ for reaction for 3h, adding 10mL of ethyl acetate, stirring for 10min, filtering, and washing a filter cake by using 2mL of ethyl acetate. Drying in vacuo afforded 0.62g of (1S,3R,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide hydrochloride having a purity of 99.5% and an ee of 99.6%.
EXAMPLE 4 preparation of (1S,3R,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide sulfate
Under the protection of nitrogen, 7mL of tert-butyl alcohol, 7mL of tetrahydrofuran, 1.0g of (1S,3S,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide hydrochloride and 0.1g of sodium hydroxide are sequentially added into a 25mL three-mouth reaction bottle and stirred, the temperature is controlled at 25 ℃ to react for 24 hours, and mixed reaction liquid of a compound I and a compound III is obtained and is directly put into the next step.
1.28g of Boc anhydride was added to the reaction solution obtained in the previous step, the reaction was stirred at 25 ℃ for 2h and HPLC followed until the reaction was complete. The reaction mixture was concentrated to dryness, extracted with dichloromethane, and the organic phase after separation was concentrated to dryness, dissolved with ethyl acetate, and recrystallized by adding 20mL of n-heptane to obtain 0.81g of a solid with an ee value of 98.0%.
The solid obtained above was added to 5mL of isopropanol at room temperature, followed by the addition of 0.64g of sulfuric acid; heating to 65 ℃ for reaction for 3h, adding 10mL of ethyl acetate, stirring for 10min, filtering, and washing a filter cake by using 2mL of ethyl acetate. Vacuum drying gave 0.73g of (1S,3R,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide sulfate having a purity of 99.5% and an ee of 99.1%.
EXAMPLE 5 preparation of (1S,3R,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide trifluoroacetate
Under the protection of nitrogen, 7mL of tert-butyl alcohol, 7mL of tetrahydrofuran, 1.0g of (1S,3S,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide methane sulfonate and 0.1g of potassium tert-butoxide are sequentially added into a 25mL three-mouth reaction bottle to be stirred, the temperature is controlled at 20 ℃ to react for 24 hours, and mixed reaction liquid of a compound I and a compound III is obtained and is directly put into the next step.
1.28g of Boc anhydride was added to the reaction solution obtained in the previous step, the reaction was stirred at 25 ℃ for 2h and HPLC followed until the reaction was complete. The reaction mixture was concentrated to dryness, extracted with dichloromethane, and the organic phase was concentrated to dryness after separation, and 20mL of a mixed solvent (n-heptane: ethyl acetate: 1:3) was added to the residue, stirred for 15min, filtered, and dried to obtain 0.87g of a solid with an ee value of 98.0%.
The solid obtained above was added to 5mL of isopropanol at room temperature, followed by addition of 0.82g of trifluoroacetic acid; heating to 70 ℃ for reaction for 3h, adding 10mL of ethyl acetate, stirring for 10min, filtering, and washing a filter cake by using 2mL of ethyl acetate. Drying in vacuo afforded 0.82g of (1S,3R,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide trifluoroacetate salt having a purity of 99.5% and an ee value of 99.3%.
Claims (7)
1. A process for the preparation of the epimer (1S,3R,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide of the saxagliptin heterocyclic intermediate and its salts, characterized in that compound II or its salt is racemic under basic conditions, then Boc protected, purified and deprotected to form a salt to give (1S,3R,5S) -2-azabicyclo [3.1.0] hexane-3-carboxamide and its salts.
2. The process according to claim 1, wherein the salt of compound ii is selected from the group consisting of hydrochloride and methanesulfonate.
3. The process according to claim 1, wherein the salt of compound I is obtained as the hydrochloride, mesylate, sulfate, trifluoroacetate salt.
4. The method of claim 1, wherein the basic conditions are selected from the group consisting of potassium tert-butoxide, sodium hydroxide, and potassium hydroxide.
5. The method of claim 1, wherein the protecting group-applying reagent is Boc anhydride.
6. The method according to claim 1, wherein the purification method is solvent pulping, column chromatography or crystallization.
7. The method according to claim 1, wherein hydrochloric acid, methanesulfonic acid, sulfuric acid, and trifluoroacetic acid are used as deprotecting reagents in the deprotection process.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102686565A (en) * | 2009-11-11 | 2012-09-19 | 百时美施贵宝公司 | Hepatitis c virus inhibitors |
| CN102741242A (en) * | 2009-12-16 | 2012-10-17 | 百时美施贵宝公司 | Hepatitis c virus inhibitors |
| US20180030056A1 (en) * | 2015-02-19 | 2018-02-01 | Bristol-Myers Squibb Company | Benzofurans substituted with bicyclic secondary benzamide as hcv inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102686565A (en) * | 2009-11-11 | 2012-09-19 | 百时美施贵宝公司 | Hepatitis c virus inhibitors |
| CN102741242A (en) * | 2009-12-16 | 2012-10-17 | 百时美施贵宝公司 | Hepatitis c virus inhibitors |
| US20180030056A1 (en) * | 2015-02-19 | 2018-02-01 | Bristol-Myers Squibb Company | Benzofurans substituted with bicyclic secondary benzamide as hcv inhibitors |
Non-Patent Citations (1)
| Title |
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| DONG JIZHE, ET AL.: "Synthesis and biological evaluation of all eight stereoisomers of DPP-IV inhibitor saxagliptin", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 22, no. 4, pages 1383 - 1393, XP028606339, DOI: 10.1016/j.bmc.2013.12.061 * |
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