GB2595768A - A synthesis method of saxagliptin intermediate - Google Patents
A synthesis method of saxagliptin intermediate Download PDFInfo
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- 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
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- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
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- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
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- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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- C07—ORGANIC CHEMISTRY
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- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
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Abstract
A synthetic methods of saxagliptin intermediate (S)-N-tert-Butoxycarbonyl-3-hydroxy-1-adamantaneglycine ((S)-N-Boc-3′-hydroxyadamantylglycine) comprising: (1) reacting adamantane 1 with bromine, aluminium bromide, and boron tribromide to give 1,3-dibromoadamanate 2; (2) dissolving 2 with diethyl acetamidomalonate in petroleum ether, adding into an acidic solution with L-arginine, refluxing for 8 hours, resulting in decarboxmethoxylation, to give bromo-1-adamantyl-D-glycine 3; (3) reacting 3 under alkaline conditions at reflux for 8 hours to give 3-hydroxy-1-adamantyl-D-glycine 4 via hydrolysis; (4) reacting 4 under alkaline conditions with tert0butoxycarbonyl anhydride (Boc anhydride) for 12 hours at room temperature to give saxagliptin intermediate 5 Boc-3-hydroxy-1-adamantyl-D-glycine. In step (1), the mass/volume ratio of adamantane and bromine may be 1 g:8 mL, the dosage of aluminium bromide is 2.2 times the molar weight of the adamantane, and the dosage of the boron tribromide is 0.3 times the molar weight of adamantane. In step (1) the bromide may be added at 0 °C and stirred for 30 minutes, then reacted at 70 °C for 48 hours. Step (2) may have a dosage of diethyl aceamidomalonate, and sodium at 1.1 times the molar weight of 2, with the reacting temperature is from 5-35 °C, and the reaction time is 8-12 hours.
Description
A SYNTHESIS METHOD OF SAXAGLIPTIN INTERMEDIATE
TECHNICAL FIELD
[0001] The present invention relates to the field of chemical pharmaceutical, in particular to a synthesis method of saxagliptin intermediate
BACKGROUND OF THE INVENTION
[0002] Diabetes has became one of the principle disease affecting human being's health; according to data newly released by the International Diabetes Mellitus, till end of the 2040, the number of adults with diabetes worldwide is expected to exceed 600million; the diabetes mainly divided into Type 1 diabetes, Type 2 diabetes, gestational diabetes and special type diabetes, wherein the number of Type 2 diabetes patients are the most common; and a relative imbalance between insulin and glucagon is the main cause of disease of the Type 2 diabetes.
[0003] Saxagliptin, bcing chcmicallt described as (1S,3S,5S)-2-{(2S)-2-Amino-2-[(1r,3R,5R,7S)-3-hydroxyadamantan-l-yl] acetyl}-2-azabicyclo[3.1.0]hexane-3-carbonitrile, is a kind of DPP-4 inhibitor; the saxagliptin is able to react on the DPP-4 with strong effectiveness and selectivity to inhibit its activity and increase a concentration of the GIP-1 and GIP, thereby a reacting time is prolonged, and the blood sugar is reduced, and the chemical structural formula of the saxagliptin is listed as follows: G1P-1 and [0004] Thereby, unnatural amino acid (S)-N-tert-Butoxycarbony1-3-hydroxy-1-adamantane glycine ((S)-F)is the key intermediate for synthesize the saxagliptin, and art present, the methods to synthesize the compounds(S)-F are mainly comprising: [0005] Method 1: W02004/052850A2, CN102070451A, Adv. Synth. Catal. 2007, 349: 1369-1378 reported all that (S)-3-Hydroxy-1-adamantane glycine is obtained by bio-enzyme catalyzing and aminating 2-(3-hydroxy-l-adamanty1)-2-oxoacetic acid, and then tertbutoxycarbonyl anhydride is applied to protect amidogen to obtain compound (S)-F; the route is the main way to synthesize the compound (S)-F with high bioenzyme catalytic efficiency and moderate reaction, however, the synthesis method is hard to realize as an uncontrolled technique and difficult obtain of the bioenzyme phanylatanine dehydrogenaae ( 0 NAOH MAO ammonium CO2 C0714 [0006] Method 2: J Nled Chem, 2005, 48(15): 5025-5037 discloses that methyl amantadane carboxyl ate was used as starting material, after being reduced by Li Al H4, amantadine formaldehyde was oxidized in DNISO/ oxaloyl chloride system, adamantanecarbaldehyde with R-2-phenylglycinol and potassium cyanide undergoes asymmetric strecker reaction to introduce chiral and cyanine, and hydrolyze the cyanine under acidic conditions to give the carboxylic acid compound, then by catalytic hydrogenation reduction, tert-butoxycarbonyl anhydride protects the amino group to give (S)-N-tert-butoxycarbony1-1-adamantylglycine, and then compound (S)-F is obtained by potassium permanganate oxidizes hydroxyl groups; the route is an asymmetric synthesis with rigor reaction condition, and toxic reagent like editpotassium cyanide is applied, which is not benefit to large scaled industrial production Kiluln04. 2% 00th 90 1.0\11, TIT. Vein rt. an rr--%/ 24a CO)2, Dal$0. C1120 g. 140 ---7 12 M HO, NOM, 80°C, le h. 78% t ili41)-r-)1 inienne to, rn-my-CNH J
COOH
[0007] Method 3: the patent CN104817476A60N discloses: Adamantane-l-carboxylic acid is oxidized to 3-hydroxyadamantane-1-carboxylic acid by the potassium permanganate with high temperature, and then directly react with sodium salt of diethyl Nialonate after reacting with thionyl chloride, and then after soda boiling and decarboxylation, 3-hydroxy-ladamantane methyl ketones(C) is obtained, and then after reacting with the potassium permanganate in low temperature, the methyl is oxidized into carboxyl, and then 2-(3-hydroxy-1-adamanty1)-2-oxoacetic acid(D) is obtained, and then compound D reacts with hydroxylammonium chloride to obtain 3-hydroxyadamantaneglyoxylic acid oxime(E), and then compound E is reduced by reducing agent and then protecting with the tertbutoxycarbonyl anhydride to obtain boc-3-Hydroxy-1-adamantyl glycine(F); the compound F is able to be resolved into (S)-N-tert-Butoxycarbony1-3-hydroxy-1-adamantane glycine ((S)-F) by resolving agent; the present method is complex in process and expensive in raw material, moreover, the strong oxidant like the potassium permanganate and active sodium metal is required to be used, thereby the operation is dangerous and not benefit to subsequent processing after reaction, and the environment is also easily to be polluted.
BRIEF SUMMARY OF THE INVENTION
[0008] The present invention provide a synthesis method of saxagliptin intermediate so as to overcome the existing technical problems.
[0009] The following technical plan is adopted by the invention to solve the above-mentioned technical problems: [0010] A synthesis method of saxagliptin intermediate, wherein the synthesis method comprises the following steps: [00U] (1) Under catalysis of aluminium bromide and boron tribromide, adamantane(Compound 1) and bromine are performing a substitution reaction, thereby 1,3-dibromoadamantane(Compound 2) is obtained [0012] (2) Under catalysis of sodium ethoxide, the compound 2 and diethyl acetamidomalonate are dissolved in petroleum ether for reacting, and then adding into acidic solutions with L-arginine for being refluxed for 8 hours, and then with decarbomethoxylation, compound 3(3-bromo-1-adamantyl-D-glycine) is yield [0013] (3) With an alkaline condition, the compound 3 is stirred and retluxed for 8 hours, and then compound 4(3-hydroxy-1-adamantyl-D-glycine) is formed by hydrolysis [0014] (4) With an alkaline condition, the compound 4 and tert-butoxycarbonyl anhydride are reacted for 12 hours in room temperature, and then compound 5 is obtained, that is the saxagliptin intermediate(Boc-3-hydroxy-l-adamantyl-D-glycine) Br H3COCHN (2) 1. Na EtO0C)-COOEt (1) Br2,AIBr3 BBrs 2. HOAc,H2SO4 L1,11K, H20 NH2
COOH SE-1 Br low
KOH (3)
OH
OH (4)
COOH NHBoc
[0015] In (1), a mass/volume ratio of the adamantane and the bromine is lg:8mL.
[0016] In (1), dosage of the aluminium bromide is 2.2 times of molar weight of the adamantane; [0017] In (1), dosage of the boron tribromide is 0.3 times of the molar weight of the adamantane; [0018] In (1), the bromine is added at Ot to be stirred for 30min; [0019] In (1), the reacting temperature is 70C and the reacting time is 48 hours; [0020] In (2), dosage of the diethyl acetamidomalonate is 1.1 times of molar weight of the compound 2, dosage of sodium is 1.1 times of molar weight of the compound 2, [0021] In (2), the reacting temperature is room temperature, wherein a scope of room temperature is 5-35C and the reacting time is 8-12 hours; [0022] In (2), the acidic solutions with the L-arginine is formed by dissolving the L-arginine into the acidic solutions, wherein a volume ratio of glacial acetic acid, concentrated sulfuric acid and water is 10:1:3; [0023] In (2), dosage of the L-arginine is 0.5-1.5 times of molar weight of the compound 2.
[0024] In (3), alkali is one or more of sodium hydroxide or potassium hydroxide, and dosage of the alkali is 1.1 times of molar weight of the compound 3.
[0025] In (4), the alkaline condition is adding one or more of the sodium hydroxide, the potassium hydroxide, the sodium carbonate, the potassium carbonate into the reaction, thereby pH is regulated to 10.
[0026] The benefits of the invention are as follows: the raw material applied in the present invention has a securable and cheap raw material, simple reaction, moderate reaction condition, high yield and excellent quality, and final product in dissolving is able to reach 99%ee value, which conforms a requirement of medicine intermediate; the present invention is stable in craft and short route, which is suitable for industrial production, obviously reduce a product cost of the saxagliptin with an important practical value.
DETAILED DESCRIPTION OF THE INVENTION
[0027] The foregoing aspects of the present invention are described in further detail by means of the following specific embodiments in the form of concrete examples_ which should not be understood by those skilled in the art as limiting the scope of the foregoing subject matter of the present invention to the following examples; all technology implemented on the basis of the foregoing aspects of the present invention is within the scope of the present invention.
[0028] Embodiment [00291 Preparation of 1,3-dibromoadamantane(compound 2): [0030] Adamantane(13.6g, 100mmol), aluminium bromide(58.6g, 220mmol) and boron tribromide(7.5g, 30mmol) are added into a reactor, and then 109mL bromine is added at 0°C to be stirred for 30min, and then the temperature raises to 70°C to be reacted for 48 hours, and then cool to room temperature after the reaction finishes, and then saturated sodium bisulfite is added to quench the reaction, and then washing with deionized water after filtering, and then 23.08 of yellow solid 1,3-dibromoadamantane is obtained with a yield of 78%.
[0031] If{-NMR MSO-d6h3.2.83(s,II-), 2.73(s,111), 2.48(s,41111 2.35-2.21(m,814).
[0032] Embodiment 2 [0033] Preparation of 3-bromo-1-adamantyl-D-glycine(compound 3): [0034] Sodium(1.7g, 74.8mmol) is added into 500mL petroleum ether, and then diethyl acetamidomalonate (16.2g,74.8mmol) is added with stirring under the room temperature, and after the sodium metal is completely dissolved, the compound 2(20.0g,68mmol) is added to react for 12 hours at the room temperature, after the reaction finishes, 200mL distilled water is added, and organic layer is isolated and the solvent is concentrated, and then Larginine(17.8g,102mmol) is dissolved into a mixed solution composed of 7.5mL concentrated sulfuric acid, 22 5mL of the distilled water and 75mL glacial acetic acid to form acidic solution, and then the acidic solution of the L-arginine is added into the concentrated solvent to stirred and refluxed for 6 hours, and then after the reaction finishes, cool to the room temperature and pouring into ice water to extract with dichlormethane, and then organic layers are combined and the solvent is evaporated, and 16.7g of white solid is obtained by r 120 reciystalization of residues with hexane, and the productivity is 85%, 1-11-113 =+25o(C= 1,CH3OH), 99 'A ee(HPLC).
[0035] 'H-NIVIR(400MHz,DIYISO-d6):612.56(s, 1H), 3.2(s, 1H),2.25(d, J=8.8Hz, 2H), 2,272.17(m, 21-1), L88-1.59(m,121-1).
[00361 Embodiment 3 [0037] Preparation of 3-bromo-l-adamantyl-D-glycine(compound 4): [0038] KOH(32.0g,57.2mmol) is dissolved into 200mL water, and then compound 3(15g,52.0mmol) is added to be stirred and refluxed for 8 hours, and after the reaction finishes, 9.6g of white solid is obtained by concentrating, extracting and recrystalizing, and the productivity is 82% and the ee value is 99%.
[0039] Embodiment 4 [007:10] Preparation of hoc-3-hydroxy-1-adaman. -D-glycine(compound 5) [0041] 3 -hydroxy-1 -adamantyl-D-glycine(2.3 g, lOmmol), potassium carb onate(0. 1g. 0.6mmol), di-tert-butyl dicarbonate(2.6g,12mmol) and 30mL tetrahydrofuran are added into the reactor to be uniformly stirred, and then react at the room temperature for 12 hours, and then the solvent is evaporated by reducing pressure, and then 50mL petroleum ether is added into residue, and then pH value is regulated to 1 with 55mo1/LHC1, thereby white solid is separated out, and then compound in formula (I) is obtained by suction filtration, drying and pressure reduction, and the productivity is 98% and ee value is 99%.
Claims (1)
- CLAIMS1. A synthesis method of saxagliptin intermediate, wherein the synthesis method comprises the following steps: (1) Under catalysis of aluminium bromide and boron tribromide, adamantane(compound 1) and bromine are performing a substitution reaction, thereby 1,3-dibromoadamantane(compound 2) is obtained; (2) Under catalysis of sodium ethoxide, the compound 2 and diethyl acetamidomalonate are dissolved in petroleum ether for reacting, and then adding into acidic solutions with Larginine for being refluxed for 8 hours, and then with decarbomethoxylation. compound 3(3-bromo-1-adamantyl-D-glycine) is yield; (3) With an alkaline condition, the compound 3 is stirred and refluxed for 8 hours, and then compound 4(3-hydroxy-l-adamantyl-D-glycine) is formed by hydrolysis; (4) With an alkaline condition, the compound 4 and tert-butoxycarbonyl anhydride are reacted for 12 hours in room temperature, and then compound 5 is obtained, that is the saxagliptin intermedi ate(B oc-3 -hydroxy-l-adam antyl -D-glyci ne) 2. The synthesis method of saxagliptin intermediate defined in claim 1, wherein a mass/volume ratio of the adamantane and the bromine in (1) is the adamantane: the bromine=1 g:8mL; dosage of the aluminium bromide is 2.2 times of molar weight of the adamantane; dosage of the boron tribromide is 0.3 times of the molar weight of the adamantane.3. The synthesis method of saxagliptin intermediate defined in claim 1, wherein in (1), the bromine is added at 0°C to be stirred for 30min, and reacting temperature is 70°C and the reacting time is 48 hours 4. The synthesis method of saxagliptin intermediate defined in claim 1, wherein in (2), dosage of the diethyl acetamidomalonate is 1.1 times of molar weight of the compound 2, dosage of sodium is 1.1 times of molar weight of the compound 2; the reacting temperature in (2) is room temperature, wherein a scope of room temperature is 5-35°C and the reacting time is 8-12 hours.5. The synthesis method of saxagliptin intermediate defined in claim 1, wherein the acidic solutions with the L-arginine in (2) is formed by dissolving the L-arginine into the acidic solutions, wherein a volume ratio of glacial acetic acid, concentrated sulfuric acid and water is 10:1:3; dosage of the L-arginine is 0.5-1.5 times of molar weight of the compound 2.6. The synthesis method of saxagliptin intermediate defined in claim I., wherein alkali in (3) is one or more of sodium hydroxide or potassium hydroxide, and dosage of the alkali is 1.1 times of molar weight of the compound 3.7. The synthesis method of saxagliptin intermediate defined in claim 1, wherein the alkaline condition in (4) is adding one or more of the sodium hydroxide, the potassium hydroxide, sodium carbonate, potassium carbonate into the reaction, thereby pH is regulated to 10.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010931972.8A CN111892478A (en) | 2020-09-08 | 2020-09-08 | Synthetic method of saxagliptin intermediate |
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| GB202105882D0 GB202105882D0 (en) | 2021-06-09 |
| GB2595768A true GB2595768A (en) | 2021-12-08 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014057495A1 (en) * | 2012-10-11 | 2014-04-17 | Lee Pharma Limited | A process for industrial preparation of [(s)-n-tert butoxycarbonyl-3-hydroxy]adamantylglycine |
| CN104098487A (en) * | 2014-07-31 | 2014-10-15 | 天津民祥生物医药科技有限公司 | Method for preparing N-tert-butyloxycarbonyl-3-hydroxy-1-adamantyl-d-glycine |
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2020
- 2020-09-08 CN CN202010931972.8A patent/CN111892478A/en not_active Withdrawn
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- 2021-04-26 GB GB2105882.1A patent/GB2595768A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014057495A1 (en) * | 2012-10-11 | 2014-04-17 | Lee Pharma Limited | A process for industrial preparation of [(s)-n-tert butoxycarbonyl-3-hydroxy]adamantylglycine |
| CN104098487A (en) * | 2014-07-31 | 2014-10-15 | 天津民祥生物医药科技有限公司 | Method for preparing N-tert-butyloxycarbonyl-3-hydroxy-1-adamantyl-d-glycine |
Non-Patent Citations (1)
| Title |
|---|
| Research on Chemical Intermediates, vol. 45, 2016, J. Li et al., A facile and economic method for the synthesis of (S)-N-Boc-3'-hydroxyadamantylglycine * |
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