CN105503698A - Method for synthesizing Saxagliptin and intermediate - Google Patents
Method for synthesizing Saxagliptin and intermediate Download PDFInfo
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- CN105503698A CN105503698A CN201410504832.7A CN201410504832A CN105503698A CN 105503698 A CN105503698 A CN 105503698A CN 201410504832 A CN201410504832 A CN 201410504832A CN 105503698 A CN105503698 A CN 105503698A
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- hydroxyadamantane
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- azabicyclo
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Abstract
A method for synthesizing Saxagliptin and its intermediate is disclosed. According to the method, propylphosphonic anhydride is used in a peptide coupling reaction and a dehydration reaction of formamide, thus reducing side reaction of racemization and decreasing toxicity of aftertreatment; and ethylene glycol diethyl ether is preferably used as a solvent in the dehydration reaction of formamide, thus increasing reaction temperature of propylphosphonic anhydride dehydration and shortening reaction time so as to reduce side reaction of racemization.
Description
Technical field
The present invention relates to a kind of method of synthesizing BMS-477118 and intermediate thereof.
Background technology
The pharmaceutically active substance that BMS-477118 Shi Shiguibao company and Astrazeneca AB develop jointly.BMS-477118 is dipeptidyl peptidase 4 (DPP4) competitive inhibitor, can reduce the deactivation rate of intestines insulinotropin, increases its haemoconcentration, thus reduces diabetes B patient blood sugar concentration on an empty stomach and after the meal in the mode of glucose dependency.After the meal, the intestines insulinotropin concentration be discharged into blood from small intestine raises, as glucagon-like-peptide-1 (GLP-1) and glucose-dependent-insulinotropic peptide (GIP), promote that pancreatic beta cell is with the mode uelralante of glucose dependency, and DPP4 can make its inactivation.GLP-1 also can suppress pancreatic alpha cells to secrete hyperglycemic-glycogenolytic factor, thus suppresses liver glucose to produce.The GLP-1 density loss of diabetes B patient, but the intestines of GLP-1 are urged pancreas islet effect and are still existed.
In March, 2010 U.S. FDA approval BMS-477118 is used for the treatment of the hyperglycemia of adults with type 2 diabetes; And in May, 2011, obtain SFDA official approval in China.This medicine can single therapy, also can control Or Metformin In Treating is combined on not good basis at N1,N1-Dimethylbiguanide.Clinical study has confirmed that BMS-477118 has the advantages such as curative effect is outstanding, persistent.
The structural formula of BMS-477118:
Have the bibliographical information synthesis of BMS-477118 and the method for purifying at present, as patent documentation W02011117393A, W02010032129A, US20060035954, US2005090539, and document J.Med.Chem., 2005,48:5025-5037 and Org.ProcessRes.Dev., 2009,13:1169_1176.The principal synthetic routes of prior art is as follows:
WO2004052850 reports a new synthetic schemes, 3-hydroxyadamantane-S-glycine under the effect of sodium hydroxide with Boc
2o is obtained by reacting 3-hydroxyadamantane-Boc-S-glycine; then 3-hydroxyadamantane-Boc-S-glycine and (1S; 3S; 5S)-2-azabicyclo [3.1.0] hexane-3-methane amide condensation; formyl radical in condensation product structure reacts with trifluoroacetic anhydride (TFAA) and is dehydrated into cyano group in ensuing reaction; product goes protection to obtain target compound again, and target compound adds water crystallization and obtains a hydration BMS-477118.Concrete synthesis as shown in the formula route one shown in:
Route one
And the difference of the method reported in WO2005094323 and route one is to adopt the method for acyl chlorides to carry out peptide linked reaction, sodium borohydride is utilized to remove the trifluoroacetyl group protecting group of nitrogen end.Concrete synthesis as shown in the formula route two shown in:
Route two
J.Med.Chem. (2005; 48; synthetic method 5025-5037) reported is that 3-hydroxyadamantane-Boc-S-glycine is first made active ester; again with (1S; 3S; 5S)-2-azabicyclo [3.1.0] hexane-3-formamide, then dewatered by trifluoroacetic anhydride, trifluoroacetic acid is removed protecting group and is obtained target product.Concrete synthesis as shown in the formula route three shown in:
Route three
Above-mentioned literature method is by making the method activation of acyl chlorides, mixed acid anhydride or active ester by 3-hydroxyadamantane-Boc-S-glycine, then carry out being obtained by reacting corresponding intermediate with corresponding amine, in scheme one, by relatively gentle for the method reaction conditions that mixed acid anhydride made by 3-hydroxyadamantane-Boc-S-glycine, but because methylsulfonyl chloride has certain pungency, also there is certain danger in use procedure, certain problem may be there is in amplification production process.And in scheme two; owing at room temperature the time of 3-hydroxyadamantane-S-glycine and trifluoroacetic acid anhydride reactant two hours need be added N; the two trifluoroacetyl group protecting group of O; 3-hydroxyadamantane-S-glycine will have the racemization (the racemization by product according to data in literature about 10%) of suitable vast scale, and the method is difficult to obtain highly purified target product.And in scheme three, utilize EDCI, the Acibenzolar of HOBt system Preparation of amino acid, according to pertinent literature, the transformation efficiency of this reaction is not high, and then affects the purity of product.
According to above-mentioned analysis, we wish to use a kind of efficient method of condensing newly, avoid the generation of racemization reaction, also avoid the product not easily removed introducing condensing agent or its generation not easily removed.
Summary of the invention
The invention provides a kind of method of synthesizing BMS-477118 and intermediate thereof, propylphosphonic anhydride is used in the dehydration reaction of peptide linked reaction and methane amide by the method, can reduce the generation of racemization side reaction, and reduces the toxicity of aftertreatment; And in methane amide dehydration reaction, preferably use ethylene glycol diethyl ether as solvent, the temperature of reaction of propylphosphonic anhydride dehydrating step can be improved, Reaction time shorten, thus the generation of racemization side reaction can be reduced.
The method of synthesis BMS-477118 of the present invention and intermediate thereof comprises the following steps:
A. under the effect of organic bases and propylphosphonic anhydride, 3-hydroxyadamantane-Boc-S-glycine and (1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-methane amide carries out peptide linked reaction and obtains 2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-methane amide }-S-G-NH2;
B. 2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S will obtained in steps A, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-methane amide }-S-G-NH2 dewaters under the effect of propylphosphonic anhydride, obtain 2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-formonitrile HCN }-S-G-NH2;
C. 2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S obtained in step B is removed; 3S; 5S)-2-azabicyclo [3.1.0] hexane-3-formonitrile HCN } Boc protecting group in-S-G-NH2 on nitrogen, obtain BMS-477118.
Preferably, the present invention can also comprise step D:
D. hydration BMS-477118 is made in the BMS-477118 hydration obtained in step C.
Method of the present invention compared with prior art, shortens the reaction times, decreases the generation of racemization side reaction, and reduces the toxicity of aftertreatment.
Accompanying drawing explanation
Fig. 1 is 2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-methane amide prepared by embodiment 1 } mass spectrum of-S-G-NH2.
Fig. 2 is 2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-formonitrile HCN prepared by embodiment 2 } mass spectrum of-S-G-NH2.
Fig. 3 is the mass spectrum of BMS-477118 prepared by embodiment 5.
Embodiment
Wide in range, preferred, preferred and most preferred definition in the present invention and scope can combine mutually.
Terminological interpretation
Herein, term " in right amount " represents that the consumption of the material modified is not crucial for reaction, as long as required object can be reached, without the need to being limited to a concrete scope, but also can once add or add several times, those skilled in the art can rule of thumb select in conjunction with practical situation, such as, control consumption by detection reaction terminal.
Herein, term " appropriate time " represents that the time of modifying is not crucial for reaction, as long as reach required object, without the need to being limited to a concrete scope, those skilled in the art can rule of thumb select in conjunction with practical situation, such as, carry out the period by detection reaction terminal.
Abbreviation used in the present invention and implication thereof are described as follows:
The implication of abridging in table 1. literary composition:
The invention provides a kind of method of synthesizing BMS-477118 and intermediate thereof, the method comprises the following steps:
A. under the effect of organic bases and propylphosphonic anhydride, 3-hydroxyadamantane-Boc-S-glycine and (1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-methane amide carries out peptide linked reaction and obtains 2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-methane amide }-S-G-NH2;
B. 2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S will obtained in steps A, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-methane amide }-S-G-NH2 dewaters under the effect of propylphosphonic anhydride, obtain 2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-formonitrile HCN }-S-G-NH2;
C. protection 2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S obtained in step B is removed, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-formonitrile HCN } Boc protecting group in-S-G-NH2 on nitrogen, obtain BMS-477118 (1S, 3S, 5S)-2-{ (2S)-2-amino-2-(3-hydroxyadamantane base) ethanoyl }-2-azabicyclo [3.1.0] hexane-3-formonitrile HCN);
Steps A
In a specific embodiment, in steps A of the present invention, in organic solvent, under the effect of appropriate organic bases and peptide coupling agent, 3-hydroxyadamantane-Boc-S-glycine and (1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-methane amide generation peptide linked reaction.
In a specific embodiment, in steps A of the present invention, the consumption of propylphosphonic anhydride is unrestricted, in right amount.Preferably with the molar amount of 3-hydroxyadamantane-Boc-S-glycine, the consumption participating in the propylphosphonic anhydride of peptide linked reaction is 0.5-20.0 equivalent, preferred 1.0-10.0 equivalent, more preferably 1.0-3.0 equivalent.
In a specific embodiment, in steps A of the present invention, organic bases can be any organic bases realizing this object known in the art, preferred triethylamine, Trimethylamine 99, diisopropyl ethyl amine, imidazoles, pyridine, piperazine, piperidines, tripropyl amine, the organic amines such as Tributylamine, more preferably triethylamine, diisopropyl ethyl amine, most preferably diisopropyl ethyl amine.Its consumption is unrestricted, and in right amount, preferably with the molar amount of 3-hydroxyadamantane-Boc-S-glycine, the consumption participating in the organic bases of peptide linked reaction is 0.5-20.0 equivalent, preferred 1.5-10.0 equivalent, more preferably 2.0-5.0 equivalent.
In a specific embodiment, in steps A of the present invention, organic solvent can be any reagent realizing this object known in the art, ethyl acetate, Isosorbide-5-Nitrae-dioxane, 1,2-ethylene dichloride, ethylene glycol diethyl ether, methylene dichloride, tetrahydrofuran (THF), ether etc., more preferably ethyl acetate, ethylene glycol diethyl ether, its consumption is unrestricted, in right amount.
In a specific embodiment, also comprise and collect and the step of purified product in steps A of the present invention, this step comprises washing, drying, filtration, concentrated, recrystallization.
In a specific embodiment, steps A of the present invention collection and in the step of purified product, the step of deionized water wash can repeatedly, and washing times is unrestricted, reach washing object.Preferred 1-5 time, more preferably 1-3 time, most preferably 2-3 time.The consumption of the deionized water of each use is unrestricted, in right amount.
In a specific embodiment, steps A of the present invention collection and in the step of purified product, siccative can be any siccative realizing this object known in the art, preferred Anhydrous potassium carbonate, anhydrous sodium carbonate, anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, molecular sieve etc., more preferably anhydrous sodium sulphate.The consumption of siccative is unrestricted, in right amount.
In a specific embodiment, steps A of the present invention collection and in the step of purified product, enrichment step can use any method realizing this object known in the art to carry out, preferred underpressure distillation or decompression rotary evaporation, air distillation or use air-flow dry up, the rotary evaporation that more preferably reduces pressure, air distillation.
In a specific embodiment, steps A of the present invention collection and in the step of purified product, re-crystallization step can use any reagent realizing this object known in the art to carry out, ethyl acetate/sherwood oil mixed system, ethyl acetate/normal hexane mixed system, ethyl acetate/Skellysolve A mixed system, ethyl acetate/normal heptane mixed system, ethyl acetate/octane mixed system, ethylacetate/ether/sherwood oil mixed system, ethylacetate/ether/normal hexane mixed system, ethylacetate/ether/Skellysolve A mixed system, ethylacetate/ether/normal heptane mixed system, ethylacetate/ether/octane mixed system, n-propyl acetate/ether/normal hexane mixed system, n-propyl acetate/normal hexane mixed system, n-propyl acetate/Skellysolve A mixed system, n-propyl acetate/normal heptane mixed system, n-propyl acetate/octane mixed system, n-propyl acetate/ether/sherwood oil mixed system, isopropyl acetate/ether/normal hexane mixed system, isopropyl acetate/n-hexane mixed system, isopropyl acetate/Skellysolve A mixed system, isopropyl acetate/normal heptane mixed system, isopropyl acetate/octane mixed system, isopropyl acetate/ether/sherwood oil mixed system, more preferably ethylacetate/ether/sherwood oil mixed system, n-propyl acetate/ether/normal hexane mixed system.
Step B
In a specific embodiment, in step B of the present invention, 2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S will obtained in steps A in organic solvent, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-methane amide }-S-G-NH2 dewaters under the effect of propylphosphonic anhydride and organic bases, obtain 2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-formonitrile HCN }-S-G-NH2;
In a specific embodiment, in step B of the present invention, the consumption of propylphosphonic anhydride is unrestricted, in right amount.Preferably with 2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-methane amide } molar amount of-S-G-NH2, the consumption participating in the propylphosphonic anhydride of peptide linked reaction is 0.5-20.0 equivalent, preferred 1.0-10.0 equivalent, more preferably 1.0-3.0 equivalent.
In a specific embodiment, in step B of the present invention, organic bases can be any organic bases realizing this object known in the art, preferred triethylamine, Trimethylamine 99, diisopropyl ethyl amine, imidazoles, pyridine, piperazine, piperidines, tripropyl amine, the organic amines such as Tributylamine, more preferably triethylamine, diisopropyl ethyl amine, most preferably diisopropyl ethyl amine.Its consumption is unrestricted, appropriate, preferably with 2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-methane amide } molar amount of-S-G-NH2, the consumption of organic bases is 0.5-20.0 equivalent, preferred 1.5-10.0 equivalent, more preferably 2.0-4.0 equivalent.
In a specific embodiment, in step B of the present invention, organic solvent is ethyl acetate, ethylene glycol diethyl ether, tetrahydrofuran (THF), methyl tertiary butyl ether, toluene, 1,2-ethylene dichloride, 1,4-dioxane, isopropyl acetate, propyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, be preferably ethyl acetate, tetrahydrofuran (THF), ethylene glycol diethyl ether, 1,4-dioxane, toluene, be more preferably ethyl acetate, ethylene glycol diethyl ether, toluene, 1,4-dioxane, most preferably is ethylene glycol diethyl ether.
In a specific embodiment, in step B of the present invention, temperature of reaction is 80-130 DEG C, preferred 100-130 DEG C, more preferably 110-130 DEG C, most preferably 120 DEG C.
In a specific embodiment, in step B of the present invention, the reaction times is generally 1-8 hour, preferred 2-6 hour, more preferably 3-5 hour.
In a specific embodiment, in step B of the present invention, reaction pressure is normal pressure, also can carry out under the pressure suitably improving or reduce.
In a specific embodiment, also comprise and collect and the step of purified product in step B of the present invention, this step comprises washing, drying, filtration, concentrated, recrystallization.
In a specific embodiment, step B of the present invention collection and in the step of purified product, with the washing of appropriate deionization and layering get the step of organic layer can repeatedly, washing times is unrestricted, reaches washing object.Preferred 1-5 time, more preferably 1-4 time, most preferably 2-3 time.The consumption of the deionized water of each use is unrestricted, in right amount.
In a specific embodiment, step B of the present invention collection and in the step of purified product, siccative can be any siccative realizing this object known in the art, preferred Anhydrous potassium carbonate, anhydrous sodium carbonate, anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, molecular sieve etc., more preferably anhydrous sodium sulphate.The consumption of siccative is unrestricted, in right amount.
In a specific embodiment, step B of the present invention collection and in the step of purified product, enrichment step can use any method realizing this object known in the art to carry out, preferred underpressure distillation or decompression rotary evaporation, air distillation or use air-flow dry up, the rotary evaporation that more preferably reduces pressure, air distillation.
Step C
In a specific embodiment; in step C of the present invention; 2-(3-hydroxyadamantane)-N-(the tert-butoxycarbonyl)-1-{1S obtained in step B is removed under the effect of lysate; 3S; 5S)-2-azabicyclo [3.1.0] hexane-3-formonitrile HCN } Boc protecting group in-S-G-NH2 on nitrogen, obtain BMS-477118.
In a specific embodiment, in step C of the present invention, the protecting group on nitrogen can be any reagent realizing this object known in the art, such as, but not limited to, Cbz, Fmoc, Alloc etc., and preferred Boc.
In a specific embodiment, in step C of the present invention, lysate is the mixing solutions of TFA/DCM, and the volume ratio of TFA/DCM is 1:1-1:10, and the volume ratio of preferred TFA/DCM is 1:3-1:8, and more preferably the volume ratio of TFA/DCM is 1:5-1:7.The consumption of lysate is every gram of 2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-formonitrile HCN }-S-G-NH2 use 5-40mL, preferred 10-30mL, more preferably 18-25mL.Reaction pressure is preferably normal pressure, also can carry out under the pressure suitably improving or reduce; Temperature of reaction is preferably room temperature (namely 20 ± 5 DEG C), also can carry out at the temperature suitably improving or reduce.
In a specific embodiment, the present invention also comprises step D: hydration BMS-477118 is made in the BMS-477118 hydration obtained in step C.
In a specific embodiment, step D of the present invention carries out under the existence of deionized water, the consumption of described deionized water is every gram of 2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-formonitrile HCN }-S-G-NH2 use 0.01-10mL, preferred 0.05-5mL, more preferably 0.08-1mL.Reaction pressure is preferably normal pressure, also can carry out under the pressure suitably improving or reduce; Temperature of reaction is preferably room temperature (namely 20 ± 5 DEG C), also can carry out at the temperature suitably improving or reduce.
In a specific embodiment, also comprise in step D of the present invention and collecting and the step of purified product.
Embodiment 1
2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-methane amide } synthesis of-S-G-NH2
By 3-hydroxyadamantane-Boc-S-glycine (purchased from Shanghai Twisun Bio-pharm Co., Ltd.) of 32.5g100mmol and the (1S of 13g103mmol, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-methane amide (purchased from Shanghai Twisun Bio-pharm Co., Ltd.) joins successively and is chilled in the 350mL ethyl acetate of 0 DEG C in advance, slowly be added dropwise in mixing solutions by the diisopropyl ethyl amine of 42.6g330mmol, the mixing solutions of gained stirs 30 minutes at 0 DEG C.The ethyl acetate solution of the propylphosphonic anhydride of 235mL50w/w%140mmol is slowly joined in above-mentioned mixing solutions, in adition process, keep temperature of reaction system to be no more than 5 DEG C.Reaction system is warming up to room temperature after stirring 30 minutes at 0 DEG C, continues stirring 4 hours.
In reaction system, add 200mL water, mixture continues stirring 20 minutes, stratification, be separated the oil reservoir continuation 100mL deionized water wash obtained, filter after 1 hour with 50g anhydrous sodium sulfate drying, filtrate rotary evaporation is concentrated into 100mL, slowly add 300mL ether, gained mixing solutions is slowly poured in 600mL normal hexane, and hold over night obtains white crystal (38.6g, yield 89.3%, HPLC purity 96.1%, ESI (m/z, %): 434 (M
++ H), 100%).
Embodiment 2
2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-formonitrile HCN } synthesis of-S-G-NH2
2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S that embodiment 1 method of 38.6g89.3mmol is prepared, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-methane amide }-S-G-NH2 joins in 160mL ethylene glycol diethyl ether, at room temperature slowly add the ethylene glycol diethyl ether solution of the 179mmol propylphosphonic anhydride of 50w/w%300mL wherein, then the diisopropyl ethyl amine of 34.9g270mmol is slowly added dropwise in mixing solutions.Mixture is heated to 100-110 DEG C of reaction 30 minutes, is then warming up to 120 DEG C, insulation reaction 3.5 hours.After being cooled to room temperature, add 400mL deionized water, continue stirring 5 minutes, add 500mL ethyl acetate to continue to stir, separatory after stratification, collected organic layer, add 100mL deionized water to organic layer, separately add 300mL ethyl acetate in above-mentioned mixing solutions, stir 30 minutes.After stratification, separatory collects ethyl acetate layer, gained ethyl acetate solution 200mL water, 200mL saturated nacl aqueous solution respectively wash once, then use 20g anhydrous sodium sulfate drying after 1 hour, carry out filtration under diminished pressure, collect filtrate, filtrate decompression rotary evaporation is concentrated into dry, resistates 80mL Virahol dissolves, in above-mentioned aqueous isopropanol, instill 200mL water, hold over night after dissolving completely, after filtration, obtain white crystal (33.1g, yield 80.1%, HPLC purity 96.7%, ESI (m/z, %): 416 (M
++ H), 100%).
Embodiment 3
2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-formonitrile HCN } synthesis of-S-G-NH2
2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S that embodiment 1 method of 19.4g44.7mmol is prepared, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-methane amide }-S-G-NH2 joins in 300mL ethyl acetate, at room temperature slowly add the ethyl acetate solution of 50w/w%100mL propylphosphonic anhydride wherein, then the diisopropyl ethyl amine of 14.5g135mmol is slowly added dropwise in mixing solutions.Mixture is heated to 78 DEG C of reactions 30 minutes, insulation reaction 12 hours.After being cooled to room temperature, add 200mL deionized water, continue stirring 30 minutes, filter, retain filter cake.Separatory after stratification, collects ethyl acetate layer, adds 200mL deionized water, stir 30 minutes to ethyl acetate layer.After stratification, separatory collects ethyl acetate layer, gained ethyl acetate solution 100mL water, 100mL saturated nacl aqueous solution respectively wash once, then use 20g anhydrous sodium sulfate drying after 1 hour, carry out filtration under diminished pressure, collect filtrate, filtrate decompression rotary evaporation is concentrated into dry, resistates 40mL Virahol dissolves, in above-mentioned aqueous isopropanol, 100mL water is instilled after dissolving completely, hold over night, white crystal (15.7g, yield 70.3%, HPLC purity 96.5%) is obtained after filtration.
Embodiment 4
2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-formonitrile HCN } synthesis of-S-G-NH2
2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S that embodiment 1 method of 38.6g89.3mmol is prepared, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-methane amide }-S-G-NH2 joins and is equipped with in the glass tube sealing of 160mL ethylene glycol diethyl ether, at room temperature slowly add the ethylene glycol diethyl ether solution of the 179mmol propylphosphonic anhydride of 50w/w%300mL wherein, then the triethylamine of 2.80g270mmol is slowly added dropwise in mixing solutions, mixing solutions stirring at room temperature 10 minutes, tighten tube sealing plug, enclosed system.Mixture is heated to 100-110 DEG C of reaction 30 minutes, is then warming up to 120 DEG C, insulation reaction 3.5 hours.After being cooled to room temperature, mixing solutions adds in 800mL deionized water, continues stirring 10 minutes, adds 500mL ethyl acetate.Separatory after stratification, collected organic layer, adds 100mL deionized water to organic layer, separately adds 300mL ethyl acetate in above-mentioned mixing solutions, stirs 30 minutes.After stratification, separatory collects ethyl acetate layer, gained ethyl acetate solution 200mL water, 200mL saturated nacl aqueous solution respectively wash once, then use 20g anhydrous sodium sulfate drying after 1 hour, carry out filtration under diminished pressure, collect filtrate, filtrate decompression rotary evaporation is concentrated into dry, resistates 80mL Virahol dissolves, in above-mentioned aqueous isopropanol, 200mL deionized water is instilled after dissolving completely, hold over night, white crystal (23.1g, yield 55.8%, HPLC purity 96.7%) is obtained after filtration.
Embodiment 5
The synthesis of BMS-477118 and hydration BMS-477118
2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S under room temperature condition, the embodiment 2 of 33.1g79.7mmol obtained, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-formonitrile HCN }-S-G-NH2 joins in 600mL methylene dichloride, stir 30 minutes, after solid fully dissolves, 100mL trifluoroacetic acid is slowly joined in above-mentioned dichloromethane solution, the solution obtained continues stirring at room temperature 1 hour, and reaction soln underpressure distillation is concentrated into 100mL.In residual solution, slowly add 500mL ethyl acetate, mixing solutions stirs 30 minutes, adds 3mL deionized water, continues stirring 1 hour, then adds 3mL deionized water, continues stirring 2 hours.Gained mixed system removes remaining methylene dichloride 45 DEG C of underpressure distillation, and volume-diminished continues stirring 12 hours to 500mL rear suspension liquid.Filtration under diminished pressure, the 50mL ethyl acetate washing of gained white solid, in triplicate, filter cake vacuum-drying 5 hours at 35 DEG C, obtains white solid (18.6g, HPLC purity 99.8%, ESI (m/z, %): 316 (M
++ H), 100%, total recovery 55.85%).
Claims (10)
1. synthesize a method for BMS-477118 and intermediate thereof, the method comprises the following steps:
A. under the effect of organic bases and propylphosphonic anhydride, 3-hydroxyadamantane-Boc-S-glycine and (1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-methane amide carries out peptide linked reaction and obtains 2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-methane amide }-S-G-NH2;
B. 2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S will obtained in steps A, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-methane amide }-S-G-NH2 dewaters under the effect of propylphosphonic anhydride, obtain 2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-formonitrile HCN }-S-G-NH2;
C. 2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{ (1S obtained in step B is removed; 3S; 5S)-2-azabicyclo [3.1.0] hexane-3-formonitrile HCN } Boc protecting group in-S-G-NH2 on nitrogen, obtain BMS-477118.
2. the process of claim 1 wherein in step, the consumption of described propylphosphonic anhydride is with the molar amount 0.5-20.0 equivalent of 3-hydroxyadamantane-Boc-S-glycine, preferred 1.0-10.0 equivalent, more preferably 1.0-3.0 equivalent.
3. the method for claim 1, wherein in step, described organic bases is triethylamine, Trimethylamine 99, diisopropyl ethyl amine, imidazoles, pyridine, piperazine, piperidines, tripropyl amine, Tributylamine, is preferably triethylamine, diisopropyl ethyl amine, is more preferably diisopropyl ethyl amine.
4. the method for claim 1, wherein steps A is carried out in organic solvent, and described organic solvent is ethyl acetate, Isosorbide-5-Nitrae-dioxane, 1,2-ethylene dichloride, ethylene glycol diethyl ether, methylene dichloride, tetrahydrofuran (THF), ether, be preferably ethyl acetate, ethylene glycol diethyl ether.
5. the method for claim 1, wherein in stepb, the consumption of described propylphosphonic anhydride is with 2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-methane amide } the molar amount 0.5-20.0 equivalent of-S-G-NH2, preferred 1.0-10.0 equivalent, more preferably 1.0-3.0 equivalent.
6. the method for claim 1, wherein step B carries out under the effect of organic bases, described organic bases is triethylamine, Trimethylamine 99, diisopropyl ethyl amine, imidazoles, pyridine, piperazine, piperidines, tripropyl amine, Tributylamine, be preferably triethylamine, diisopropyl ethyl amine, be more preferably diisopropyl ethyl amine.
7. the method for claim 1, wherein step B carries out in organic solvent, described organic solvent is ethyl acetate, ethylene glycol diethyl ether, tetrahydrofuran (THF), methyl tertiary butyl ether, toluene, 1,2-ethylene dichloride, 1,4-dioxane, isopropyl acetate, propyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, be preferably ethyl acetate, tetrahydrofuran (THF), ethylene glycol diethyl ether, 1,4-dioxane, toluene, be more preferably ethyl acetate, ethylene glycol diethyl ether, toluene, 1,4-dioxane, most preferably is ethylene glycol diethyl ether.
8. the process of claim 1 wherein that step B carries out under the temperature of reaction of 80-130 DEG C, preferably carry out under the temperature of reaction of 100-130 DEG C, more preferably 110-130 DEG C, most preferably 120 DEG C.
9. the method for claim 1, wherein step C carries out under the existence of lysate, described lysate is the mixing solutions of TFA/DCM, the volume ratio of TFA/DCM is 1:1-1:10, the volume ratio of preferred TFA/DCM is 1:3-1:8, more preferably the volume ratio of TFA/DCM is 1:5-1:7, the consumption of lysate is every gram of 2-(3-hydroxyadamantane)-N-(tert-butoxycarbonyl)-1-{1S, 3S, 5S)-2-azabicyclo [3.1.0] hexane-3-formonitrile HCN }-S-G-NH2 use 5-40mL lysate, preferred 10-30mL, more preferably 18-25mL.
10. the method for any one of claim 1-9, also comprises step D: hydration BMS-477118 is made in the BMS-477118 hydration obtained in step C.
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Cited By (2)
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| CN111205216A (en) * | 2020-03-11 | 2020-05-29 | 连云港恒运药业有限公司 | Method for preparing saxagliptin |
| CN114621068A (en) * | 2022-03-31 | 2022-06-14 | 沧州那瑞化学科技有限公司 | Preparation method of 3-hydroxy-1-adamantane methyl ketone and method for synthesizing saxagliptin |
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| CN102070451A (en) * | 2002-12-09 | 2011-05-25 | 布里斯托尔-迈尔斯斯奎布公司 | Methods and compounds producing dipeptidyl peptidase IV inhibitors and intermediates thereof |
| 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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| CN102070451A (en) * | 2002-12-09 | 2011-05-25 | 布里斯托尔-迈尔斯斯奎布公司 | Methods and compounds producing dipeptidyl peptidase IV inhibitors and intermediates thereof |
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111205216A (en) * | 2020-03-11 | 2020-05-29 | 连云港恒运药业有限公司 | Method for preparing saxagliptin |
| CN111205216B (en) * | 2020-03-11 | 2022-03-29 | 连云港恒运药业有限公司 | Method for preparing saxagliptin |
| CN114621068A (en) * | 2022-03-31 | 2022-06-14 | 沧州那瑞化学科技有限公司 | Preparation method of 3-hydroxy-1-adamantane methyl ketone and method for synthesizing saxagliptin |
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