CN105712890A - Purification technology of vildagliptin intermediate 3-amino-1-adamantanol - Google Patents
Purification technology of vildagliptin intermediate 3-amino-1-adamantanol Download PDFInfo
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- CN105712890A CN105712890A CN201510958793.2A CN201510958793A CN105712890A CN 105712890 A CN105712890 A CN 105712890A CN 201510958793 A CN201510958793 A CN 201510958793A CN 105712890 A CN105712890 A CN 105712890A
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- vildagliptin
- filter cake
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- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 title claims abstract description 26
- 229960001254 vildagliptin Drugs 0.000 title claims abstract description 26
- 238000000746 purification Methods 0.000 title claims abstract description 12
- 238000005516 engineering process Methods 0.000 title abstract description 8
- DWPIPTNBOVJYAD-BQKDNTBBSA-N (5s,7r)-3-aminoadamantan-1-ol Chemical compound C([C@H](C1)C2)[C@@H]3CC2(N)CC1(O)C3 DWPIPTNBOVJYAD-BQKDNTBBSA-N 0.000 title abstract 3
- 238000000034 method Methods 0.000 claims abstract description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000012043 crude product Substances 0.000 claims abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 20
- 239000012065 filter cake Substances 0.000 claims description 15
- 230000008569 process Effects 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 11
- 239000000706 filtrate Substances 0.000 claims description 9
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 7
- 239000006228 supernatant Substances 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 238000011049 filling Methods 0.000 claims description 4
- 239000002253 acid Substances 0.000 abstract description 15
- 239000003513 alkali Substances 0.000 abstract description 10
- 239000013078 crystal Substances 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- CMQCNTNASCDNGR-UHFFFAOYSA-N toluene;hydrate Chemical compound O.CC1=CC=CC=C1 CMQCNTNASCDNGR-UHFFFAOYSA-N 0.000 abstract description 3
- 230000001105 regulatory effect Effects 0.000 abstract 2
- 230000001276 controlling effect Effects 0.000 abstract 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- 239000001117 sulphuric acid Substances 0.000 description 7
- 235000011149 sulphuric acid Nutrition 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 229960001280 amantadine hydrochloride Drugs 0.000 description 5
- WOLHOYHSEKDWQH-UHFFFAOYSA-N amantadine hydrochloride Chemical compound [Cl-].C1C(C2)CC3CC2CC1([NH3+])C3 WOLHOYHSEKDWQH-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229910017604 nitric acid Inorganic materials 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 2
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 2
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000013505 freshwater Substances 0.000 description 2
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 2
- 229960003105 metformin Drugs 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000010979 pH adjustment Methods 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 102000051325 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- 101000976075 Homo sapiens Insulin Proteins 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical class C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)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(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 229940127017 oral antidiabetic Drugs 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- ALSCEGDXFJIYES-UHFFFAOYSA-N pyrrolidine-2-carbonitrile Chemical compound N#CC1CCCN1 ALSCEGDXFJIYES-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a purification technology of vildagliptin intermediate 3-amino-1-adamantanol. According to the purification technology, a water system (water, water-alcohol or water-toluene) is used, and methods of regulating acid for dissolving and regulating alkali for separating out are adopted, so that a 3-amino-1-adamantanol crude product can be purified. The purification technology is remarkable in purification effect and capable of controlling crystal forms precisely to facilitate raw control for preparing vildagliptin in next step.
Description
Technical field
The present invention relates to pharmaceutical technology field, particularly relate to the purifying process of a kind of vildagliptin intermediate 3-amino-1-adamantane alcohol.
Background technology
Diabetes are the metabolic syndromes caused by h and E factor combined effect, can cause the absolute and relative hyposecretion of human insulin, cause the metabolism disorders such as internal sugar, protein, fat, are a kind of chronic diseases that human health risk is very big.
Vildagliptin (English: Vildagliptin), it is happy that trade name is preferred dimension, is a kind of have selectivity, competitiveness, reversible DPP-4 (dipeptidyl peptidase-4) inhibitor class oral antidiabetic, is used for treating type ii diabetes.Be uniquely a kind of no matter can the material of glucagon suppression when hyperglycemia or hypoglycemia.
On JIUYUE 28th, 2007, the vildagliptin (vildagliptin, trade name: Galvus) of Novartis Co., Ltd obtains EU Committee's approval, lists with Ireland in 27 European Union member countries and Norway.
Approval in 2011 is at the compound preparation of China's import vildagliptin tablet and vildagliptin and metformin.Galvus is that in same types of drug, unique one can with metformin, the medicine that the antidiabetic drug such as thiazole two alkanone is used in combination.
Vildagliptin is that the researcher DdwinB.Villhauer of Novartis studied discovery during adamantane derivative in 1998.The chemistry of vildagliptin is called (S)-1-[[(3-hydroxyl-1-amantadine) amino] acetyl group] tetrahydro pyrrolidine-2-formonitrile HCN, and relative molecular mass is 303.4.
The chemical constitution of vildagliptin contains a hand-type carbon atom, the structure focusing on skeleton of its study on the synthesis work and the introducing of hand-type carbon atom.Theoretical according to reverse reaction, vildagliptin can being divided into two fragments synthesize: (S)-1-(2-chloracetyl chloride)-2-itrile group pyrrolidine (compound 1) and 3-amino-1-adamantane alcohol (compound 2), reaction equation is as follows:
Summary of the invention
It is an object of the invention to for the technological deficiency existed in prior art, and the purifying process of a kind of vildagliptin intermediate 3-amino-1-adamantane alcohol is provided.
A kind of technique preparing vildagliptin intermediate 3-amino-1-adamantane alcohol is the technical scheme is that, it is characterised in that comprise the following steps for realizing the purpose of the present invention:
(1) acid A is poured in there-necked flask, drip water, under magnetic agitation, be dividedly in some parts amantadine hydrochloride；Then reduce reacting liquid temperature and be 0-5 DEG C；
(2) being slowly added dropwise acid B, dropping process keeps reacting liquid temperature to be 0-5 DEG C；Dropwise, keep thermotonus 2h, then raise temperature to 20 DEG C, continue reaction 12h；
(3) react complete, under ice-water bath, add alkali liquor and regulate pH >=12；Filtering insoluble matter, filtrate concentrates；
(4) filtrate after step (3) being concentrated is placed in reflux in toluene 1.5h, takes supernatant crystallize, sucking filtration, after filtration cakes torrefaction and get final product.
Described acid A and acid B is combined as: concentrated sulphuric acid and fuming nitric aicd, concentrated nitric acid and oleum, sulphuric acid and nitric acid, oleum and fuming nitric aicd.
Preferably, described acid A and acid being combined as of B: concentrated sulphuric acid and fuming nitric aicd.
The alkali liquor added in described step (3) is potassium hydroxide solution, sodium hydroxide solution, solution of potassium carbonate or sodium carbonate liquor.
Preferably, the alkali liquor added in described step (3) is potassium hydroxide solution.
The feature of this technique preparing 3-amino-1-adamantane alcohol is: pass through amantadine hydrochloride, use sulfonitric system (concentrated sulphuric acid-fuming nitric aicd, concentrated nitric acid-oleum, sulfonitric, oleum-fuming nitric aicd, preferred: concentrated sulphuric acid-fuming nitric aicd system), use lye pH adjustment to control oxidisability, oxidation step prepares 3-amino-1-adamantane alcohol；This preparation technology reacts quickly, yield high.
Present invention also offers the purifying process of a kind of vildagliptin intermediate 3-amino-1-adamantane alcohol, it is characterised in that comprise the following steps:
(1) 3-amino-1-adamantane alcohol crude product is poured into equipped with in the beaker of ethanol and stir；Continuing to drip hydrochloric acid in beaker, be adjusted to pH less than 4, temperature controls at 15-20 DEG C, is cooled to 15 DEG C, stirs 1.5h, obtains filter cake A after filtration；
(2) filter cake A prepared by step (1) is poured in the beaker filling water, under stirring, adds sodium hydrate aqueous solution, be adjusted to pH more than 12, maintain the temperature at about 30 DEG C, and continue stirring 1h after filter to obtain filter cake B；
(3) with water wash filter cake B, it is spin-dried for filtrate, stops stirring after being subsequently placed in reflux in toluene 1h, after standing, take supernatant, crystallize 1h under the temperature conditions of 5-10 DEG C, filter, dry, obtain the 3-amino-1-adamantane alcohol after purification.
Above-mentioned purifying process is to make fresh water supply system (water, water-alcohol or water-toluene, it is preferable that water-ethanol), uses the method that acid adjustment dissolving, alkali tune precipitate out, thus reaching the purpose of purification 3-aminoadamantan alcohol crude product.The purification effect of this purifying process is obvious, and can be accurately controlled crystal formation, it is simple to next step raw material preparing vildagliptin controls.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in further detail.Should be appreciated that specific embodiment described herein is only in order to explain the present invention, is not intended to limit the present invention.
A kind of technique preparing vildagliptin intermediate 3-amino-1-adamantane alcohol, it is characterised in that comprise the following steps:
(1) acid A is poured in there-necked flask, drip water, under magnetic agitation, be dividedly in some parts amantadine hydrochloride；Then reduce reacting liquid temperature and be 0-5 DEG C；
(2) being slowly added dropwise acid B, dropping process keeps reacting liquid temperature to be 0-5 DEG C；Dropwise, keep thermotonus 2h, then raise temperature to 20 DEG C, continue reaction 12h；
(3) react complete, under ice-water bath, add alkali liquor and regulate pH >=12；Filtering insoluble matter, filtrate concentrates；
(4) filtrate after step (3) being concentrated is placed in reflux in toluene 1.5h, takes supernatant crystallize, sucking filtration, after filtration cakes torrefaction and get final product.
Described acid A and acid B is combined as: concentrated sulphuric acid and fuming nitric aicd, concentrated nitric acid and oleum, sulphuric acid and nitric acid, oleum and fuming nitric aicd.
Preferably, described acid A and acid being combined as of B: concentrated sulphuric acid and fuming nitric aicd.
The alkali liquor added in described step (3) is potassium hydroxide solution, sodium hydroxide solution, solution of potassium carbonate or sodium carbonate liquor.
Preferably, the alkali liquor added in described step (3) is potassium hydroxide solution.
The feature of this technique preparing 3-amino-1-adamantane alcohol is: pass through amantadine hydrochloride, use sulfonitric system (concentrated sulphuric acid-fuming nitric aicd, concentrated nitric acid-oleum, sulfonitric, oleum-fuming nitric aicd, preferred: concentrated sulphuric acid-fuming nitric aicd system), use lye pH adjustment to control oxidisability, oxidation step prepares 3-amino-1-adamantane alcohol；This preparation technology reacts quickly, yield high.
Embodiment:
The step preparing 3-amino-1-adamantane alcohol is: pour in there-necked flask by 46.94g concentrated sulphuric acid, drips 0.7g water, is dividedly in some parts amantadine hydrochloride 10g altogether under magnetic agitation.Then reducing reacting liquid temperature to 0-5 DEG C, start to be slowly added dropwise 7.75g fuming nitric aicd, dropping process heat release is more apparent, keeps reacting liquid temperature 0-5 DEG C；Dropwise, after reactant liquor reacts 2h at this temperature, then raise temperature to 20 DEG C, continue reaction 12h.
Reaction equation is:
Reacting complete, under ice-water bath, 50%KOH solution adjusts pH >=12, filters insoluble matter, and filtrate concentrates, and a small amount of toluene band water, then by it in reflux in toluene 1.5h, takes supernatant crystallize, sucking filtration, and filtration cakes torrefaction obtains 8.2g crude product, and yield is 85%, and purity is 97.5%.
Present invention also offers the purifying process of a kind of vildagliptin intermediate 3-amino-1-adamantane alcohol, it is characterised in that comprise the following steps:
(1) 3-amino-1-adamantane alcohol crude product is poured into equipped with in the beaker of ethanol and stir；Continuing to drip hydrochloric acid in beaker, be adjusted to pH less than 4, temperature controls at 15-20 DEG C, is cooled to 15 DEG C, stirs 1.5h, obtains filter cake A after filtration；
(2) filter cake A prepared by step (1) is poured in the beaker filling water, under stirring, adds sodium hydrate aqueous solution, be adjusted to pH more than 12, maintain the temperature at about 30 DEG C, and continue stirring 1h after filter to obtain filter cake B；
(3) with water wash filter cake B, it is spin-dried for filtrate, stops stirring after being subsequently placed in reflux in toluene 1h, after standing, take supernatant, crystallize 1h under the temperature conditions of 5-10 DEG C, filter, dry, obtain the 3-amino-1-adamantane alcohol after purification.
Above-mentioned purifying process is to make fresh water supply system (water, water-alcohol or water-toluene, it is preferable that water-ethanol), uses the method that acid adjustment dissolving, alkali tune precipitate out, thus reaching the purpose of purification 3-aminoadamantan alcohol crude product.The purification effect of this purifying process is obvious, and can be accurately controlled crystal formation, it is simple to next step raw material preparing vildagliptin controls.
Embodiment:
A kind of purifying process of vildagliptin intermediate 3-amino-1-adamantane alcohol, comprise the following steps: by 20g crude product (gas phase purity less than 80%), pour in the beaker equipped with 31.6g ethanol, after stirring 5min, start to drip hydrochloric acid (14.3g), it is adjusted to pH less than 4, temperature controls at 15-20 DEG C, is cooled to 15 DEG C, stirs 1.5h, filter, with a small amount of ethanol (7.9g) drip washing filter cake.
Then filter cake is poured in the beaker filling (35g) water, add sodium hydrate aqueous solution (10g sodium hydroxide and 20g water) alkali tune under stirring, be adjusted to pH more than 12, maintain the temperature at about 30 DEG C, and filter after continuing stirring 1h, with 25g-30g water wash filter cake.
It is spin-dried for filtrate, 20ml toluene band water, after reflux in toluene 1h, then stops stirring, stand 1min and take supernatant in 5-10 DEG C of crystallize 1h, filter, dry, obtaining 3-amino-1-adamantane alcohol crude product 10.4g, GC and show that purity is 98%, impurity (appearance time 12.19) has 2%.
The above is only the preferred embodiment of the present invention; it should be pointed out that, for those skilled in the art, under the premise without departing from the principles of the invention; can also making some improvements and modifications, these improvements and modifications also should be regarded as protection scope of the present invention.
Claims (1)
1. the purifying process of a vildagliptin intermediate 3-amino-1-adamantane alcohol, it is characterised in that comprise the following steps:
(1) 3-amino-1-adamantane alcohol crude product is poured into equipped with in the beaker of ethanol and stir；Continuing to drip hydrochloric acid in beaker, be adjusted to pH less than 4, temperature controls at 15-20 DEG C, is cooled to 15 DEG C, stirs 1.5h, obtains filter cake A after filtration；
(2) filter cake A prepared by step (1) is poured in the beaker filling water, under stirring, adds sodium hydrate aqueous solution, be adjusted to pH more than 12, maintain the temperature at about 30 DEG C, and continue stirring 1h after filter to obtain filter cake B；
(3) with water wash filter cake B, it is spin-dried for filtrate, stops stirring after being subsequently placed in reflux in toluene 1h, after standing, take supernatant, crystallize 1h under the temperature conditions of 5-10 DEG C, filter, dry, obtain the 3-amino-1-adamantane alcohol after purification.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510958793.2A CN105712890A (en) | 2015-12-18 | 2015-12-18 | Purification technology of vildagliptin intermediate 3-amino-1-adamantanol |
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| CN201510958793.2A CN105712890A (en) | 2015-12-18 | 2015-12-18 | Purification technology of vildagliptin intermediate 3-amino-1-adamantanol |
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| CN105712890A true CN105712890A (en) | 2016-06-29 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107325010A (en) * | 2017-08-14 | 2017-11-07 | 四川众邦制药有限公司 | The safe preparation method and device of a kind of adamantanol |
| CN114088849A (en) * | 2021-11-18 | 2022-02-25 | 河北合佳医药科技集团股份有限公司 | A method for determining the residual amount of 3-amino-1-adamantanol in vildagliptin by a pre-column derivatization method |
-
2015
- 2015-12-18 CN CN201510958793.2A patent/CN105712890A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107325010A (en) * | 2017-08-14 | 2017-11-07 | 四川众邦制药有限公司 | The safe preparation method and device of a kind of adamantanol |
| CN114088849A (en) * | 2021-11-18 | 2022-02-25 | 河北合佳医药科技集团股份有限公司 | A method for determining the residual amount of 3-amino-1-adamantanol in vildagliptin by a pre-column derivatization method |
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