CN104725349A - Polycrystalline A-type crystal of alogliptin polycrystalline, preparation method and production purpose thereof - Google Patents
Polycrystalline A-type crystal of alogliptin polycrystalline, preparation method and production purpose thereof Download PDFInfo
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- CN104725349A CN104725349A CN201310716537.3A CN201310716537A CN104725349A CN 104725349 A CN104725349 A CN 104725349A CN 201310716537 A CN201310716537 A CN 201310716537A CN 104725349 A CN104725349 A CN 104725349A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000013078 crystal Substances 0.000 title claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 10
- ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 title abstract description 10
- 229960001667 alogliptin Drugs 0.000 title abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 48
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 43
- 238000006471 dimerization reaction Methods 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 9
- 238000001291 vacuum drying Methods 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 239000012535 impurity Substances 0.000 claims description 5
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 238000004458 analytical method Methods 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 230000007704 transition Effects 0.000 claims description 4
- 238000010521 absorption reaction Methods 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- 229910017488 Cu K Inorganic materials 0.000 claims description 2
- 229910017541 Cu-K Inorganic materials 0.000 claims description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- XDFORSMZCYHNBG-UHFFFAOYSA-N benzonitrile;hydrochloride Chemical compound Cl.N#CC1=CC=CC=C1 XDFORSMZCYHNBG-UHFFFAOYSA-N 0.000 claims 1
- 238000002329 infrared spectrum Methods 0.000 claims 1
- 239000006227 byproduct Substances 0.000 abstract description 18
- 238000006243 chemical reaction Methods 0.000 abstract description 15
- 239000000539 dimer Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 19
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 9
- 229960000935 dehydrated alcohol Drugs 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 238000005755 formation reaction Methods 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- 239000012452 mother liquor Substances 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 238000009413 insulation Methods 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 5
- GGPNYXIOFZLNKW-ZJIMSODOSA-N (3r)-piperidin-3-amine;dihydrochloride Chemical compound Cl.Cl.N[C@@H]1CCCNC1 GGPNYXIOFZLNKW-ZJIMSODOSA-N 0.000 description 4
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 2
- 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 description 2
- 102100039994 Gastric inhibitory polypeptide Human genes 0.000 description 2
- 102400000322 Glucagon-like peptide 1 Human genes 0.000 description 2
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 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(N)=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 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- UIERETOOQGIECD-UHFFFAOYSA-N Angelic acid Natural products CC=C(C)C(O)=O UIERETOOQGIECD-UHFFFAOYSA-N 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229960000447 alogliptin benzoate Drugs 0.000 description 1
- KEJICOXJTRHYAK-XFULWGLBSA-N alogliptin benzoate Chemical compound OC(=O)C1=CC=CC=C1.C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 KEJICOXJTRHYAK-XFULWGLBSA-N 0.000 description 1
- 230000005260 alpha ray Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- UIERETOOQGIECD-ARJAWSKDSA-N angelic acid Chemical compound C\C=C(\C)C(O)=O UIERETOOQGIECD-ARJAWSKDSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 210000003298 dental enamel Anatomy 0.000 description 1
- 239000013070 direct material Substances 0.000 description 1
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 1
- 238000012362 drug development process Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- AKQXKEBCONUWCL-UHFFFAOYSA-N tert-butyl 3-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(N)C1 AKQXKEBCONUWCL-UHFFFAOYSA-N 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 238000002076 thermal analysis method Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a polycrystalline A-type crystal of alogliptin polycrystalline and a preparation method thereof. The high-purity crystal can be precipitated out of a system, a dimer by-product in the reaction is effectively removed, production efficiency is raised, and production cost is reduced. The polycrystalline A-type crystal is an anhydrous tetrahydrofuran solvated compound, has good stability and is convenient to store and transport.
Description
Technical field
The present invention relates to the crystal of medical compounds, particularly, the present invention relates to Egelieting hydrochloride polymorph A N-type waferN, its preparation method and production purposes.
Background technology
SYR-322 (Alogliptin benzoate) is serine protease DPP IV (DPP-IV) inhibitor of Japanese Takeda company research and development, the level of glucagon-like peptide 1 in body (GLP-1) and glucose-dependent-insulinotropic polypeptide (GIP) can be maintained, promote the secretion of Regular Insulin, thus play hypoglycemic curative effect.Obtain the listing approval of Japanese MHLW in April, 2010.Chemical structure is as follows:
Molecular formula: C
18h
21n
5o
2c
7h
6o
2molecular weight: 461.51
Egelieting chemical name: 2-[[6-[(3R)-3-amino-piperidino]-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl] methyl] cyanobenzene.
Significantly suppress DPP-IV Alogliptin high selectivity, good for diabetes B patient tolerance, without dose-limiting toxicity, do not occur drug accumulation phenomenon when multiple dose administration, the infull patient of Liver and kidney function is also without the need to adjusting dosage and Pharmacokinetic Results also unable to take food thing impact.Also do not find severely adverse event and dead case under study for action, do not have patient to drop by the wayside because of untoward reaction yet.In the untoward reaction found, modal is headache, also has constipation and hypoglycemia in addition.
Therefore the SYR-322 production technique that exploitation one is good, can greatly reduce production cost, reduces the price of medicine, for diabetic brings more welfare.
Egelieting hydrochloride is a key intermediate in SYR-322 production technique, according to international monopoly WO2007035629, Egelieting is preferably by 2-(the chloro-3-methyl-2 of 6-, 4-dioxo-3,4-dihydro-2-H-pyrimidine-1-ylmethyl) be separated with additive salt after the synthetic method that starts of cyanobenzene and (R)-3-amino piperidine dihydrochloride, be such as separated with hydrochloride, benzoate, trifluoroacetate or tosylate.But this preparation method can cause the generation of the dimerization by product of general formula (A) usually, and be difficult to remove from target product:
Chinese patent CN102942556 then adopts expensive N-Boc-3-amido piperidine hydrochlorate or N-Boc-3-amino piperidine raw material to replace material (R)-3-amino piperidine dihydrochloride, avoid the dimerization by product producing general formula (A) in technique, but its cost substantially increases.
Therefore we need to produce 2-[[6-[(3R)-3-amino-piperidino]-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl] methyl] the improving one's methods of cyanobenzene acid salt, especially effectively remove the dimerization by product of general formula (A) and be applicable to carrying out with low cost the method for scale operation simultaneously.
The dimerization by product of general formula (A) must not be more than 0.1% in the requirement of finished product SYR-322, so the amount controlling this impurity in intermediate is particularly important, it directly affects drug quality, if the amount of this impurity meets requirements for pharmaceuticals in intermediate, so just directly control quality risk.
Polymorphism refers to that element or compound form the phenomenon with the solid state of different physicochemical property with different crystal formations.Different polymorphs bodies is different in structures and characteristics.Various physical properties, as solubleness, density, stability, fusing point etc. all change with crystal formation difference.Medical solid forms molecular crystal usually, is easy to obtain polymorphous variant.Meanwhile, in drug research field, polymorphic further comprises the polycomponent such as organic solvate, hydrate crystalline form.The different physical and chemical performance of these different crystal forms or processability directly have influence on safety, the effective performance of medicine sometimes.Therefore the important research content that crystal formation is studied and control becomes in drug development process, it directly affects the final quality of medicine.
Summary of the invention
An aspect of of the present present invention provides the polymorph A N-type waferN of compound shown in formula I
Described polymorph A N-type waferN uses the alpha-emitting XRPD(X-ray powder diffraction of Cu-K) spectrum as shown in Figure 1, its X-ray powder diffraction data are as following table:
| Diffraction angle 2 θ (°) | D-value (0.1nm) | Relative intensity (%) |
| 9.03 | 9.79 | 100 |
| 12.94 | 6.83 | 11.9 |
| 15.37 | 5.76 | 18.2 |
| 16.93 | 5.23 | 11.8 |
| 18.24 | 4.86 | 54.4 |
| 18.66 | 4.75 | 61.6 |
| 21.24 | 4.18 | 21.6 |
| 21.99 | 4.04 | 69.5 |
| 23.08 | 3.85 | 15.1 |
| 24.44 | 3.64 | 13.9 |
| 25.34 | 3.51 | 19.3 |
| 25.78 | 3.45 | 27.7 |
| 28.56 | 3.12 | 15.9 |
| 29.95 | 2.98 | 11.7 |
The IR(infrared absorption of described polymorph A type) spectrum as shown in Figure 2,3077,2961,2848,2224,1703,1597,1513,1381,1207,1127,869cm-
1there is absorption peak at place.
The DSC(means of differential scanning calorimetry of described polymorph A type measures) collection of illustrative plates as shown in Figure 3, wherein the initial value of endothermic transition temperature is at 82.9 DEG C; Second endothermic transition temperature is at 180.9 DEG C, thermogravimetic analysis (TGA) (TGA) measured value is 11.5% simultaneously, sample water content detection result is 0.1%, solvents tetrahydrofurane content detection result 11%, the weight that sample reduces should be solvent evaporates, can find out that from DSC collection of illustrative plates temperature that solvents tetrahydrofurane volatilizees away is at about 180.9 DEG C, the boiling point of tetrahydrofuran (THF) is 65-66 DEG C, therefore judge that tetrahydrofuran (THF) is not free solvent in the sample to which, solvated compounds with compound formation, so can judge that polymorph A N-type waferN is as anhydrous tetrahydro furan solvated compounds.
Thermal analyses (TGA and DSC) instrument and testing conditions information as follows:
INSTRUMENT MODEL: U.S. PerkinElmer Thermal Analysis differential thermal analyzer
Condition determination: temperature rise rate: 15 DEG C/min; Atmosphere: nitrogen;
X-ray diffractometer information is as follows:
INSTRUMENT MODEL: Japanese Rigaku Corporation D/max-γ A type diffractometer
Condition determination: Cu target K alpha-ray; Pipe pressure: 40KV; Guan Liu: 50mA; Slit: DS1 °, RS:0.15mm, SS:1 °.
The invention still further relates to the preparation method of Egelieting hydrochloride polymorph A type, wherein:
Described polymorph A type is prepared as follows:
(1) Egelieting is dissolved in ether solvent;
(2), at stirring is cooled to-5 ~ 20 DEG C, 1 ~ 5 angelic acid is added;
(3)-5 ~ 20 DEG C of crystallizatioies;
(4) step (3) gained solid is 40 ~ 80 DEG C, vacuum-drying 6 ~ 8 hours under 0 ~ 10KPa condition.
Further, the ether solvent described in preparation method's step (1) of the present invention is tetrahydrofuran (THF), 2-methyltetrahydrofuran, ether, methyl tertiary butyl ether or its mixture, preferred tetrahydrofuran (THF);
Further, the ether solvent consumption described in preparation method's step (1) of the present invention is 1 ~ 10 times of volume; Preferably 4 ~ 6 times of volumes;
Further, the acid described in preparation method's step (1) of the present invention is hydrochloric acid, acetic acid, phenylformic acid, oxalic acid or Hydrogen bromide, is preferably hydrochloric acid;
Further, the hydrochloric acid consumption described in preparation method's step (2) of the present invention is 1 ~ 5 equivalent, preferably 1 ~ 2 equivalent;
Further, the cooling conditions of preparation method's step (2) of the present invention is: cooling temperature at-5 ~ 20 DEG C, preferably 0 ~ 10 DEG C;
Further, the crystallization condition of preparation method's step (3) of the present invention is: recrystallization temperature at-5 ~ 20 DEG C, preferably 0 ~ 10 DEG C;
Further, with the sample obtained by the preparation method of polymorph A N-type waferN, the dimerization impurity of general formula contained by it (A) is less than 0.1%, with this sample for raw material, can prepare highly purified SYR-322 bulk drug.
HPLC testing conditions:
Chromatographic column: Thermo BDS C8(250 × 4.6mm, 5 μm), column temperature: 30 DEG C, determined wavelength: 278nm,
Flow velocity: 1.0ml/min, sample size: 10 μ l, working time: 30min,
The potassium dihydrogen phosphate (containing 0.3% triethylamine) of mobile phase A: 0.04mol/L, adjusts pH to 3.0 by strong phosphoric acid
Mobile phase B: acetonitrile
According to the form below carries out gradient elution:
| Time(min) | A(%) | B(%) |
| 0 | 85 | 15 |
| 3 | 85 | 15 |
| 20 | 50 | 50 |
| 25 | 50 | 50 |
| 26 | 85 | 15 |
| 30 | 85 | 15 |
Working time: 30 minutes
Accompanying drawing 8 is the dimerization by product reference substance HPLC collection of illustrative plates of general formula (A), and appearance time is 19.5min, is purchased from TLC PHARMACHEM company outside this impurity.
Accompanying drawing explanation
Fig. 1 is the X-diffraction powder diffraction light spectrogram of the polymorph A N-type waferN of embodiments of the invention 5;
Fig. 2 is the infrared spectrogram of the polymorph A N-type waferN of embodiments of the invention 5;
Fig. 3 is Differential scanning calorimetry figure and the thermogravimetic analysis (TGA) figure of the polymorph A N-type waferN of embodiments of the invention 5;
Fig. 4 is that the filtrate HPLC of embodiments of the invention 1 detects collection of illustrative plates;
Fig. 5 is that the HPLC of the polymorph A N-type waferN of embodiments of the invention 2 detects collection of illustrative plates;
Fig. 6 is that the HPLC of the polymorph A N-type waferN of embodiments of the invention 7 detects collection of illustrative plates;
Fig. 7 is that the HPLC of the polymorph A N-type waferN of embodiments of the invention 8 detects collection of illustrative plates;
Fig. 8 is that the HPLC of the dimerization by product reference substance of general formula (A) detects collection of illustrative plates.
Embodiment
Be described below in detail embodiments of the invention, it should be noted that embodiment described below is exemplary, only for explaining the present invention, and can not limitation of the present invention be interpreted as.In addition, if do not clearly not stated, adopted in the following embodiments all reagent are, and market can be buied, or can according to text or the synthesis of known method, for the reaction conditions do not listed, be also that those skilled in the art easily obtain.
Prepared by embodiment 1 Egelieting reaction solution
400ml dehydrated alcohol is added in 1L tri-mouthfuls of reaction flasks, stir, then 80.5g2-(the chloro-3-methyl-2 of 6-is added, 4-dioxo-3,4-dihydro-2-H-pyrimidine-1-ylmethyl) cyanobenzene, (R)-3-amino piperidine dihydrochloride of 53.1g and 68.1g sodium carbonate, system is warming up to 75 DEG C of reactions, direct material has been reacted.
After having reacted, system is cooled to less than 40 DEG C, crosses and filter inorganic salt, use 80ml absolute alcohol washing leaching cake 2 times respectively.Collection mother liquor is for subsequent use.
HPLC detected result is as accompanying drawing 4: have the dimerization by product per-cent 3.8%, 19.5min of (B) to be the appearance time of the dimerization by product of general formula (A) in mother liquor.
The polymorph A type preparation of embodiment 2 Egelieting hydrochloride
By the mother liquor of 112ml embodiment 1, concentrated removal solvent, add 80.5ml tetrahydrofuran (THF) and dissolve, transfer to 250ml three products reaction flask, magnetic agitation, system is cooled to 0 ~ 5 DEG C, drip 1.5 equivalent hydrochloric acid, temperature controls at 0-10 DEG C.Drip and finish, 0 ~ 10 DEG C of insulation 1h.Suction filtration, with 10ml dehydrated alcohol by filter cake washing twice, 50 ~ 60 DEG C of vacuum-dryings obtain the polycrystalline Type B product 18.6g of Egelieting hydrochloride.
HPLC detected result is shown in accompanying drawing 5: have the dimerization by product of general formula (A) not detect in product, and 19.5min is the appearance time of the dimerization by product of general formula (A).
The A crystal formation preparation of embodiment 3 Egelieting hydrochloride
By the mother liquor of 56ml embodiment 1, concentrated removal solvent, add 48.3ml tetrahydrofuran (THF) and dissolve, transfer to 100ml three products reaction flask, magnetic agitation, system is cooled to 0 ~ 5 DEG C, drip 1 equivalent hydrochloric acid, temperature controls at-5 ~ 0 DEG C.Drip and finish ,-5 ~ 0 DEG C of insulation 1h.Suction filtration, with 10ml dehydrated alcohol by filter cake washing twice, 50 ~ 60 DEG C of vacuum-dryings obtain the polycrystalline Type B product 9.0g of Egelieting hydrochloride.
HPLC detected result: dimerization by product per-cent≤0.1% having general formula (A) in product.
The A crystal formation preparation of embodiment 4 Egelieting hydrochloride
Get the mother liquor of 56ml embodiment 1, concentrated removal solvent, add 32.2ml2-methyltetrahydrofuran and dissolve, transfer to 100ml three products reaction flask, stir clearly molten, system is cooled to 0 ~ 5 DEG C, drip 2 equivalent hydrochloric acid, temperature keeps below 10 DEG C.Drip and finish, 0 ~ 10 DEG C of insulation 1h.Suction filtration, with 10ml dehydrated alcohol by filter cake washing twice, 70 ~ 80 DEG C of vacuum-dryings obtain the polycrystalline Type B product 9.5g of Egelieting hydrochloride.
HPLC detected result: dimerization by product per-cent≤0.1% having general formula (A) in product.
The polymorph A type preparation of embodiment 5 Egelieting hydrochloride
Get the mother liquor of 56ml embodiment 1, concentrated removal solvent, add 80.5ml tetrahydrofuran (THF) and dissolve, transfer to 100ml three products reaction flask, stir clearly molten, system is cooled to 0 ~ 5 DEG C, drip 5 equivalent hydrochloric acid, temperature controls at 0 ~ 10 DEG C.Drip and finish, 10 ~ 20 DEG C of insulation 1h.Suction filtration, with 10ml dehydrated alcohol by filter cake washing twice, 40 ~ 50 DEG C of vacuum-dryings obtain the polycrystalline Type B product 9.5g of Egelieting hydrochloride.
HPLC detected result: dimerization by product per-cent≤0.1% having general formula (A) in product.
The A crystal formation preparation of embodiment 6 Egelieting hydrochloride
By the mother liquor of 50ml embodiment 1, concentrated removal solvent, add 40.3ml2-methyltetrahydrofuran, stir clearly molten, system is cooled to 0 ~ 5 DEG C, drip hydrochloric acid 3 equivalent, temperature keeps below 10 DEG C.Drip and finish, 0 ~ 10 DEG C of insulation 1h.Suction filtration, with 10ml dehydrated alcohol by filter cake washing twice, 50 ~ 60 DEG C of vacuum-dryings obtain the polymorph A type product 8.9g of Egelieting hydrochloride.
HPLC detected result: dimerization by product per-cent≤0.1% having (B) in product.
The polymorph A type preparation of embodiment 7 Egelieting hydrochloride
30.2L dehydrated alcohol is added in 100L reactor, stir after opening and add 7.9kg2-(the chloro-3-methyl-2 of 6-, 4-dioxo-3,4-dihydro-2-H-pyrimidine-1-ylmethyl) cyanobenzene, (R)-3-amino piperidine dihydrochloride 5.4kg and sodium carbonate 6.7kg.Be warming up to 75 DEG C of reactions 20 hours.
After reaction terminates, be cooled to 40 DEG C, filter.Filtrate is transferred in 100L enamel reaction still; By filtrate control in temperature≤50 DEG C concentrate out ethanol.Add 35Kg tetrahydrofuran (THF), cool to 0 ~ 10 DEG C, drip hydrochloric acid 1.5 equivalent, temperature 0 ~ 10 DEG C in controlling.Drip off 0 ~ 10 DEG C of insulation 1 hour, centrifugal, vacuum-drying obtains 10.3kg white solid.
Detected result is shown in accompanying drawing 6: product HPLC purity 99.7%, 19.5min is dimerization by product per-cent 0.1%, moisture 0.15%.
Prepared by embodiment 8 SYR-322
The product 9.3kg of Example 7 is added in 37.2kg water and stirs, then adds 3.9kg sodium carbonate, stirs clarification.Use 30L dichloromethane extraction, separate methylene dichloride, concentrated removal methylene dichloride, adds 45L dehydrated alcohol and 3.6kg phenylformic acid, is warming up to 70-80 DEG C of reaction 3h.Be cooled to room temperature, suction filtration, obtain 9.9kg white solid.
HPLC detected result is shown in accompanying drawing 7: the dimerization by product not detecting general formula (A) in product, and 19.5min is the appearance time of the dimerization by product of general formula (A).
Embodiment 9 stability experiment
For investigating the stable of the polymorph A N-type waferN of Egelieting hydrochloride, Acceleration study being carried out to it and has investigated.
Egelieting hydrochloride prepared by Example 7, is placed on 40 DEG C/75%R.H. condition lower 30 days, investigates its stability, the results are shown in Table 1.
The method of concrete study on the stability can with reference to the method for Chinese Pharmacopoeia 2010 editions second annex XIX C; Purity detecting HPLC method, can with reference to the method for Chinese Pharmacopoeia 2010 editions second annex VD; The detection of crystal formation is with the method for embodiment.
The stability test of table 1 polymorph A type
Above data show, the anhydrous polymorphic A N-type waferN that the present invention obtains, and its purity has satisfactory stability at typical condition, and convenient storage and transport, can reduce in production process and store risk.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, those of ordinary skill in the art can change above-described embodiment within the scope of the invention when not departing from principle of the present invention and aim, revising, replacing and modification.
Claims (9)
1. the polymorph A N-type waferN of an Egelieting hydrochloride, it is characterized in that: described polymorph A N-type waferN uses the alpha-emitting X-ray powder diffraction methods of Cu-K, it is 9.03 ° ± 0.2 ° that its X-ray powder diffraction comprises 2 θ, 12.94 ° ± 0.2 °, 15.37 ° ± 0.2 °, 16.93 ° ± 0.2 °, 18.24 ° ± 0.2 °, 18.66 ° ± 0.2 °, 21.24 ° ± 0.2 °, 21.99 ° ± 0.2 °, 23.08 ° ± 0.2 °, 24.44 ° ± 0.2 °, 25.34 ° ± 0.2 °, 25.78 ° ± 0.2 °, 28.56 ° ± 0.2 °, the characteristic peak of 29.95 ° ± 0.2 °.
2. polymorph A N-type waferN according to claim 1, is characterized in that: infrared spectra 3077,2961,2848,2224,1703,1597,1513,1381,1207,1127,869cm
-1there is absorption peak at place, and the initial value of its DSC endothermic transition temperature is at 82.9 DEG C, and the second endothermic transition temperature is at 180.9 DEG C, and the data of TGA thermogravimetic analysis (TGA) are simultaneously 11.5%.
3. polymorph A N-type waferN according to claim 1 and 2, wherein said A N-type waferN form is anhydrous tetrahydro furan solvated compounds.
4. the preparation method of the polymorph A N-type waferN according to any one of claim 1-3, wherein,
Described polymorph A N-type waferN is prepared as follows:
(1) Egelieting is dissolved in ether solvent;
(2), at stirring is cooled to-5 ~ 20 DEG C, the acid of 1 ~ 5 equivalent is added;
(3)-5 ~ 20 DEG C of crystallizatioies;
(4) step (3) gained solid was at 40-80 DEG C, under 0-10KPa condition vacuum-drying 6-8 hour.
5. preparation method according to claim 4, is characterized in that: ether solvent described in step (1) is tetrahydrofuran (THF), 2-methyltetrahydrofuran, ether, methyl tertiary butyl ether or its mixture, is preferably tetrahydrofuran (THF); Described ether solvent consumption is 1 ~ 10 times of volume, is preferably 4 ~ 6 times of volumes.
6. preparation method according to claim 4, is characterized in that: acid described in step (2) is hydrochloric acid, acetic acid, phenylformic acid, oxalic acid or Hydrogen bromide, is preferably hydrochloric acid; Described hydrochloric acid consumption is 1 ~ 5 equivalent, preferably 1 ~ 2 equivalent.
7. preparation method according to claim 4, is characterized in that: the cooling temperature of step (2) is 0 ~ 10 DEG C.
8. preparation method according to claim 4, is characterized in that: the recrystallization temperature of step (3) is 0 ~ 10 DEG C.
9. polymorph A shape crystal according to claim 1 and 2 is manufacturing 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2 containing the dimerization impurity being less than 0.1% general formula (A), 4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] application of benzonitrile hydrochloride.
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Cited By (2)
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| CN106496194A (en) * | 2016-09-13 | 2017-03-15 | 合肥拓锐生物科技有限公司 | A kind of dimeric preparation method of Egelieting |
| CN114057685A (en) * | 2020-07-31 | 2022-02-18 | 西安新通药物研究有限公司 | Preparation method of alogliptin benzoate with high yield |
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| CN101360723A (en) * | 2005-09-16 | 2009-02-04 | 武田药品工业株式会社 | Process for preparing pyrimidinedione derivatives |
| CN101360735A (en) * | 2005-09-16 | 2009-02-04 | 武田药品工业株式会社 | Polymorphs of benzoate salt of 2-[[6-[(3r)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2h)-pyrimidinyl]methyl]-benzonitrile and methods of use therefor |
| CN102127057A (en) * | 2004-03-15 | 2011-07-20 | 武田药品工业株式会社 | Dipeptidyl peptidase inhibitors |
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| CN102127057A (en) * | 2004-03-15 | 2011-07-20 | 武田药品工业株式会社 | Dipeptidyl peptidase inhibitors |
| CN101360723A (en) * | 2005-09-16 | 2009-02-04 | 武田药品工业株式会社 | Process for preparing pyrimidinedione derivatives |
| CN101360735A (en) * | 2005-09-16 | 2009-02-04 | 武田药品工业株式会社 | Polymorphs of benzoate salt of 2-[[6-[(3r)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2h)-pyrimidinyl]methyl]-benzonitrile and methods of use therefor |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106496194A (en) * | 2016-09-13 | 2017-03-15 | 合肥拓锐生物科技有限公司 | A kind of dimeric preparation method of Egelieting |
| CN114057685A (en) * | 2020-07-31 | 2022-02-18 | 西安新通药物研究有限公司 | Preparation method of alogliptin benzoate with high yield |
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