CN104725350A - Polycrystalline B-type crystal of alogliptin hydrochloride, preparation method and production purpose thereof - Google Patents
Polycrystalline B-type crystal of alogliptin hydrochloride, preparation method and production purpose thereof Download PDFInfo
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- CN104725350A CN104725350A CN201310717030.XA CN201310717030A CN104725350A CN 104725350 A CN104725350 A CN 104725350A CN 201310717030 A CN201310717030 A CN 201310717030A CN 104725350 A CN104725350 A CN 104725350A
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- 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
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- 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
Abstract
The invention discloses a polycrystalline B-type crystal of alogliptin hydrochloride and a preparation method thereof. The polycrystalline B-type crystal is prepared by an x-ray powder diffraction method of Cu-K alpha radiation, and the x-ray powder diffraction comprises peaks with 2 theta being 8.87+/-0.2 degrees, 12.67+/-0.2 degrees, 14.39+/-0.2 degrees, 14.84+/-0.2 degrees, 16.33+/-0.2 degrees, 18.66+/-0.2 degrees, 19.12+/-0.2 degrees, 20.20+/-0.2 degrees, 22.49+/-0.2 degrees, 24.18+/-0.2 degrees, 24.54+/-0.2 degrees, 25.48+/-0.2 degrees, 27.31+/-0.2 degrees, 28.83+/-0.2 degrees, 30.18+/-0.2 degrees, 32.97+/-0.2 degrees, 36.85+/-0.2 degrees and 38.76+/-0.2 degrees. The high-purity crystal obtained can be precipitated out of a system, a dimer by-product in the reaction can be effectively removed, production efficiency is raised, and production cost is reduced.
Description
Technical field
The present invention relates to the crystal of medical compounds, particularly, the present invention relates to the polycrystalline Type B of Egelieting hydrochloride, 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-4 Alogliptin high selectivity, good for diabetes B patient tolerance, without dose-limiting toxicity, drug accumulation phenomenon is there is not when multiple dose administration, the full patient of Liver and kidney function also without the need to adjust dosage and Pharmacokinetic Results also the impact of unable to take food thing also do not find that severely adverse event and dead case do not have patient to drop by the wayside in the untoward reaction found because of untoward reaction yet under study for action, modal is headache, also has constipation and hypoglycemia in addition.
Therefore the SYR-322 production technique that exploitation one is good, can reduce cost greatly, reduces the price of streat drug, can bring more welfare to diabetic.
Egelieting hydrochloride is as the intermediate of in production technique, according to prior art, such as 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.Described preparation method causes the dimerization by product producing general formula (A) usually, and it is 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 upper patent material (R)-3-amino piperidine dihydrochloride to avoid producing in technique the dimerization by product of general formula (A), and therefore cost has uprised greatly.
Therefore need to produce 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] 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
Another aspect provides the polycrystalline Type B of compound shown in formula I, described polycrystalline Type B uses the alpha-emitting XRPD(X-ray powder diffraction of Cu-K) spectrum as shown in Figure 4, wherein X-ray powder diffraction data are as following table:
| Diffraction angle 2 θ (°) | D-value (0.1nm) | Relative intensity (%) |
| 8.87 | 9.97 | 68.9 |
| 12.67 | 6.98 | 18.6 |
| 14.39 | 6.15 | 21.7 |
| 14.84 | 5.97 | 60.7 |
| 16.33 | 5.42 | 48.4 |
| 18.66 | 4.75 | 14 |
| 19.12 | 4.64 | 100 |
| 20.20 | 4.39 | 12.8 |
| 22.49 | 3.95 | 70.8 |
| 24.18 | 3.68 | 52.9 |
| 24.54 | 3.63 | 17 |
| 25.48 | 3.49 | 66.1 |
| 27.31 | 3.26 | 25.8 |
| 28.83 | 3.09 | 38.8 |
| 30.18 | 2.96 | 15.5 |
| 32.97 | 2.71 | 12.7 |
| 36.85 | 2.44 | 12.7 |
| 38.76 | 2.32 | 10.6 |
The IR(infrared absorption of described polycrystalline Type B) spectrum as shown in Figure 5,3057,2941,2829,2222,1698,1614,1577,1533,1450,1366,1212,1120,845,770cm
-1there is absorption peak at place.
The DSC(means of differential scanning calorimetry of described polycrystalline Type B measures) collection of illustrative plates is as shown in Figure 6, wherein the initial value of endothermic transition temperature is at about 112.0 DEG C, thermogravimetic analysis (TGA) (TGA) data are 4.7% simultaneously, its water content detection result is 5.0%, the matter water-containing of 1 crystal water is 4.6% in theory, three's data are substantially identical, can judge that polycrystalline Type B is as monohydrate.
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 present invention relates to the preparation method of Egelieting hydrochloride crystal, wherein:
Described polycrystalline Type B is prepared as follows:
(1) Egelieting is dissolved in 1-10 volume alcoholic 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 alcoholic solvent described in method one step (1) is ethanol, methyl alcohol, propyl carbinol, Virahol or n-propyl alcohol or its mixture, is preferably ethanol;
Further, the alcoholic solvent consumption described in method one step (1) is 1 ~ 10 volume; Preferably 4 ~ 6 volumes;
Further, the acid described in method one step (1) is hydrochloric acid, acetic acid, phenylformic acid, oxalic acid or Hydrogen bromide, is preferably hydrochloric acid;
Further, the hydrochloric acid consumption described in method one step (2) is 1 ~ 5 equivalent, preferably 1 ~ 2 equivalent;
Further, the cooling conditions of method one step (2) is: cooling temperature at-5 ~ 20 DEG C, preferably 0 ~ 10 DEG C;
Further, the crystallization condition of method one step (3) is: recrystallization temperature at-5 ~ 20 DEG C, preferably 0 ~ 10 DEG C;
Further, with the sample obtained by the preparation method of polycrystalline Type B for raw material, the highly purified bulk drug SYR-322 that can prepare.
HPLC testing conditions:
Chromatographic column: Thermo BDS C8250 × 4.6mm5 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
| 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
Remarks: Fig. 8 is the dimerization by product reference substance HPLC 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 crystal (polycrystalline Type B) of embodiments of the invention 2;
Fig. 2 is the infrared spectrogram of the crystal (polycrystalline Type B) of embodiments of the invention 2;
Fig. 3 is Differential scanning calorimetry (DSC) figure and thermogravimetic analysis (TGA) (TGA) figure of the crystal (polycrystalline Type B) of embodiments of the invention 2;
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 crystal (polycrystalline Type B) of embodiments of the invention 2 detects collection of illustrative plates;
Fig. 6 is that the HPLC of the SYR-322 of embodiments of the invention 8 detects collection of illustrative plates;
Fig. 7 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 ethanol washing filter cake 2 times respectively.Collect mother liquor (HPLC detected result is shown in accompanying drawing 4: have the dimerization by product per-cent 3.8%, 19.5min of general formula (A) to be the appearance time of the dimerization by product of general formula (A) in mother liquor) for subsequent use.
The polycrystalline Type B preparation of embodiment 2 Egelieting hydrochloride
By the mother liquor of 112ml embodiment 1, concentrated removal solvent, add 80.6ml anhydrous alcohol solution, 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, the polycrystalline Type B product 17.6g(HPLC detected result that 50 ~ 60 DEG C of vacuum-drying obtains Egelieting hydrochloride is shown in accompanying drawing 5: dimerization by product per-cent≤0.1% having general formula (A) in product, and 19.5min is the appearance time of the dimerization by product of general formula (A)).
The B crystal form preparation of embodiment 3 Egelieting hydrochloride
By the mother liquor of 56ml embodiment 1, concentrated removal solvent, add 40.3ml anhydrous alcohol solution, 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 8.7g(HPLC detected result of Egelieting hydrochloride: dimerization by product per-cent≤0.1% having general formula (A) in product).
The B crystal form preparation of embodiment 4 Egelieting hydrochloride
Get the mother liquor of 56ml embodiment 1, concentrated removal solvent, add 32.2ml dissolve with methanol, 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 6.5g(HPLC detected result of Egelieting hydrochloride: dimerization by product per-cent≤0.1% having general formula (A) in product).
The polycrystalline Type B preparation of embodiment 5 Egelieting hydrochloride
Get the mother liquor of 56ml embodiment 1, concentrated removal solvent, add 80.5ml anhydrous alcohol solution, 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 8.5g(HPLC detected result of Egelieting hydrochloride: dimerization by product per-cent≤0.1% having general formula (A) in product).
The polycrystalline Type B preparation of embodiment 6 Egelieting hydrochloride
Get the mother liquor of 56ml embodiment 1, concentrated removal solvent, add 80.5ml Virahol and dissolve, transfer to 100ml three products reaction flask, stir clearly molten, system is cooled to 10 ~ 20 DEG C, drip 1.5 equivalent hydrochloric acid, temperature keeps below 10 ~ 20 DEG C.Drip and finish, 10 ~ 20 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 8.3g(HPLC detected result of Egelieting hydrochloride: dimerization by product per-cent≤0.1% having general formula (A) in product).
The polycrystalline Type B preparation of embodiment 7 Egelieting hydrochloride
Get the mother liquor of 56ml embodiment 1, concentrated removal solvent, add 80.5ml anhydrous alcohol solution, transfer to 100ml three products reaction flask, stir clearly molten, system is cooled to 0 ~ 5 DEG C, drip acetic acid 2 equivalent, temperature keeps below 10 DEG C.Drip and finish, 10 ~ 20 DEG C of insulation 1h.Suction filtration, with 10ml dehydrated alcohol by filter cake washing twice, 50 ~ 60 DEG C of vacuum-dryings obtain Egelieting acetate product 7.9g(HPLC detected result: dimerization by product per-cent≤0.1% having (B) in product).
Prepared by embodiment 8 SYR-322
The product 9.3g of Example 2 is added in 37.2g water and stirs, then adds 3.9g sodium carbonate, stirs clarification.Use 30ml dichloromethane extraction, separate methylene dichloride, concentrated removal methylene dichloride, adds 45ml dehydrated alcohol and 3.6g phenylformic acid, is warming up to 70-80 DEG C of reaction 3h.Be cooled to room temperature, suction filtration, obtain 9.9g white solid (HPLC detected result is shown in accompanying drawing 6: the appearance time having the dimerization by product per-cent of general formula (A) to be 0.01%, 19.5min to be the dimerization by product of general formula (A) in product).
Embodiment 9 stability experiment
For investigating the stable of the polycrystalline Type B of Egelieting hydrochloride, carried out Acceleration study to it and investigated, test-results is in table 1;
Egelieting hydrochloride prepared by Example 2, 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 V D; The detection of crystal formation is with the method for embodiment.
The stability test of table 1 polycrystalline Type B
Above data show, moisture polycrystalline Type B is stored under normal temperature condition exists degraded risk, should store under cryogenic, or directly carry out lower step production in process of production, reduce period of storage to storage.
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 (10)
1. an Egelieting hydrochloride polycrystalline Type B crystal, wherein said polycrystalline Type B crystal uses the alpha-emitting X-ray powder diffraction methods of Cu-K, it is 8.87 ° ± 0.2 ° that its X-ray powder diffraction comprises 2 θ, 12.67 ° ± 0.2 °, 14.39 ° ± 0.2 °, 14.84 ° ± 0.2 °, 16.33 ° ± 0.2 °, 18.66 ° ± 0.2 °, 19.12 ° ± 0.2 °, 20.20 ° ± 0.2 °, 22.49 ° ± 0.2 °, 24.18 ° ± 0.2 °, 24.54 ° ± 0.2 °, 25.48 ° ± 0.2 °, 27.31 ° ± 0.2 °, 28.83 ° ± 0.2 °, 30.18 ° ± 0.2 °, 32.97 ° ± 0.2 °, 36.85 ° ± 0.2 °, the peak of 38.76 ° ± 0.2 °.
2. according to polycrystalline Type B crystal according to claim 1, it is characterized in that: described polycrystalline Type B has powder x-ray diffraction figure as shown in Figure 1 substantially, it is 8.87 ° ± 0.2 ° that its X-ray powder diffraction comprises 2 θ, 12.67 ° ± 0.2 °, 14.37 ° ± 0.2 °, 14.84 ° ± 0.2 °, 16.33 ° ± 0.2 °, 18.66 ° ± 0.2 °, 19.12 ° ± 0.2 °, 20.20 ° ± 0.2 °, 22.49 ° ± 0.2 °, 24.18 ° ± 0.2 °, 24.54 ° ± 0.2 °, 25.48 ° ± 0.2 °, 27.31 ° ± 0.2 °, 28.83 ° ± 0.2 °, 30.18 ° ± 0.2 °, 32.97 ° ± 0.2 °, 36.85 ° ± 0.2 °, the peak of 38.76 ° ± 0.2 °.
3. Egelieting hydrochloride crystal according to claim 1 and 2, is characterized in that:
Described polycrystalline Type B has infrared spectra as shown in Figure 2,3057,2941,2829,2222,1698,1614,1577,1533,1450,1366,1212,1120,845, there is absorption peak at 770cm-1 place;
Described polycrystalline Type B has DSC(TGA as shown in Figure 3) collection of illustrative plates, the initial value of endothermic transition temperature is at about 112.0 DEG C, and thermogravimetic analysis (TGA) (TGA) data are 4.7% simultaneously, and its water content detection result is 5.0%.
4. polycrystalline Type B crystal according to claim 1 and 2, wherein said Type B crystal is monohydrate.
5. the preparation method of the polycrystalline Type B crystalline substance according to any one of claim 1-4, wherein,
Described polycrystalline Type B crystal is prepared as follows:
(1) Egelieting is dissolved in 1 ~ 10 volume alcoholic solvent;
(2) 1 ~ 5 angelic acid is added at stirring-5 ~ 20 DEG C;
(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.
6. preparation method according to claim 5, is characterized in that: the alcoholic solvent described in step (1) is ethanol, methyl alcohol, propyl carbinol, Virahol or n-propyl alcohol or its mixture, is preferably ethanol; Alcoholic solvent consumption described in step (1) is 1 ~ 10 times of volume, preferred 4-6 times volume.
7. preparation method according to claim 5, is characterized in that: the acid described in step (2) is hydrochloric acid, acetic acid, phenylformic acid, oxalic acid or Hydrogen bromide, is preferably hydrochloric acid.
8. preparation method according to claim 7, is characterized in that: described hydrochloric acid consumption is 1 ~ 5 equivalent, preferably 1 ~ 2 equivalent.
9. preparation method according to claim 5, is characterized in that: the cooling temperature of step (2) at-5 ~ 20 DEG C, preferably 0 ~ 10 DEG C; The recrystallization temperature of step (3) at-5 ~ 20 DEG C, preferably 0 ~ 10 DEG C.
10. manufacturing 2-[6-[3 (R)-amino piperidine-1-base]-3-methyl-2 containing the dimerization impurity being less than 0.1% general formula (A) according to the Egelieting hydrochloride of claim 1 crystallization B form, 4-dioxo-1,2,3,4-tetrahydropyrimidine-1-ylmethyl] application in benzonitrile hydrochloride.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101360723A (en) * | 2005-09-16 | 2009-02-04 | 武田药品工业株式会社 | Process for the preparation of pyrimidinedione derivatives |
| CN102127057A (en) * | 2004-03-15 | 2011-07-20 | 武田药品工业株式会社 | Dipeptidyl peptidase inhibitors |
| WO2013046229A1 (en) * | 2011-09-26 | 2013-04-04 | Hetero Research Foundation | Novel salts of alogliptin |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 the preparation of pyrimidinedione derivatives |
| WO2013046229A1 (en) * | 2011-09-26 | 2013-04-04 | Hetero Research Foundation | Novel salts of alogliptin |
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Application publication date: 20150624 |