CN114262331A - A kind of preparation method of sitagliptin phosphate monohydrate - Google Patents
A kind of preparation method of sitagliptin phosphate monohydrate Download PDFInfo
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- CN114262331A CN114262331A CN202010970808.8A CN202010970808A CN114262331A CN 114262331 A CN114262331 A CN 114262331A CN 202010970808 A CN202010970808 A CN 202010970808A CN 114262331 A CN114262331 A CN 114262331A
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- 229960004034 sitagliptin Drugs 0.000 title claims abstract description 58
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 title claims abstract description 57
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 238000003756 stirring Methods 0.000 claims abstract description 48
- 238000001816 cooling Methods 0.000 claims abstract description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 19
- 239000012065 filter cake Substances 0.000 claims abstract description 17
- 238000010438 heat treatment Methods 0.000 claims abstract description 16
- 239000008213 purified water Substances 0.000 claims abstract description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000000243 solution Substances 0.000 claims abstract description 10
- 238000001291 vacuum drying Methods 0.000 claims abstract description 10
- 238000001914 filtration Methods 0.000 claims abstract description 9
- 238000005406 washing Methods 0.000 claims abstract description 7
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 5
- 239000011259 mixed solution Substances 0.000 claims abstract description 3
- 238000009413 insulation Methods 0.000 claims abstract 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 239000012046 mixed solvent Substances 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 239000012535 impurity Substances 0.000 abstract description 11
- 238000000034 method Methods 0.000 abstract description 5
- 239000013078 crystal Substances 0.000 abstract description 4
- 239000000047 product Substances 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000007086 side reaction Methods 0.000 abstract description 2
- 239000007788 liquid Substances 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 238000004321 preservation Methods 0.000 description 7
- 229910019142 PO4 Inorganic materials 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 230000001603 reducing effect Effects 0.000 description 5
- 238000002386 leaching Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 3
- GQPYTJVDPQTBQC-KLQYNRQASA-N (3r)-3-amino-1-[3-(trifluoromethyl)-6,8-dihydro-5h-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one;phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O.C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F GQPYTJVDPQTBQC-KLQYNRQASA-N 0.000 description 2
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 1
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
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- 150000003456 sulfonamides Chemical class 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开一种西格列汀磷酸盐一水合物的制备方法，包括如下步骤：(a)将西格列汀溶于第一种溶剂，开启搅拌；(b)向上述溶液滴加纯化水，开启加热并保温搅拌；(c)向上述溶清液中滴加磷酸和另一种溶剂的混合液，滴加完毕，升温并保温搅拌；(d)开启梯度降温，并保温搅拌；(e)过滤，洗涤滤饼，真空干燥即得磷酸西格列汀一水合物纯品。本发明所述方法，易于操作、晶型稳定、工艺重现性好；另外该制备方法的实施可以有效减少工艺中的副反应杂质，大大提高了产品的质量，降低了溶剂残留的风险，极大地节约了生产成本。The invention discloses a preparation method of sitagliptin phosphate monohydrate, comprising the following steps: (a) dissolving sitagliptin in a first solvent, and starting stirring; (b) adding purified water dropwise to the solution , turn on heating and thermal insulation stirring; (c) dropwise add the mixed solution of phosphoric acid and another kind of solvent in above-mentioned clear liquid, dropwise complete, heat up and thermal insulation stirring; (d) open gradient cooling, and thermal insulation stirring; (e) ) filtration, washing the filter cake, and vacuum drying to obtain pure sitagliptin phosphate monohydrate. The method of the invention has the advantages of easy operation, stable crystal form and good process reproducibility; in addition, the implementation of the preparation method can effectively reduce the side reaction impurities in the process, greatly improve the quality of the product, reduce the risk of solvent residues, and greatly reduce the risk of solvent residues. Great savings in production costs.
Description
Technical Field
The invention belongs to the technical field of medical industry, and particularly relates to a preparation method of a dipeptidyl peptidase-IV inhibitor-sitagliptin phosphate monohydrate.
Background
Sitagliptin phosphate monohydrate, chemical name (2R) -4-oxo-4- [3- (trifluoromethyl) -5, 6-dihydro [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl ] -1- (2,4, 5-trifluorophenyl) butan-2-amine dihydrogen phosphate monohydrate, formula: C16H20F6N5O6P, CAS number 654671-77-9, structural formula as follows:
sitagliptin phosphate monohydrate is a peptidylpeptidase-IV inhibitor (trade name janivia) developed by Merck corporation, usa, and is approved by FDA in the united states for marketing as the first DPP-IV inhibitor at 10 months 2006, and is clinically used for treating insulin resistance and insulin a, beta cell dysfunction during type 2 diabetes; can inhibit beta cell apoptosis, promote beta cell regeneration, increase beta cell number of diabetic patients, obviously reduce blood sugar, and has good blood sugar reducing effect on patients with failure of sulfonamides. The product has the advantages of good tolerance, safety and effectiveness, light side effect and the like, is concerned by a plurality of pharmaceutical chemistry workers at home and abroad, and has good market prospect.
Therefore, in order to obtain sitagliptin phosphate monohydrate with high quality and high yield, a preparation method needs to be developed.
Disclosure of Invention
The invention provides a preparation method of sitagliptin phosphate monohydrate, which is easy to operate, stable in crystal form and good in process reproducibility; in addition, the implementation of the preparation method can effectively reduce the side reaction impurities in the process, greatly improve the product quality, reduce the risk of solvent residue and greatly save the production cost.
The invention is realized by the following technical scheme: a preparation method of sitagliptin phosphate monohydrate comprises the following steps:
(a) dissolving sitagliptin in a first solvent, and starting stirring;
(b) dropwise adding purified water into the solution, starting heating, keeping the temperature and stirring;
(c) dropwise adding a mixed solution of phosphoric acid and another solvent into the clear solution, heating, keeping the temperature and stirring after dropwise adding;
(d) opening gradient cooling, and stirring while keeping the temperature;
(e) filtering, washing a filter cake, and drying in vacuum to obtain the pure sitagliptin phosphate monohydrate.
The invention provides a preparation method of sitagliptin phosphate monohydrate, wherein a first solvent used in step (a) is selected from one or more of n-propanol, tert-butanol, acetonitrile, ethanol, ethyl acetate, tetrahydrofuran, methanol and isopropanol, and preferably n-propanol, ethanol or isopropanol.
The invention provides a preparation method of sitagliptin phosphate monohydrate, wherein the dosage of a first solvent used in the step (a) relative to a sitagliptin raw material is 1.6-4 ml/g, and preferably 1.9-3 ml/g.
The invention provides a preparation method of sitagliptin phosphate monohydrate, wherein the dosage of the purified water in the step (b) relative to the sitagliptin raw material is 0.5-2.2 ml/g, and preferably 1-1.2 ml/g.
The preparation method of sitagliptin phosphate monohydrate provided by the invention has the advantages that the heat preservation stirring temperature in the step (b) is 40-50 ℃, and preferably 40-48 ℃.
The invention provides a preparation method of sitagliptin phosphate monohydrate, wherein the heat preservation stirring time in the step (b) is 5-60 min, preferably 20-40 min.
The invention provides a preparation method of sitagliptin phosphate monohydrate, wherein the molar amount of the phosphoric acid used in the step (c) is 0.8-1.3 times of the molar amount of sitagliptin, and preferably 0.85-1.1 times of the molar amount of the sitagliptin.
The invention provides a preparation method of sitagliptin phosphate monohydrate, wherein the second solvent used in the step (c) is selected from one or more of isopropanol, methyl tert-butyl ether, n-propanol, acetonitrile, methanol and tetrahydrofuran, and preferably methanol or isopropanol.
The invention provides a preparation method of sitagliptin phosphate monohydrate, wherein the dosage of a second preferable solvent methanol used in the step (c) is 0.5-6 times of the weight of sitagliptin by volume, and preferably 2-4 times of the weight of sitagliptin by volume.
The invention provides a preparation method of sitagliptin phosphate monohydrate, wherein the heat preservation stirring temperature in the step (c) is 65-83 ℃, and preferably 68-75 ℃.
The invention provides a preparation method of sitagliptin phosphate monohydrate, wherein the heat preservation stirring time in the step (c) is 10-60 min, preferably 15-30 min.
The invention provides a preparation method of sitagliptin phosphate monohydrate, wherein the gradient cooling mode in the step (d) is that the temperature is firstly reduced to 58-62 ℃ at the speed of 2-10 ℃/h, and is preferably reduced to 60 ℃ at the speed of 3-6 ℃/h.
The invention provides a preparation method of sitagliptin phosphate monohydrate, wherein the gradient cooling mode in the step (d) is that the temperature is reduced to 48-52 ℃ at the speed of 3-10 ℃/h, and preferably is reduced to 50 ℃ at the speed of 5-8 ℃/h.
The invention provides a preparation method of sitagliptin phosphate monohydrate, wherein the gradient cooling mode in the step (d) is to cool the sitagliptin phosphate monohydrate to 38-42 ℃ at the speed of 5-15 ℃/h, and preferably to cool the sitagliptin phosphate monohydrate to 40 ℃ at the speed of 8-12 ℃/h.
The invention provides a preparation method of sitagliptin phosphate monohydrate, wherein the temperature of heat preservation stirring in the step (d) is 18-35 ℃, and preferably 20-28 ℃.
The invention provides a preparation method of sitagliptin phosphate monohydrate, wherein the heat preservation stirring time in the step (d) is 6-24 hours, and preferably 12-16 hours.
The invention provides a preparation method of sitagliptin phosphate monohydrate, wherein the washing solvent in the step (e) is a mixed solvent of methanol and water, and the volume ratio of the methanol to the water is 15: 1-5: 1, preferably 8: 1-12: 1.
The invention provides a preparation method of sitagliptin phosphate monohydrate, wherein the dosage of the mixed solvent for washing in the step (e) is 1.5-4 times of the weight of sitagliptin, and preferably 1.6-3 times of the weight of sitagliptin.
The invention provides a preparation method of sitagliptin phosphate monohydrate, wherein the vacuum drying temperature in the step (e) is 35-55 ℃, the vacuum drying time is 8-24 hours, preferably 40-45 ℃, and the drying time is 14-20 hours.
The invention utilizes the solubility difference and gradient cooling of the impurities and the sitagliptin in the mixed solvent to control the product quality and the crystal form, and the obtained sitagliptin phosphate monohydrate has high yield, good purity, stable crystal form, simple production method and easy control, thereby achieving the purpose of large-scale industrial production. The preparation method has obvious impurity removal effect, can reduce the total impurity level of about 2.5 percent to be undetected, and ensures that the purity of the prepared sitagliptin phosphate monohydrate is about 100.00 percent and the yield is more than 95 percent.
Detailed Description
The following specific examples of the invention are provided to illustrate possible implementations, but not to limit the invention. In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1:
adding self-made 50.0g of sitagliptin (HPLC purity 98.3%, impurity 1.7%) and 95mL of n-propanol, stirring, dropwise adding 50mL of purified water, heating to 45 ℃, stirring for 20min to dissolve, and continuously dropwise adding a solution containing 12.1g of 85% H3PO4And 110mL of methanol, heating to 68 ℃ after dripping, preserving heat and stirring for 20 min; starting gradient cooling, and firstly cooling to 60 ℃ at 3 ℃/h; then reducing the temperature to 50 ℃ at a speed of 5 ℃/h; and finally, cooling to 40 ℃ at a speed of 10 ℃/h, then continuously cooling to 22 ℃, preserving heat, stirring for 12h, filtering, leaching a filter cake by using 150mL of mixed solvent with the volume ratio of methanol to water being 8:1, collecting the filter cake, and carrying out vacuum drying on the filter cake at 40 ℃ for 18 h to obtain 62.1g of white powdery solid, wherein the HPLC purity reaches 100.00%.
Example 2:
adding self-made 50.0g of sitagliptin (HPLC purity is 97.9%, impurity is 2.1%) and 120mL of isopropanol into the mixture, starting stirring, dropwise adding 55mL of purified water, starting heating to 50 ℃, stirring for 30min, dissolving, and continuously dropwise adding the solution containing 13.2g of 85% H3PO4Mixing with 150mL of isopropanol, heating to 75 ℃ after dripping, keeping the temperature and stirring for 30 min; starting gradient cooling, and firstly cooling to 60 ℃ at the speed of 5 ℃/h; then the temperature is reduced to 50 ℃ at 8 ℃/h; finally, the temperature is reduced to 40 ℃ at the speed of 8 ℃/h, then the temperature is continuously reduced to 25 ℃, the temperature is kept and the stirring is carried out for 16h, the filtration is carried out, the filter cake is leached by 120mL of mixed solvent with the volume ratio of methanol to water being 10:1, the filter cake is collected and mixed with 45 ℃Vacuum drying at 61.1g of white powdery solid was obtained for 16 hours with HPLC purity of 100.00%.
Example 3:
adding self-made 50.0g of sitagliptin (HPLC purity 98.6%, impurity 1.4%) and 150mL of isopropanol into the mixture, starting stirring, dropwise adding 50mL of purified water, starting heating to 48 ℃, stirring for 40min, dissolving, and continuously dropwise adding the solution containing 14.5g of 85% H3PO4Mixing with 200mL of isopropanol, heating to 75 ℃ after dripping, keeping the temperature and stirring for 20 min; starting gradient cooling, and firstly cooling to 60 ℃ at a speed of 4 ℃/h; then reducing the temperature to 50 ℃ at a speed of 5 ℃/h; and finally, cooling to 40 ℃ at a speed of 10 ℃/h, then continuously cooling to 23 ℃, preserving heat, stirring for 12h, filtering, leaching a filter cake by using 100mL of mixed solvent with the volume ratio of isopropanol to water being 8:1, collecting the filter cake, and vacuum-drying for 14h at 45 ℃ to obtain 61.8g of white powdery solid with the HPLC purity of 100.00 percent.
Example 4:
adding self-made 50.0g of sitagliptin (HPLC purity 98.6%, impurity 1.4%) and 110mL of isopropanol into the mixture, starting stirring, dropwise adding 60mL of purified water, starting heating to 45 ℃, stirring for 20min to dissolve, and continuously dropwise adding the mixture containing 13.8g of 85% H3PO4Mixing with 180mL of isopropanol, heating to 75 ℃ after dripping, keeping the temperature and stirring for 15 min; starting gradient cooling, and firstly cooling to 60 ℃ at the speed of 6 ℃/h; then the temperature is reduced to 50 ℃ at 8 ℃/h; and finally, cooling to 40 ℃ at the speed of 12 ℃/h, then continuously cooling to 20 ℃, preserving heat, stirring for 16h, filtering, leaching a filter cake by using 120mL of mixed solvent with the volume ratio of isopropanol to water being 10:1, collecting the filter cake, and drying in vacuum at 40 ℃ for 20h to obtain 61.5g of white powdery solid, wherein the HPLC purity reaches 100.00%.
Example 5:
adding self-made 50.0g of sitagliptin (HPLC purity is 99.5%, impurity is 0.5%) and 120mL of isopropanol into the mixture, starting stirring, dropwise adding 58mL of purified water, starting heating to 45 ℃, stirring for 40min, dissolving, and continuously dropwise adding the solution containing 13.2g of 85% H3PO4And 110mL of methanol, heating to 68 ℃ after dripping, keeping the temperature and stirring for 25 min; starting gradient cooling, and firstly cooling to 60 ℃ at the speed of 5 ℃/h; then reducing the temperature to 50 ℃ at a speed of 5 ℃/h; finally, the temperature is reduced to 40 ℃ at a speed of 10 ℃/h, then the temperature is continuously reduced to 28 ℃, the heat preservation and the stirring are carried out for 14h, the filtration is carried out, and a filter cakeEluting with 80mL of mixed solvent with the volume ratio of methanol to water of 12:1, collecting filter cakes, and vacuum-drying the filter cakes at 40 ℃ for 20 hours to obtain 62.0g of white powdery solid with the HPLC purity of 100.00 percent.
Example 6:
adding self-made 50.0g of sitagliptin (HPLC purity is 99.3%, impurity is 0.7%) and 110mL of ethanol, stirring, dropwise adding 60mL of purified water, heating to 40 ℃, stirring for 30min, dissolving, and continuously dropwise adding 14.6g of 85% H3PO4Mixing with 125mL of methanol, heating to 68 ℃ after dripping, keeping the temperature and stirring for 20 min; starting gradient cooling, and firstly cooling to 60 ℃ at the speed of 5 ℃/h; then reducing the temperature to 50 ℃ at 6 ℃/h; and finally, cooling to 40 ℃ at the speed of 8 ℃/h, then continuously cooling to 25 ℃, preserving heat, stirring for 12h, filtering, leaching a filter cake by using 90mL of mixed solvent with the volume ratio of methanol to water being 8:1, collecting the filter cake, and carrying out vacuum drying on the filter cake at the temperature of 44 ℃ for 18 h to obtain 61.1g of white powdery solid, wherein the HPLC purity reaches 100.00%.
Claims (10)
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| CN116082346A (en) * | 2023-04-12 | 2023-05-09 | 宙晟智维生命科学(上海)有限公司 | High-fluidity sitagliptin phosphate monohydrate crystal and preparation method thereof |
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