CN103467445A - Preparation method of alogliptin benzoate - Google Patents
Preparation method of alogliptin benzoate Download PDFInfo
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- CN103467445A CN103467445A CN2012101872681A CN201210187268A CN103467445A CN 103467445 A CN103467445 A CN 103467445A CN 2012101872681 A CN2012101872681 A CN 2012101872681A CN 201210187268 A CN201210187268 A CN 201210187268A CN 103467445 A CN103467445 A CN 103467445A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 229960000447 alogliptin benzoate Drugs 0.000 title abstract 2
- 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 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 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 claims description 21
- 239000000460 chlorine Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 238000005457 optimization Methods 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 9
- 238000009776 industrial production Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 206010012601 diabetes mellitus Diseases 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 238000010992 reflux Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 4
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical class [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 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
- 238000002386 leaching Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- SPSGXIKFKZUBFM-UHFFFAOYSA-N 3-chloro-6-methyl-1H-pyrimidine-2,4-dione Chemical compound ClN1C(NC(=CC1=O)C)=O SPSGXIKFKZUBFM-UHFFFAOYSA-N 0.000 description 1
- PKUFNWPSFCOSLU-UHFFFAOYSA-N 6-chloro-1h-pyrimidine-2,4-dione Chemical compound ClC1=CC(=O)NC(=O)N1 PKUFNWPSFCOSLU-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- IDDAQARKHUGOPH-UHFFFAOYSA-N benzene oxalonitrile Chemical compound C1=CC=CC=C1.N#CC#N IDDAQARKHUGOPH-UHFFFAOYSA-N 0.000 description 1
- 125000006278 bromobenzyl group Chemical group 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 230000005182 global health Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000006362 insulin response pathway Effects 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- GINQYTLDMNFGQP-UHFFFAOYSA-N n,n-dimethylformamide;methylsulfinylmethane Chemical compound CS(C)=O.CN(C)C=O GINQYTLDMNFGQP-UHFFFAOYSA-N 0.000 description 1
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- -1 phenyl aldehyde Chemical class 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a preparation method of alogliptin benzoate (formula 1). The method is easily available in raw materials, mild in reaction conditions, simple in operation and applicable to large-scale industrial production.
Description
Technical field
The present invention relates to the preparation method of medicine, be specifically related to a kind of improved method for preparing SYR-322 (formula I), SYR-322 is the inhibitor of dipeptidyl peptidase-4 (DPP-4), is used for the treatment of type II diabetes.
Background technology
Due to the change of growth in the living standard, dietary structure, rhythm of life and the few moving factors such as mode of life of sitting that day is becoming tight more, whole world onset diabetes rate rapid development, diabetes have become the chronic disease of the third-largest serious threat human health after tumour, cardiovascular pathological changes.Current global diabetic subject has surpassed 1.2 hundred million people, China patient people the second in the world of live in groups, and the onset diabetes rate of China is up to 9.6% at present, and in future 50 years, diabetes will be Chinese serious public health problems.In seeing that from enquiry data Chinese diabetes present situation is very severe, China has become the fastest-rising area of global range diabetes and has become world's diabetes the first big country at present.
Type II diabetes, referring to adult fall ill or non insulin dependent diabetes, is a kind of common disease, and its sickness rate raises gradually in the whole world.The latest data of announcing according to International Diabetes Federation (IDF) shows, the whole world suffers from diabetes at present, has 97% for type II diabetes.Type II diabetes is because the patient is bad or have insulin resistant to insulin response, can't produce enough Regular Insulin.This disease is normal and fat, hypertension is extremely relevant with lipid level.Predicting the year two thousand thirty whole world number of patients will be over 4.35 hundred million people.
Because diabetes have become global health concerns point, for the research interest of this situation, increase sharply.Suppress the treatment approach that DPP-4 is considered to new treatment type II diabetes, in a series of compounds of DPP-4 inhibitor, SYR-322 has shown anti-diabetic effect (WO2005095381) well.Egelieting is a kind of effective DPP-IV inhibitor class medicine in recent years gone on the market in Japan, and its structural formula is as follows:
A kind of method for preparing Egelieting is disclosed in Chinese patent application CN1926128, shown in following route 1:
In this reaction scheme, under NaH and LiBr existence, alkylated reaction, in the DMF-DMSO mixed solvent, occurs and obtains compound 2, yield 54% in 6-chlorouracil and 2-brooethyl benzene cyanogen.With methyl iodide and NaH, alkylated reaction occurring in DMF/THF prepares 1,3-, bis-substituted uracils 3), yield is 72%.The total recovery of this three one step process is in about 20-25%, and yield is lower, and compound 4 purity that prepare are not high, still needs to find that yield is higher is more suitable for the industrial method for preparing Egelieting or its salt.
Summary of the invention
The invention discloses a novel method for preparing SYR-322, the method step is short, reaction conditions is simple, raw material cheaply is easy to get can obtain high-purity product simultaneously.
The preparation method of a kind of SYR-322 provided by the invention comprises the following steps:
The new preparation method of a kind of SYR-322 (formula I), its structural formula is as follows:
The method comprises the following steps:
A) formula 4 compounds and formula 5 compounds obtain formula 6 under the alkali effect;
B) the acid Water Under solution of formula 6 compounds obtains formula 7;
C) formula 7 salifies obtain SYR-322 salt (formula 1).
Preferably, in described step (a): X=Cl in formula 4 compounds, Br.
Preferably, in described step (a): R=H in formula 5 compounds, Cl, Br, the alkyl of C1 ~ C5, the alkoxyl group of C1 ~ C5.
Preferably, the preferred chlorine of X in described step (a) formula 4 compounds.
Preferably, the preferred hydrogen of R in described step (a) formula 5 compounds, chlorine, methyl, more preferably hydrogen.
Preferably, the mol ratio of described step (a) formula 4 compounds and formula 5 compounds is 1:0.8 ~ 1:2; The alcohol that solvent is C1 ~ C5, temperature of reaction is 0 ~ 100 ℃.
Preferably, the preferred 1:1 ~ 1:1.5 of mol ratio of formula 4 compounds and formula 5, more preferably 1:1.2; The solvent particular methanol.
Preferably, in described step (b), hydrolysising condition is acid hydrolysis; The alcohol that organic solvent is C1 ~ C5; Temperature of reaction is 0 ~ 70 ℃.
Preferably, acid hydrolysis condition optimization Yan Suan ﹑ Liu Suan ﹑ tosic acid, more preferably hydrochloric acid in described step (b); The preferred room temperature of temperature of reaction.
Preparation method of the present invention has no bibliographical information, and raw material used in the present invention all can conveniently be buied by commercially available, and also can prepare according to currently known methods (WO 2010109468) by starting raw material (formula 4), be suitable for suitability for industrialized production voluntarily.Preparation method's raw material of the present invention is easy to get, and low price is easy and simple to handle, reaction yield is high, is suitable for suitability for industrialized production.
Embodiment
Below by following examples, the invention will be further elaborated.
Embodiment mono-
The preparation of formula 5:
(R)-3-amino-piperadine (43g) is dissolved in 300mL toluene, and phenyl aldehyde (45g) room temperature is added drop-wise in above-mentioned solution, continues to stir 3 hours, removes toluene under reduced pressure, obtains 78g oily matter, is directly used in next step reaction.
The preparation of formula 4:
In 0 ℃, N
2under protective condition; add 6-methyl-3-chlorouracil (200g) in the 10L there-necked flask; with DMF/DMSO (4.5L; 5/1) solution makes it to dissolve, and adds wherein 60% NaH (54.8g, 1.36mol); stir 30 minutes; add again LiBr (87g, 1mol), continue to stir after 20 minutes; drip wherein adjacent itrile group bromobenzyl (244g; 1.25mol), after reacting 1 hour, move to room temperature and continue reaction; TLC follows the trail of to the raw material complete reaction; remove solvent under reduced pressure, residue adds 1.2L water, with CH
2cl
2extraction (1L * 3 time), merge organic phase, with anhydrous Na
2sO
4drying, filter, and removes solvent under reduced pressure and obtain reddish-brown resistates 380g, with 3 times of amount dehydrated alcohols, refluxes 1 hour, is cooled to room temperature, filters dry 3 hours of filter cake 50 degree.Use again CH
2cl
2(300mL) make it to dissolve under reflux temperature, drip wherein sherwood oil (3L), have a large amount of solids to separate out, stirring at room 2h, filter, and 50 dry 3 hours of degree, obtain 260.7 faint yellow solids (yield 70%, 165 ~ 167 ℃ of fusing points).
1H?NMR(400MHZ,CDCl
3)：δ7.70-7.71(m,1H)，7.58-7.62(m,1H)，7.42-7.45(m,1H)，7.23-7.25(m,1H)，6.00(s,1H)，5.51(s,2H)，3.37(s,3H)。
The preparation of formula 6 and formula 7:
2-(the chloro-3-methyl-2 of 6-, 4-dioxo-3, 4-dihydro-2-H-pyrimidine-1-ylmethyl)-benzyl cyanogen (100g), formula 5 compounds (75.2g) and sodium bicarbonate (193g) and 34g activated molecular sieve (4A) are in anhydrous MeOH (2L), 100 ° of C reflux, stir 3h, point plate to reaction finishes, be cooled to room temperature (25 degree), add 1LHCl(3mol/L) stir 2 hours, until formula 6 compounds disappear, decompression steams methyl alcohol, with 300ml washed with dichloromethane water, remove organic layer, water is regulated PH to 9 with saturated sodium carbonate, add 500mL ethyl acetate extraction product, the organic phase anhydrous sodium sulfate drying, be spin-dried for solvent, obtain thick product yellow solid 226g.
1H?NMR(400MHZ,CDCl
3)：δ7.79-7.82(m,2H)，7.67-7.71(m,3H)，7.52-7.54(m,1H)，7.34-7.36(m,1H)，7.13-7.15(m,1H)，5.43(s,1H)，5.24-5.39(m,2H)，4.28(s,4H)，3.31-3.32(m,1H)，3.28(s,3H)，3.26(s,3H)，3.18-3.22(m,1H)，2.69(m,2H)，2.03-2.06(m,1H)，1.80-1.83(m,1H)，1.61-1.68(m,1H)，1.45-1.47(m,1H)。
The preparation of SYR-322:
Egelieting free alkali (100g) is added to the 200mL ethyl acetate, reflux complete molten after, add the 35.9g phenylformic acid to be dissolved in the solution that the 200mL ethyl acetate becomes, after return stirring 30 minutes, filter the ethyl acetate washing leaching cake, obtain solid 112.4g, yield: 80.6%.Purity: 99.82%, maximum single assorted 0.04.
1H?NMR(400MHZ,CDCl
3)：δ8.00-8.02(m,2H)，7.62-7.63(d,1H)，7.52-7.54(m,2H)，7.48-7.50(m,2H)，7.39-7.43(t,1H)，7.19-7.20(d,1H)，5.35(s,1H)，5.23-5.24(m,2H)，4.46(s,5H)，3.29(s,3H)，3.12-3.14(m,2H)，2.85-2.88(m,1H)，2.58(m,2H)，1.97-1.99(m,2H)，1.77-1.78(m,1H)，1.56-1.58(m,1H)，1.24-1.26(m,1H)。
Chromatographic condition:
Chromatographic column Aglient XDB C184.6*150mm, 5um
Moving phase: methyl alcohol: 0.1%TFA=45:55
Flow velocity: 1.0ml/min
Column temperature: 35 ℃
Detect wavelength: 278nm
Embodiment bis-:
The preparation of formula 5:
(R)-3-amino-piperadine (50g) is dissolved in 300mL toluene, and p-tolyl aldehyde (66g) room temperature is added drop-wise in above-mentioned solution, continues to stir 3 hours, removes toluene under reduced pressure, obtains 81g oily matter, is directly used in next step reaction.
The preparation of formula 6 and formula 7:
2-(the chloro-3-methyl-2 of 6-, 4-dioxo-3, 4-dihydro-2-H-pyrimidine-1-ylmethyl)-benzyl cyanogen (100g), formula 5 compounds (80.7g) and sodium bicarbonate (193g) and 34g activated molecular sieve (4A) are in anhydrous MeOH (2L), 100 ° of C reflux, stir 3h, point plate to reaction finishes, be cooled to room temperature (25 degree), add 1LHCl(3mol/L) stir 2 hours, until formula 6 compounds disappear, decompression steams methyl alcohol, with 300ml washed with dichloromethane water, remove organic layer, water is regulated PH to 9 with saturated sodium carbonate, add 500mL ethyl acetate extraction product, the organic phase anhydrous sodium sulfate drying, be spin-dried for solvent, obtain thick product yellow solid 217g.
1H?NMR(400MHZ,CDCl
3)：δ7.79-7.81(m,2H)，7.68-7.72(m,3H)，7.53-7.55(m,1H)，7.34-7.36(m,1H)，7.13-7.15(m,1H)，5.42(s,1H)，5.23-5.38(m,2H)，4.28(s,4H)，3.31-3.33(m,1H)，3.27(s,3H)，3.26(s,3H)，3.18-3.22(m,1H)，2.69(m,2H)，2.01-2.05(m,1H)，1.80-1.83(m,1H)，1.61-1.67(m,1H)，1.44-1.46(m,1H)。
The preparation of SYR-322:
Egelieting free alkali (100g) is added to the 200mL ethyl acetate, reflux complete molten after, add the 35.9g phenylformic acid to be dissolved in the solution that the 200mL ethyl acetate becomes, after return stirring 30 minutes, filter the ethyl acetate washing leaching cake, obtain solid 100.8g, yield: 74% purity 99.84%, single assorted 0.07%.
The preparation method of a kind of SYR-322 disclosed in this invention, raw material all can conveniently be buied by commercially available, also can prepare voluntarily according to currently known methods (WO 2010109468) by starting raw material (formula 4), be suitable for suitability for industrialized production, the preparation method of a kind of SYR-322 disclosed in this invention, raw material is easy to get, low price, easy and simple to handle, reaction yield is high, is suitable for suitability for industrialized production.
Claims (9)
1. the preparation method of a SYR-322, its structural formula is suc as formula 1:
It is characterized in that, the method comprises the following steps:
A) formula 4 compounds and formula 5 compounds obtain formula 6 under the alkali effect;
B) the acid Water Under solution of formula 6 compounds obtains formula 7;
C) formula 7 salifies obtain SYR-322 salt (formula 1).
2. the preparation method of a kind of SYR-322 according to claim 1, is characterized in that, in described step a), and X=Cl in formula 4 compounds, Br.
3. the preparation method of a kind of SYR-322 according to claim 1, is characterized in that, in described step a), and R=H in formula 5 compounds, Cl, Br, the alkyl of C1 ~ C5, the alkoxyl group of C1 ~ C5.
4. the preparation method of a kind of SYR-322 according to claim 2, is characterized in that, in described step a), and the preferred Cl of X in formula 4 compounds.
5. the preparation method of a kind of SYR-322 according to claim 3, is characterized in that, in described step a), and the preferred hydrogen of R in formula 5 compounds, chlorine, methyl, more preferably hydrogen.
6. according to the preparation method of a kind of SYR-322 of claim 3, it is characterized in that, in described step a), the mol ratio of formula 4 compounds and formula 5 compounds is 1:0.8 ~ 1:2; The alcohol that solvent is C1 ~ C5, temperature of reaction is 0 ~ 100 ℃.
7. according to the preparation method of a kind of SYR-322 of claim 6, it is characterized in that, the mol ratio of formula 4 compounds and formula 5 is 1:1 ~ 1:1.5, more preferably 1:1.2; The solvent particular methanol.
8. the preparation method of a kind of SYR-322 according to claim 1, is characterized in that, in described step b), hydrolysising condition is acid hydrolysis; The alcohol that organic solvent is C1 ~ C5; Temperature of reaction is 0 ~ 70 ℃.
9. according to the method for claim 1, it is characterized in that described step, b) middle acid hydrolysis condition optimization Yan Suan ﹑ Liu Suan ﹑ tosic acid, more preferably hydrochloric acid; The preferred room temperature of temperature of reaction.
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| CN201210187268.1A CN103467445B (en) | 2012-06-08 | 2012-06-08 | Preparation method of alogliptin benzoate |
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| CN103467445B CN103467445B (en) | 2015-02-11 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103819450A (en) * | 2014-01-25 | 2014-05-28 | 浙江永宁药业股份有限公司 | Novel method for preparing alogliptin benzoate |
| CN106749177A (en) * | 2016-12-30 | 2017-05-31 | 湖南千金湘江药业股份有限公司 | A kind of process for purification of SYR-322 |
| CN110642833A (en) * | 2019-09-10 | 2020-01-03 | 株洲千金药业股份有限公司 | Dynamic resolution method of R-configuration alogliptin and preparation method of high-purity R-configuration alogliptin |
| CN110950840A (en) * | 2019-12-31 | 2020-04-03 | 江苏天和制药有限公司 | Preparation method of trelagliptin succinate |
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| US5703208A (en) * | 1994-06-17 | 1997-12-30 | Corvas International, Inc. | 3-amino-2-oxo-1-piperidineacetic derivatives as enzyme inhibitors |
| CN1926128A (en) * | 2004-03-15 | 2007-03-07 | 武田药品工业株式会社 | Dipeptidyl peptidase inhibitors |
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| US5703208A (en) * | 1994-06-17 | 1997-12-30 | Corvas International, Inc. | 3-amino-2-oxo-1-piperidineacetic derivatives as enzyme inhibitors |
| CN1926128A (en) * | 2004-03-15 | 2007-03-07 | 武田药品工业株式会社 | Dipeptidyl peptidase inhibitors |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103819450A (en) * | 2014-01-25 | 2014-05-28 | 浙江永宁药业股份有限公司 | Novel method for preparing alogliptin benzoate |
| CN103819450B (en) * | 2014-01-25 | 2016-08-24 | 浙江永宁药业股份有限公司 | A kind of new preparation process of SYR-322 |
| CN106749177A (en) * | 2016-12-30 | 2017-05-31 | 湖南千金湘江药业股份有限公司 | A kind of process for purification of SYR-322 |
| CN110642833A (en) * | 2019-09-10 | 2020-01-03 | 株洲千金药业股份有限公司 | Dynamic resolution method of R-configuration alogliptin and preparation method of high-purity R-configuration alogliptin |
| CN110950840A (en) * | 2019-12-31 | 2020-04-03 | 江苏天和制药有限公司 | Preparation method of trelagliptin succinate |
| CN110950840B (en) * | 2019-12-31 | 2022-03-15 | 江苏天和制药有限公司 | Preparation method of trelagliptin succinate |
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| CN103467445B (en) | 2015-02-11 |
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