CN103435538A - (R)-3-amino piperidine hydrochloride preparation method - Google Patents
(R)-3-amino piperidine hydrochloride preparation method Download PDFInfo
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- CN103435538A CN103435538A CN201310343679XA CN201310343679A CN103435538A CN 103435538 A CN103435538 A CN 103435538A CN 201310343679X A CN201310343679X A CN 201310343679XA CN 201310343679 A CN201310343679 A CN 201310343679A CN 103435538 A CN103435538 A CN 103435538A
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- amido
- alcohol
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- ITYKBOIQLYMDTI-NUBCRITNSA-N (3r)-piperidin-3-amine;hydrochloride Chemical compound Cl.N[C@@H]1CCCNC1 ITYKBOIQLYMDTI-NUBCRITNSA-N 0.000 title abstract 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 56
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000000243 solution Substances 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000011259 mixed solution Substances 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 93
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 229960002510 mandelic acid Drugs 0.000 claims description 27
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 238000002156 mixing Methods 0.000 claims description 17
- 230000006340 racemization Effects 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 230000035484 reaction time Effects 0.000 claims description 15
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 13
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 238000000605 extraction Methods 0.000 claims description 11
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- 239000007844 bleaching agent Substances 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 8
- 239000011707 mineral Substances 0.000 claims description 8
- 235000010755 mineral Nutrition 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 7
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 7
- 229940011051 isopropyl acetate Drugs 0.000 claims description 7
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 235000015320 potassium carbonate Nutrition 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 5
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 5
- 229940093916 potassium phosphate Drugs 0.000 claims description 5
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 5
- 235000011009 potassium phosphates Nutrition 0.000 claims description 5
- 235000017550 sodium carbonate Nutrition 0.000 claims description 5
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 5
- 239000012044 organic layer Substances 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 21
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 abstract 2
- SUOFSJISCGONMN-SECBINFHSA-N 1-[(3R)-3-aminopiperidin-1-yl]pentan-1-one Chemical compound C(CCCC)(=O)N1C[C@@H](CCC1)N SUOFSJISCGONMN-SECBINFHSA-N 0.000 abstract 2
- 239000005708 Sodium hypochlorite Substances 0.000 abstract 1
- 230000001105 regulatory effect Effects 0.000 abstract 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 27
- 230000006837 decompression Effects 0.000 description 16
- 238000003756 stirring Methods 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 235000011152 sodium sulphate Nutrition 0.000 description 12
- 230000003287 optical effect Effects 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 8
- 239000002994 raw material Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 238000011084 recovery Methods 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 230000001476 alcoholic effect Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- JMQGGPRJQOQKRT-UHFFFAOYSA-N diphenyl hydrogen phosphate;azide Chemical compound [N-]=[N+]=[N-].C=1C=CC=CC=1OP(=O)(O)OC1=CC=CC=C1 JMQGGPRJQOQKRT-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- XIWBSOUNZWSFKU-UHFFFAOYSA-N ethyl piperidine-3-carboxylate Chemical compound CCOC(=O)C1CCCNC1 XIWBSOUNZWSFKU-UHFFFAOYSA-N 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- -1 piperidines acetate Chemical class 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- WQKGAJDYBZOFSR-UHFFFAOYSA-N potassium;propan-2-olate Chemical compound [K+].CC(C)[O-] WQKGAJDYBZOFSR-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- LMHHRCOWPQNFTF-UHFFFAOYSA-N s-propan-2-yl azepane-1-carbothioate Chemical compound CC(C)SC(=O)N1CCCCCC1 LMHHRCOWPQNFTF-UHFFFAOYSA-N 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- YONLFQNRGZXBBF-KBPBESRZSA-N (2s,3s)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-KBPBESRZSA-N 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000013456 study Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Landscapes
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of organic synthesis, particularly relates to an (R)-3-amino piperidine hydrochloride preparation method, and aims to solve the technical problems about high cost, relatively low yield and difficulty in industrialization in an existing synthesis method. The technical scheme to solve the technical problems by the invention is to provide the (R)-3-amino piperidine hydrochloride preparation method. The preparation method comprises the following steps: a, enabling D-mandelic acid and racemic 3-piperidine amide to react in an organic solvent to generate D-mandelic acid organic salt of (R)-3-piperidine amide; b, regulating the pH of the product prepared in the step a to 10-11 and enabling the product to react with pivaloyl chloride to prepare (R)-N-valeryl-3-piperidine amide; c, enabling the (R)-N-valeryl-3-piperidine amide to react in a sodium hypochlorite solution to prepare the product (R)-N-valeryl-3-amino piperidine; d, enabling the (R)-N-valeryl-3-amino piperidine to react in a mixed solution of hydrochloric acid and alcohol to prepare the (R)-3-amino piperidine hydrochloride. The invention provides the novel method with low cost and high yield for preparing the (R)-3-amino piperidine hydrochloride.
Description
Technical field
The invention belongs to the organic synthesis field, be specifically related to the preparation method of (R)-3-amido piperidine hydrochlorate.
Technical background
(R)-3-amido piperidine hydrochlorate is the crucial chiral intermediate of synthetic treatment type ii diabetes medicine BI 1356 and Egelieting.Diabetes are one of maximum diseases of harm humans health.The whole world is died from every year on average the cardiovascular and cerebrovascular patient and is surpassed more than 1,500 ten thousand people.In developed country's II diabetes, are second largest reasons of crowd's death.
Clinical studyes show in a large number, and antidiabetic thing BI 1356 and Egelieting are one of best medicines for the treatment of diabetes.This medicine is efficient, safety, is the choice drug of hypoglycemic.In addition, these two medicines can also be for preventing fracture, treatment osteoporosis, being used as immunomodulator etc.
At present, the method for having reported synthetic (R)-3-amido piperidine hydrochlorate mainly contains following two lines:
The first: be disclosed in WO0300496, this route be take ethyl nipecotate as starting raw material, through D-tartrate, splits, repeatedly after crystallization, dissociate, upper benzyl makes (R) N-benzyl-ethyl nipecotate, and this ester makes acid through hydrolysis, and acid is again through reacting with diphenyl phosphate azide, reset simultaneously, make (R)-1-N-benzyl-3-N-tertbutyloxycarbonyl-amino piperidine, then pass through debenzylation and de-tertbutyloxycarbonyl and salify, make (R)-3-amido piperidine hydrochlorate.The shortcoming of this route is: 1) the starting raw material ethyl nipecotate is more expensive, and the diphenyl phosphate azide used in addition is also very expensive chemical reagent; 2) when splitting, need repeatedly recrystallization, can make optical purity (R)-3-amido piperidine hydrochlorate; 3) route is long.In a word, this route steps is relatively many, and the chemical reagent of starting material and use is more expensive, and overall yield is low, and total recovery is less than 10%, and cost is high.Its reaction formula is:
It two is to be disclosed in WO2011160037.This route be take the 3-aminopyridine as starting raw material; first pass through acetylize; hydrogenation makes 3-N-acetylamino piperidines acetate, this salt under the effect of concentrated hydrochloric acid, deacetylate; make the 3-amido piperidine hydrochlorate; this salt through alkaline hydrolysis from, then split by the D-dibenzoyl tartaric acid, repeatedly after crystallization; be dissociated into hydrochloride, make (R)-3-amido piperidine hydrochlorate.The shortcoming of this route is: 1) need high-pressure hydrogenation, palladium carbon consumption is relatively large; 2) when splitting, need repeatedly recrystallization, can make optical purity (R)-3-amido piperidine hydrochlorate; 3) route is relatively long.In a word, this route steps is relatively many, and overall yield is low, and total recovery is less than 20%, and cost is high, is not easy to industrialization.Its reaction formula is:
Summary of the invention
The technical problem to be solved in the present invention is that existing synthetic method cost is high, yield is lower, is difficult to industrialization.
The technical scheme that the present invention solves the problems of the technologies described above is to provide a kind of preparation method of (R)-3-amido piperidine hydrochlorate, comprises the following steps:
A, the 3-piperidine amides of D-amygdalic acid and racemization is reacted in organic solvent, filter after reaction finishes, obtain the D-amygdalic acid organic salt of (R)-3-piperidine amides;
B, organic salt that step a is obtained in the mixing solutions of alcohol and water with mineral alkali adjust pH to 10～11, then with the pivaloyl chloride reaction, after reaction finishes, reaction solution is through extraction, drying is concentrated into dryly, obtains (R)-N-pivaloyl group-3-piperidine amides;
C, (R)-N-pivaloyl group-3-piperidine amides is reacted in the chlorine bleach liquor, after reaction finishes, reaction solution is through extraction, and organic layer drying, distillation, obtain product (R)-N-pivaloyl group-3-amino piperidine;
D, (R)-N-pivaloyl group-3-amino piperidine is reacted in hydrochloric acid and pure mixing solutions, make (R)-3-amido piperidine hydrochlorate.
Wherein, in preparation method's step a of above-mentioned (R)-3-amido piperidine hydrochlorate, the mol ratio of described D-amygdalic acid and 3-piperidine amides is 1.05: 1～2.0: 1.Preferably, the mol ratio of D-amygdalic acid and 3-piperidine amides is 1.1: 1～1.5: 1.
Wherein, in aforesaid method step a, described organic solvent is: the mixed solution of a kind of composition in a kind of and toluene in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, methylene dichloride, methyl tertiary butyl ether, tetrahydrofuran (THF), dioxane, acetone, butanone, ethyl acetate, isopropyl acetate, the volume ratio of mixing is 1: 1.
Wherein, in aforesaid method step a, described temperature of reaction is 20～100 ℃, and the reaction times is 1～24 hour.Preferably, temperature of reaction is 30～80 ℃, and the reaction times is 5～12 hours.
Wherein, in aforesaid method step b, described mineral alkali is: a kind of in sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, potassiumphosphate.
Wherein, in aforesaid method step b, described alcohol is: a kind of in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol.
Wherein, in aforesaid method step b, temperature described and the pivaloyl chloride reaction is-20～80 ℃, and the time is 1～24 hour.Preferably, temperature of reaction is 0～30 ℃, and the reaction times is 5～12 hours.
Wherein, in aforesaid method step c, described chlorine bleach liquor's mass concentration is 2%～30%; Preferably, chlorine bleach liquor's mass concentration is 5～15%.
Wherein, in aforesaid method step c, described temperature of reaction is 0～100 ℃, and the reaction times is 1～24 hour.Preferably, temperature of reaction is 20～70 ℃, and the reaction times is 5～12 hours.
Wherein, in the step b and c of aforesaid method, described extraction solvent used is a kind of in methylene dichloride, ether, methyl tertiary butyl ether, butanone, ethyl acetate, isopropyl acetate.
Wherein, in the aforesaid method steps d, described concentration of hydrochloric acid is 10%～35%.Preferably, concentration of hydrochloric acid is 15～30%.
Wherein, in the aforesaid method steps d, described alcohol is a kind of in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol.
Wherein, in the aforesaid method steps d, described hydrochloric acid and pure mixing solutions, the volume ratio of its mixing is Yan Suan ︰ alcohol=1: 0.5～1:10.
Wherein, in the aforesaid method steps d, described temperature of reaction is 0～100 ℃, and the reaction times is 1～48 hour.Preferably, temperature of reaction is 20～70 ℃, and the reaction times is 5～24 hours.
Further, in the preparation method of above-mentioned (R)-3-amido piperidine hydrochlorate, can be by step a mother liquor after filtering concentrate, remove organic solvent, use mineral alkali adjust pH to 10～11 in water, to contain S is configured as main 3-piperidine amides and extracts, the organic layer drying, be concentrated into dry, add alcoholic solvent, add again organic alkali to be reacted, after reaction finishes, add the shrend reaction of going out, organic solvent is extracted, dry, the concentrated 3-piperidine amides that makes racemization, can continue to make with the D-amygdalic acid organic salt of D-amygdalic acid and (R)-3-piperidine amides.Wherein, described alcoholic solvent is a kind of in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol; The volume ratio Wei Chun ︰ water of its mixing=1～1 ︰ 1～20; Described mineral alkali be a kind of in sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, potassiumphosphate; Described organic alkali is a kind of in sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, sodium propylate, potassium propylate, sodium isopropylate, potassium isopropoxide, sodium tert-butoxide, potassium tert.-butoxide; The described temperature that adds organic alkali to be reacted is 10～120 ℃, and the time is 1～24 hour; Preferably, temperature of reaction is 30～90 ℃, and the reaction times is 6～12 hours.
The principal reaction formula the present invention relates to is:
Beneficial effect of the present invention is: technical scheme provided by the invention, synthetic route is novel, brief, the reaction conditions gentleness, be easy to suitability for industrialized production, production cost is low, raw material of the present invention cheaply is easy to get simultaneously, raw material availability is high, (S)-3-piperidine amides can be recycled in racemization, it is high that each walks reaction yield, the optical purity of product >=99.5%, the 3-piperidine amides utilization ratio of racemization of take is 80% calculating, the total recovery of method preparation (R)-3-amido piperidine hydrochlorate provided by the invention can reach 57.5% left and right.
Embodiment
(R) preparation method of-3-amido piperidine hydrochlorate comprises the following steps:
A, by the 3-piperidine amides of D-amygdalic acid and racemization in organic solvent, under 30～80 ℃, react and within 5～12 hours, make D-amygdalic acid and (R)-3-piperidine amides organic salt precipitation, filter, obtain the D-amygdalic acid organic salt of (R)-3-piperidine amides;
B, by the D-amygdalic acid and (R)-3-piperidine amides organic salt through in the mixing solutions of alcohol and water with inorganic tune pH to 10～11, with pivaloyl chloride, react again, under 0～30 ℃, react 5～12 hours, reaction is extracted with organic solvent after finishing, drying, concentrated (the R)-N-pivaloyl group-3-piperidine amides that makes;
C, by (R)-N-pivaloyl group-3-piperidine amides in 5～15% chlorine bleach liquor; under 20～70 ℃, react 5～12 hours, after reaction finishes; with organic solvent, extracted, organic layer drying, underpressure distillation go out product (R)-N-pivaloyl group-3-amino piperidine.
D, by (R)-N-pivaloyl group-3-amino piperidine in 15～30% hydrochloric acid and pure mixing solutions, in 20～70 ℃, react 5～24 hours; after reaction finishes, the finished product are separated out, suction filtration; decompression drying, make (R)-3-amido piperidine hydrochlorate.
Wherein, in preparation method's step a of above-mentioned (R)-3-amido piperidine hydrochlorate, the mol ratio of described D-amygdalic acid and 3-piperidine amides is 1.05: 1～2.0: 1, is preferably 1.1: 1～1.5: 1;
Wherein, in aforesaid method step a, described organic solvent is: the mixed solution of a kind of composition in a kind of and toluene in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, methylene dichloride, methyl tertiary butyl ether, tetrahydrofuran (THF), dioxane, acetone, butanone, ethyl acetate, isopropyl acetate, the volume ratio of mixing is 1: 1.
Wherein, in aforesaid method step b, described mineral alkali is: a kind of in sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, potassiumphosphate.
Wherein, in aforesaid method step b, described alcohol is: a kind of in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol.
Wherein, in the step b and c of aforesaid method, described extraction solvent used is a kind of in methylene dichloride, ether, methyl tertiary butyl ether, butanone, ethyl acetate, isopropyl acetate.
Wherein, in the aforesaid method steps d, described alcohol is a kind of in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol.
Wherein, in the aforesaid method steps d, described hydrochloric acid and pure mixing solutions, the volume ratio of its mixing is Yan Suan ︰ alcohol=1 ︰ 0.5～1 ︰ 10.
Further, the mother liquor of step a can be concentrated, in water with inorganic adjusting PH with base to 10～11, take out and to contain S and be configured as main 3-piperidine amides and extract with organic solvent extracting, dry, concentrated, add alcoholic solvent, then add organic alkali to be reacted, under 30～90 ℃, react 6～12 hours, after reaction finishes, add the shrend reaction of going out, organic solvent is extracted, drying, the concentrated 3-piperidine amides made after racemization, can continue to make with the D-amygdalic acid organic salt of D-amygdalic acid and (R)-3-piperidine amides.Wherein, described alcoholic solvent is a kind of in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol; The volume ratio Wei Chun ︰ water of its mixing=1～1 ︰ 1～20; Described mineral alkali be a kind of in sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, potassiumphosphate; Described organic alkali is a kind of in sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, sodium propylate, potassium propylate, sodium isopropylate, potassium isopropoxide, sodium tert-butoxide, potassium tert.-butoxide.
For the ease of detecting the optical purity of the finished product (R)-3-amido piperidine hydrochlorate, need on 1,3 nitrogen of (R)-3-amido piperidine hydrochlorate, with tertbutyloxycarbonyl, replace respectively.Testing conditions is: chiral chromatographic column: chiralpak AD-H4.6 * 250; Detector; UV-detector; Moving phase; Normal hexane; Flow velocity; 1.0 ml/min; Wavelength: 215 nanometers; Column temperature: room temperature.
Embodiment 1
A, the 3-piperidine amides of the D-amygdalic acid of 51.0 grams and 29.0 gram racemizations is joined in 500 milliliters of reaction flasks, add the methyl tert-butyl ether of 80 milliliters and the Virahol of 80 milliliters again in reaction flask, be heated to 70 ℃, react 6 hours, reaction finishes nature and is cooled to 20 ℃, at this temperature, stir 3 hours, a large amount of solids are separated out, suction filtration, decompression drying, obtain D-amygdalic acid organic salt 26.7 grams of (R)-3-piperidine amides, yield 42.0%.
B, organic salt by the D-amygdalic acid of 26.7 grams and (R)-3-piperidine amides, the sodium hydroxide of 10 grams joins in 500 milliliters of reaction flasks, add the ethanol of 90 milliliters and the water of 60 milliliters again in reaction flask, after adding, stir after 30 minutes, the pivaloyl chloride that adds 13.0 grams, under 5 ℃, reaction is 10 hours, TLC follows the tracks of after completion of the reaction, to the shrend that adds 120 grams in the reaction solution reaction of going out, use the t-butyl methyl ether extraction product, add gac, after dried over sodium sulfate, filter, concentrating under reduced pressure falls solvent, obtain product (R)-N-pivaloyl group-3-piperidine amides 19.0 grams, yield 94.0%.
C, (R)-N-pivaloyl group of 19.0 grams-3-piperidine amides is joined in 500 milliliters of reaction flasks; add again 200 milliliters of 6% chlorine bleach liquores; be heated to 45 ℃; react 10 hours; TLC follows the tracks of reaction; after completion of the reaction, be cooled to room temperature, to the shrend that adds 150 grams in the reaction solution reaction of going out; be extracted with ethyl acetate product; add gac, after dried over sodium sulfate, filter; filtrate decompression concentrates solvent; decompression steams product, obtains product (R)-N-pivaloyl group-3-amino piperidine 16.1 grams, yield 85.0%.
D, 16.1 grams (R)-N-pivaloyl group-3-amino piperidine is joined in the reaction flask of 500 milliliters; add again the n-propyl alcohol of 70 milliliters of 25% hydrochloric acid and 90 milliliters, be heated to 55 ℃, react 12 hours; reaction finishes nature and is cooled to 25 ℃; at this temperature, stir 2 hours, a large amount of solids are separated out, suction filtration; decompression drying; obtain (R)-3-amido piperidine hydrochlorate of product 13.6 grams, yield 90.3%, optical purity 99.6%.
In addition, the remaining filtrated stock by step a, be evaporated to dryly, adds water and the 10.0 gram sodium hydroxide of 150 grams, after stirring 20 minutes, by ethyl acetate, extracted, and after dried over sodium sulfate, filters, and concentrating under reduced pressure falls solvent; To the ethanol that adds 65 milliliters in the product after concentrated, add again 12.0 gram sodium ethylates, be heated to, under 78 degree, react 9 hours, after being down to room temperature, add 250 gram water, be extracted with ethyl acetate the 3-piperidine amides after racemization, after dried over sodium sulfate, filter, concentrating under reduced pressure falls solvent, obtains 3-piperidine amides 16.4 grams of racemization, the rate of recovery 56.6%.
The 3-piperidine amides of 16.4 gram racemizations of above-mentioned gained and 20.5 gram D-amygdalic acids are joined in the reaction flask of 250 milliliters, add the isopropyl acetate of 45 milliliters and the propyl carbinol of 45 milliliters again in reaction flask, be heated to 70 ℃, react 5 hours, reaction is cooled to 20 ℃ after finishing naturally, at this temperature, stir 2 hours, a large amount of solids are separated out, suction filtration, decompression drying, obtain D-amygdalic acid organic salt 15.1 grams of (R)-3-piperidine amides, yield 41.0%.
Embodiment 2
A, the 3-piperidine amides of the D-amygdalic acid of 18.0 grams and 14.0 gram racemizations is joined in 250 milliliters of reaction flasks, add the ethyl acetate of 40 milliliters and the n-propyl alcohol of 40 milliliters again in reaction flask, be heated to 65 ℃, react 4 hours, reaction finishes nature and is cooled to 20 ℃, at this temperature, stir 2 hours, a large amount of solids are separated out, suction filtration, decompression drying, obtain D-amygdalic acid organic salt 12.7 grams of (R)-3-piperidine amides, yield 41.5%.
B, organic salt by the D-amygdalic acid of 12.7 grams and (R)-3-piperidine amides, the sodium carbonate of 13 grams joins in 250 milliliters of reaction flasks, add the ethanol of 25 milliliters and the water of 30 milliliters again in reaction flask, after adding, stir after 20 minutes, the pivaloyl chloride that adds 7.0 grams, under 10 ℃, reaction is 8 hours, TLC follows the tracks of after completion of the reaction, to the shrend that adds 70 grams in the reaction solution reaction of going out, use the dichloromethane extraction product, add gac, after dried over sodium sulfate, filter, filtrate decompression concentrates solvent, obtain product (R)-N-pivaloyl group-3-piperidine amides 9.1 grams, yield 94.0%.
C, (R)-N-pivaloyl group of 9.1 grams-3-piperidine amides is joined in 250 milliliters of reaction flasks; add again 100 milliliters of 8% chlorine bleach liquores; be heated to 60 ℃; react 6 hours; TLC follows the tracks of reaction; after completion of the reaction, be cooled to room temperature, to the shrend that adds 90 grams in the reaction solution reaction of going out; use the t-butyl methyl ether extraction product; add gac, after dried over sodium sulfate, filter; filtrate decompression concentrates solvent; decompression steams product, obtains product (R)-N-pivaloyl group-3-amino piperidine 6.8 grams, yield 86.0%.
D, 6.8 grams (R)-N-pivaloyl group-3-amino piperidine is joined in the reaction flask of 250 milliliters; add again the ethanol of 20 milliliters of 30% hydrochloric acid and 40 milliliters, be heated to 65 ℃, react 8 hours; reaction finishes nature and is cooled to 20 ℃; at this temperature, stir 1 hour, a large amount of solids are separated out, suction filtration; decompression drying; obtain (R)-3-amido piperidine hydrochlorate of product 5.8 grams, yield 91.5%, optical purity 99.7%.
In addition, the remaining filtrated stock by step a, be evaporated to dryly, adds water and the 7.0 gram sodium hydroxide of 100 grams, after stirring 20 minutes, by ethyl acetate, extracted, and after dried over sodium sulfate, filters, and concentrating under reduced pressure falls solvent; To the propyl carbinol that adds 30 milliliters in the product after concentrated, add again 6.0 gram sodium methylates, be heated to, under 90 degree, react 7 hours, after being down to room temperature, add 100 gram water, be extracted with ethyl acetate the 3-piperidine amides after racemization, after dried over sodium sulfate, filter, concentrating under reduced pressure falls solvent, obtains 3-piperidine amides 7.7 grams of racemization, the rate of recovery 55.0%.
Embodiment 3
A, the 3-piperidine amides of the D-amygdalic acid of 490 grams and 280 gram racemizations is joined in 3000 milliliters of reaction flasks, add the ethyl acetate of 900 milliliters and the ethanol of 900 milliliters again in reaction flask, be heated to 60 ℃, react 10 hours, reaction finishes nature and is cooled to 15 ℃, at this temperature, stir 4 hours, a large amount of solids are separated out, suction filtration, decompression drying, obtain D-amygdalic acid organic salt 263.4 grams of (R)-3-piperidine amides, yield 43.0%.
B, organic salt by the D-amygdalic acid of 263.4 grams and (R)-3-piperidine amides, the salt of wormwood of 300 grams joins in 2000 milliliters of reaction flasks, add the methyl alcohol of 600 milliliters and the water of 900 milliliters again in reaction flask, after adding, stir after 40 minutes, the pivaloyl chloride that adds 117.5 grams, under 15 ℃, reaction is 12 hours, TLC follows the tracks of after completion of the reaction, to the shrend that adds 800 grams in the reaction solution reaction of going out, be extracted with ethyl acetate product, add gac, after dried over sodium sulfate, filter, filtrate decompression concentrates solvent, obtain product (R)-N-pivaloyl group-3-piperidine amides 184.7 grams, yield 92.6%.
C, (R)-N-pivaloyl group of 184.7 grams-3-piperidine amides is joined in 2000 milliliters of reaction flasks; add again 900 milliliters of 10% chlorine bleach liquores; be heated to 55 ℃; react 11 hours; TLC follows the tracks of reaction; after completion of the reaction, be cooled to room temperature, to the shrend that adds 700 grams in the reaction solution reaction of going out; use the dichloromethane extraction product; add gac, after dried over sodium sulfate, filter; filtrate decompression concentrates solvent; decompression steams product, obtains product (R)-N-pivaloyl group-3-amino piperidine 134.2 grams, yield 83.7%.
D, 134.2 grams (R)-N-pivaloyl group-3-amino piperidine is joined in the reaction flask of 2000 milliliters; add again the butanols of 600 milliliters of 30% hydrochloric acid and 750 milliliters, be heated to 45 ℃, react 28 hours; reaction finishes nature and is cooled to 15 ℃; at this temperature, stir 4 hours, a large amount of solids are separated out, suction filtration; decompression drying; obtain (R)-3-amido piperidine hydrochlorate of product 113.0 grams, yield 90.1%, optical purity 99.5%.
In addition, the remaining filtrated stock by step a, be evaporated to dryly, adds water and the 130.0 gram sodium hydroxide of 1200 grams, after stirring 30 minutes, by ethyl acetate, extracted, and after dried over sodium sulfate, filters, and concentrating under reduced pressure falls solvent; To the trimethyl carbinol that adds 600 milliliters in the product after concentrated, add again 150 gram sodium tert-butoxides, be heated to, under 82 degree, react 8 hours, after being down to room temperature, add 1000 gram water, be extracted with ethyl acetate the 3-piperidine amides after racemization, after dried over sodium sulfate, filter, concentrating under reduced pressure falls solvent, obtains 3-piperidine amides 156.2 grams of racemization, the rate of recovery 55.8%.
Above experiment shows, technical scheme provided by the invention, and new technology, brief, be easy to suitability for industrialized production, and production cost is low simultaneously, and raw material of the present invention cheaply is easy to get, and raw material availability is high, and it is high that each walks reaction yield, the optical purity of product >=99.5%.
Claims (11)
1. the preparation method of (R)-3-amido piperidine hydrochlorate comprises the following steps:
A, the 3-piperidine amides of D-amygdalic acid and racemization is reacted in organic solvent, filter after reaction finishes, obtain the D-amygdalic acid organic salt of (R)-3-piperidine amides;
B, organic salt that step a is obtained in the mixing solutions of alcohol and water with mineral alkali adjust pH to 10～11, then with the pivaloyl chloride reaction, after reaction finishes, reaction solution is through extraction, drying is concentrated into dryly, obtains (R)-N-pivaloyl group-3-piperidine amides;
C, (R)-N-pivaloyl group-3-piperidine amides is reacted in the chlorine bleach liquor, after reaction finishes, reaction solution is through extraction, and organic layer drying, distillation, obtain product (R)-N-pivaloyl group-3-amino piperidine;
D, (R)-N-pivaloyl group-3-amino piperidine is reacted in hydrochloric acid and pure mixing solutions, make (R)-3-amido piperidine hydrochlorate.
2. the preparation method of (R)-3-amido piperidine hydrochlorate according to claim 1, it is characterized in that: in step a, the mol ratio of described D-amygdalic acid and 3-piperidine amides is 1.05: 1～2.0: 1; Preferably, the mol ratio of D-amygdalic acid and 3-piperidine amides is 1.1: 1～1.5: 1.
3. the preparation method of (R)-3-amido piperidine hydrochlorate according to claim 1, it is characterized in that: in step a, described organic solvent is: the mixed solution of a kind of composition in a kind of and toluene in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, methylene dichloride, methyl tertiary butyl ether, tetrahydrofuran (THF), dioxane, acetone, butanone, ethyl acetate, isopropyl acetate, the volume ratio of mixing is 1: 1.
4. the preparation method of (R)-3-amido piperidine hydrochlorate according to claim 1, it is characterized in that: in step a, described temperature of reaction is 20～100 ℃; The described reaction times is 1～24 hour; Preferably, temperature of reaction is 30～80 ℃; The preferred reaction time is 5～12 hours.
5. the preparation method of (R)-3-amido piperidine hydrochlorate according to claim 1, it is characterized in that: in step b, described mineral alkali is a kind of in sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, potassiumphosphate; Described alcohol is a kind of in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol.
6. the preparation method of (R)-3-amido piperidine hydrochlorate according to claim 1 is characterized in that: in step b, temperature described and the pivaloyl chloride reaction is-20～80 ℃, and the time is 1～24 hour; Preferably, temperature of reaction is 0～30 ℃, and the reaction times is 5～12 hours.
7. the preparation method of (R)-3-amido piperidine hydrochlorate according to claim 1, it is characterized in that: in step c, described chlorine bleach liquor's mass concentration is 2%～30%; Preferably, chlorine bleach liquor's mass concentration is 5～15%.
8. the preparation method of (R)-3-amido piperidine hydrochlorate according to claim 1, it is characterized in that: in step c, described temperature of reaction is 0～100 ℃, and the reaction times is 1～24 hour; Preferably, temperature of reaction is 20～70 ℃, and the reaction times is 5～12 hours.
9. the preparation method of (R)-3-amido piperidine hydrochlorate according to claim 1, it is characterized in that: in step b and c, described extraction solvent used is a kind of in methylene dichloride, ether, methyl tertiary butyl ether, butanone, ethyl acetate, isopropyl acetate.
10. the preparation method of (R)-3-amido piperidine hydrochlorate according to claim 1, it is characterized in that: in steps d, described concentration of hydrochloric acid is 10%～35%; Preferably, concentration of hydrochloric acid is 15～30%; Described alcohol is a kind of in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol; Described hydrochloric acid and pure mixing solutions, the volume ratio of its mixing is Yan Suan ︰ alcohol=1: 0.5～1:10.
11. the preparation method of (R)-3-amido piperidine hydrochlorate according to claim 1 is characterized in that: in steps d, described temperature of reaction is 0～100 ℃, and the reaction times is 1～48 hour; Preferably, temperature of reaction is 20～70 ℃, and the reaction times is 5～24 hours.
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| CN106831540A (en) * | 2017-03-09 | 2017-06-13 | 爱斯特（成都）生物制药股份有限公司 | It is a kind of（S）The preparation method of 3 piperidine carboxylic acids |
| CN108409639A (en) * | 2018-04-23 | 2018-08-17 | 爱斯特（成都）生物制药股份有限公司 | (S) preparation of -3-Boc- aminomethylpiperidines and structural confirmation new method |
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Effective date of registration: 20150820 Address after: Chengdu City, Wenjiang province 611137 Sichuan Strait science and Technology Industry Development Park No. 488 West Ke Lin Lu Applicant after: AstaTech (Chengdu) Pharmaceutical Co.,Ltd. Address before: 610064 No. 9, South Garden Road, Chengdu hi tech Zone, Sichuan, 1 Applicant before: ASTATECH (CHENGDU) PHARMACEUTICAL Co.,Ltd. |
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| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C53 | Correction of patent of invention or patent application | ||
| CI01 | Publication of corrected invention patent application |
Correction item: Patentee|Address Correct: AstaTech (Chengdu) Pharmaceutical Co., Ltd.|Chengdu City, Wenjiang province 611137 Sichuan Strait science and Technology Industry Development Park No. 488 West Ke Lin Lu False: AstaTech (Chengdu) Pharmaceutical Co., Ltd.|610064 No. 9, South Garden Road, Chengdu hi tech Zone, Sichuan, 1 Number: 43 Volume: 31 |
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| CI03 | Correction of invention patent |
Correction item: Patentee|Address Correct: AstaTech (Chengdu) Pharmaceutical Co., Ltd.|Chengdu City, Wenjiang province 611137 Sichuan Strait science and Technology Industry Development Park No. 488 West Ke Lin Lu False: AstaTech (Chengdu) Pharmaceutical Co., Ltd.|610064 No. 9, South Garden Road, Chengdu hi tech Zone, Sichuan, 1 Number: 43 Page: The title page Volume: 31 |
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| ERR | Gazette correction | ||
| C56 | Change in the name or address of the patentee | ||
| CP03 | Change of name, title or address |
Address after: Wenjiang District 610000 of Sichuan city of Chengdu province Chengdu Strait science and Technology Industry Development Park No. 488 West Ke Lin Lu Patentee after: ASTATECH (CHENGDU) BIOPHARMACEUTICAL Corp. Address before: Chengdu City, Wenjiang province 611137 Sichuan Strait science and Technology Industry Development Park No. 488 West Ke Lin Lu Patentee before: AstaTech (Chengdu) Pharmaceutical Co.,Ltd. |
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| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Process for the preparation of (R) -3- piperidine hydrochloride Effective date of registration: 20170822 Granted publication date: 20151028 Pledgee: Chengdu SME financing Company Limited by Guarantee Pledgor: ASTATECH (CHENGDU) BIOPHARMACEUTICAL Corp. Registration number: 2017510000052 |
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| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20180801 Granted publication date: 20151028 Pledgee: Chengdu SME financing Company Limited by Guarantee Pledgor: ASTATECH (CHENGDU) BIOPHARMACEUTICAL Corp. Registration number: 2017510000052 |