CN103435538B - (R) preparation method of-3-amido piperidine hydrochlorate - Google Patents
(R) preparation method of-3-amido piperidine hydrochlorate Download PDFInfo
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 90
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 62
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 31
- 229960002510 mandelic acid Drugs 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 238000002156 mixing Methods 0.000 claims abstract description 18
- 230000006340 racemization Effects 0.000 claims abstract description 18
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000007844 bleaching agent Substances 0.000 claims abstract description 11
- 239000000460 chlorine Substances 0.000 claims abstract description 11
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 11
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims abstract description 9
- 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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 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
- 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
- 238000001914 filtration Methods 0.000 claims description 3
- 239000011259 mixed solution Substances 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 4
- 238000005516 engineering process Methods 0.000 abstract description 3
- 238000010189 synthetic method Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 27
- 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
- 230000006837 decompression Effects 0.000 description 11
- 239000000284 extract Substances 0.000 description 8
- 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
- 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
- 239000002253 acid Substances 0.000 description 4
- 230000001476 alcoholic effect Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 206010012601 diabetes mellitus Diseases 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
- 150000007513 acids Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 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
- 229940079593 drug Drugs 0.000 description 2
- XIWBSOUNZWSFKU-UHFFFAOYSA-N ethyl piperidine-3-carboxylate Chemical compound CCOC(=O)C1CCCNC1 XIWBSOUNZWSFKU-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000012452 mother liquor Substances 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
- 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
- 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
- -1 piperidines acetate Chemical class 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000007858 starting material Substances 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 organic synthesis field, be specifically related to the preparation method of (R)-3-amido piperidine hydrochlorate.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 the preparation method of one (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 the D-amygdalic acid organic salt of generation (R)-3-piperidine amides; B, by the product of step a through toning pH to 10 ~ 11, then with pivaloyl chloride reaction, obtained (R)-N-pivaloyl group-3-piperidine amides; C, (R)-N-pivaloyl group-3-piperidine amides are obtained by reacting product (R)-N-pivaloyl group-3-amino piperidine in chlorine bleach liquor.Obtained (the R)-3-amido piperidine hydrochlorate of d, (R)-N-pivaloyl group-3-amino piperidine reaction in the mixing solutions of hydrochloric acid and alcohol.The present invention provides the novel method of a kind of low cost, high yield for preparing (R)-3-amido piperidine hydrochlorate.
Description
Technical field
The invention belongs to 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 synthesis treatment type ii diabetes medicine BI 1356 and Egelieting.Diabetes are one of maximum diseases of harm humans health.Cardiovascular and cerebrovascular patient ten thousand people more than more than 1500 are died from the whole world every year on average.In the second largest reason that developed country's II diabetes are crowd's death.
A large amount of clinical study shows, antidiabetic thing BI 1356 and Egelieting treat one of best medicine of diabetes.This medicine is efficient, safety, is the choice drug of hypoglycemic.In addition, these two medicines can also be used for preventing fracture, treatment osteoporosis, as immunomodulator etc.
At present, reported that the method for synthesis (R)-3-amido piperidine hydrochlorate mainly contains following two lines:
The first: be disclosed in WO0300496, this route take ethyl nipecotate as starting raw material, splits, repeatedly after crystallization through D-tartrate, dissociate, upper benzyl obtains (R) N-benzyl-ethyl nipecotate, and this ester is through being hydrolyzed obtained acid, and acid is again through reacting with diphenyl phosphate azide, reset simultaneously, obtained (R)-1-N-benzyl-3-N-t-butoxycarbonyl-amino piperidines, then through debenzylation and de-tertbutyloxycarbonyl and salify, obtained (R)-3-amido piperidine hydrochlorate.The shortcoming of this route is: 1) 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, needing repeatedly recrystallization, optical purity (R)-3-amido piperidine hydrochlorate can be obtained; 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 be disclosed in WO2011160037.This route with 3-aminopyridine for starting raw material; first through acetylize; hydrogenation obtains 3-N-acetylamino piperidines acetate, this salt under the effect of concentrated hydrochloric acid, deacetylate; obtained 3-amido piperidine hydrochlorate; this salt through alkaline hydrolysis from, then to split by D-dibenzoyl tartaric acid, repeatedly after crystallization; be dissociated into hydrochloride, obtained (R)-3-amido piperidine hydrochlorate.The shortcoming of this route is: 1) need high-pressure hydrogenation, and palladium carbon consumption is relatively large; 2) when splitting, needing repeatedly recrystallization, optical purity (R)-3-amido piperidine hydrochlorate can be obtained; 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 the preparation method of one (R)-3-amido piperidine hydrochlorate, comprises the following steps:
A, reacted in organic solvent by the 3-piperidine amides of D-amygdalic acid and racemization, reaction terminates rear filtration, obtains the D-amygdalic acid organic salt of (R)-3-piperidine amides;
B, the organic salt obtained by step a are used mineral alkali adjust pH to 10 ~ 11, then are reacted with pivaloyl chloride, after reaction terminates in the mixing solutions of alcohol and water, reaction solution is through extraction, drying, is concentrated into dry, obtains (R)-N-pivaloyl group-3-piperidine amides;
C, reacted in chlorine bleach liquor by (R)-N-pivaloyl group-3-piperidine amides, after reaction terminates, 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 to be reacted in the mixing solutions of hydrochloric acid and alcohol, obtained (R)-3-amido piperidine hydrochlorate.
Wherein, in the preparation method step a of above-mentioned (R)-3-amido piperidine hydrochlorate, described D-amygdalic acid and the mol ratio of 3-piperidine amides are 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, and the volume ratio of mixing is 1: 1.
Wherein, in aforesaid method step a, described temperature of reaction is 20 ~ 100 DEG C, and the reaction times is 1 ~ 24 hour.Preferably, temperature of reaction is 30 ~ 80 DEG C, and the reaction times is 5 ~ 12 hours.
Wherein, in aforesaid method step b, described mineral alkali is: the one in sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, potassiumphosphate.
Wherein, in aforesaid method step b, described alcohol is: the one in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol.
Wherein, in aforesaid method step b, described is-20 ~ 80 DEG C with the temperature of pivaloyl chloride reaction, and the time is 1 ~ 24 hour.Preferably, temperature of reaction is 0 ~ 30 DEG C, and the reaction times is 5 ~ 12 hours.
Wherein, in aforesaid method step c, the mass concentration of described chlorine bleach liquor is 2% ~ 30%; Preferably, the mass concentration of chlorine bleach liquor is 5 ~ 15%.
Wherein, in aforesaid method step c, described temperature of reaction is 0 ~ 100 DEG C, and the reaction times is 1 ~ 24 hour.Preferably, temperature of reaction is 20 ~ 70 DEG C, and the reaction times is 5 ~ 12 hours.
Wherein, in the step b of aforesaid method and c, described extraction solvent used is the one in methylene dichloride, ether, methyl tertiary butyl ether, butanone, ethyl acetate, isopropyl acetate.
Wherein, in aforesaid method steps d, described concentration of hydrochloric acid is 10% ~ 35%.Preferably, concentration of hydrochloric acid is 15 ~ 30%.
Wherein, in aforesaid method steps d, described alcohol is the one in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol.
Wherein, in aforesaid method steps d, described hydrochloric acid and the mixing solutions of alcohol, the volume ratio of its mixing is Yan Suan ︰ alcohol=1: 0.5 ~ 1:10.
Wherein, in aforesaid method steps d, described temperature of reaction is 0 ~ 100 DEG C, and the reaction times is 1 ~ 48 hour.Preferably, temperature of reaction is 20 ~ 70 DEG C, and the reaction times is 5 ~ 24 hours.
Further, in the preparation method of above-mentioned (R)-3-amido piperidine hydrochlorate, step a mother liquor concentrations after filtering can be fallen, removing organic solvent, with mineral alkali adjust pH to 10 ~ 11 in water, extract being configured as main 3-piperidine amides containing S, organic layer drying, be concentrated into dry, add alcoholic solvent, add organic alkali again to react, after reaction terminates, add shrend to go out reaction, organic solvent extracts, dry, the 3-piperidine amides of concentrated obtained racemization, the organic salt obtaining D-amygdalic acid and (R)-3-piperidine amides with D-amygdalic acid can be continued.Wherein, described alcoholic solvent is the one in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol; Its mixing volume ratio Wei Chun ︰ water=1 ~ 1 ︰ 1 ~ 20; Described mineral alkali be one in sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, potassiumphosphate; Described organic alkali is the one in sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, sodium propylate, potassium propylate, sodium isopropylate, potassium isopropoxide, sodium tert-butoxide, potassium tert.-butoxide; Described to add the temperature that organic alkali carries out reacting be 10 ~ 120 DEG C, and the time is 1 ~ 24 hour; Preferably, temperature of reaction is 30 ~ 90 DEG C, and the reaction times is 6 ~ 12 hours.
The principal reaction formula that the present invention relates to is:
Beneficial effect of the present invention is: technical scheme provided by the invention, synthetic route is novel, brief, reaction conditions is gentle, be easy to suitability for industrialized production, production cost is low, raw material of the present invention is cheaply easy to get simultaneously, raw material availability is high, (S)-3-piperidine amides can recycle in racemization, each step reaction yield is high, optical purity >=99.5% of product is 80% calculating with the 3-piperidine amides utilization ratio of racemization, and the total recovery of method preparation (R)-3-amido piperidine hydrochlorate provided by the invention can reach about 57.5%.
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, at 30 ~ 80 DEG C, react 5 ~ 12 hours obtained D-amygdalic acids and (R)-3-piperidine amides organic salt precipitation, filter, obtain the D-amygdalic acid organic salt of (R)-3-piperidine amides;
B, by 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, react with pivaloyl chloride again, at 0 ~ 30 DEG C, react 5 ~ 12 hours, reaction terminates rear organic solvent and extracts, drying, concentrated obtained (R)-N-pivaloyl group-3-piperidine amides;
C, by (R)-N-pivaloyl group-3-piperidine amides in the chlorine bleach liquor of 5 ~ 15%; at 20 ~ 70 DEG C; react 5 ~ 12 hours; after reaction terminates; extract with organic solvent, 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 the mixing solutions of 15 ~ 30% hydrochloric acid and alcohol, in 20 ~ 70 DEG C, react 5 ~ 24 hours; after reaction terminates, the finished product are separated out, suction filtration; decompression drying, obtained (R)-3-amido piperidine hydrochlorate.
Wherein, in the preparation method step a of above-mentioned (R)-3-amido piperidine hydrochlorate, described D-amygdalic acid and the mol ratio of 3-piperidine amides are 1.05: 1 ~ 2.0: 1, are 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, and the volume ratio of mixing is 1: 1.
Wherein, in aforesaid method step b, described mineral alkali is: the one in sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, potassiumphosphate.
Wherein, in aforesaid method step b, described alcohol is: the one in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol.
Wherein, in the step b of aforesaid method and c, described extraction solvent used is the one in methylene dichloride, ether, methyl tertiary butyl ether, butanone, ethyl acetate, isopropyl acetate.
Wherein, in aforesaid method steps d, described alcohol is the one in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol.
Wherein, in aforesaid method steps d, described hydrochloric acid and the mixing solutions of alcohol, the volume ratio of its mixing is Yan Suan ︰ alcohol=1 ︰ 0.5 ~ 1 ︰ 10.
Further, the mother liquor concentrations of step a can be fallen, with inorganic adjusting PH with base to 10 ~ 11 in water, be configured as main 3-piperidine amides with organic solvent extracting taking-up containing S to extract, dry, concentrated, add alcoholic solvent, then add organic alkali and react, at 30 ~ 90 DEG C, react 6 ~ 12 hours, after reaction terminates, add shrend and to go out reaction, organic solvent extracts, drying, the 3-piperidine amides after concentrated obtained racemization, can continue the organic salt obtaining D-amygdalic acid and (R)-3-piperidine amides with D-amygdalic acid.Wherein, described alcoholic solvent is the one in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol; Its mixing volume ratio Wei Chun ︰ water=1 ~ 1 ︰ 1 ~ 20; Described mineral alkali be one in sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, potassiumphosphate; Described organic alkali is the one 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 to replace with tertbutyloxycarbonyl respectively on 1,3 nitrogen of (R)-3-amido piperidine hydrochlorate.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 D-amygdalic acid of 51.0 grams and the 3-piperidine amides of 29.0 grams of racemizations are joined in 500 milliliters of reaction flasks, the methyl tert-butyl ether of 80 milliliters and the Virahol of 80 milliliters is added again in reaction flask, be heated to 70 DEG C, react 6 hours, reaction terminates Temperature fall to 20 DEG C, stir 3 hours at this temperature, a large amount of solid is separated out, suction filtration, decompression drying, obtain the D-amygdalic acid organic salt 26.7 grams of (R)-3-piperidine amides, yield 42.0%.
B, by the organic salt of the D-amygdalic acid of 26.7 grams with (R)-3-piperidine amides, the sodium hydroxide of 10 grams joins in 500 milliliters of reaction flasks, the ethanol of 90 milliliters and the water of 60 milliliters is added again in reaction flask, after adding, stir after 30 minutes, add the pivaloyl chloride of 13.0 grams, react 10 hours at 5 DEG C, TLC follows the tracks of after completion of the reaction, the shrend adding 120 grams in reaction solution is gone out reaction, use 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-3-piperidine amides of 19.0 grams is joined in 500 milliliters of reaction flasks; add the chlorine bleach liquor 200 milliliters of 6% again; be heated to 45 DEG C; react 10 hours; TLC follows the tracks of reaction; after completion of the reaction, be cooled to room temperature, the shrend adding 150 grams in reaction solution is gone out reaction; be extracted with ethyl acetate product; add gac, after dried over sodium sulfate, filter; filtrate reduced in volume falls solvent; decompression steams product, obtains product (R)-N-pivaloyl group-3-amino piperidine 16.1 grams, yield 85.0%.
D, 16.1 grams of (R)-N-pivaloyl group-3-amino piperidines are joined in the reaction flask of 500 milliliters; add the hydrochloric acid 70 milliliters of 25% and the n-propyl alcohol of 90 milliliters again, be heated to 55 DEG C, react 12 hours; reaction terminates Temperature fall to 25 DEG C; stir 2 hours at this temperature, a large amount of solid is 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 filtrated stock remaining by step a, is evaporated to dry, adds water and 10.0 grams of sodium hydroxide of 150 grams, stir after 20 minutes, extract by ethyl acetate, and after dried over sodium sulfate, filter, concentrating under reduced pressure falls solvent; The ethanol of 65 milliliters is added in the product after concentrated, add 12.0 grams of sodium ethylates again, under being heated to 78 degree, react 9 hours, after being down to room temperature, add 250 grams of 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 the 3-piperidine amides 16.4 grams of racemization, the rate of recovery 56.6%.
The 3-piperidine amides of 16.4 of above-mentioned gained grams of racemizations and 20.5 grams of D-amygdalic acids are joined in the reaction flask of 250 milliliters, the isopropyl acetate of 45 milliliters and the propyl carbinol of 45 milliliters is added again in reaction flask, be heated to 70 DEG C, react 5 hours, reaction terminates rear Temperature fall to 20 DEG C, stir 2 hours at this temperature, a large amount of solid is separated out, suction filtration, decompression drying, obtain the D-amygdalic acid organic salt 15.1 grams of (R)-3-piperidine amides, yield 41.0%.
Embodiment 2
A, the D-amygdalic acid of 18.0 grams and the 3-piperidine amides of 14.0 grams of racemizations are joined in 250 milliliters of reaction flasks, the ethyl acetate of 40 milliliters and the n-propyl alcohol of 40 milliliters is added again in reaction flask, be heated to 65 DEG C, react 4 hours, reaction terminates Temperature fall to 20 DEG C, stir 2 hours at this temperature, a large amount of solid is separated out, suction filtration, decompression drying, obtain the D-amygdalic acid organic salt 12.7 grams of (R)-3-piperidine amides, yield 41.5%.
B, by the organic salt of the D-amygdalic acid of 12.7 grams with (R)-3-piperidine amides, the sodium carbonate of 13 grams joins in 250 milliliters of reaction flasks, the ethanol of 25 milliliters and the water of 30 milliliters is added again in reaction flask, after adding, stir after 20 minutes, add the pivaloyl chloride of 7.0 grams, react 8 hours at 10 DEG C, TLC follows the tracks of after completion of the reaction, the shrend adding 70 grams in reaction solution is gone out reaction, use dichloromethane extraction product, add gac, after dried over sodium sulfate, filter, filtrate reduced in volume falls solvent, obtain product (R)-N-pivaloyl group-3-piperidine amides 9.1 grams, yield 94.0%.
C, (R)-N-pivaloyl group-3-piperidine amides of 9.1 grams is joined in 250 milliliters of reaction flasks; add the chlorine bleach liquor 100 milliliters of 8% again; be heated to 60 DEG C; react 6 hours; TLC follows the tracks of reaction; after completion of the reaction, be cooled to room temperature, the shrend adding 90 grams in reaction solution is gone out reaction; use t-butyl methyl ether extraction product; add gac, after dried over sodium sulfate, filter; filtrate reduced in volume falls solvent; decompression steams product, obtains product (R)-N-pivaloyl group-3-amino piperidine 6.8 grams, yield 86.0%.
D, 6.8 grams of (R)-N-pivaloyl group-3-amino piperidines are joined in the reaction flask of 250 milliliters; add the hydrochloric acid 20 milliliters of 30% and the ethanol of 40 milliliters again, be heated to 65 DEG C, react 8 hours; reaction terminates Temperature fall to 20 DEG C; stir 1 hour at this temperature, a large amount of solid is 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 filtrated stock remaining by step a, is evaporated to dry, adds water and 7.0 grams of sodium hydroxide of 100 grams, stir after 20 minutes, extract by ethyl acetate, and after dried over sodium sulfate, filter, concentrating under reduced pressure falls solvent; The propyl carbinol of 30 milliliters is added in the product after concentrated, add 6.0 grams of sodium methylates again, under being heated to 90 degree, react 7 hours, after being down to room temperature, add 100 grams of 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 the 3-piperidine amides 7.7 grams of racemization, the rate of recovery 55.0%.
Embodiment 3
A, the D-amygdalic acid of 490 grams and the 3-piperidine amides of 280 grams of racemizations are joined in 3000 milliliters of reaction flasks, the ethyl acetate of 900 milliliters and the ethanol of 900 milliliters is added again in reaction flask, be heated to 60 DEG C, react 10 hours, reaction terminates Temperature fall to 15 DEG C, stir 4 hours at this temperature, a large amount of solid is separated out, suction filtration, decompression drying, obtain the D-amygdalic acid organic salt 263.4 grams of (R)-3-piperidine amides, yield 43.0%.
B, by the organic salt of the D-amygdalic acid of 263.4 grams with (R)-3-piperidine amides, the salt of wormwood of 300 grams joins in 2000 milliliters of reaction flasks, the methyl alcohol of 600 milliliters and the water of 900 milliliters is added again in reaction flask, after adding, stir after 40 minutes, add the pivaloyl chloride of 117.5 grams, react 12 hours at 15 DEG C, TLC follows the tracks of after completion of the reaction, the shrend adding 800 grams in reaction solution is gone out reaction, be extracted with ethyl acetate product, add gac, after dried over sodium sulfate, filter, filtrate reduced in volume falls solvent, obtain product (R)-N-pivaloyl group-3-piperidine amides 184.7 grams, yield 92.6%.
C, (R)-N-pivaloyl group-3-piperidine amides of 184.7 grams is joined in 2000 milliliters of reaction flasks; add the chlorine bleach liquor 900 milliliters of 10% again; be heated to 55 DEG C; react 11 hours; TLC follows the tracks of reaction; after completion of the reaction, be cooled to room temperature, the shrend adding 700 grams in reaction solution is gone out reaction; use dichloromethane extraction product; add gac, after dried over sodium sulfate, filter; filtrate reduced in volume falls solvent; decompression steams product, obtains product (R)-N-pivaloyl group-3-amino piperidine 134.2 grams, yield 83.7%.
D, 134.2 grams of (R)-N-pivaloyl group-3-amino piperidines are joined in the reaction flask of 2000 milliliters; add the hydrochloric acid 600 milliliters of 30% and the butanols of 750 milliliters again, be heated to 45 DEG C, react 28 hours; reaction terminates Temperature fall to 15 DEG C; stir 4 hours at this temperature, a large amount of solid is 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 filtrated stock remaining by step a, is evaporated to dry, adds water and 130.0 grams of sodium hydroxide of 1200 grams, stir after 30 minutes, extract by ethyl acetate, and after dried over sodium sulfate, filter, concentrating under reduced pressure falls solvent; The trimethyl carbinol of 600 milliliters is added in the product after concentrated, add 150 grams of sodium tert-butoxides again, under being heated to 82 degree, react 8 hours, after being down to room temperature, add 1000 grams of 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 the 3-piperidine amides 156.2 grams of racemization, the rate of recovery 55.8%.
More than experiment shows, technical scheme provided by the invention, new technology, brief, and be easy to suitability for industrialized production, production cost is low simultaneously, and raw material of the present invention is cheaply easy to get, and raw material availability is high, and each step reaction yield is high, optical purity >=99.5% of product.
Claims (9)
1. the preparation method of (R)-3-amido piperidine hydrochlorate, comprises the following steps:
A, reacted in organic solvent by the 3-piperidine amides of D-amygdalic acid and racemization, reaction terminates rear filtration, obtains the D-amygdalic acid organic salt of (R)-3-piperidine amides; 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, and the volume ratio of mixing is 1: 1; Described D-amygdalic acid and the mol ratio of 3-piperidine amides are 1.05: 1 ~ 2.0: 1; Described temperature of reaction is 20 ~ 100 DEG C; The described reaction times is 1 ~ 24 hour;
B, the organic salt obtained by step a are used mineral alkali adjust pH to 10 ~ 11, then are reacted with pivaloyl chloride, after reaction terminates in the mixing solutions of alcohol and water, reaction solution is through extraction, drying, is concentrated into dry, obtains (R)-N-pivaloyl group-3-piperidine amides; Described mineral alkali is the one in sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, potassiumphosphate; Described alcohol is the one in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol; Described is-20 ~ 80 DEG C with the temperature of pivaloyl chloride reaction, and the time is 1 ~ 24 hour;
C, reacted in chlorine bleach liquor by (R)-N-pivaloyl group-3-piperidine amides, after reaction terminates, reaction solution is through extraction, and organic layer drying, distillation, obtain product (R)-N-pivaloyl group-3-amino piperidine; The mass concentration of described chlorine bleach liquor is 2% ~ 30%; Described temperature of reaction is 0 ~ 100 DEG C, and the reaction times is 1 ~ 24 hour;
D, (R)-N-pivaloyl group-3-amino piperidine to be reacted in the mixing solutions of hydrochloric acid and alcohol, obtained (R)-3-amido piperidine hydrochlorate; Described concentration of hydrochloric acid is 10% ~ 35%; Described alcohol is the one in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol; Described hydrochloric acid and the mixing solutions of alcohol, the volume ratio of its mixing is Yan Suan ︰ alcohol=1: 0.5 ~ 1:10; Described temperature of reaction is 0 ~ 100 DEG C, and the reaction times is 1 ~ 48 hour.
2. the preparation method of (R)-3-amido piperidine hydrochlorate according to claim 1, is characterized in that: the D-amygdalic acid described in step a and the mol ratio of 3-piperidine amides are 1.1: 1 ~ 1.5: 1.
3. the preparation method of (R)-3-amido piperidine hydrochlorate according to claim 1, is characterized in that: the temperature of reaction described in step a is 30 ~ 80 DEG C; Reaction times is 5 ~ 12 hours.
4. the preparation method of (R)-3-amido piperidine hydrochlorate according to claim 1, it is characterized in that: the temperature of reaction described in step b is 0 ~ 30 DEG C, the reaction times is 5 ~ 12 hours.
5. the preparation method of (R)-3-amido piperidine hydrochlorate according to claim 1, is characterized in that: the mass concentration of chlorine bleach liquor described in step c is 5 ~ 15%.
6. the preparation method of (R)-3-amido piperidine hydrochlorate according to claim 1, it is characterized in that: the temperature of reaction described in step c is 20 ~ 70 DEG C, 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 b and c, described extraction solvent used is the one in methylene dichloride, ether, methyl tertiary butyl ether, butanone, ethyl acetate, isopropyl acetate.
8. the preparation method of (R)-3-amido piperidine hydrochlorate according to claim 1, is characterized in that: the concentration of hydrochloric acid described in steps d is 15 ~ 30%.
9. the preparation method of (R)-3-amido piperidine hydrochlorate according to claim 1, it is characterized in that: the temperature of reaction described in steps d is 20 ~ 70 DEG C, the reaction times is 5 ~ 24 hours.
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| CN105675782B (en) * | 2016-01-23 | 2017-04-12 | 河北科技大学 | 3-aminopiperdine chiral purity analysis method |
| CN105801580B (en) * | 2016-04-21 | 2018-04-20 | 无锡佰翱得生物科学有限公司 | For synthesizing the intermediate of BI 1356, its preparation method and the preparation method of BI 1356 |
| CN106831540B (en) * | 2017-03-09 | 2019-06-11 | 爱斯特（成都）生物制药股份有限公司 | A kind of preparation method of (S)-nipecotic acid |
| CN108409639B (en) * | 2018-04-23 | 2021-05-11 | 爱斯特（成都）生物制药股份有限公司 | Preparation and structure confirmation method of (S) -3-Boc-aminomethyl piperidine |
| CN113121414B (en) * | 2020-01-15 | 2024-03-29 | 鲁南制药集团股份有限公司 | Synthesis method of trelagliptin intermediate |
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