CN117447285A - Preparation method of chiral impurity of beta-lactamase inhibitor intermediate - Google Patents
Preparation method of chiral impurity of beta-lactamase inhibitor intermediate Download PDFInfo
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- CN117447285A CN117447285A CN202311392541.9A CN202311392541A CN117447285A CN 117447285 A CN117447285 A CN 117447285A CN 202311392541 A CN202311392541 A CN 202311392541A CN 117447285 A CN117447285 A CN 117447285A
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- piperidine
- ethyl acetate
- carboxylic acid
- benzyloxy amino
- solution
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- 239000012535 impurity Substances 0.000 title claims abstract description 27
- 239000003781 beta lactamase inhibitor Substances 0.000 title claims abstract description 22
- 229940126813 beta-lactamase inhibitor Drugs 0.000 title claims abstract description 22
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims abstract description 88
- 238000000034 method Methods 0.000 claims abstract description 32
- 235000006408 oxalic acid Nutrition 0.000 claims abstract description 29
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000012452 mother liquor Substances 0.000 claims abstract description 19
- 239000002994 raw material Substances 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 240
- 239000013078 crystal Substances 0.000 claims description 43
- 239000002904 solvent Substances 0.000 claims description 32
- 238000001035 drying Methods 0.000 claims description 24
- 239000012065 filter cake Substances 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 24
- 239000000126 substance Substances 0.000 claims description 21
- 239000003513 alkali Substances 0.000 claims description 18
- -1 (2 s,5 s) -5- (benzylamino) -piperidine-2-carboxylic acid ethyl ester sulfate Chemical compound 0.000 claims description 17
- 238000001816 cooling Methods 0.000 claims description 16
- 238000010438 heat treatment Methods 0.000 claims description 16
- 239000000725 suspension Substances 0.000 claims description 16
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-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
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 239000011345 viscous material Substances 0.000 claims description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 8
- 238000004090 dissolution Methods 0.000 claims description 8
- PYUXATUBICTSNB-DFQHDRSWSA-N ethyl (2s,5r)-5-(phenylmethoxyamino)piperidine-2-carboxylate;oxalic acid Chemical compound OC(=O)C(O)=O.C1N[C@H](C(=O)OCC)CC[C@H]1NOCC1=CC=CC=C1 PYUXATUBICTSNB-DFQHDRSWSA-N 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 238000002386 leaching Methods 0.000 claims description 8
- 230000001105 regulatory effect Effects 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- 238000000967 suction filtration Methods 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 6
- PYUXATUBICTSNB-LMRHVHIWSA-N ethyl (2R,5S)-5-(phenylmethoxyamino)piperidine-2-carboxylate oxalic acid Chemical compound CCOC(=O)[C@H]1CC[C@@H](CN1)NOCC2=CC=CC=C2.C(=O)(C(=O)O)O PYUXATUBICTSNB-LMRHVHIWSA-N 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- NUKZAGXMHTUAFE-UHFFFAOYSA-N hexanoic acid methyl ester Natural products CCCCCC(=O)OC NUKZAGXMHTUAFE-UHFFFAOYSA-N 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 238000005303 weighing Methods 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 abstract description 8
- 230000008025 crystallization Effects 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 150000003839 salts Chemical class 0.000 abstract description 3
- 238000000605 extraction Methods 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 17
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- RTCIKUMODPANKX-JBUOLDKXSA-M avibactam sodium Chemical compound [Na+].NC(=O)[C@@H]1CC[C@H]2N(OS([O-])(=O)=O)C(=O)N1C2 RTCIKUMODPANKX-JBUOLDKXSA-M 0.000 description 6
- 229960001496 avibactam sodium Drugs 0.000 description 5
- 238000003908 quality control method Methods 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 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 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 229960002379 avibactam Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- LVFGWOQWXQLVRO-XJDKXYGGSA-N (6r,7r)-7-[[(2e)-2-(2-amino-1,3-thiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino)acetyl]amino]-8-oxo-3-(pyridin-1-ium-1-ylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;[(2s,5r)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl] hydrogen sulfate Chemical compound NC(=O)[C@@H]1CC[C@H]2N(OS(O)(=O)=O)C(=O)N1C2.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)/C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 LVFGWOQWXQLVRO-XJDKXYGGSA-N 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- NDCUAPJVLWFHHB-UHNVWZDZSA-N avibactam Chemical compound C1N2[C@H](C(N)=O)CC[C@@]1([H])N(OS(O)(=O)=O)C2=O NDCUAPJVLWFHHB-UHNVWZDZSA-N 0.000 description 1
- 229940091875 avycaz Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229960000484 ceftazidime Drugs 0.000 description 1
- NMVPEQXCMGEDNH-TZVUEUGBSA-N ceftazidime pentahydrate Chemical compound O.O.O.O.O.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 NMVPEQXCMGEDNH-TZVUEUGBSA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 159000000000 sodium salts Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of chiral impurities of a beta-lactamase inhibitor intermediate, which takes crystallization mother liquor for preparing (2S, 5R) -5- (benzyloxy amino) -piperidine-2-ethyl formate oxalate or crystallization mother liquor for preparing (2R, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate oxalate as extraction raw materials, and separates (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate sulfate or (2R, 5R) -5- (benzyloxy amino) -piperidine-2-ethyl formate sulfate by a method of sulfuric acid selective resolution salt formation, and then prepares diastereoisomers (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate oxalate or (2R, 5R) -5- (benzyloxy amino) -piperidine-2-ethyl formate oxalate with high purity through processes of free and oxalic acid salification crystallization and the like. The method is simple, the purity is high, and the ee% of the prepared chiral isomer is over 99.5%.
Description
Technical Field
The invention belongs to the technical field of compound preparation methods, and particularly relates to a preparation method of chiral impurities of a beta-lactamase inhibitor intermediate.
Background
Avibam Sodium (Avibam Sodium, NXL-104) belongs to diazabicyclo octanone compound, is jointly developed by Forest Lab and Abelikang, and is purchased for Forest Lab in 2 months 2014, development rights are obtained, and the compound preparation AVYCAZ of ceftazidime and Avibam Sodium in 25 days 2015 is approved to be marketed in the United states. The avibactam sodium is the best novel beta-lactamase inhibitor at present, and compared with three beta-lactamase inhibitors on the market in the prior art, the avibactam sodium has the characteristic of long acting, and the avibactam sodium is in reversible covalent combination with enzyme and does not induce the generation of beta-lactamase.
The synthesis of the avibactam sodium reported in the literature in the prior art mainly takes N-t-butoxycarbonyl-L-pyroglutamic acid ethyl ester as a starting material, and key intermediates (2S, 5R) -5- (benzyloxy amino) -piperidine-2-ethyl formate oxalate are obtained through the steps of ring opening, chloro, cyclization, reduction, splitting into salts and the like, and the avibactam sodium is obtained through amidation, cyclization, deprotection, formation of tetrabutylammonium sulfonate and finally sodium salt exchange reaction. (2S, 5R) -5- (Benzyloxy amino) -piperidine-2-carboxylic acid ethyl ester oxalate is a key starting material for synthesis of avibactam, and has two chiral carbon atoms in the structure, and three chiral isomers exist: two diastereomers, ethyl (2 s,5 s) -5- (benzylamino) -piperidine-2-carboxylate oxalate and ethyl (2 r,5 r) -5- (benzylamino) -piperidine-2-carboxylate oxalate, respectively, one enantiomer, ethyl (2 r,5 s) -5- (benzylamino) -piperidine-2-carboxylate oxalate. In the process of drug development, the quality control of the chiral impurities of the intermediates is an important link, and a certain amount of reference substances are required for establishing quality standards, so that the development of the synthesis method of the chiral impurities of the intermediates is an important task of drug research.
Disclosure of Invention
The invention aims to solve the quality control problem of chiral impurities in a pharmaceutical intermediate, and provides a preparation method of chiral impurities in the intermediate of a beta-lactamase inhibitor, which can take a crystal mother liquor for preparing the intermediate (2S, 5R) -5- (benzyloxy amino) -piperidine-2-ethyl formate oxalate as a raw material, simply extract and separate the intermediate chiral impurities (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate oxalate with high purity, and further analyze the content of the intermediate chiral impurities, thereby providing a basis for quality control of the chiral impurities in the pharmaceutical intermediate.
The invention is realized by the following technical scheme: a process for preparing chiral impurities of a β -lactamase inhibitor intermediate, the process comprising the steps of:
a. concentrating the mother liquor obtained after separating (2S, 5R) -5- (benzyloxy amino) -piperidine-2-carboxylic acid ethyl ester oxalate under reduced pressure to obtain a sticky substance;
b. adding a certain amount of ethyl acetate solvent into the viscous substance, stirring and dissolving to prepare a dissolving solution;
c. dripping dilute alkali liquor into the dissolution liquid, adjusting the pH value of the system to be 8-9, transferring into a separating funnel, standing and layering, and separating ethyl acetate solution;
d. slowly dripping dilute sulfuric acid into an ethyl acetate solution, regulating the pH value of a system to be 2-3, stopping, cooling the reaction solution to 10-60 ℃, stirring and crystallizing for 3-5 hours, carrying out suction filtration, washing a filter cake with ethyl acetate, and drying the washed filter cake at 45-65 ℃ to obtain (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate sulfate crystals;
e. adding the (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate sulfate crystal obtained in the step d into an ethyl acetate solvent, starting stirring, dripping dilute alkali liquor, adjusting the pH value of the system to 8-9, transferring into a separating funnel, standing for layering, separating ethyl acetate solution, adding anhydrous sodium sulfate into the ethyl acetate solution, drying, and concentrating to obtain (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate;
f. weighing a certain amount of oxalic acid, adding the oxalic acid into a solvent to prepare oxalic acid suspension, dissolving the prepared (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate free oily substance with 0.8-1.2 times of ethyl acetate, dripping the solution into the oxalic acid suspension, heating a solution system in the dripping process, completely dissolving suspended solids, and then preserving the temperature to 40-60 ℃ for 2-3 hours;
g. stopping heating the solution system in the step f, cooling and crystallizing for 8-12 h at natural temperature, filtering, leaching the filter cake once by using ethyl acetate, and drying at 45-65 ℃ to obtain (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate oxalate crystals.
Preferably, the mass ratio of the weight of the sticky matters to the solvent ethyl acetate in the step b is 1:8-12.
Preferably, the dilute alkali solution used in step c and step e is one or more of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and ammonia water.
Preferably, in the step d, the concentration of the dilute sulfuric acid is 1-4 mol/L; more preferably, the concentration of the dilute sulfuric acid is 2mol/L.
Preferably, in the step d, the temperature of the reaction solution is reduced to 10-30 ℃; more preferably, the reaction solution is cooled to 15 to 25 ℃.
Preferably, in the step e, the mass ratio of the (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate sulfate crystal to the ethyl acetate solvent is 1:8-12.
Preferably, in the step f, the mass ratio of oxalic acid to solvent is 1:8-12; the solvent is one or more of ethyl acetate, methyl acetate, butyl acetate and methyl tertiary butyl ether.
The above-mentioned method of the present invention is also applicable to the preparation of (2R, 5R) -5- (benzyloxy amino) -piperidine-2-carboxylic acid ethyl ester oxalate crystals from the mother liquor obtained by separating the enantiomer of (2R, 5S) -5- (benzyloxy amino) -piperidine-2-carboxylic acid ethyl ester oxalate under reduced pressure to give a viscous material;
in the step a, the mother liquor obtained after the separation of the (2S, 5R) -5- (benzyloxy amino) -piperidine-2-carboxylic acid ethyl ester oxalate is decompressed and concentrated into a sticky substance, and the mother liquor obtained after the separation of the (2R, 5S) -5- (benzyloxy amino) -piperidine-2-carboxylic acid ethyl ester oxalate is decompressed and concentrated into a sticky substance;
in step d, (2 s,5 s) -5- (benzylamino) -piperidine-2-carboxylic acid ethyl ester sulfate crystals are (2 r,5 r) -5- (benzylamino) -piperidine-2-carboxylic acid ethyl ester sulfate crystals;
in step e, (2 s,5 s) -5- (benzylamino) -piperidine-2-carboxylic acid ethyl ester is (2 r,5 r) -5- (benzylamino) -piperidine-2-carboxylic acid ethyl ester;
in step f, (2 s,5 s) -5- (benzylamino) -piperidine-2-carboxylic acid ethyl ester is (2 r,5 r) -5- (benzylamino) -piperidine-2-carboxylic acid ethyl ester;
in step g, (2 s,5 s) -5- (benzylamino) -piperidine-2-carboxylic acid ethyl ester oxalate crystals were (2 r,5 r) -5- (benzylamino) -piperidine-2-carboxylic acid ethyl ester oxalate crystals.
The beneficial effects of the invention are as follows:
according to the invention, the (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate oxalate mother liquor or (2R, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate mother liquor is taken as a raw material, the corresponding (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate sulfate or (2R, 5R) -5- (benzyloxy amino) -piperidine-2-ethyl formate sulfate is separated by a method of selective separation into salts by sulfuric acid, and then the corresponding high-purity diastereoisomer (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate oxalate or (2R, 5R) -5- (benzyloxy amino) -piperidine-2-ethyl formate oxalate is prepared through processes of free and oxalic acid salt formation crystallization and the like.
The preparation method is simple, the purity is high, and the ee value of the chiral isomer prepared by the method is more than 99.5%. The chiral isomer impurity prepared by the method has important significance for quality control of key intermediates and quality control of finished products.
Detailed Description
The present invention will be described in detail with reference to specific examples.
Example 1: a process for preparing chiral impurities of a β -lactamase inhibitor intermediate, the process comprising the steps of:
a. concentrating the mother liquor obtained after separating (2S, 5R) -5- (benzyloxy amino) -piperidine-2-carboxylic acid ethyl ester oxalate under reduced pressure to obtain a sticky substance;
b. adding ethyl acetate solvent into the viscous substance according to the mass ratio of 1:10, stirring and dissolving to prepare a dissolving solution;
c. dropwise adding sodium bicarbonate dilute alkali solution into the dissolution solution, adjusting the pH value of the system to be 8.5, transferring into a separating funnel, standing and layering, and separating ethyl acetate solution;
d. slowly dripping dilute sulfuric acid with the concentration of 2mol/L into an ethyl acetate solution, regulating the pH value of a system to be 2.5, stopping, cooling the reaction solution to 18-23 ℃, stirring and crystallizing for 4 hours, carrying out suction filtration, washing a filter cake with ethyl acetate, and drying the washed filter cake at 48-53 ℃ to obtain (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate sulfate crystals;
e. adding the (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate sulfate crystal obtained in the step d into an ethyl acetate solvent according to the mass ratio of 1:10, starting stirring, dropwise adding sodium bicarbonate diluted alkali solution, adjusting the pH value to 8.5, transferring into a separating funnel, standing and layering to separate ethyl acetate solution, adding anhydrous sodium sulfate into the ethyl acetate solution, drying, and concentrating to obtain (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate;
f. adding oxalic acid into an ethyl acetate solvent according to a mass ratio of 1:10 to prepare oxalic acid suspension, dissolving prepared (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate free oily substance with 1 time of ethyl acetate, dripping into the oxalic acid suspension, heating a solution system in the dripping process, completely dissolving suspended solid, and then preserving heat to 48-53 ℃ for 2.5h for crystallization;
g. stopping heating the solution system in the step f, cooling and crystallizing for 10 hours at natural temperature, filtering, leaching the filter cake once by using ethyl acetate, and drying at 48-53 ℃ to obtain (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate oxalate crystals.
The (2S, 5S) -5- (benzylamino) -piperidine-2-carboxylic acid ethyl ester oxalate crystals prepared in this example had an ee value of 99.8%.
Example 2: a process for preparing chiral impurities of a β -lactamase inhibitor intermediate, the process comprising the steps of:
a. concentrating the mother liquor obtained after separating (2S, 5R) -5- (benzyloxy amino) -piperidine-2-carboxylic acid ethyl ester oxalate under reduced pressure to obtain a sticky substance;
b. adding ethyl acetate solvent into the viscous substance according to the mass ratio of 1:8, stirring and dissolving to prepare a dissolving solution;
c. dropwise adding sodium carbonate dilute alkali solution into the dissolution solution, adjusting the pH value of the system to be 8, transferring into a separating funnel, standing and layering, and separating ethyl acetate solution;
d. slowly dripping dilute sulfuric acid with the concentration of 3mol/L into an ethyl acetate solution, regulating the pH value of a system to be=3, stopping, cooling the reaction solution to 15-20 ℃, stirring and crystallizing for 5 hours, carrying out suction filtration, washing a filter cake by using ethyl acetate, and drying the washed filter cake at 45-50 ℃ to obtain (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate sulfate crystals;
e. adding the (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate sulfate crystal obtained in the step d into an ethyl acetate solvent according to the mass ratio of 1:8, starting stirring, dropwise adding sodium carbonate dilute alkali solution, adjusting the pH value to be 8, transferring into a separating funnel, standing and layering to separate ethyl acetate solution, adding anhydrous sodium sulfate into the ethyl acetate solution, drying and concentrating to obtain (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate;
f. adding oxalic acid into methyl acetate solvent according to the mass ratio of 1:8 to prepare oxalic acid suspension, dissolving prepared (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate free oily substance with 0.8 times of ethyl acetate, dripping into the oxalic acid suspension, heating a solution system in the dripping process, keeping the temperature to 40-45 ℃ after the suspended solid is completely dissolved, and crystallizing for 3 hours;
g. stopping heating the solution system in the step f, cooling and crystallizing for 8 hours at natural temperature, filtering, leaching the filter cake once by using ethyl acetate, and drying at the temperature of 45-50 ℃ to obtain (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate oxalate crystals.
The (2S, 5S) -5- (benzylamino) -piperidine-2-carboxylic acid ethyl ester oxalate crystals prepared in this example had an ee value of 99.6%.
Example 3: a process for preparing chiral impurities of a β -lactamase inhibitor intermediate, the process comprising the steps of:
a. concentrating the mother liquor obtained after separating (2S, 5R) -5- (benzyloxy amino) -piperidine-2-carboxylic acid ethyl ester oxalate under reduced pressure to obtain a sticky substance;
b. adding ethyl acetate solvent into the viscous substance according to the mass ratio of 1:12, stirring and dissolving to prepare a dissolving solution;
c. dropwise adding ammonia water diluted alkali liquor into the dissolution liquid, adjusting the pH value of the system to be 9, transferring the system into a separating funnel, standing and layering, and separating ethyl acetate solution;
d. slowly dripping dilute sulfuric acid with the concentration of 2.5mol/L into an ethyl acetate solution, regulating the pH value of the system to be 2, stopping, cooling the reaction solution to the temperature of 20-25 ℃, stirring and crystallizing for 3 hours, carrying out suction filtration, washing a filter cake with ethyl acetate, and drying the washed filter cake at the temperature of 60-65 ℃ to obtain (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate sulfate crystals;
e. adding the (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate sulfate crystal obtained in the step d into an ethyl acetate solvent according to the mass ratio of 1:12, starting stirring, dropwise adding ammonia water diluted alkali liquor, adjusting the pH value to be 9, transferring into a separating funnel, standing and layering to separate ethyl acetate solution, adding anhydrous sodium sulfate into the ethyl acetate solution, drying, and concentrating to obtain (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate;
f. adding oxalic acid into a butyl acetate solvent according to a mass ratio of 1:12 to prepare oxalic acid suspension, dissolving prepared (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate free oily substance with 1.2 times of ethyl acetate, dripping into the oxalic acid suspension, heating a solution system in the dripping process, fully dissolving suspended solid, and then preserving heat to 50-55 ℃ for 2h for crystallization;
g. stopping heating the solution system in the step f, cooling and crystallizing for 12h at natural temperature, filtering, leaching the filter cake once by using ethyl acetate, and drying at 60-65 ℃ to obtain (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate oxalate crystals.
The (2S, 5S) -5- (benzylamino) -piperidine-2-carboxylic acid ethyl ester oxalate crystals prepared in this example had an ee value of 99.7%.
Example 4: a process for preparing chiral impurities of a β -lactamase inhibitor intermediate, the process comprising the steps of:
a. concentrating the mother liquor obtained after separating (2R, 5S) -5- (benzyloxy amino) -piperidine-2-carboxylic acid ethyl ester oxalate under reduced pressure to obtain a sticky substance;
b. adding ethyl acetate solvent into the viscous substance according to the mass ratio of 1:10, stirring and dissolving to prepare a dissolving solution;
c. dropwise adding ammonia water diluted alkali liquor into the dissolution liquid, adjusting the pH value of the system to be 8.5, transferring into a separating funnel, standing and layering, and separating ethyl acetate solution;
d. slowly dripping dilute sulfuric acid with the concentration of 2mol/L into an ethyl acetate solution, regulating the pH value of a system to be 2.5, stopping, cooling the reaction solution to 18-23 ℃, stirring and crystallizing for 4 hours, carrying out suction filtration, washing a filter cake with ethyl acetate, and drying the washed filter cake at 48-53 ℃ to obtain (2R, 5R) -5- (benzyloxy amino) -piperidine-2-ethyl formate sulfate crystals;
e. adding the (2R, 5R) -5- (benzyloxy amino) -piperidine-2-ethyl formate sulfate crystal obtained in the step d into an ethyl acetate solvent according to the mass ratio of 1:10, starting stirring, dropwise adding ammonia water diluted alkali liquor, adjusting the pH value to 8.5, transferring into a separating funnel, standing and layering to separate ethyl acetate solution, adding anhydrous sodium sulfate into the ethyl acetate solution, drying, and concentrating to obtain (2R, 5R) -5- (benzyloxy amino) -piperidine-2-ethyl formate;
f. adding oxalic acid into an ethyl acetate solvent according to a mass ratio of 1:10 to prepare oxalic acid suspension, dissolving prepared (2R, 5R) -5- (benzyloxy amino) -piperidine-2-ethyl formate free oily substance with 1 time of ethyl acetate, dripping into the oxalic acid suspension, heating a solution system in the dripping process, completely dissolving suspended solids, and then preserving heat to 48-53 ℃ for 2.5h for crystallization;
g. stopping heating the solution system in the step f, cooling and crystallizing for 10 hours at natural temperature, filtering, leaching the filter cake once by using ethyl acetate, and drying at 48-53 ℃ to obtain (2R, 5R) -5- (benzyloxy amino) -piperidine-2-ethyl formate oxalate crystals.
The (2R, 5R) -5- (benzyloxyamino) -piperidine-2-carboxylic acid ethyl ester oxalate crystals prepared in this example had an ee value of 99.7%.
Example 5: a process for preparing chiral impurities of a β -lactamase inhibitor intermediate, the process comprising the steps of:
a. concentrating the mother liquor obtained after separating (2R, 5S) -5- (benzyloxy amino) -piperidine-2-carboxylic acid ethyl ester oxalate under reduced pressure to obtain a sticky substance;
b. adding ethyl acetate solvent into the viscous substance according to the mass ratio of 1:12, stirring and dissolving to prepare a dissolving solution;
c. dropwise adding sodium carbonate dilute alkali solution into the dissolution solution, adjusting the pH value of the system to be 8, transferring into a separating funnel, standing and layering, and separating ethyl acetate solution;
d. slowly dripping dilute sulfuric acid with the concentration of 2.5mol/L into an ethyl acetate solution, regulating the pH value of the system to be 2, stopping, cooling the reaction solution to 15-20 ℃, stirring and crystallizing for 3 hours, carrying out suction filtration, washing a filter cake with ethyl acetate, and drying the washed filter cake at 45-50 ℃ to obtain (2R, 5R) -5- (benzyloxy amino) -piperidine-2-ethyl formate sulfate crystals;
e. adding the (2R, 5R) -5- (benzyloxy amino) -piperidine-2-ethyl formate sulfate crystal obtained in the step d into an ethyl acetate solvent according to the mass ratio of 1:12, starting stirring, dropwise adding sodium carbonate dilute alkali solution, adjusting the pH value to be 8, transferring into a separating funnel, standing and layering to separate ethyl acetate solution, adding anhydrous sodium sulfate into the ethyl acetate solution, drying, and concentrating to obtain (2R, 5R) -5- (benzyloxy amino) -piperidine-2-ethyl formate;
f. adding oxalic acid into methyl acetate solvent according to the mass ratio of 1:12 to prepare oxalic acid suspension, dissolving prepared (2R, 5R) -5- (benzyloxy amino) -piperidine-2-ethyl formate free oily substance with 1.2 times of ethyl acetate, dripping into the oxalic acid suspension, heating a solution system in the dripping process, keeping the temperature to 50-55 ℃ after the suspended solid is completely dissolved, and crystallizing for 2h;
g. stopping heating the solution system in the step f, cooling and crystallizing for 12h at natural temperature, filtering, leaching the filter cake once by using ethyl acetate, and drying at the temperature of 45-50 ℃ to obtain (2R, 5R) -5- (benzyloxy amino) -piperidine-2-ethyl formate oxalate crystals.
The (2R, 5R) -5- (benzyloxyamino) -piperidine-2-carboxylic acid ethyl ester oxalate crystals prepared in this example had an ee value of 99.6%.
Example 6: a process for preparing chiral impurities of a β -lactamase inhibitor intermediate, the process comprising the steps of:
a. concentrating the mother liquor obtained after separating (2R, 5S) -5- (benzyloxy amino) -piperidine-2-carboxylic acid ethyl ester oxalate under reduced pressure to obtain a sticky substance;
b. adding ethyl acetate solvent into the viscous substance according to the mass ratio of 1:8, stirring and dissolving to prepare a dissolving solution;
c. dropwise adding sodium bicarbonate dilute alkali solution into the dissolution solution, adjusting the pH value of the system to be 9, transferring into a separating funnel, standing and layering, and separating ethyl acetate solution;
d. slowly dripping dilute sulfuric acid with the concentration of 3mol/L into an ethyl acetate solution, regulating the pH value of a system to be=3, stopping, cooling the reaction solution to the temperature of 20-25 ℃, stirring and crystallizing for 5 hours, carrying out suction filtration, washing a filter cake with ethyl acetate, and drying the washed filter cake at the temperature of 60-65 ℃ to obtain (2R, 5R) -5- (benzyloxy amino) -piperidine-2-ethyl formate sulfate crystals;
e. adding the (2R, 5R) -5- (benzyloxy amino) -piperidine-2-ethyl formate sulfate crystal obtained in the step d into an ethyl acetate solvent according to the mass ratio of 1:8, starting stirring, dropwise adding sodium bicarbonate diluted alkali solution, adjusting the pH value to be 9, transferring into a separating funnel, standing and layering to separate ethyl acetate solution, adding anhydrous sodium sulfate into the ethyl acetate solution, drying, and concentrating to obtain (2R, 5R) -5- (benzyloxy amino) -piperidine-2-ethyl formate;
f. adding oxalic acid into a butyl acetate solvent according to a mass ratio of 1:8 to prepare oxalic acid suspension, dissolving prepared (2R, 5R) -5- (benzyloxy amino) -piperidine-2-ethyl formate free oily substance with 0.8 times of ethyl acetate, dripping into the oxalic acid suspension, heating a solution system in the dripping process, fully dissolving suspended solids, and then preserving heat to 40-45 ℃ for 3h of crystallization;
g. stopping heating the solution system in the step f, cooling and crystallizing for 8 hours at natural temperature, filtering, leaching the filter cake once by using ethyl acetate, and drying at 60-65 ℃ to obtain (2R, 5R) -5- (benzyloxy amino) -piperidine-2-ethyl formate oxalate crystals.
The (2R, 5R) -5- (benzyloxyamino) -piperidine-2-carboxylic acid ethyl ester oxalate crystals prepared in this example had an ee value of 99.5%.
Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.
Claims (8)
1. A process for preparing chiral impurities of a β -lactamase inhibitor intermediate, the process comprising the steps of:
a. concentrating the mother liquor obtained after separating (2S, 5R) -5- (benzyloxy amino) -piperidine-2-carboxylic acid ethyl ester oxalate under reduced pressure to obtain a sticky substance;
b. adding a certain amount of ethyl acetate solvent into the viscous substance, stirring and dissolving to prepare a dissolving solution;
c. dripping dilute alkali liquor into the dissolution liquid, adjusting the pH value of the system to be 8-9, transferring into a separating funnel, standing and layering, and separating ethyl acetate solution;
d. slowly dripping dilute sulfuric acid into an ethyl acetate solution, regulating the pH value of a system to be 2-3, stopping, cooling the reaction solution to 10-60 ℃, stirring and crystallizing for 3-5 hours, carrying out suction filtration, washing a filter cake with ethyl acetate, and drying the washed filter cake at 45-65 ℃ to obtain (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate sulfate crystals;
e. adding the (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate sulfate crystal obtained in the step d into an ethyl acetate solvent, starting stirring, dripping dilute alkali liquor, adjusting the pH value of the system to 8-9, transferring into a separating funnel, standing for layering, separating ethyl acetate solution, adding anhydrous sodium sulfate into the ethyl acetate solution, drying, and concentrating to obtain (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate;
f. weighing a certain amount of oxalic acid, adding the oxalic acid into a solvent to prepare oxalic acid suspension, dissolving the prepared (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate free oily substance with 0.8-1.2 times of ethyl acetate, dripping the solution into the oxalic acid suspension, heating a solution system in the dripping process, completely dissolving suspended solids, and then preserving the temperature to 40-60 ℃ for 2-3 hours;
g. stopping heating the solution system in the step f, cooling and crystallizing for 8-12 h at natural temperature, filtering, leaching the filter cake once by using ethyl acetate, and drying at 45-65 ℃ to obtain (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate oxalate crystals.
2. The process for preparing chiral impurities of a β -lactamase inhibitor intermediate according to claim 1, characterized in that: the mass ratio of the weight of the sticky matters to the solvent ethyl acetate in the step b is 1:8-12.
3. The process for preparing chiral impurities of a β -lactamase inhibitor intermediate according to claim 2, characterized in that: the dilute alkali solution used in the step c and the step e is one or more of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and ammonia water.
4. A process for the preparation of chiral impurities of a β -lactamase inhibitor intermediate according to claim 3, characterized in that: in the step d, the concentration of the dilute sulfuric acid is 1-4 mol/L.
5. The method for preparing chiral impurities of a beta-lactamase inhibitor intermediate according to claim 4, wherein the method comprises the steps of: in the step d, the temperature of the reaction liquid is reduced to 10-30 ℃.
6. The method for preparing chiral impurities of a beta-lactamase inhibitor intermediate according to claim 5, characterized in that: in the step e, the mass ratio of the (2S, 5S) -5- (benzyloxy amino) -piperidine-2-ethyl formate sulfate crystal to the ethyl acetate solvent is 1:8-12.
7. The method for preparing chiral impurities of a beta-lactamase inhibitor intermediate according to claim 6, characterized in that: in the step f, the mass ratio of oxalic acid to solvent is 1:8-12; the solvent is one or more of ethyl acetate, methyl acetate, butyl acetate and methyl tertiary butyl ether.
8. The process for producing a chiral impurity of a β -lactamase inhibitor intermediate according to any one of claims 1 to 7, which comprises concentrating under reduced pressure a mother liquor isolated from (2 r,5 s) -5- (benzyloxy amino) -piperidine-2-carboxylic acid ethyl ester oxalate enantiomer (2 r,5 s) -5- (benzyloxy amino) -piperidine-2-carboxylic acid ethyl ester oxalate to a thick substance as a raw material to produce (2 r,5 r) -5- (benzyloxy amino) -piperidine-2-carboxylic acid ethyl ester oxalate crystals; the method is characterized in that:
in the step a, the mother liquor obtained after the separation of the (2S, 5R) -5- (benzyloxy amino) -piperidine-2-carboxylic acid ethyl ester oxalate is decompressed and concentrated into a sticky substance, and the mother liquor obtained after the separation of the (2R, 5S) -5- (benzyloxy amino) -piperidine-2-carboxylic acid ethyl ester oxalate is decompressed and concentrated into a sticky substance;
in step d, (2 s,5 s) -5- (benzylamino) -piperidine-2-carboxylic acid ethyl ester sulfate crystals are (2 r,5 r) -5- (benzylamino) -piperidine-2-carboxylic acid ethyl ester sulfate crystals;
in step e, (2 s,5 s) -5- (benzylamino) -piperidine-2-carboxylic acid ethyl ester is (2 r,5 r) -5- (benzylamino) -piperidine-2-carboxylic acid ethyl ester;
in step f, (2 s,5 s) -5- (benzylamino) -piperidine-2-carboxylic acid ethyl ester is (2 r,5 r) -5- (benzylamino) -piperidine-2-carboxylic acid ethyl ester;
in step g, (2 s,5 s) -5- (benzylamino) -piperidine-2-carboxylic acid ethyl ester oxalate crystals were (2 r,5 r) -5- (benzylamino) -piperidine-2-carboxylic acid ethyl ester oxalate crystals.
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