CN106432060A - Preparation method for chiral isomers of key intermediate of Avibactam sodium - Google Patents
Preparation method for chiral isomers of key intermediate of Avibactam sodium Download PDFInfo
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- CN106432060A CN106432060A CN201610852889.5A CN201610852889A CN106432060A CN 106432060 A CN106432060 A CN 106432060A CN 201610852889 A CN201610852889 A CN 201610852889A CN 106432060 A CN106432060 A CN 106432060A
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- Prior art keywords
- piperidines
- ethyl formate
- dope
- benzyloxy amino
- benzyloxy
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- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 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 title abstract description 4
- 229960001496 avibactam sodium Drugs 0.000 title abstract description 3
- 238000004440 column chromatography Methods 0.000 claims abstract description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 123
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 98
- 239000003513 alkali Substances 0.000 claims description 48
- 239000000203 mixture Substances 0.000 claims description 43
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 38
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 38
- 239000000047 product Substances 0.000 claims description 37
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 238000003756 stirring Methods 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 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 claims description 24
- 229910052708 sodium Inorganic materials 0.000 claims description 24
- 239000011734 sodium Substances 0.000 claims description 24
- 239000012043 crude product Substances 0.000 claims description 21
- 239000011521 glass Substances 0.000 claims description 21
- 238000002425 crystallisation Methods 0.000 claims description 19
- 230000008025 crystallization Effects 0.000 claims description 19
- 239000003208 petroleum Substances 0.000 claims description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 239000000741 silica gel Substances 0.000 claims description 18
- 229910002027 silica gel Inorganic materials 0.000 claims description 18
- GEVPUGOOGXGPIO-UHFFFAOYSA-N oxalic acid;dihydrate Chemical compound O.O.OC(=O)C(O)=O GEVPUGOOGXGPIO-UHFFFAOYSA-N 0.000 claims description 16
- 238000001953 recrystallisation Methods 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 15
- 238000004587 chromatography analysis Methods 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 239000000706 filtrate Substances 0.000 claims description 12
- 239000012452 mother liquor Substances 0.000 claims description 12
- 238000000926 separation method Methods 0.000 claims description 11
- 239000000499 gel Substances 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- 239000008213 purified water Substances 0.000 claims description 10
- 239000000377 silicon dioxide Substances 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 239000012046 mixed solvent Substances 0.000 claims description 9
- 238000004062 sedimentation Methods 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 6
- 230000006837 decompression Effects 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 5
- 239000012071 phase Substances 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 4
- XYEOALKITRFCJJ-UHFFFAOYSA-N o-benzylhydroxylamine Chemical compound NOCC1=CC=CC=C1 XYEOALKITRFCJJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 3
- WUTIIZNUZXLPGK-UHFFFAOYSA-N C(C)OC=O.N1=CC=CC=C1 Chemical compound C(C)OC=O.N1=CC=CC=C1 WUTIIZNUZXLPGK-UHFFFAOYSA-N 0.000 claims 1
- -1 (2R,5S)-methyl-5-[(benzyloxy)amino]-piperidine-2-carboxylate ethanedioate Chemical compound 0.000 abstract description 9
- 150000003839 salts Chemical class 0.000 abstract description 7
- 238000005516 engineering process Methods 0.000 abstract description 6
- 238000001514 detection method Methods 0.000 abstract description 3
- 239000007788 liquid Substances 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 3
- IUNNPTAJAWRVJI-KZCZEQIWSA-N methyl (2s,5r)-5-(phenylmethoxyamino)piperidine-2-carboxylate;oxalic acid Chemical compound OC(=O)C(O)=O.C1N[C@H](C(=O)OC)CC[C@H]1NOCC1=CC=CC=C1 IUNNPTAJAWRVJI-KZCZEQIWSA-N 0.000 abstract 1
- 238000007670 refining Methods 0.000 abstract 1
- 238000001035 drying Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 9
- 239000010410 layer Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 229960004261 cefotaxime Drugs 0.000 description 4
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 description 4
- XEEVLJKYYUVTRC-UHFFFAOYSA-N oxomalonic acid Chemical compound OC(=O)C(=O)C(O)=O XEEVLJKYYUVTRC-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 102000006635 beta-lactamase Human genes 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000003908 quality control method Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 108090000204 Dipeptidase 1 Proteins 0.000 description 2
- 239000003781 beta lactamase inhibitor Substances 0.000 description 2
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- MKHQXFGLCBKWMI-UHFFFAOYSA-N n-phenylmethoxypiperidin-1-amine Chemical class C=1C=CC=CC=1CONN1CCCCC1 MKHQXFGLCBKWMI-UHFFFAOYSA-N 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 150000003952 β-lactams Chemical class 0.000 description 2
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 2
- XPNGNIFUDRPBFJ-UHFFFAOYSA-N (2-methylphenyl)methanol Chemical compound CC1=CC=CC=C1CO XPNGNIFUDRPBFJ-UHFFFAOYSA-N 0.000 description 1
- 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
- 241000894006 Bacteria Species 0.000 description 1
- 108020004256 Beta-lactamase Proteins 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 229960002379 avibactam Drugs 0.000 description 1
- 229940091875 avycaz Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 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
- 238000012912 drug discovery process Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 239000000686 essence Substances 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003388 sodium compounds Chemical class 0.000 description 1
- 159000000000 sodium salts Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- MCZDHTKJGDCTAE-UHFFFAOYSA-M tetrabutylazanium;acetate Chemical compound CC([O-])=O.CCCC[N+](CCCC)(CCCC)CCCC MCZDHTKJGDCTAE-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method for chiral isomers in a key intermediate of Avibactam sodium. The preparation method comprises the steps that (2S,5R)-methyl-5-[(benzyloxy)amino]-piperidine-2-carboxylate ethanedioate or (2R,5S)-methyl-5-[(benzyloxy)amino]-piperidine-2-carboxylate ethanedioate is firstly synthesized and then separated, mother liquid is obtained, and (2S,5S)-methyl-5-[(benzyloxy)amino]-piperidine-2-carboxylate ethanedioate or (2R,5R)-methyl-5-[(benzyloxy)amino]-piperidine-2-carboxylate ethanedioate is obtained by taking the mother liquid as a starting material through the steps of concentrating, salt removing, column chromatography, salt forming, refining and the like. According to the preparation method, the preparation technology is simple, the obtained chiral isomers are high in chiral purity, and the quality of the chiral isomers can meet the requirements of purity detection on the chiral isomers of the intermediate.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is related to a kind of side of the chiral isomer of AVM hereinafter Batan sodium key intermediate
Method is and in particular to the preparation method of the chiral isomer of (2S, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates.
Background technology
AVM hereinafter Batan sodium (Avibactam Sodium, NXL-104) belongs to diazabicyclo octanone compound, by Forest
Lab and AstraZeneca are developed jointly, 2014 2 months Arstwyth purchase Forest Lab, acquirement development rights, 2015 2 months 25
Day cefotaxime and AVM hereinafter Batan sodium compound preparation AVYCAZ approval are in U.S.'s listing.AVM hereinafter Batan sodium is to be expected most at present
Novel ss-lactam enzyme inhibitor, compared with three kinds beta-lactamase inhibitor of listing, have long-acting and with enzyme invertibity
Covalent bond, and beta-lactamase will not be induced to produce.
Cefotaxime is a kind of cephalosporin class antimicrobial, to some Gram-negatives and gram-positive bacterium
There is external activity.The bactericidal effect of cefotaxime is by combining mediation with PBP (PBPs).AVM hereinafter bar
Smooth sodium is a kind of beta-lactamase inhibitor of non-beta lactams, inactivate some beta-lactamases and protect cefotaxime from
Some beta-lactamase degradeds.
The AVM hereinafter Batan sodium synthesis that document is reported is mainly with N- tertbutyloxycarbonyl-ethyl L-pyroglutamate as starting material
Material, through open loop, chloro, cyclization, reduces, splits into salt and obtain key intermediate (2S, 5R) -5- (benzyloxy amino)-piperidines -2- formic acid
Ethoxal salt, oxalates through amidatioon, cyclization, deprotection, become sulfonic acid tetrabutyl ammonium acetate salt, after through sodium salt exchange reaction
Obtain AVM hereinafter Batan sodium.The key that (2S, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates synthesizes for AVM hereinafter Batan
Intermediate, has two asymmetric carbon atoms in its structure, there are three chiral isomers：It is respectively (2S, 5S) -5- (benzyloxy ammonia
Base)-piperidines -2- Ethyl formate oxalates, (2R, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates, (2R, 5R) -
5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates.
In drug discovery process, the quality control of intermediate is an important link, and the foundation of quality standard needs
A certain amount of reference substance, so the synthetic method exploitation of impurity is a vital task of drug research.
Content of the invention
In consideration of it, the purpose of the present invention is by crucial separation and process for purification, obtain AVM hereinafter Batan key intermediate
Two chiral isomer (2S, 5S) -5- (benzyloxy ammonia in (2S, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates
Base)-piperidines -2- Ethyl formate oxalates and (2R, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates, for centre
The quality control of body provides reliable impurity reference substance.
To achieve the above object, the technical scheme is that and be achieved in that：
A kind of preparation method of the chiral isomer of AVM hereinafter Batan sodium key intermediate, described AVM hereinafter Batan sodium is crucial middle
Body is (2S, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates, and described chiral isomer is (2S, 5S) -5- (benzyl
Oxygen amino)-piperidines -2- Ethyl formate oxalates, the method comprising the steps of：
S1, (2S, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates will be synthesized after separate the mother liquor that obtains and subtract
Pressure is condensed into dope 1；
Ethyl acetate and purified water is added in S2, dope 1, regulation pH value to alkaline, branch vibration layer, organic phase drying,
Filter, be concentrated to give dope 2；
S3, dope 2 obtain (2S, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali through column chromatography for separation
The mixture of (2S, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali；
S4, mixture is dissolved in acetone, the methanol solution of dropping oxalic acid dihydrate, heating stirring；
S5, cooling crystallization, solids removed by filtration；
S6, filtrate heating, then crystallization of lowering the temperature, solids removed by filtration；
S7, filtrate is concentrated after, gained crude product with being recrystallized in the mixed liquor of acetone and ethanol, obtain (2S, 5S)-
5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates highly finished product.
Further, in described step S3, comprise the following steps：
(1) dope 2 is dissolved in dichloromethane, adds 200～300 mesh column chromatography silica gels to mix sample, evaporated under reduced pressure, must mix sample
Sample, wherein, dope 2 is 1 with mixing sample silica gel mass ratio:1～5；
(2) 200～300 mesh column chromatography silica gels are added in petroleum ether, be stirring evenly and then adding into glass chromatography column, sink
Fall, pillar is compacted by pressurization, will mix all product and add to glass chromatography column, wherein, the quality of dope 2 and fixing phase silica gel
Than for 1:10～50；
(3) eluted with the mixed solvent of petroleum ether and ethyl acetate, collect impact point evaporated under reduced pressure, dissociated
The mixture of alkali, wherein, petroleum ether：The volume ratio of ethyl acetate is 1～5:1.
Further, in described step S4, heating-up temperature is 60～65 DEG C, the mol ratio of oxalic acid dihydrate and free alkali
For 0.8～2:1, free alkali：Acetone：The mass volume ratio (g/mL/mL) of methyl alcohol is 1:10～30:1.
Further, the recrystallization temperature in described step S5 is 40～50 DEG C；In described step S6, recrystallization temperature be 30～
40℃.
Further, the recrystallization temperature in described step S7 is -10～10 DEG C；Crude product：Acetone：The mass volume ratio of ethanol
(g/mL/mL) it is 1:1～20:2.
A kind of preparation method of the chiral isomer of AVM hereinafter Batan sodium key intermediate, described AVM hereinafter Batan sodium is crucial middle
Body is (2S, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates, and described chiral isomer is (2R, 5R) -5- (benzyl
Oxygen amino)-piperidines -2- Ethyl formate oxalates, the method comprising the steps of：
S1, (2R, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates will be synthesized after separate the mother liquor that obtains and subtract
Pressure is condensed into dope 1；
Ethyl acetate and purified water is added in S2, dope 1, regulation pH value to alkaline, branch vibration layer, organic phase drying,
Filter, be concentrated to give dope 2；
S3, dope 2 obtain (2R, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali through column chromatography for separation
The mixture of (2R, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali；
S4, mixture is dissolved in ethyl acetate, the methanol solution of dropping oxalic acid dihydrate, heating stirring；
S5, cooling crystallization, obtain (2R, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate crude product；
S6, crude product heating stirring in the mixed liquor of toluene and methyl alcohol, filter while hot (2R, 5R) -5- (benzyloxy amino) -
Piperidines -2- Ethyl formate first time highly finished product；
S7, first time highly finished product are recrystallized in the mixed liquor of ethyl acetate and methyl alcohol, obtain (2R, 5R) -5- (benzyl
Oxygen amino)-piperidines -2- Ethyl formate oxalates highly finished product.
Further, in described step S3, comprise the following steps：
(1) dope 2 is dissolved in dichloromethane, adds 200～300 mesh column chromatography silica gels to mix sample, evaporated under reduced pressure, must mix sample
Sample, wherein, dope 2 is 1 with mixing sample silica gel mass ratio:1～5；
(2) 200～300 mesh column chromatography silica gels are added in petroleum ether, be stirring evenly and then adding into glass chromatography column, sink
Fall, pillar is compacted by pressurization, will mix all product and add to glass chromatography column, wherein, the quality of dope 2 and fixing phase silica gel
Than for 1:10～50；
(3) eluted with the mixed solvent of petroleum ether and ethyl acetate, collect impact point evaporated under reduced pressure, dissociated
The mixture of alkali, wherein, petroleum ether：The volume ratio of ethyl acetate is 1～5:1.
Further, in described step S4, heating-up temperature is 60～65 DEG C, the mol ratio of oxalic acid dihydrate and free alkali
For 0.8～2:1, free alkali：Ethyl acetate：The mass volume ratio (g/mL/mL) of methyl alcohol is 1；1～20:1.
Further, in described step S5, recrystallization temperature is 10～50 DEG C.
Further, in described step S6, filtration temperature is 40～80 DEG C, crude product：Toluene：Methanol quality volume ratio (g/
ML/mL it is) 1:1～20:2.
Further, the recrystallization temperature in described step S7 is 0～50 DEG C；First time highly finished product：Ethyl acetate：Methyl alcohol
Mass volume ratio (g/mL/mL) is 1:1～20:2.
Compared with prior art, beneficial effects of the present invention are：
The present invention pass through synthesis (2S, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates mother liquor or (2R,
5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates mother liquor be starting material, concentrated, solution salt, column chromatography, become salt,
The step process such as refined respectively obtains (2S, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates or (2R, 5R) -5-
(benzyloxy amino)-piperidines -2- Ethyl formate oxalates.The preparation technology of the present invention is relatively easy, and purity is high, and the present invention prepares
Chiral isomer ee% be 100%.
Chiral isomer impurity prepared by the present invention, for the quality control of key intermediate, and the quality of finished product
Control significant.
Brief description
For the technical scheme being illustrated more clearly that in the embodiment of the present invention, will make to required in embodiment description below
Accompanying drawing is briefly described.
Fig. 1 is the HPLC collection of illustrative plates of (2S, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates；
Fig. 2 is the ESI-MS collection of illustrative plates of (2S, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates；
Fig. 3 is (2S, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates1H-NMR collection of illustrative plates；
Fig. 4 is the HPLC collection of illustrative plates of (2R, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates；
Fig. 5 is the ESI-MS collection of illustrative plates of (2R, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates；
Fig. 6 is (2R, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates1H-NMR collection of illustrative plates.
Specific embodiment
It is noted that described further below is all exemplary it is intended to provide further to the required present invention
Bright, unless otherwise stated, the present invention use all technology and scientific terminology have common with the technical field of the invention
The identical meanings that technical staff is generally understood that.
Describe the present invention below in conjunction with specific embodiments and the drawings in detail it is therefore an objective to make advantages of the present invention fuller and more accurate, and
The unrestricted present invention.It should be appreciated by those skilled in the art that the method that the present invention is not limited to these embodiments and use, appoint
What is replaced on an equal basis to the present invention, is combined, improved or is modified, and is both contained in the present invention.
The chirality of AVM hereinafter Batan key intermediate (2S, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates is different
The preparation of one of structure body (2S, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates, comprises the following steps：
S1, (2S, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates will be synthesized after separate the mother liquor that obtains in
40～80 DEG C carry out reduced pressure concentration and become dope 1, preferably 40～50 DEG C.
Add ethyl acetate and purified water in S2, dope 1, adjust pH value to alkalescence with saturated sodium bicarbonate aqueous solution,
Branch vibration layer, organic layer anhydrous sodium sulfate drying, filters, is concentrated to give free alkali dope 2, and wherein, pH is 7～10, preferably
For 8～9.
S3, dope 2 obtain (2S, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali through column chromatography for separation
The mixture of (2S, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali, wherein, comprises the following steps：
(1) dope 2 is dissolved in dichloromethane, adds 200～300 mesh column chromatography silica gels to mix sample, evaporated under reduced pressure, must mix sample
Sample, wherein dope 2 are 1 with mixing sample silica gel mass ratio:1～5, preferably 1:1～2；
(2) 200～300 mesh column chromatography silica gels are added to petroleum ether, are stirring evenly and then adding into glass chromatography column,
Sedimentation, pillar is compacted by pressurization, will mix all product and add to glass chromatography column, wherein the matter of dope 2 and fixing phase silica gel
Amount ratio is 1:10～50, preferably 1:10～30；
(3) eluted with the mixed solvent of petroleum ether and ethyl acetate, collected impact point evaporated under reduced pressure, obtain (2S,
5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali and (2S, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate
The mixture of free alkali, wherein petroleum ether：The volume ratio of ethyl acetate is 1～5:1, preferably 2～3:1.
S4, mixture is dissolved in acetone, the methanol solution of dropping oxalic acid dihydrate, is heated to 60～65 DEG C of stirrings 30
Minute, wherein the mol ratio of oxalic acid dihydrate and free alkali is 0.8～2:1, preferably 0.9～1.1:1, free alkali：Acetone：First
The mass volume ratio (g/mL/mL) of alcohol is 1:10～30:1, preferably 1:15～25:1.
S5, cooling crystallization, solids removed by filtration, wherein recrystallization temperature are 40～50 DEG C, preferably 40～45 DEG C.
S6, filtrate heating, then crystallization of lowering the temperature, solids removed by filtration, wherein recrystallization temperature are 30～40 DEG C, preferably 30～
35℃.
S7, filtrate is concentrated after, gained crude product is recrystallized with the mixed liquor of acetone and ethanol, obtain (2S, 5S) -5-
(benzyloxy amino)-piperidines -2- Ethyl formate oxalates highly finished product, wherein recrystallization temperature are -10～10 DEG C, preferably 0～5 DEG C；Slightly
Product：Acetone：The mass volume ratio (g/mL/mL) of ethanol is 1:1～20:2, preferably 1:8～12:2.
Embodiment 1
The preparation of (2S, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates, comprises the following steps：
S1, (2S, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates will be synthesized after separate the mother liquor that obtains in
40～50 DEG C of reduced pressure concentrations, obtain 16g dope 1, HPLC detection (2S, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate grass
The mass ratio of hydrochlorate and (2S, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates is 25:75.
Add 90mL ethyl acetate and 50mL purified water in S2, dope 1, adjust pH value with saturated sodium bicarbonate aqueous solution
For 8～9, branch vibration layer, organic layer anhydrous sodium sulfate drying, filters, is concentrated to give 11.8g dope 2.
S3, dope 2 obtain (2S, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali through column chromatography for separation
The mixture of (2S, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali, wherein, comprises the following steps：
(1) dope 2 is dissolved in 60mL dichloromethane, adds 15g 200～300 mesh column chromatography silica gel to mix sample, decompression
It is evaporated, all product must be mixed；
(2) 250g 200～300 mesh column chromatography silica gel is added to 1.5L dichloromethane, be stirring evenly and then adding into glass
In glass chromatographic column, sedimentation, pillar is compacted by pressurization, will mix all product and add to glass chromatography column；
(3) use petroleum ether：Volume ratio=3 of ethyl acetate:1 mixed solvent is eluted, and collects impact point and reduces pressure
Be evaporated, obtain (2S, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali and (2S, 5S) -5- (benzyloxy amino)-piperidines -
The mixture 9g of 2- Ethyl formate free alkali.
S4, mixture is dissolved in 180mL acetone, the methanol solution of dropping oxalic acid dihydrate, its mesoxalic acid two is hydrated
The addition of thing is 4.4g, and methyl alcohol is 9mL, is heated to 60～65 DEG C and stirs 30 minutes.
S5, it is cooled to 40～45 DEG C of crystallizations 2 hours, solids removed by filtration.
S6, filtrate are heated to 50～60 DEG C and stir 30 minutes, then are cooled to 30～35 DEG C of crystallizations 2 hours, filter, and remove solid
Body.
S7, filtrate concentrate, and obtain crude product 5g, add in acetone and the mixed liquor of ethanol and are recrystallized, and acquisition (2S, 5S)-
5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates, comprises the following steps：
(1) after filtrate being concentrated, add the mixed liquor of 50mL acetone and 10mL ethanol in gained crude product, be heated to 50～60
DEG C, maintain 30 minutes；
(2) it is cooled to 0～5 DEG C of crystallization 4 hours, filters, gained solid obtains (2S, 5S) -5- in 40～50 DEG C of drying under reduced pressure
(benzyloxy amino)-piperidines -2- Ethyl formate oxalates 3.1g, yield 19.4% (in terms of dope 1), ee value 100%.
The HPLC collection of illustrative plates being obtained (2S, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates is as shown in Figure 1；
The ESI-MS collection of illustrative plates of (2S, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates is as shown in Figure 2；(2S, 5S) -5- (benzyl
Oxygen amino)-piperidines -2- Ethyl formate oxalates1H-NMR collection of illustrative plates is as shown in Figure 3.
ESI-MS(m/z)：279.16(M+H)
1H-NMR(400MHz,DMSO):δ8.57(br,4H),7.36-7.29(m,5H),4.63(t,2H),4.22-4.12
(m,3H),3.16-3.05(m,3H),1.93-1.77(m,2H),1.77-1.74(m,1H),1.48-1.47(m,1H),1.22
(t,3H).
Embodiment 2
The preparation of (2S, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates, comprises the following steps：
S1, (2S, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates will be synthesized after separate the mother liquor that obtains in
40～50 DEG C of reduced pressure concentrations, obtain 23.2g dope 1.
Add 120mL ethyl acetate and 70mL purified water in S2, dope 1, adjust pH with saturated sodium bicarbonate aqueous solution
It is worth for 8～9, branch vibration layer, organic layer anhydrous sodium sulfate drying, filters, is concentrated to give 16.3g dope 2.
S3, dope 2 obtain (2S, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali through column chromatography for separation
The mixture of (2S, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali, wherein, comprises the following steps：
(1) dope is dissolved in 100mL dichloromethane, adds 25g 200～300 mesh column chromatography silica gel to mix sample, decompression
It is evaporated, all product must be mixed；
(2) 350g 200～300 mesh column chromatography silica gel is added to 2L dichloromethane, be stirring evenly and then adding into glass
In chromatographic column, sedimentation, pillar is compacted by pressurization, will mix all product and add to glass chromatography column；
(3) use petroleum ether：Volume ratio=3 of ethyl acetate:1 mixed solvent is eluted, and collects impact point and reduces pressure
Be evaporated, obtain (2S, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali and (2S, 5S) -5- (benzyloxy amino)-piperidines -
The mixture 11.3g of 2- Ethyl formate free alkali.
S4, mixture is dissolved in 220mL acetone, the methanol solution of dropping oxalic acid dihydrate, its mesoxalic acid two is hydrated
The addition of thing is 5.2g, and methyl alcohol is 11.3mL, is heated to 60～65 DEG C and stirs 30 minutes.
S5, it is cooled to 40～45 DEG C of crystallizations 2 hours, solids removed by filtration.
S6, filtrate are heated to 50～60 DEG C and stir 30 minutes, then are cooled to 30～35 DEG C of crystallizations 2 hours, filter, and remove solid
Body.
S7, filtrate are concentrated to give crude product 6.3g, add in acetone and the mixed liquor of ethanol and are recrystallized, and acquisition (2S, 5S)-
5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates, wherein, comprises the following steps：
(1), after concentrating filtrate, gained crude product adds acetone and the 12.6mL alcohol mixeding liquid of 63mL, is heated to 50～60
DEG C, maintain 30 minutes；
(2) it is cooled to 0～5 DEG C of crystallization 4 hours, filters, gained solid obtains (2S, 5S) -5- in 40～50 DEG C of drying under reduced pressure
(benzyloxy amino)-piperidines -2- Ethyl formate oxalates 4.0g, yield 17.2% (in terms of dope 1), ee value 100%.
The chirality of AVM hereinafter Batan key intermediate (2S, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates is different
The preparation of two (2R, 5R) -5- (benzyloxy amino) of structure body-piperidines -2- Ethyl formate oxalates, comprises the following steps：
S1, (2R, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates will be synthesized after separate the mother liquor that obtains in
40～80 DEG C carry out reduced pressure concentration and become dope 1, preferably 40～50 DEG C.
Add ethyl acetate and purified water in S2, dope, adjust pH value to alkalescence with saturated sodium bicarbonate aqueous solution, point
Remove water layer, organic layer anhydrous sodium sulfate drying, filter, be concentrated to give dope 2, wherein pH is 7～10, preferably 8～9.
S3, dope 2 obtain (2R, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali through column chromatography for separation
The mixture of (2R, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali, wherein, comprises the following steps：
(1) dope 2 adds 200～300 mesh column chromatography silica gels to mix sample, evaporated under reduced pressure, must mix all product, wherein dope
2 is 1 with mixing sample silica gel mass ratio:1～5, preferably 1:1～2；
(2) 200～300 mesh column chromatography silica gels are added to petroleum ether, are stirring evenly and then adding into glass chromatography column,
Sedimentation, pillar is compacted by pressurization, will mix all product and add to glass chromatography column, wherein the matter of dope 2 and fixing phase silica gel
Amount ratio is 1:10～50, preferably 1:10～30；
(3) eluted with the mixed solvent of petroleum ether and ethyl acetate, collected impact point evaporated under reduced pressure, obtain (2R,
5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali and (2R, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate
The mixture of free alkali, wherein petroleum ether：The volume ratio of ethyl acetate is 1～5:1, preferably 2～3:1.
S4, mixture is dissolved in ethyl acetate, the methanol solution of dropping oxalic acid dihydrate, is heated to 60～65 DEG C and stirs
Mix 30 minutes, the wherein mol ratio of oxalic acid dihydrate and free alkali is 0.8～2:1, preferably 0.9～1.1:1；Free alkali：Second
Acetoacetic ester：The mass volume ratio (g/mL/mL) of methyl alcohol is 1:1～20:1, preferably 1:8～12:1.
S5, cooling crystallization, filter (2R, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates crude product, wherein
Recrystallization temperature is 10～50 DEG C, preferably 20～30 DEG C.
S6, crude product heating stirring certain time in toluene-methanol, filter while hot (2R, 5R) -5- (benzyloxy amino) -
Piperidines -2- Ethyl formate first time highly finished product, wherein filtration temperature are 40～80 DEG C, preferably 50～60 DEG C；Wherein crude product：First
Benzene：Methanol quality volume ratio (g/mL/mL) is 1:1～20:2, preferably 1:10:2；
S7, first time highly finished product are recrystallized in the mixed liquor of ethyl acetate and methyl alcohol, obtain (2R, 5R) -5-
(benzyloxy amino)-piperidines -2- Ethyl formate oxalates, wherein first time highly finished product：Ethyl acetate：The mass volume ratio of methyl alcohol
(g/mL/mL) it is 1:1～20:2, preferably 1:8～12:2；Wherein recrystallization temperature is 0～50 DEG C, preferably 20～30 DEG C.
Embodiment 3
The preparation of (2R, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates, comprises the following steps：
S1, (2R, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates will be synthesized after separate the mother liquor that obtains in
40～50 DEG C of reduced pressure concentrations, obtain 18.1g dope 1, HPLC detection (2R, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate
Oxalates and (2R, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates mass ratio are 20:80.
Add 150mL ethyl acetate and 100mL purified water in S2, dope 1, adjust pH with saturated sodium bicarbonate aqueous solution
It is worth for 8～9, branch vibration layer, organic layer anhydrous sodium sulfate drying, filters, is concentrated to give 12.8g dope 2.
S3, dope 2 obtain (2R, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali through column chromatography for separation
The mixture of (2R, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali, wherein, comprises the following steps：
(1) dope is dissolved in 80mL dichloromethane, adds 20g 200～300 mesh column chromatography silica gel to mix sample, decompression is steamed
Dry, all product must be mixed；
(2) 250g 200～300 mesh column chromatography silica gel is added to 1.8L dichloromethane, be stirring evenly and then adding into glass
In glass chromatographic column, sedimentation, pillar is compacted by pressurization, will mix all product and add to glass chromatography column；
(3) use petroleum ether：Volume ratio=3 of ethyl acetate:1 mixed solvent is eluted, and collects impact point and reduces pressure
Be evaporated, obtain (2R, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali and (2R, 5R) -5- (benzyloxy amino)-piperidines -
The mixture 8g of 2- Ethyl formate free alkali.
S4, mixture is dissolved in 80mL ethyl acetate, the methanol solution of dropping oxalic acid dihydrate, its mesoxalic acid two water
The addition of compound is 3.6g, and methyl alcohol is 8mL, is heated to 60～65 DEG C and stirs 30 minutes.
S5, it is cooled to 20～30 DEG C of crystallizations 6 hours, obtain (2R, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalic acid
Salt crude product 9.5g.
S6, crude product add to the mixed liquor of toluene (95mL)-methyl alcohol (19mL), are heated to 50～60 DEG C and stir 2 hours,
Filter while hot, dry (2R, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate first time highly finished product 6.2g.
S7, first time highly finished product are added recrystallized to the mixed liquor of ethyl acetate and methyl alcohol, obtain (2R,
5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates, wherein, comprises the following steps：
(1) first time highly finished product add to the ethyl acetate and 12.4mL methyl alcohol mixed liquor of 62mL, are heated to 50～60
DEG C, maintain 30 minutes；
(2) be cooled to 20～30 DEG C of crystallizations 4 hours, filter, gained solid in 40～50 DEG C of drying under reduced pressure obtain (2R, 5R)-
5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates 4.7g, yield 26.0% (in terms of dope 1), ee value 100%.
The HPLC collection of illustrative plates being obtained (2R, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates is as shown in Figure 4；
The ESI-MS collection of illustrative plates of (2R, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates is as shown in Figure 5；(2R, 5R) -5- (benzyl
Oxygen amino)-piperidines -2- Ethyl formate oxalates1H-NMR collection of illustrative plates is as shown in Figure 6.
ESI-MS(m/z)：279.16(M+1)
1H-NMR(400MHz,DMSO):δ7.36-7.29(m,5H),6.98(br,4H),4.62(t,2H),4.20-4.14
(m,2H),3.98-3.97(m,1H),3.07(d,2H),3.02-2.98(m,1H),1.89-1.82(m,2H),1.73-1.72
(m,1H),1.48-1.47(m,1H),1.21(t,3H).
Embodiment 4
The preparation of (2R, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates, comprises the following steps：
S1, by synthesis (2R, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates mother liquor subtract in 40～50 DEG C
Pressure concentrates, and obtains 10.2g dope 1.
Add 80mL ethyl acetate and 50mL purified water in S2, dope 1, adjust pH value with saturated sodium bicarbonate aqueous solution
For 8～9, branch vibration layer, organic layer anhydrous sodium sulfate drying, filters, is concentrated to give 7.2g dope 2.
S3, dope 2 obtain (2R, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali through column chromatography for separation
The mixture of (2R, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali, wherein, comprises the following steps：
(1) dope is dissolved in 50mL dichloromethane, adds 10g 200～300 mesh column chromatography silica gel to mix sample, decompression is steamed
Dry, all product must be mixed；
(2) 160g 200～300 mesh column chromatography silica gel is added to 1.8L dichloromethane, be stirring evenly and then adding into glass
In glass chromatographic column, sedimentation, pillar is compacted by pressurization, will mix all product and add to glass chromatography column；
(3) use petroleum ether：Volume ratio=3 of ethyl acetate:1 mixed solvent is eluted, and collects impact point and reduces pressure
Be evaporated, obtain (2R, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali and (2R, 5R) -5- (benzyloxy amino)-piperidines -
The mixture 5.2g of 2- Ethyl formate free alkali.
S4, mixture is dissolved in 52mL ethyl acetate, the ethanol solution of dropping oxalic acid dihydrate, its mesoxalic acid two water
The addition of compound is 2.4g, and ethanol is 5.2mL, is heated to 60～65 DEG C and stirs 30 minutes.
S5, it is cooled to 20～30 DEG C of crystallizations 6 hours, filter (2R, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate
Oxalates solid 6.2g.
S6, crude product add to the mixed liquor of toluene (62mL)-methyl alcohol (12.4mL), are heated to 50～60 DEG C of stirrings 2 little
When, filter while hot, dry (2R, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate first time highly finished product 3.8g.
S7, first time highly finished product are added recrystallized to the mixed liquor of ethyl acetate and methyl alcohol, obtain (2R,
5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates, wherein, comprises the following steps：
(1) first time highly finished product add to 38mL ethyl acetate and 7.6mL methyl alcohol mixed liquor, are heated to 50～60 DEG C,
Maintain 30 minutes；
(2) be cooled to 20～30 DEG C of crystallizations 4 hours, filter, gained solid in 40～50 DEG C of drying under reduced pressure obtain (2R, 5R)-
5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates 2.8g, yield 27.5% (in terms of dope 1), ee value 100%.
The preparation technology of the present invention is relatively easy, and the AVM hereinafter Batan sodium prepared by method of the present invention is crucial middle
Chiral isomer (2S, the 5S) -5- (benzyloxy amino) of body-piperidines -2- Ethyl formate oxalates or (2R, 5R) -5- (benzyloxy ammonia
Base)-high ee the value of piperidines -2- Ethyl formate oxalic acid purity salt is 100%.
The foregoing is only presently preferred embodiments of the present invention, not in order to limit the present invention, all essences in the present invention
Within god and principle, any modification, equivalent substitution and improvement made etc., should be included within the scope of the present invention.
Claims (10)
1. a kind of preparation method of the chiral isomer of AVM hereinafter Batan sodium key intermediate, described AVM hereinafter Batan sodium key intermediate
For (2S, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates, described chiral isomer is (2S, 5S) -5- (benzyloxy
Amino)-piperidines -2- Ethyl formate oxalates is it is characterised in that the method comprising the steps of：
S1, (2S, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates will be synthesized after separate obtain mother liquor decompression dense
Shorten dope 1 into；
Add ethyl acetate and purified water in S2, dope 1, adjust pH value to alkalescence, branch vibration layer, organic phase is dried, filtration,
It is concentrated to give dope 2；
S3, dope 2 through column chromatography for separation obtain (2S, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali and
The mixture of (2S, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali；
S4, mixture is dissolved in acetone, the methanol solution of dropping oxalic acid dihydrate, heating stirring；
S5, cooling crystallization, solids removed by filtration；
S6, filtrate heating, then crystallization of lowering the temperature, solids removed by filtration；
S7, filtrate is concentrated after, gained crude product is recrystallized with the mixed liquor of acetone and ethanol, obtain (2S, 5S) -5- (benzyl
Oxygen amino)-piperidines -2- Ethyl formate oxalates highly finished product.
2. a kind of preparation method of the chiral isomer of AVM hereinafter Batan sodium key intermediate, described AVM hereinafter Batan sodium key intermediate
For (2S, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates, described chiral isomer is (2R, 5R) -5- (benzyloxy
Amino)-piperidines -2- Ethyl formate oxalates is it is characterised in that the method comprising the steps of：
S1, (2R, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate oxalates will be synthesized after separate obtain mother liquor decompression dense
Shorten dope 1 into；
Add ethyl acetate and purified water in S2, dope 1, adjust pH value to alkalescence, branch vibration layer, organic phase is dried, filtration,
It is concentrated to give dope 2；
S3, dope 2 through column chromatography for separation obtain (2R, 5S) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali and
The mixture of (2R, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate free alkali；
S4, mixture is dissolved in ethyl acetate, the methanol solution of dropping oxalic acid dihydrate, heating stirring；
S5, cooling crystallization, obtain (2R, 5R) -5- (benzyloxy amino)-piperidines -2- Ethyl formate crude product；
S6, crude product heating stirring in the mixed liquor of toluene and methyl alcohol, filters (2R, 5R) -5- (benzyloxy amino)-piperazine while hot
Pyridine -2- Ethyl formate first time highly finished product；
S7, first time highly finished product are recrystallized in the mixed liquor of ethyl acetate and methyl alcohol, obtain (2R, 5R) -5- (benzyloxy ammonia
Base)-piperidines -2- Ethyl formate oxalates highly finished product.
3. the preparation method of the chiral isomer of AVM hereinafter Batan sodium key intermediate according to claim 1 or claim 2, its feature exists
In, in described step S3, comprising the following steps：
(1) dope 2 is dissolved in dichloromethane, adds 200～300 mesh column chromatography silica gels to mix sample, evaporated under reduced pressure, must mix all
Product, wherein, dope 2 is 1 with mixing sample silica gel mass ratio:1～5；
(2) 200～300 mesh column chromatography silica gels are added in petroleum ether, be stirring evenly and then adding into glass chromatography column, sedimentation,
Pillar is compacted by pressurization, will mix all product and add to glass chromatography column, wherein, the mass ratio of dope 2 and fixing phase silica gel
For 1:10～50；
(3) eluted with the mixed solvent of petroleum ether and ethyl acetate, collected impact point evaporated under reduced pressure, obtained the mixed of free alkali
Compound, wherein, petroleum ether：The volume ratio of ethyl acetate is 1～5:1.
4. according to claim 1 the chiral isomer of AVM hereinafter Batan sodium key intermediate preparation method it is characterised in that
In described step S4, heating-up temperature is 60～65 DEG C, and the mol ratio of oxalic acid dihydrate and free alkali is 0.8～2:1, dissociate
Alkali：Acetone：The mass volume ratio (g/mL/mL) of methyl alcohol is 1:10～30:1.
5. according to claim 2 the chiral isomer of AVM hereinafter Batan sodium key intermediate preparation method it is characterised in that
In described step S4, heating-up temperature is 60～65 DEG C, and the mol ratio of oxalic acid dihydrate and free alkali is 0.8～2:1, dissociate
Alkali：Ethyl acetate：The mass volume ratio (g/mL/mL) of methyl alcohol is 1:1～20:1.
6. according to claim 1 the chiral isomer of AVM hereinafter Batan sodium key intermediate preparation method it is characterised in that
Recrystallization temperature in described step S5 is 40～50 DEG C；In described step S6, recrystallization temperature is 30～40 DEG C.
7. according to claim 1 the chiral isomer of AVM hereinafter Batan sodium key intermediate preparation method it is characterised in that
Recrystallization temperature in described step S7 is -10～10 DEG C；Crude product：Acetone：The mass volume ratio (g/mL/mL) of ethanol is 1:1～
20:2.
8. according to claim 2 the chiral isomer of AVM hereinafter Batan sodium key intermediate preparation method it is characterised in that
In described step S5, recrystallization temperature is 10～50 DEG C.
9. according to claim 2 the chiral isomer of AVM hereinafter Batan sodium key intermediate preparation method it is characterised in that
In described step S6, filtration temperature is 40～80 DEG C, crude product：Toluene：The mass volume ratio (g/mL/mL) of methyl alcohol is 1:1～20:
2.
10. the preparation method of the chiral isomer of AVM hereinafter Batan sodium key intermediate according to claim 2, its feature exists
In the recrystallization temperature in described step S7 is 0～50 DEG C；First time highly finished product：Ethyl acetate：Mass volume ratio (the g/ of methyl alcohol
ML/mL it is) 1:1～20:2.
Priority Applications (1)
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| CN107941969A (en) * | 2017-11-07 | 2018-04-20 | 中山奕安泰医药科技有限公司 | The detection method of 2 formamide of (2S, 5R) Atenolol phenylpiperidines |
| CN108362789A (en) * | 2018-01-19 | 2018-08-03 | 珠海优润医药科技有限公司 | A kind of high-efficiency liquid chromatography method for detecting of AVM hereinafter Batan sodium optical isomer |
| EP3546451A4 (en) * | 2017-08-18 | 2020-08-05 | Xinfa Pharmaceutical Co., Ltd | Improved method for preparation of 5r |
| CN117447285A (en) * | 2023-10-25 | 2024-01-26 | 赤峰迪生药业有限责任公司 | Preparation method of chiral impurity of beta-lactamase inhibitor intermediate |
| WO2025086317A1 (en) * | 2023-10-23 | 2025-05-01 | 江西富祥药业股份有限公司 | Purification method for avibactam sodium intermediate and avibactam sodium intermediate |
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| CN117447285A (en) * | 2023-10-25 | 2024-01-26 | 赤峰迪生药业有限责任公司 | Preparation method of chiral impurity of beta-lactamase inhibitor intermediate |
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