CN106699756B - The synthetic method of beta lactamase restrainer AVM hereinafter Batan - Google Patents
The synthetic method of beta lactamase restrainer AVM hereinafter Batan Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The present invention relates to a kind of synthetic methods of beta lactamase restrainer AVM hereinafter Batan, belong to the preparation technical field of beta lactamase restrainer.The present invention is the following steps are included: (1) with compound 2 is raw material, with R1NH2Reaction generates compound 3；(2) in organic solvent, compound 3 and biocatalyst generate compound 4 in the presence of glucose or sucrose；(3) compound 4 and trifluoroacetic acid anhydride reactant generate compound 5；(4) compound 5 and R2ONH2Reaction generates compound 6；(5) compound 6 hydrolyzes under alkaline condition generates compound 7；(6) compound 7 and triphosgene reaction generate compound 8；(7) in organic solvent, compound 8 is reacted with ammonium formate in the presence of a catalyst generates compound 9, and catalyst is Pd/C system；(8) compound 9 is reacted with sulfonating agent generates product 1.Present invention process is stablized, high income, safety easy to operate, and production cost is low.
Description
Technical field
The present invention relates to a kind of synthetic methods of beta lactamase restrainer AVM hereinafter Batan, belong to beta lactamase restrainer
Preparation technical field.
Background technique
2004, Novexel company begin one's study DBOs class compound and find AVM hereinafter Batan have the interior acyl of preferable β-
Amine enzyme inhibition.AVM hereinafter Batan is novel ss-lactam enzyme inhibitor, and suppression zymogram is wide, and mechanism of action and classical β-are interior
Lactamase inhibitor has the difference of essence, have it is long-acting and with enzyme invertibity covalent bond, and beta-lactamase will not be induced to produce
It is raw.The compound product of cefotaximes in 2015 and AVM hereinafter Batan is ratified to list in the U.S., trade name Avycaz.
AVM hereinafter Batan belongs to DBOs class compound, Chinese chemical name: [(1R, 2S, 5R) -2- (carbamoyl) -7- oxygen
Generation -1,6- diazabicyclo [3.2.1] octyl- 6- yl] sulfuric acid monoester.
Patent WO086241 is disclosed with compound 11 as raw material, and the method for synthesis AVM hereinafter Batan is reacted by 15 steps,
See synthetic route 1.The synthetic route: when synthesizing compound 13 using the method for substitution, open loop, cyclization, by-product is high, pure
It there are isomers (ee% 75%) when changing difficulty big, synthesis compound 14, needs to split, when deprotection uses H2Removing,
Complicated for operation, there are certain risk, whole synthesis step is tediously long, and ultimate yield is lower.
Patent CN 103649051 discloses the method with compound 26 for Material synthesis AVM hereinafter Batan, sees synthetic route 2.
The route also uses the method for open loop cyclization again when synthesizing compound 29, and by-product is high, exists when synthesizing compound 30
Isomers, when deprotection, also use H2, operation difficulty is big, and route process is cumbersome, and ultimate yield is lower.
Summary of the invention
The purpose of the present invention is to provide a kind of synthetic method of beta lactamase restrainer AVM hereinafter Batan, process stabilizing,
High income, safety easy to operate, production cost is low, is suitble to industrialized production.
The synthetic method of beta lactamase restrainer AVM hereinafter Batan of the present invention, with ((the S) -5- oxo -2 of compound 2
Piperidine carboxylic acid) be raw material, be substituted, restore, protecting, replacing, hydrolyzing, being cyclized, being deprotected, the process of sulfonation, finally synthesize Ah
Batan is tieed up, sees synthetic route 3.Specifically includes the following steps:
It (1) is raw material with compound 2, with R1NH2Reaction generates compound 3；
(2) in organic solvent, compound 3 and biocatalyst generate compound 4 in the presence of glucose or sucrose；
(3) compound 4 and trifluoroacetic acid anhydride reactant generate compound 5；
(4) compound 5 and R2ONH2Reaction generates compound 6；
(5) compound 6 hydrolyzes under alkaline condition generates compound 7；
(6) compound 7 and triphosgene reaction generate compound 8；
(7) in organic solvent, compound 8 is reacted with ammonium formate in the presence of a catalyst generates compound 9, and catalyst is
Pd/C system；
(8) compound 9 is reacted with sulfonating agent generates product 1；
Reaction equation is as follows:
In step (1), the reaction time is 1~20h；R1For Bn, t-Bu, Fmoc, Alloc, Teoc, Pmb or Dmb.
In step (2), the glucose or sucrose provide carbon source for reaction；The reaction time is 1~72h, reaction
Temperature is 5~40 DEG C；Organic solvent is methylene chloride, ethyl acetate or acetone；Biocatalyst is yeast, preferably bread ferment
It is female.
In step (3), the reaction time is 0.5~12h, and reaction temperature is -20~0 DEG C.
In step (4), the reaction time is 1~20h；R2For Bn, t-Bu, Fmoc, Alloc, Teoc, Pmb or Dmb.
In step (5), the reaction time is 0.5~10h；Alkali is sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate or three
Ethamine.
In step (6), the reaction time be 1~for 24 hours, reaction temperature be -40~10 DEG C.
In step (7), organic solvent is methanol, methylene chloride, acetone or ethyl acetate.
In step (8), the reaction time is 1~48h；Sulfonating agent is sulfuric acid, in sulfur trioxide or its complex compound, chlorosulfonic acid
It is a kind of.
Compared with the prior art, the present invention has the following beneficial effects:
The present invention is when synthesizing compound 4, and the step of without open loop, cyclization, by-product is few, is selected using biocatalysis
The reduction of selecting property, ee% are up to 99%, when carrying out the removing of crucial protecting group using ammonium formate and Pd/C system, do not use H2,
Safety easy to operate.Present invention process is stablized, and W-response route is brief, and post-processing is simple, whole high income, is suitble to industrialization
Production.
Specific embodiment
Below with reference to embodiment, the present invention is further illustrated, but it is not intended to limit implementation of the invention.
Embodiment 1
(1) compoundSynthesis:
- 2 piperidine carboxylic acid (25.0g, 174.6mmol) of (S) -5- oxo is added in there-necked flask, methylene chloride (300ml) stirs
It mixes, 2,6- lutidines (1g, 9mmol), benzylamine hydrochloride (26.5g, 184.8mmol), temperature rising reflux 2h, with purifying is added
Water and saturated sodium chloride solution washing, liquid separation, concentration obtain light brown oily compound 3 (42.83g, 171.1mmol, yield
98%)
(2) compoundSynthesis:
Purified water (600ml) is added in there-necked flask, glucose (20g), citric acid (0.5g), PEG 2000 (0.1g),
Disodium hydrogen phosphate (0.5g), baker yeast (40g), 30 DEG C of constant temperature stir 1h, be added in three batches compound 3 (40g,
Ethyl acetate solution (300ml) 172.2mmol), every batch of interval 1h, after adding 30 DEG C of insulation reactions for 24 hours, filtering, liquid separation,
Water phase is extracted with ethyl acetate, merges organic phase, concentration, the whole crystalline substance of n-hexane filters, and vacuum drying obtains off-white powder chemical combination
Object 4 (38.3g, 163.6mmol, yield 95%).Optically active body ee value 99%.
(3) compoundSynthesis:
Tetrahydrofuran (500ml), compound 4 (35g, 149.4mmol) are added in there-necked flask, in -7 DEG C of addition triethylamines
(80g, 788.8mmol) stirs 30min, trifluoroacetic anhydride (65g, 323.3mmol) used time 1h is added dropwise, and temperature maintains -5 DEG C
~-7 DEG C, purified water (500ml) is added after the reaction was completed, 15 DEG C of stirring 30min, liquid separation, with tetrahydrofuran aqueous phase extracted 2 times,
Merge organic phase, successively with 5% sodium bicarbonate aqueous solution (500ml), saturated sodium-chloride water solution (400ml), purified water
(200ml) washing is evaporated under reduced pressure organic phase, and the whole crystalline substance of n-hexane filters, and vacuum drying obtains buff white solid compound 5
(47.8g, 144.9mmol, yield 97%).
(4) compoundSynthesis:
Chloroform (500ml), compound 5 (40g, 121.1mmol) are added in there-necked flask, stirring and dissolving is cooled to-
It 20 DEG C, is added 2,6- lutidines (3g, 27mmol), is added dropwise Trifluoromethanesulfonic anhydride (65g, 230.3mmol), -20~-25
DEG C reaction 30min, be added benzyloxy amine (29g, 235.4mmol), maintain temperature -5~0 DEG C react 20h, be added purified water
(300ml) stirring, liquid separation, successively with aqueous citric acid solution (200ml), 5% sodium bicarbonate aqueous solution (300ml), saturation chlorination
Sodium solution (300ml) washing, water layer chloroform extraction merge organic phase, and anhydrous sodium sulfate is dry, is concentrated under reduced pressure, obtains oily
Shape compound 6 (50.1g, 115.0mmol, yield 95%).
(5) compoundSynthesis:
Methanol (200ml), compound 6 (45g, 103.3mmol) are added in there-necked flask, 20% potassium carbonate is added dropwise in stirring
Solution (100ml) reacts 1h, and concentrated hydrochloric acid (2ml) is added after the reaction was completed, stirs 10min, is extracted with ethyl acetate, with purifying
Water and saturated sodium-chloride water solution wash organic phase, are concentrated under reduced pressure, obtain oily compound 7 (34.4g, 101.3mmol, yield
98%).
(6) compoundSynthesis:
In there-necked flask be added chloroform (600ml), compound 7 (30g, 88.4mmol), triphosgene (39.3g,
132.5mmol), stirring is cooled to -15 DEG C, and pyridine (10g, 126.4mmol) used time 1h is added dropwise, and drips 20 DEG C or so reactions after finishing
3h is added purified water (300ml), liquid separation, with chloroform extraction water phase, merges organic phase, successively water-soluble with 5% sodium bicarbonate
Liquid (200ml), saturated sodium-chloride water solution (200ml) washing, anhydrous sodium sulfate is dry, and organic phase is concentrated under reduced pressure, and n-hexane is whole
Crystalline substance filters, and vacuum drying obtains pulverulent solids compound 8 (29.7g, 81.3mmol, yield 92%).
(7) compoundSynthesis:
Methanol (1000ml), compound 8 (25g, 68.4mmol) are added in there-necked flask, is added 10%Pd/C (40g), stirs
10min is mixed, is added ammonium formate (42g), is heated to reflux, reacts 2h, diatomite filtering, methanol washing is evaporated under reduced pressure, and vacuum is dry
It is dry, obtain solid chemical compound 9 (12.4g, 67.0mmol, yield 98%)
(8) productSynthesis:
DMF (50ml), compound 10 (5g, 27mmol) are added in there-necked flask, sulfur trioxide pyridine complex is added
(4.5g) is warming up to 30 DEG C, is stirred to react 16h, and filtering is washed with ethyl acetate, and organic phase is concentrated, and vacuum drying obtains solid
Product 1 (6.9g, 26.0mmol, yield 96%).
Embodiment 2
Other are identical as in embodiment 1, unlike:
(1) in synthesis compoundWhen, compound 2 and R1NH2Reaction generates compound 3, R1For Teoc；It heats up back
It flows 1h (yield 96%).
(2) in synthesis compoundWhen, glucose is changed to sucrose；Organic solvent ethyl acetate is changed to
Acetone；After adding raw material, in 5 DEG C of insulation reaction 72h (yield 94%, optical activity ee value 99%).
(3) in synthesis compoundWhen, 0.5h is reacted after trifluoroacetic anhydride is added dropwise, temperature maintains -20 DEG C
(yield 96%).
(4) in synthesis compoundWhen, after benzyloxy amine is added, thermotonus 1h is maintained, wherein R1For Teoc,
R2For Alloc (yield 96%).
(5) in synthesis compoundWhen (wherein R1For Teoc, R2For Alloc), solution of potassium carbonate is changed to
Sodium hydroxide solution；It reacts 0.5h (yield 97%).
(6) in synthesis compoundWhen (wherein R1For Teoc, R2For Alloc), after pyridine is added dropwise
It is reacted for 24 hours (yield 93%) at -40 DEG C.
(7) in synthesis compoundWhen, organic solvent is changed to methylene chloride (yield 96%).
(8) in synthesis compoundWhen, sulfonating agent is changed to sulfuric acid, is stirred to react 1h (yield
96%).
Embodiment 3
Other are identical as in embodiment 1, unlike:
(1) in synthesis compoundWhen, compound 2 and R1NH2Reaction generates compound 3, R1For Dmb；It heats up back
It flows 20h (yield 97%).
(2) in synthesis compoundWhen, glucose is changed to sucrose；Organic solvent ethyl acetate is changed to
Methylene chloride；After adding raw material, in 40 DEG C of insulation reaction 1h (yield 95%, optical activity ee value 98%).
(3) in synthesis compoundWhen, 12h is reacted after trifluoroacetic anhydride is added dropwise, temperature maintains 0 DEG C and (receives
Rate 96%).
(4) in synthesis compoundWhen, after benzyloxy amine is added, thermotonus 10h is maintained, wherein R1For
Teoc, R2For Fmoc (yield 96%).
(5) in synthesis compoundWhen (wherein R1For Teoc, R2For Fmoc), solution of potassium carbonate is changed to three
Ethylamine solution；It reacts 10h (yield 97%).
(6) in synthesis compoundWhen (wherein R1For Teoc, R2For Fmoc), after pyridine is added dropwise
In 10 DEG C of reaction 10h (yield 94%).
(7) in synthesis compoundWhen, organic solvent is changed to ethyl acetate (yield 96%).
(8) in synthesis compoundWhen, sulfonating agent is changed to chlorosulfonic acid, 48h is stirred to react and (receives
Rate 97%).
Claims (1)
1. a kind of synthetic method of beta lactamase restrainer AVM hereinafter Batan, it is characterised in that the following steps are included:
(1) compoundSynthesis:
- 2 piperidine carboxylic acid 25.0g of (S) -5- oxo, methylene chloride 300ml stirring are added in there-necked flask, 2,6- dimethyl is added
Pyridine 1g, benzylamine hydrochloride 26.5g, temperature rising reflux 2h are washed, liquid separation with purified water and saturated sodium chloride solution, and concentration obtains shallowly
3 42.83g of brown oil compound, yield 98%；
(2) compoundSynthesis:
Purified water 600ml, glucose 20g, 2000 0.1g of citric acid 0.5g, PEG, disodium hydrogen phosphate are added in there-necked flask
0.5g, baker yeast 40g, 30 DEG C of constant temperature stir 1h, the ethyl acetate solution 300ml of 3 40g of compound are added in three batches, often
Crowd interval 1h, after adding 30 DEG C of insulation reactions for 24 hours, filtering, liquid separation is extracted with ethyl acetate water phase, merges organic phase, dense
Contracting, the whole crystalline substance of n-hexane filter, and vacuum drying obtains 4 38.3g of off-white powder compound, yield 95%；Optically active body ee value
99%；
(3) compoundSynthesis:
Tetrahydrofuran 500ml, 4 35g of compound are added in there-necked flask, in -7 DEG C of addition triethylamine 80g, stirs 30min, drop
Add trifluoroacetic anhydride 65g, used time 1h, temperature maintains -5 DEG C~-7 DEG C, purified water 500ml is added after the reaction was completed, 15 DEG C are stirred
Mix 30min, liquid separation merges organic phase with tetrahydrofuran aqueous phase extracted 2 times, successively with 5% sodium bicarbonate aqueous solution 500ml, satisfy
It being washed with sodium-chloride water solution 400ml, purified water 200ml, is evaporated under reduced pressure organic phase, the whole crystalline substance of n-hexane filters, vacuum drying,
Obtain 5 47.8g of buff white solid compound, yield 97%；
(4) compoundSynthesis:
Chloroform 500ml, 5 40g of compound are added in there-necked flask, stirring and dissolving is cooled to -20 DEG C, and 2,6- diformazan is added
Yl pyridines 3g, dropwise addition Trifluoromethanesulfonic anhydride 65g, -20~-25 DEG C of reaction 30min, addition benzyloxy amine 29g, maintenance temperature -5~
0 DEG C of reaction 20h, is added purified water 300ml stirring, and aqueous citric acid solution 200ml, 5% sodium bicarbonate aqueous solution are successively used in liquid separation
300ml, saturated sodium chloride solution 300ml washing, water layer chloroform extraction merge organic phase, and anhydrous sodium sulfate is dry, subtracts
Pressure concentration, obtains 6 50.1g of oily compound, yield 95%；
(5) compoundSynthesis:
Methanol 200ml, 6 45g of compound are added in there-necked flask, 20% solution of potassium carbonate 100ml is added dropwise in stirring, 1h is reacted,
Concentrated hydrochloric acid 2ml is added after the reaction was completed, stirs 10min, is extracted with ethyl acetate, is washed with purified water and saturated sodium-chloride water solution
Organic phase is washed, is concentrated under reduced pressure, obtains 7 34.4g of oily compound, yield 98%；
(6) compoundSynthesis:
Chloroform 600ml, 7 30g of compound, triphosgene 39.3g are added in there-necked flask, stirring is cooled to -15 DEG C, is added dropwise
Pyridine 10g, used time 1h, drip 20 DEG C or so reaction 3h after finishing, addition purified water 300ml, liquid separation, with chloroform extraction water phase,
Merge organic phase, is successively washed with 5% sodium bicarbonate aqueous solution 200ml, saturated sodium-chloride water solution 200ml, anhydrous sodium sulfate
It is dry, organic phase is concentrated under reduced pressure, the whole crystalline substance of n-hexane filters, and vacuum drying obtains pulverulent solids compound 829.7g, yield
92%；
(7) compoundSynthesis:
Methanol 1000ml, 8 25g of compound are added in there-necked flask, 10%Pd/C40g is added, stirs 10min, ammonium formate is added
42g is heated to reflux, and reacts 2h, diatomite filtering, and methanol washing is evaporated under reduced pressure, and vacuum drying obtains solid chemical compound 9
12.4g, yield 98%；
(8) productSynthesis:
DMF50ml, 10 5g of compound are added in there-necked flask, sulfur trioxide pyridine complex 4.5g is added, is warming up to 30 DEG C,
It is stirred to react 16h, filters, is washed with ethyl acetate, organic phase is concentrated, vacuum drying obtains 1 6.9g of solid product, yield
96%.
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| CN107922411B (en) | 2015-08-10 | 2021-07-02 | 桑多斯股份公司 | Crystal form C of avibactam sodium |
| KR102482826B1 (en) * | 2016-08-26 | 2022-12-28 | 산도즈 아게 | Avibactam free acid |
| WO2018234962A1 (en) * | 2017-06-20 | 2018-12-27 | Wockhardt Limited | Process for o-sulfonation of 1,6-diazabicyclo[3.2.1]octane compounds |
| CN109400607B (en) * | 2017-08-16 | 2021-11-05 | 江苏奥赛康药业有限公司 | Abamebactam intermediate and preparation method thereof |
| CN107501265B (en) * | 2017-10-09 | 2019-05-28 | 台州职业技术学院 | A kind of 7- oxo-diazabicylo [3,2,1] octane derivatives compound and its preparation method and application |
| CN109956941B (en) * | 2017-12-25 | 2020-08-04 | 新发药业有限公司 | Simple preparation method of abamectin |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| FR2812635B1 (en) * | 2000-08-01 | 2002-10-11 | Aventis Pharma Sa | NOVEL HETEROCYCLIC COMPOUNDS, PREPARATION AND USE AS MEDICAMENTS IN PARTICULAR AS ANTI-BACTERIALS |
| FR2835186B1 (en) * | 2002-01-28 | 2006-10-20 | Aventis Pharma Sa | NOVEL HETEROCYCLIC COMPOUNDS ACTIVE AS BETA-LACTAMASES INHIBITORS |
| FR2921060B1 (en) * | 2007-09-14 | 2012-06-15 | Novexel | NOVEL PROCESS FOR PREPARING DISUBSIDED PIPERIDINE AND NOVEL INTERMEDIATES |
| SG191320A1 (en) * | 2010-12-22 | 2013-07-31 | Meiji Seika Pharma Co Ltd | Optically-active diazabicyclooctane derivative and method for manufacturing same |
| JP6023800B2 (en) * | 2011-06-17 | 2016-11-09 | アストラゼネカ アクチボラグ | Process for producing a heterocyclic compound containing trans-7-oxo-6- (sulfooxy) -1,6-diazabicyclo [3,2,1] octane-2-carboxamide and a salt thereof |
| CA2869051A1 (en) * | 2012-03-30 | 2013-10-03 | Cubist Pharmaceuticals, Inc. | Isoxazole .beta.-lactamase inhibitors |
| EP2857401B8 (en) * | 2012-05-30 | 2019-11-20 | Meiji Seika Pharma Co., Ltd. | NOVEL ß-LACTAMASE INHIBITOR AND METHOD FOR PRODUCING SAME |
| EP2970338A1 (en) * | 2013-03-14 | 2016-01-20 | Merck Sharp & Dohme Corp. | Crystalline form of a beta-lactamase inhibitor |
| HUE049027T2 (en) * | 2013-09-24 | 2020-08-28 | Meiji Seika Pharma Co Ltd | Production method for diazabicyclooctane derivatives and intermediates |
| CN105348173B (en) * | 2015-12-02 | 2017-12-15 | 中山奕安泰医药科技有限公司 | The method of asymmetric catalytic hydrogenation method synthesis AVM hereinafter Batan intermediate 5 |
| CN105753867B (en) * | 2016-03-24 | 2018-03-27 | 齐鲁制药有限公司 | A kind of preparation method of improved AVM hereinafter Batan sodium midbody compound |
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