CN106632397B - A kind of preparation method of -1 beta oxidation object of -3 α of 6 α-bromine penam-diphenylmethyl carboxylate - Google Patents
A kind of preparation method of -1 beta oxidation object of -3 α of 6 α-bromine penam-diphenylmethyl carboxylate Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/86—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with only atoms other than nitrogen atoms directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/865—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with only atoms other than nitrogen atoms directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 6
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
- C07C245/12—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom
- C07C245/14—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom having diazo groups bound to acyclic carbon atoms of a carbon skeleton
- C07C245/16—Diazomethane
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/87—Compounds being unsubstituted in position 3 or with substituents other than only two methyl radicals attached in position 3, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
Abstract
The invention discloses -3 α of one kind 6 α-bromine penam--1 beta oxidation object of diphenylmethyl carboxylate preparation methods.This method is using acetone as catalyst, and Benzophenonehydrazones are in acid condition by KMnO4Oxidation reaction generates the reaction solution of hexichol diazomethane, then instills in -3 α of 6 α-bromine penam--1 beta oxidation object of carboxylic acid and obtains product.This method is simple with method, uses the advantages such as safety and environmental protection, product purity height, high income.
Description
Technical field
The present invention relates to a kind of Tazobactam Sodium intermediates --- -3 α of 6 α-bromine penam--1 beta oxidation object of diphenylmethyl carboxylate
Preparation method, belong to pharmaceutical technology field.
Background technique
Tazobactam Sodium is the novel penicillanic acid sulfones beta-lactamase inhibitor of Japanese roc drugmaker exploitation, is current
Best one of the beta-lactamase inhibitor of clinical application effect, with stability is high, activity is low, toxicity is low, Inhibiting enzyme activity is strong
The features such as.1992, compound medicine Tazobactam Sodium/Piperacillin (1:8) of Tazobactam Sodium was listed in France for the first time, for treating
Various bacteria infection.
Bromo, oxidation, carboxyl successively pass through using 6-APA as raw material in the synthetic method of Tazobactam Sodium at present, most of producer
Protection, reduction, thermal cracking, chloromethylation, Azide, dual oxide, cyclization addition, deprotection and etc. be made Tazobactam Sodium, such as
Shown in chemical equation 1.In above-mentioned reaction process, carboxy protective generates -3 α of 6 α-bromine penam-diphenylmethyl carboxylate -
1 beta oxidation object (compound 3) is extremely important in entire reaction.
Current Tazobactam Sodium intermediate reported in the literature --- -3 α of 6 α-bromine penam--1 beta oxidation object of diphenylmethyl carboxylate
Synthetic method there are two types of: (1) with to methoxy-benzyl chlorine protect；(2) with diphenyl diazomethane or the like protection.Mesh
It is preceding using more for second method, the key of this method is the synthesis of diphenyl diazomethane.Diphenyl diazomethane
Synthetic method have mercuric oxide method, electrolytic manganese dioxide method, chloramine-t method, Peracetic acid method etc. according to the literature.Due to oxidation
Mercury method, electrolytic manganese dioxide method environmental pollution are bigger, and chloramine-t method cost is too high, so industrialized production at present is most
Diphenyl diazomethane is prepared using Peracetic acid method.
But Peracetic acid method (as shown in the reaction equation 2), which prepares hexichol diazomethane, to be had the disadvantage that
(1) Peracetic acid property is especially unstable, and heat is acutely decomposed, or even explodes, and is producing and storing process
In be a huge hidden danger.
(2) preparation of Peracetic acid needs acetic acid, and acetic acid is also generated in preparation process, carboxyl is contained in acetic acid, generation
Hexichol diazomethane can be reacted with the carboxyl of acetic acid, generated a large amount of by-products (as shown in reaction equation 3), led to product quality
Difference, yield it is low (detected in reaction process through TLC, generate a bigger impurity, it is verified be determined as hexichol diazomethane and
What acetic acidreaction generated).
Summary of the invention
The present invention overcomes above-mentioned the deficiencies in the prior art, provide -3 α of one kind 6 α-bromine penam-diphenylmethyl carboxylate -
The preparation method of 1 beta oxidation object.This method is using acetone as catalyst, and Benzophenonehydrazones are in acid condition by KMnO4Oxidation
Reaction generates the reaction solution of hexichol diazomethane, then instills in -1 beta oxidation object (compound 2) of -3 α of 6 α-bromine penam-carboxylic acid
Obtain product.This method is simple with method, uses the advantages such as safety and environmental protection, product purity height, high income.
The technical scheme is that -3 α of one kind 6 α-bromine penam--1 beta oxidation object of diphenylmethyl carboxylate preparation side
Method, characterized in that
(1) Benzophenonehydrazones are added in water, acetone (catalyst) and the mixed system of methylene chloride, are cooled to -5~5
DEG C inorganic acid is added, then maintains -5~5 DEG C solid potassium permanganate is added portionwise, finish 1~5h of insulation reaction；After the reaction was completed,
Through filtering, stratification, for organic layer after sodium bicarbonate solution is washed and is washed, the hexichol diazomethane solution for obtaining high-purity is standby
With；
(2) -3 α of 6 α-bromine penam--1 beta oxidation object of carboxylic acid is added to the in the mixed solvent of methylene chloride and acetone, is dropped
The hexichol diazomethane solution of above-mentioned steps (1) is added dropwise to -5~5 DEG C for temperature, drips and finishes 1~5h of insulation reaction；After the reaction was completed through carbon
After sour hydrogen sodium solution is washed and is washed, evaporated under reduced pressure, then be beaten to obtain product through organic solvent.
Reaction equation is as follows.
Preferably, the inorganic acid of the step (1) is nitric acid, sulfuric acid etc..
Preferably, the molar ratio of step (1) Benzophenonehydrazones, acetone, potassium permanganate and inorganic acid is 1:1~4:1
~3:0.5~1.0.
Preferably, the molar ratio of (2) 6 α of step--1 beta oxidation object of -3 α of bromine penam-carboxylic acid and Benzophenonehydrazones is
1:1.02~1.20.
Preferably, the volume ratio of water and methylene chloride is 10:3~5 in the step (1).
Preferably, the volume ratio of step (2) methylene chloride and acetone is 10:8~12.
Preferably, step (2) mashing is the mixed solvent of toluene and petroleum ether with organic solvent, volume ratio 10:8~
12.30~50 DEG C of 0.5~2h of mashing after addition mixed solvent, are then cooled to 0~5 DEG C, filter, and drying obtains product.
The beneficial effects of the present invention are:
(1) catalyst of the acetone as reaction, can generate a kind of reactive intermediate, then in acid item with Benzophenonehydrazones
Oxidant KMnO is added under part4After can be easily converted to hexichol diazomethane.Thus, the present invention can be extremely unstable by property
Fixed Peracetic acid is changed into mild potassium permanganate, and the safety of reaction greatly improves, and improves product purity and yield；
(2) reaction solution of first step reaction of the present invention can directly be added dropwise to -3 α of 6 α-bromine penam-after simply washing
Product is obtained in -1 beta oxidation object of carboxylic acid, simplifies reaction step；
(3) present invention have preparation method it is simple, using safety and environmental protection, product purity high (>=99.0%), high income (>=
88.0%) advantages such as.
Specific embodiment
The present invention is further illustrated combined with specific embodiments below, but the protection scope of this patent is not limited to
This.
6 α of the raw materials used in the present invention--1 beta oxidation object of -3 α of bromine penam-carboxylic acid is by described in patent CN102643292A
Method preparation, -1 beta oxidation object of -3 α of obtained 6 α-bromine penam-carboxylic acid through ethyl alcohol recrystallization be made, content >=99%.
Hexichol diazomethane standard items are prepared by mercuric oxide method, are detailed in Baidupedia: the preparation of hexichol diazomethane.
Embodiment 1:
(1) preparation of hexichol diazomethane
32g Benzophenonehydrazones are dissolved in 100ml methylene chloride, 40ml water is added, 40ml acetone is cooled to -2~2 DEG C,
It is slowly added to 10ml concentrated nitric acid (concentration 65%), continues to be cooled to -2~2 DEG C, 55g potassium permanganate is added portionwise in 35min,
It finishes, keeps the temperature 1.5h.It filters after the reaction was completed, filter cake 50ml eluent methylene chloride.Stratification discards water layer, organic layer
The washing of 400ml saturated sodium bicarbonate solution is added, layering adds the washing of 400mll saturated sodium bicarbonate solution, is layered, then
400ml water washing is added.(brownish red) is stored for future use in -5~5 DEG C.Sampling is TLC with hexichol diazomethane standard items and is compareed,
Position consistency as the result is shown, and an only spot.(based on content >=99%).
The preparation of (2) 6 α--1 beta oxidation object of -3 α of bromine penam-diphenylmethyl carboxylate
6 α of 45g--1 beta oxidation object of -3 α of bromine penam-carboxylic acid is added in 100ml methylene chloride, 100ml acetone is added,
- 2~2 DEG C are cooled to, the dichloromethane solution of the hexichol diazomethane of above-mentioned preparation is slowly added dropwise, drop finishes, insulation reaction 1.5h.
The washing of 200ml saturated sodium bicarbonate solution is added after the reaction was completed, then layering is added 100ml and purifies water washing, layering has
Machine layer is evaporated under reduced pressure to dry.100ml toluene pet ether (1:1) 30 DEG C of mashing 1h are added, are cooled to 0~5 DEG C, filter, drying obtains
White solid 62.16g.Yield: 88.3%, purity: 99.5%.Mp149~151 DEG C (149.6~151.2 DEG C of document).IR,1H-NMR meets structure feature.
Embodiment 2:
(1) preparation of hexichol diazomethane
32g Benzophenonehydrazones are dissolved in 100ml methylene chloride, 40ml water is added, 40ml acetone is cooled to -2~2 DEG C,
It is slowly added to 10ml concentrated nitric acid (concentration 65%), continues to be cooled to -2~2 DEG C, 60g potassium permanganate is added portionwise in 40min,
It finishes, insulation reaction 2h, filters, filter cake 50ml eluent methylene chloride.Stratification, discards water layer, and 400ml is added in organic layer
Saturated sodium bicarbonate solution washing, layering add the washing of 400mll saturated sodium bicarbonate solution, then 400ml is added in layering
Water washing.(brownish red) is stored for future use in -5~5 DEG C.Sampling is TLC with hexichol diazomethane standard items and is compareed, as the result is shown position
It sets unanimously, and an only spot.(based on content >=99%).
The preparation of (2) 6 α--1 beta oxidation object of -3 α of bromine penam-diphenylmethyl carboxylate
6 α of 45g--1 beta oxidation object of -3 α of bromine penam-carboxylic acid is added in 100ml methylene chloride, 100ml acetone is added,
- 2~2 DEG C are cooled to, the dichloromethane solution of the hexichol diazomethane of above-mentioned preparation is slowly added dropwise, drop finishes, and insulation reaction 2h adds
Enter the washing of 200ml saturated sodium bicarbonate solution, then layering is added 100ml and purifies water washing, layering, organic layer vacuum distillation
It is extremely dry.100ml toluene pet ether (1:1) 40 DEG C of mashing 2h are added, are cooled to 0~5 DEG C, filter, drying obtains white solid
62.92g.Yield: 89.4%, purity: 99.6%.
Embodiment 3:
(1) preparation of hexichol diazomethane
33g Benzophenonehydrazones are dissolved in 100ml methylene chloride, 40ml water is added, 40ml acetone is cooled to -2~2 DEG C,
It is slowly added to 11ml concentrated nitric acid (concentration 65%), continues to be cooled to -2~2 DEG C, 60g potassium permanganate is added portionwise in 35min,
It finishes, insulation reaction 2h, filters, filter cake 50ml eluent methylene chloride.Stratification, discards water layer, and 400ml is added in organic layer
Saturated sodium bicarbonate solution washing, layering add the washing of 400mll saturated sodium bicarbonate solution, then 400ml is added in layering
Water washing.(brownish red) is stored for future use in -5~5 DEG C.Sampling is TLC with hexichol diazomethane standard items and is compareed, as the result is shown position
It sets unanimously, and an only spot.(based on content >=99%).
The preparation of (2) 6 α--1 beta oxidation object of -3 α of bromine penam-diphenylmethyl carboxylate
6 α of 45g--1 beta oxidation object of -3 α of bromine penam-carboxylic acid is added in 100ml methylene chloride, 100ml acetone is added,
- 2~2 DEG C are cooled to, the dichloromethane solution of the hexichol diazomethane of above-mentioned preparation is slowly added dropwise, drop finishes, and insulation reaction 2h adds
Enter the washing of 200ml saturated sodium bicarbonate solution, then stratification is added 100ml and purifies water washing, layering, organic layer decompression
It distills to dry.100ml toluene pet ether (1:1) 50 DEG C of mashing 2h are added, are cooled to 0~5 DEG C, filter, drying obtains white solid
63.21g.Yield: 89.8%, purity: 99.5%.
Reference examples: the preparation (acetone is not added) of hexichol diazomethane
The acetone of the step of embodiment 1 (1) is replaced using isometric methylene chloride, and remaining reaction and post-processing are identical,
TLC is with hexichol diazomethane standard items through detection sampling to compare, and as a result there is the spot of apparent unreacted raw material.By its
Product hexichol diazomethane content is surveyed after being evaporated, the content of hexichol diazomethane is 32.1% in product.In proved response system
It is added without acetone, reaction yield is very low.
Claims (8)
1. -3 α of one kind 6 α-bromine penam--1 beta oxidation object of diphenylmethyl carboxylate preparation method, characterized in that
- 1 beta oxidation object of -3 α of the 6 α-bromine penam-diphenylmethyl carboxylate are as follows:
Preparation method specifically includes the following steps:
(1) Benzophenonehydrazones are added in the mixed system of water, acetone and methylene chloride, are cooled to -5~5 DEG C of addition inorganic acids,
It maintains -5~5 DEG C solid potassium permanganate is added portionwise again, finishes 1~5h of insulation reaction；After the reaction was completed, it is filtered, stands and divide
It is spare to obtain hexichol diazomethane solution after sodium bicarbonate solution is washed and is washed for layer, organic layer；
(2) -3 α of 6 α-bromine penam--1 beta oxidation object of carboxylic acid is added to the in the mixed solvent of methylene chloride and acetone, is cooled down
The hexichol diazomethane solution of above-mentioned steps (1) is added dropwise to -5~5 DEG C, drips and finishes 1~5h of insulation reaction；After the reaction was completed through carbonic acid
After hydrogen sodium solution is washed and is washed, evaporated under reduced pressure, then be beaten to obtain product through organic solvent.
2.-3 α of one kind 6 α-bromine penam as described in claim 1-- 1 beta oxidation object of diphenylmethyl carboxylate preparation method,
It is characterized in, the inorganic acid of the step (1) is nitric acid or sulfuric acid.
3.-3 α of one kind 6 α-bromine penam as described in claim 1-- 1 beta oxidation object of diphenylmethyl carboxylate preparation method,
Be characterized in, step (1) Benzophenonehydrazones, acetone, potassium permanganate and inorganic acid molar ratio be 1:1~4:1~3:0.5~
1.0。
4.-3 α of one kind 6 α-bromine penam as described in claim 1-- 1 beta oxidation object of diphenylmethyl carboxylate preparation method,
Be characterized in, the molar ratios of (2) 6 α of step--1 beta oxidation object of -3 α of bromine penam-carboxylic acid and Benzophenonehydrazones be 1:1.02~
1.20。
5.-3 α of one kind 6 α-bromine penam as described in claim 1-- 1 beta oxidation object of diphenylmethyl carboxylate preparation method,
It is characterized in, the volume ratio of water and methylene chloride is 10:3~5 in the step (1).
6.-3 α of one kind 6 α-bromine penam as described in claim 1-- 1 beta oxidation object of diphenylmethyl carboxylate preparation method,
It is characterized in, the volume ratio of methylene chloride and acetone is 10:8~12 in the step (2).
7. -3 α of one kind 6 α-bromine penam--1 beta oxidation object of diphenylmethyl carboxylate as described in any one of claim 1-6
Preparation method, characterized in that step (2) mashing is the mixed solvent of toluene and petroleum ether, volume ratio with organic solvent
10:8~12.
8.-3 α of one kind 6 α-bromine penam as claimed in claim 7-- 1 beta oxidation object of diphenylmethyl carboxylate preparation method,
It is characterized in, 30~50 DEG C of 0.5~2h of mashing after mixed solvent are added in the step (2), are then cooled to 0~5 DEG C, filter, and dry
It is dry, obtain product.
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| CN109824696A (en) * | 2017-11-23 | 2019-05-31 | 北京世纪润辉生物科技有限公司 | A kind of preparation method of the alpha-brominated penam sulfoxide acid benzhydryl ester of Tazobactam Sodium key intermediate 6 |
| CN108822132A (en) * | 2018-08-29 | 2018-11-16 | 上海晋景化学有限公司 | A kind of preparation method of Tazobactam Sodium intermediate 6- bromine benzhydryl s-oxopenicillanate |
| CN109503627A (en) * | 2018-11-28 | 2019-03-22 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of Tazobactam Sodium intermediate |
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| JPS54125620A (en) * | 1978-03-22 | 1979-09-29 | Sagami Chem Res Center | Preparation of diazomethane derivative |
| JP3047059B2 (en) * | 1993-12-17 | 2000-05-29 | 大塚化学株式会社 | Method for producing diazomethane derivative |
| JP2009537546A (en) * | 2006-05-16 | 2009-10-29 | ギリアード サイエンシーズ， インコーポレイテッド | Integrase inhibitor |
| CN101100444B (en) * | 2007-07-27 | 2010-06-23 | 浙江工业大学 | Method for synthesizing diphenyldiazomethane |
| CN101570544B (en) * | 2009-05-27 | 2011-07-13 | 浙江工业大学 | Preparation method of 3-hydroxymethyl-7beta-phenylacetyl-3-cephalo-4-diphenylmethyl carboxylate |
| CN101696213B (en) * | 2009-10-28 | 2012-01-11 | 沧州那瑞化学科技有限公司 | Synthetic method of 7-MAC intermediate |
| CN101935324B (en) * | 2010-09-08 | 2012-09-05 | 景德镇市富祥药业有限公司 | Method for preparing penicillanic acid sulfoxide diphenyl methyl ester |
| CN102020663B (en) * | 2010-11-24 | 2013-04-03 | 山东鑫泉医药有限公司 | Tazobactam synthesis method |
| CN102675342A (en) * | 2011-03-15 | 2012-09-19 | 四平市精细化学品有限公司 | Preparation method of 7 beta-amino-7 alpha-methoxy-3-((1-methyl-1H-tetrazole-5-group) sulfomethyl)-3-cephem-4-diphenylmethyl carboxylate |
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Effective date of registration: 20200319 Address after: No. 10678, Wenliang Road, Dongjia street, Licheng District, Jinan City, Shandong Province Co-patentee after: Shandong Anshun Pharmaceutical Co.,Ltd. Patentee after: Shandong Anxin Pharmaceutical Co.,Ltd. Address before: 250105 No. 849 Dong Jia town, Licheng District, Shandong, Ji'nan Co-patentee before: Shandong Anshun Pharmaceutical Co.,Ltd. Patentee before: QILU TIANHE PHARMACEUTICAL Co.,Ltd. |
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