CN100486964C - Process of synthesizing (2S-trans)-3-methyl-4-oxo-1-azacyclo butyl sulfonic acid - Google Patents
Process of synthesizing (2S-trans)-3-methyl-4-oxo-1-azacyclo butyl sulfonic acid Download PDFInfo
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Abstract
The present invention relates to process of synthesizing (2S-trans)-3-amino-2-methyl-4-oxo-1-azacyclo butyl sulfonic acid. The process includes the following steps: 1. reaction of L-threonine and matter to protect its amino group; 2 condensation of L-threonine with protected amino group and aminosulfonic acid to obtain threonyl aminosulfonic acid with protected amino group; 3. reaction of threonyl aminosulfonic acid with protected amino group and methylsulfnyl chloride to protect hydroxyl radicap in threonine segment; 4. cyclization reaction to form protected quaternary ammonium salt of azacyclo butyl sulfonic acid; and 5. deprotection to obtain (2S-trans)-3-amino-2-methyl-4-oxo-1-azacyclo butyl sulfonic acid.
Description
Technical field:
The present invention relates to the novel method of a kind of synthetic (2S-is trans)-3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid.
Background technology:
(2S-is trans)-3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid is the key intermediate of synthetic aztreonam.Aztreonam is a kind of antibacterials of U.S. Shi Guibao company exploitation, and 1984 in Italy's listing, and it is a kind of monocycle beta-lactam microbiotic that can synthetic.Antimicrobial spectrum mainly comprises Gram-negative bacteria, as intestinal bacteria, klebsiella bacillus, serratia marcecens, Proteus mirabilis, hemophilus influenzae, citrobacter, Pseudomonas aeruginosa, gonococcus etc.Clinical respiratory tract due to the responsive Gram-negative bacteria, pulmonary infection, urinary tract infections, abdominal cavity infection, bone and the infection of joint, skin and soft tissue inflammation and gynecological infection, and the gonorrhoea etc. of being mainly used in.Because of this product can enter cerebrospinal fluid, can be used for meningitis.Because the anti-enzyme of this product is strong, other medicines when insensitive, are used this product Chang Youxiao.
Aztreonam is a kind of monobactam (monobactam) microbiotic, is disclosed among the US4775670.This route is to react in the presence of dicyclohexylcarbodiimide (DCC), N-hydroxybenzotriazole with 2-(2-amino-4-thiazolyl)-2-(1-phenylbenzene methoxy carbonyl-1-methyl ethoxy) acetimidic acid and (2S-is trans)-3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid, takes off the diphenyl-methyl protection with trifluoroacetic acid/phenylmethylether then and obtains aztreonam.Synthetic route is as follows,
Reported a kind of new synthetic method in US5194604, synthetic route is as follows
This route is to be raw material with 2-(2-amino-4-thiazolyl)-2-(1-carboxyl-1-methyl ethoxy) acetimidic acid; earlier with trimethylchlorosilane reaction protection propionic acid part; take off the protection of propionic acid part then with N-hydroxy-succinamide activation acetate part simultaneously, obtain aztreonam with this actives and (2S-is trans)-3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid reaction at last.
In nearest document, as the method for being mentioned among the US20040063682 is to obtain the aztreonam tert-butyl ester, obtain aztreonam with trifluoroacetic acid hydrolysis then with 2-(2-amino-4-thiazolyl)-2-(1-tertbutyloxycarbonyl-1-methyl ethoxy) acetimidic acid and (2S-is trans)-3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid, benzothiazole-2-thiol ester reaction.Synthetic route is as follows,
More than all use a key intermediate (2S-is trans)-3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid in three routes.Document about this compound is also abundanter.Main has
(1) synthetic method of reporting among the US4775670,
(2) reported method among the US4946838,
The operational path of synthetic (2S-is trans)-3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid all relates to the amino sulfonated step that goes up, and this step productive rate is lower, and uses the great toxicity chlorsulfonic acid, is difficult for operating in industrialization.
Summary of the invention:
The invention provides the novel method of a kind of synthetic (2S-is trans)-3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid.
Method of the present invention comprises following steps:
1) L-Threonine and the substance reaction that its amino is protected are protected the amino of L-Threonine
2) Threonine of amido protecting and thionamic acid condensation obtain the threonyl dithiocarbamic acid of amido protecting
3) reaction of the threonyl dithiocarbamic acid of amido protecting and methylsulfonyl chloride is with the hydroxyl protection in the Threonine fragment
4) form the nitrogen-containing heterocyclic ring butyl sulfonic acid quaternary ammonium salt of protecting through ring-closure reaction
5) deprotection obtains (2S-is trans)-3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid
Wherein the material that its amino is protected in the step 1) is selected from: BOC (tertbutyloxycarbonyl) acid anhydrides, chloroformic acid benzyl ester
Wherein
Step 2) Fan Ying condensing agent is selected from N, N-dicyclohexylcarbodiimide and I-hydroxybenzotriazole.
Step 2) is reflected in the anhydrous tetrahydro furan and carries out.
Step 2) range of reaction temperature is-15 ℃～30 ℃.
Step 2) reaction adopts alkali as acid binding agent, and described alkali is selected from triethylamine and N-methylmorpholine
Step 2) reaction adopts quaternary ammonium salt as phase transfer reagent, and described quaternary ammonium salt is selected from 4-butyl ammonium hydrogen sulfate.
Step 2) reaction product is extracted with solvent, and extraction agent is selected from: methylene dichloride, chloroform, ethyl acetate, ether.
Step 4) adopts alkali as acid binding agent, and described alkali is selected from yellow soda ash, sodium bicarbonate, salt of wormwood and saleratus.
Step 5) adopts acid as acidity regulator, and described acid is selected from formic acid, hydrochloric acid and sulfuric acid.
Synthetic route of the present invention is as follows:
Wherein, A is the amido protecting group,
Concrete steps are described below:
Step 1) protection L-Threonine amino
A is tertbutyloxycarbonyl or carbobenzoxy-(Cbz), is reflected at alkali and participates in reacting in the mixed phase of water or water and organic solvent down;
Step 2) introduces the thionamic acid fragment
Be reflected in the anhydrous tetrahydro furan and carry out, will bathe with cryosel and be chilled to-5 ℃, add HoBt (I-hydroxybenzotriazole, add DCC (N, N-dicyclohexylcarbodiimide), stir, add thionamic acid and alkali, reaction is spent the night, and filters, the elimination insolubles, use the tetrahydrofuran (THF) washing leaching cake, merging filtrate is evaporated to dried, add 0.5M potassium dihydrogen phosphate dissolving enriched material, use organic solvent extraction, divide and remove organic layer, aqueous phase adds 4-butyl ammonium hydrogen sulfate, shake well, use organic solvent extraction, merge organic phase, anhydrous sodium sulfate drying, filter concentrated obtaining;
Step 3) protection hydroxyl fragment
Be reflected in the methylene dichloride and carry out, need to add alkali in the reaction, low temperature or room temperature reaction, 1～12 hour reaction times,
The step 4) cyclization
Be reflected in water and the organic phase two-phase and carry out, adopt mineral alkali catalysis, reflux 1 hour is divided the phase of anhydrating, and the dry organic phase that concentrates obtains product;
The step 5) deprotection obtains finished product
Select corresponding deprotection method according to the blocking group that step 1) adopts, tertbutyloxycarbonyl uses formic acid to remove, and carbobenzoxy-(Cbz) adopts the method for palladium hydrocarbonize to remove, the quaternary ammonium salt acid dissociation, and product is separated out, and filtration obtains.
Alkali described in the step 1) is: triethylamine, described organic solvent is: dioxane.
Step 2) alkali described in is: triethylamine, described organic solvent is: tetrahydrofuran (THF).
Alkali described in the step 3) is: triethylamine.
Alkali described in the step 4) is: salt of wormwood, described organic phase is: 1,2-ethylene dichloride.
Synthetic method of the present invention, adopt solid-state thionamic acid to substitute chlorsulfonic acid and introduce sulfonic acid group, NH3, two kinds of serious raw materials of environmental pollution of chlorsulfonic acid have been avoided using, and technological operation is simple, need not to separate directly to obtain finished product, productive rate improves, and is with low cost, the reaction conditions gentleness is suitable for suitability for industrialized production.
Embodiment:
Further specify the present invention by the following examples, but not as limitation of the present invention.
Embodiment 1:
Steps A:
In the there-necked flask of 2L, add 350ml water and 350ml1,4-dioxane, stir, add 67.3gL-Threonine, 94.5ml triethylamine, 181g tert-Butyl dicarbonate, room temperature reaction spends the night, the reaction of some plate finishes, and adds ethyl acetate 500ml, stirs 30 minutes, divide and remove organic layer, it is 2～3 that water layer is regulated pH with hydrochloric acid, with ethyl acetate 300 * 3 extractions, merge organic layer, use anhydrous sodium sulfate drying, filter, concentrate colorless oil 115g, productive rate 93%.
Step B
Get steps A product 11.2g and be dissolved in the 250ml there-necked flask, bathe with cryosel and be chilled to-5 ℃, add the 7.2g1-hydroxybenzotriazole with the 100ml tetrahydrofuran (THF), add N, N-dicyclohexylcarbodiimide 11.7g stirred 30 minutes, added 5.5g thionamic acid and 5.7g triethylamine, behind the low-temp reaction 1 hour, remove ice bath, room temperature reaction spends the night, and filters, the elimination insolubles, use the tetrahydrofuran (THF) washing leaching cake, merging filtrate is evaporated to dried, add 500ml0.5M potassium dihydrogen phosphate dissolving enriched material, use the 150ml dichloromethane extraction, divide and remove organic layer, aqueous phase adds 23g tetrabutyl hydrogen sulfate ammonia, shake well 30 minutes, with methylene dichloride 150ml * 3 extractions, merge organic phase, anhydrous sodium sulfate drying, filter, concentrate-yellow oil.Be directly used in the next step.
Above-mentioned oily matter with the dissolving of 100ml methylene dichloride, is added the 7.92g triethylamine, be chilled to-5 ℃, drip the 7.2g methylsulfonyl chloride, low-temp reaction 5 hours, reaction finishes, and washes with water, branch vibration layer, the dry after-filtration of organic phase concentrate-red oil 24.4g, productive rate 76%.
Step C
Get the 250ml there-necked flask, add 10g salt of wormwood, 40ml water and 140ml 1,2-ethylene dichloride are with step B products obtained therefrom 20ml 1, the dissolving of 2-ethylene dichloride adds in the there-necked flask, reflux 1 hour, reaction finishes, anhydrous sodium sulfate drying, filter dense compile brown oil 16g, productive rate 78.7%.
Step D
To go up the step product and mix with the 50ml anhydrous formic acid, and have gas to emit, the adularescent solid is separated out gradually, stirs 5 hours, and filtration drying gets white solid ((2S-is trans)-3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid) 3.87g, productive rate 70%.
Liquid Detection purity〉98.5%.
Embodiment 2:
Steps A:
In the there-necked flask of 2L, add 350ml water and 350ml 1,4-dioxane, stir, add 67.3g L-Threonine, 94.5ml triethylamine, drip the 144g chloroformic acid benzyl ester, after dropwising, room temperature reaction spends the night, and the reaction of some plate finishes, and adds ethyl acetate 500ml, stirred 30 minutes, and divided and remove organic layer, it is 2～3 that water layer is regulated pH with hydrochloric acid, with ethyl acetate 300 * 3 extractions, merge organic layer, use anhydrous sodium sulfate drying, filter, concentrate colorless oil 136g, productive rate 95%.
Step B
Get steps A product 13g and be dissolved in the 250ml there-necked flask, bathe with cryosel and be chilled to-5 ℃, add the 7.2g1-hydroxybenzotriazole with the 100ml tetrahydrofuran (THF), add N, N-dicyclohexylcarbodiimide 11.7g stirred 30 minutes, added 5.5g thionamic acid and 5.7g triethylamine, behind the low-temp reaction 1 hour, remove ice bath, room temperature reaction spends the night, and filters, the elimination insolubles, use the tetrahydrofuran (THF) washing leaching cake, merging filtrate, concentrating under reduced pressure as for, add 500ml0.5M potassium dihydrogen phosphate dissolving enriched material, use the 150ml dichloromethane extraction, divide and remove organic layer, aqueous phase adds 23g tetrabutyl hydrogen sulfate ammonia, shake well 30 minutes, with methylene dichloride 150ml * 3 extractions, merge organic phase, anhydrous sodium sulfate drying, filter, concentrate-yellow oil.Be directly used in the next step.
Above-mentioned oily matter with the dissolving of 100ml methylene dichloride, is added the 7.92g triethylamine, be chilled to-5 ℃, drip the 7.2g methylsulfonyl chloride, low-temp reaction 5 hours, reaction finishes, and washes with water, branch vibration layer, the dry after-filtration of organic phase concentrate-red oil 26.6g, productive rate 80%.
Step C
Get the 250ml there-necked flask, add 10g salt of wormwood, 40ml water and 140ml 1,2-ethylene dichloride are with step B products obtained therefrom 20ml 1, the dissolving of 2-ethylene dichloride adds in the there-necked flask, reflux 1 hour, reaction finishes, anhydrous sodium sulfate drying, filtering and concentrating gets brown oil 16.34g, productive rate 72%.
Step D
To go up step product 100ml dissolve with methanol, add 0.5g10% palladium carbon, atmospheric hydrogenation spends the night, remove by filter palladium carbon, add 10ml formic acid, the adularescent solid is separated out, and filtration drying gets white solid ((2S-is trans)-3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid) 4.4g, productive rate 83%.
Liquid Detection purity〉98.5%.
Claims (6)
1. method for preparing (2S-is trans)-3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid is characterized in that reaction formula is as follows:
Wherein:
Step 1 is L-Threonine and the substance reaction that its amino is protected, and the amino of L-Threonine is protected, and wherein A is that amino protecting group is selected from: tertbutyloxycarbonyl, carbobenzoxy-(Cbz);
Step 2 is the Threonine of amido protecting and the threonyl dithiocarbamic acid that the thionamic acid condensation obtains amido protecting, condensing agent is selected from N in the reaction, N-dicyclohexylcarbodiimide and I-hydroxybenzotriazole, adopt alkali as acid binding agent, described alkali is selected from triethylamine and N-methylmorpholine, adopt quaternary ammonium salt as phase transfer reagent, described quaternary ammonium salt is selected from 4-butyl ammonium hydrogen sulfate;
Step 3 is that the threonyl dithiocarbamic acid and the methylsulfonyl chloride of amido protecting reacts the hydroxyl protection in the Threonine fragment;
Step 4 is the nitrogen-containing heterocyclic ring butyl sulfonic acid quaternary ammonium salts that form protection through ring-closure reaction, adopts alkali as acid binding agent in the reaction, and described alkali is selected from yellow soda ash, sodium bicarbonate, salt of wormwood and saleratus;
Step 5 is that deprotection obtains (2S-is trans)-3-amino-2-methyl-4-oxo-1-nitrogen-containing heterocyclic ring butyl sulfonic acid, adopts acid as acidity regulator in the reaction, and described acid is selected from formic acid, hydrochloric acid and sulfuric acid.
2, the method for claim 1 is characterized in that step 2) be reflected in the anhydrous tetrahydro furan and carry out.
3, the method for claim 1 is characterized in that step 2) range of reaction temperature be-15 ℃～30 ℃.
4, the method for claim 1 is characterized in that step 2) reaction product extract with solvent, extraction agent is selected from: methylene dichloride, chloroform, ethyl acetate, ether.
5, the method for claim 1 is characterized in that, the process following steps:
Step 1) protection L-Threonine amino
A is tertbutyloxycarbonyl or carbobenzoxy-(Cbz), is reflected at alkali and participates in reacting in the mixed phase of water or water and organic solvent down;
Step 2) introduces the thionamic acid fragment
Be reflected in the anhydrous tetrahydro furan and carry out, bathe with cryosel and be chilled to-5 ℃, add I-hydroxybenzotriazole, add N, the N-dicyclohexylcarbodiimide stirs, add thionamic acid and alkali, reaction is spent the night, and filters, the elimination insolubles, use the tetrahydrofuran (THF) washing leaching cake, merging filtrate is evaporated to dried, add 0.5M potassium dihydrogen phosphate dissolving enriched material, use organic solvent extraction, divide and remove organic layer, aqueous phase adds 4-butyl ammonium hydrogen sulfate, shake well, use organic solvent extraction, merge organic phase, anhydrous sodium sulfate drying, filter concentrated obtaining;
Step 3) protection hydroxyl fragment
Be reflected in the methylene dichloride and carry out, need to add alkali in the reaction, low temperature or room temperature reaction, 1～12 hour reaction times,
The step 4) cyclization
Be reflected in water and the organic phase two-phase and carry out, adopt mineral alkali catalysis, reflux 1 hour is divided the phase of anhydrating, and the dry organic phase that concentrates obtains product;
The step 5) deprotection obtains finished product
Select corresponding deprotection method according to the blocking group that step 1) adopts, tertbutyloxycarbonyl uses formic acid to remove, and carbobenzoxy-(Cbz) adopts the method for palladium hydrocarbonize to remove, the quaternary ammonium salt acid dissociation, and product is separated out, and filtration obtains.
6, the method for claim 5 is characterized in that,
Alkali described in the step 1) is: triethylamine, and described organic solvent is: dioxane;
Step 2) alkali described in is: triethylamine, and described organic solvent is: tetrahydrofuran (THF);
Alkali described in the step 3) is: triethylamine;
Alkali described in the step 4) is: salt of wormwood, described organic phase is: 1,2-ethylene dichloride.
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100586930C (en) * | 2008-09-17 | 2010-02-03 | 重庆莱美药业股份有限公司 | Preparation method of aztreonam intermediate (3S-trans)-3-amido-4-methyl-2-oxo-1-sulfoazetidine |
| CN102807519A (en) * | 2012-08-14 | 2012-12-05 | 济南瑞丰医药科技有限公司 | Preparation method of aztreonam side-chain small ring |
| CN104326944A (en) * | 2014-11-04 | 2015-02-04 | 崇州合瑞科技有限公司 | Method for preparing Boc-L-threonine |
| CN104592081B (en) * | 2015-02-06 | 2017-03-08 | 石家庄万业化工科技有限公司 | A kind of synthetic method of aztreonam main ring |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4775670A (en) * | 1980-09-29 | 1988-10-04 | E. R. Squibb & Sons, Inc. | 2-oxo-1-azetidinesulfonic acid salts |
| US4826973A (en) * | 1984-07-20 | 1989-05-02 | E. R. Squibb & Sons, Inc. | Delta form of aztreonam and preparation thereof |
| US4946838A (en) * | 1981-07-13 | 1990-08-07 | E. R. Squibb & Sons, Inc. | Crystalline anhydrous aztreonam |
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2006
- 2006-12-15 CN CNB2006101652737A patent/CN100486964C/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4775670A (en) * | 1980-09-29 | 1988-10-04 | E. R. Squibb & Sons, Inc. | 2-oxo-1-azetidinesulfonic acid salts |
| US4946838A (en) * | 1981-07-13 | 1990-08-07 | E. R. Squibb & Sons, Inc. | Crystalline anhydrous aztreonam |
| US4826973A (en) * | 1984-07-20 | 1989-05-02 | E. R. Squibb & Sons, Inc. | Delta form of aztreonam and preparation thereof |
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