CN103044415A - Synthesis method for aztreonam - Google Patents
Synthesis method for aztreonam Download PDFInfo
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Abstract
The invention provides a synthesis method for aztreonam. The synthesis method for the aztreonam particularly comprises the following steps: preparing 2-[[(Z)-1-(2-amino-4-thiazolyl)-2-chlorine-2-oxo ethylidene]amino]oxygen-2-methyl propionic acid hydrochloride (IV) by using (2-amino thiazolyl-4-yl)-2-(tert-butyl oxycarbonyl)-isopropoxy iminodiacetic acid (III) as a starting material under the action of a BTC/TPPO system and HCl gas; and performing condensation on aztreonam parent nucleus (II) to directly obtain the aztreonam. Compared with the traditional process, the new process has the characteristics as follows: (1) an acyl chloride method is adopted, so damage to beta-lactam ring by strong acid in the traditional process is avoided from the source; (2) residue of 2-mercaptobenzothiazole (M) of the product is eliminated from the source; (3) the used reaction reagent triphenylphosphine oxide (TPPO) can be recycled and is environment-friendly; and (4) in the aztreonam product, the yield is high and the purity is over 99 percent, so important industrialized application prospect is achieved.
Description
(1) technical field
The present invention relates to a kind of synthetic method of aztreonam, belong to field of medicine and chemical technology.
(2) background technology
Aztreonam is a kind of monocycle beta-lactam antibiotics of synthetic, be disclosed among the US4775670, chemical name is: [2S-[2 α, 3 β (Z)]]-2-[[[1-(2-amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo group-3-azetidinyl) amino]-2-oxo ethylidene] amino] oxo]-2 Methylpropionic acid, molecular formula: C
13H
17N
5O
8S
2, molecular weight: 435.44, structural formula (I):
The aztreonam Main Function is in the aerobic or double anaerobic type Gram-negative bacteria of susceptibility and Pseudomonas aeruginosa, such as intestinal bacteria, klebsiella spp, serratia marcecens, Proteus mirabilis, the positive Bacillus proteus of indoles, citrobacter, hemophilus influenzae, Pseudomonas aeruginosa and other pseudomonass, some enterobacter, gonococcus etc.Be mainly used in clinically treating the various infection due to the responsive aerobic gram-negative bacteria, as: the abdominal cavity infections such as urinary tract infections, lower respiratory infection, bloodstream infection, skin soft-tissue infection, peritonitis, genital tract infection etc.
The main method of the synthetic aztreonam of tradition is the MEAM method.US7601832, US7145017 has described with α-(thiazolamine-4-yl)-α-[(spy-butoxy carbonyl) isopropyl oxygen imino] acetic acid mercaptobenzothiazole ester and (has been called for short: TAEM) with (3S-is trans)-3-amino-4-methyl-2-oxo-1-azetidin alkyl sulfonic acid (II, be called for short: the aztreonam parent nucleus) be raw material, condensation under the triethylamine effect, obtain [2S-[2 α, 3 β (Z)]]-2-[[[1-(2-amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo group-3-azetidinyl) amino]-2-oxo ethylidene] amino] oxo]-the 2 Methylpropionic acid tert-butyl ester, reheat to 60 ℃ of conditions, use excessive hydrochloric acid or trifluoroacetic acid, slough the tertiary butyl, obtain aztreonam (I).
This method Atom economy is relatively poor, by product M very obstinate, thus affect quality product; In addition, the tertiary butyl is sloughed in heating under strong acidic condition, destroys easily the aztreonam beta-lactam nucleus, affects productive rate and quality.If the use trifluoroacetic acid, toxicity is large and uneconomical, can't reclaim, and is big for environment pollution.Chinese invention patent CN101514200 adopts acetic acid/hydrochloric acid to unite the method deprotection of use, although reduced temperature of reaction, nitration mixture makes waste liquid more difficult.
(3) summary of the invention
In order to overcome the shortcoming of prior art, the invention provides that a raw material is easy to get, gentle, easy and simple to handle, the eco-friendly aztreonam synthetic method of reaction conditions.
The technical solution used in the present invention is:
A kind of synthetic method of aztreonam as shown in the formula (I), described method comprises the steps:
(1) as shown in the formula (III) (thiazolamine-4 base)-2-(special butoxy carbonyl)-isopropyl oxygen imino acetic acid is in organic solvent A, drip the solution that contains the dichloro triphenylphosphine in (under preferred-15 ~-5 ℃) under-30 ~ 30 ℃, (under preferred-15 ~-5 ℃) reaction 1 ~ 10h under-30 ~ 30 ℃ after dropwising; Then in reaction system, pass into HCl gas to saturated, behind-30 ~ 30 ℃ (under preferred-5 ~ 5 ℃) lower insulated and stirred 0.5 ~ 2h, add low polar solvent B toward reaction system, crystallize out after stirring, suction filtration obtains filter cake A and filtrate A, and filter cake A drying obtains suc as formula the 2-[[(Z shown in (IV))-1-(2-amino-4-thiazolyl)-2-chloro-2-oxo ethylidene] amino] oxygen-2 Methylpropionic acid hydrochloride; The described solution that contains the dichloro triphenylphosphine is to react the solution that makes by triphenylphosphine oxide and two (trichloromethyl) carbonic ether in organic solvent D; Described organic solvent D and organic solvent A are identical solvents; Described (thiazolamine-4 base)-2-(special butoxy carbonyl)-isopropyl oxygen imino acetic acid, the molar ratio of dichloro triphenylphosphine as shown in the formula (III) is 1.0: 1.0 ~ 1.5, preferred 1:1.2; The amount of substance of described dichloro triphenylphosphine measures with the amount of substance of triphenylphosphine oxide;
(2) as shown in the formula (II) aztreonam parent nucleus mixes with organic solvent C, water, adding alkaline matter makes reaction solution become clarification, under-25 ~ 25 ℃ (under preferred 0 ~ 5 ℃) add step (1) gained suc as formula the 2-[[(Z shown in (IV))-1-(2-amino-4-thiazolyl)-2-chloro-2-oxo ethylidene] amino] oxygen-2 Methylpropionic acid hydrochloride, (under preferred 0 ~ 5 ℃) insulated and stirred reaction 0.5 ~ 5h under-25 ~ 25 ℃; Reaction finishes afterreaction liquid and obtains as shown in the formula (I) aztreonam through separation and purification; Described as shown in the formula (II) the aztreonam parent nucleus, suc as formula the 2-[[(Z shown in (IV))-1-(2-amino-4-thiazolyl)-2-chloro-2-oxo ethylidene] amino] molar ratio of oxygen-2 Methylpropionic acid hydrochloride and alkaline matter is 1.0: 1.0 ~ 2.0: 3.0 ~ 6.0.
In the step of the present invention (1), the described solution that contains the dichloro triphenylphosphine be by triphenylphosphine oxide (be called for short TPPO) and two (trichloromethyl) carbonic ethers (being called for short BTC) in organic solvent D, react under the room temperature and made in 2 ~ 3 hours, described triphenylphosphine oxide is 1:0.335 ~ 0.5 with the ratio of the amount of substance of two (trichloromethyl) carbonic ethers.The solution that contains the dichloro triphenylphosphine is being used for step (1) and (thiazolamine-4 the base)-2-(special butoxy carbonyl) shown in the formula (III)-when isopropyl oxygen imino acetic acid reacts, wherein the amount of substance of dichloro triphenylphosphine namely calculates with the amount of substance of triphenylphosphine oxide, and this is the known metering method of ability technician.Described organic solvent D and organic solvent A are identical solvents, and the consumption of described organic solvent D is generally 2 ~ 5 times of triphenylphosphine oxide quality.
Further, described triphenylphosphine oxide can reclaim by the reaction by-product in the step (1) and obtain, concrete, in the described step (1), after described filtrate A concentrating under reduced pressure reclaims solvent, residuum obtains triphenylphosphine oxide with the toluene recrystallization, can be used for preparing the dichloro triphenylphosphine with two (trichloromethyl) carbonic ether.Therefore, in the inventive method, prepare the dichloro triphenylphosphine as reaction raw materials by triphenylphosphine oxide, reclaim by-product again and obtain triphenylphosphine oxide in building-up process, triphenylphosphine oxide can recycle.
The reaction formula of the present invention's reaction is as follows:
Further, organic solvent A described in the step (1) is following one or more mixture: methylene dichloride, 1,2-ethylene dichloride, trichloromethane, acetone, ethyl acetate, acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran, N, dinethylformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), be preferably methylene dichloride or 1,2-ethylene dichloride.The consumption of described organic solvent A is preferably 1 ~ 5 times of (thiazolamine-4 the base)-2-(special butoxy carbonyl) shown in the formula (III)-isopropyl oxygen imino quality of acetic acid.
Described low polar solvent B is following one or more mixture: sherwood oil, normal hexane, hexanaphthene, Skellysolve A, pentamethylene, benzene,toluene,xylene are preferably sherwood oil or normal hexane.The consumption of described low polar solvent B is preferably 2 ~ 10 times of (thiazolamine-4 the base)-2-(special butoxy carbonyl) shown in the formula (III)-isopropyl oxygen imino quality of acetic acid.
Further, the organic solvent C described in the described step (2) is following one or more mixture: acetone, acetonitrile, methyl alcohol, ethanol, DMF, N,N-dimethylacetamide, tetrahydrofuran (THF) are preferably acetone or acetonitrile.The mass ratio of described organic solvent C and water is 0.05 ~ 30: 1, is preferably 9: 1.The total mass consumption of described organic solvent C, water is 2 ~ 8 times of aztreonam parent nucleus quality as shown in the formula (II).
In the described step (2), described alkaline matter is following one or more mixing: triethylamine, Tri-n-Propylamine, tri-isopropyl amine, quadrol, quinoline, pyridine, 2-picoline, 3-picoline, 4-picoline, 2,6-lutidine, ammoniacal liquor are preferably triethylamine or ammoniacal liquor.When described alkaline matter was ammoniacal liquor, the amount of substance of described alkaline matter i.e. NH to contain in the ammoniacal liquor
3Amount of substance measure.This metering method as well known to those skilled in the art.
In the described step (2), described reaction solution separation purification method is: after reaction finishes, reaction solution adds water, filtration, liquor B is that the preferred adjust pH of 1.0 ~ 3.0(is 1.5 ~ 2.0 with the diluted mineral acid adjust pH), there is crystal to separate out, leave standstill suction filtration behind 1 ~ 3h, filter cake C drying obtains aztreonam as shown in the formula (I).Described diluted mineral acid is the mineral acid of mass percentage concentration 5 ~ 20%, and described mineral acid is following one or more mixing: hydrochloric acid, sulfuric acid, phosphoric acid.Described diluted mineral acid is preferably the hydrochloric acid of 10wt%.Described reaction solution adds water, and the consumption of water is generally 2 ~ 5 times of as shown in the formula (II) aztreonam parent nucleus quality.
The temperature of reaction of step of the present invention (1) is preferably-15 ~-5 ℃; The temperature of reaction of described step (2) is preferably 0 ~ 5 ℃.
Beneficial effect of the present invention is: the present invention adopts chloride method, side chain with just carried out taking off tertiary butyl conservation treatment before the aztreonam parent nucleus is connected, avoided the traditional technology strong acid to the destruction of beta-lactam nucleus from the source.Traditional technology is to adopt active ester method, after the condensation reaction, must slough the tertiary butyl through the strong acid hydrolysis, just makes the aztreonam product, and strong acid destructible beta-lactam nucleus causes product yield and purity not high.And the inventive method had both been got rid of when using the strong acid hydrolysis to slough the tertiary butyl in the prior art destruction that can cause beta-lactam nucleus, had also reduced the spent acid amount that produces, and had improved yield and the purity of product.And the inventive method Atom economy is good, and residual except 2-mercaptobenzothiazole (M) gets on from the source; Used recyclable the applying mechanically of reaction reagent TPPO, environmental friendliness; The aztreonam product yield that the present invention obtains is higher, and purity is more than 99%, thereby has important industrial applications prospect.
(4) embodiment
Below with specific embodiment technical scheme of the present invention is described, but protection scope of the present invention is not limited to this.
(1) contains the preparation of the solution of dichloro triphenylphosphine
Embodiment 1:
In the 500mL there-necked flask, adding 50.7g(0.182 mol) triphenylphosphine oxide (TPPO), 100g methylene dichloride, 25 ℃ of lower droppings by 18.1g(0.061 mol) solution of two (trichloromethyl) carbonic ether (BTC) and 50g methylene dichloride, dropwise insulation reaction 2h, make the solution that contains the dichloro triphenylphosphine.
Embodiment 2
In the 500mL there-necked flask, adding 50.7g(0.182 mol) triphenylphosphine oxide (TPPO), 100g 1, the 2-ethylene dichloride, 25 ℃ of lower droppings by 18.1g(0.061 mol) two (trichloromethyl) carbonic ether (BTC) and 50g 1, the solution of 2-ethylene dichloride, dropwise insulation reaction 2h, make the solution that contains the dichloro triphenylphosphine.
(2) 2-[[(Z)-and 1-(2-amino-4-thiazolyl)-2-chloro-2-oxo ethylidene] amino] preparation of oxygen-2 Methylpropionic acid hydrochloride (IV)
Embodiment 3:
In the 1L four-hole bottle, add 50.0g(0.152 mol) compound (III), 50g methylene dichloride ,-15 ℃ of lower dichloro triphenylphosphine solution that embodiment 1 makes, insulation reaction 3h of dripping.Be warming up to 0 ℃, pass into HCl gas to saturated, insulated and stirred 1h.Add the 400g sherwood oil, stir 30min.Suction filtration, filter cake vacuum-drying obtains compound (IV) 45.4 g, yield 82.3%.Mother liquor steams and desolventizes, and solid reclaims triphenylphosphine oxide 46.4g, the rate of recovery 91.5% with 300g toluene recrystallization.
Embodiment 4:
In the 1L four-hole bottle, add 50.0g(0.152 mol) compound (III), 50g 1,2-ethylene dichloride ,-15 ℃ of lower dichloro triphenylphosphine solution that embodiment 2 makes, insulation reaction 3h of dripping.Be warming up to 0 ℃, pass into HCl gas to saturated, insulated and stirred 1h.Add the 400g sherwood oil, stir 30min.Suction filtration, filter cake vacuum-drying obtains compound (IV) 43.9g, yield 79.6%.Mother liquor steams and desolventizes, and solid reclaims triphenylphosphine oxide 47.1g, the rate of recovery 92.9% with 300g toluene recrystallization.
Embodiment 5:
In the 1L four-hole bottle, add 50.0g(0.152 mol) compound (III), 50g methylene dichloride, the 20 ℃ of lower dichloro triphenylphosphine solution that make by embodiment 1 method, insulation reaction 1.5h of dripping.Be cooled to 0 ℃, pass into HCl gas to saturated, insulated and stirred 1h.Add the 400g sherwood oil, stir 30min.Suction filtration, filter cake vacuum-drying obtains compound (IV) 34.3g, yield 68.4%.Mother liquor steams and desolventizes, and solid reclaims triphenylphosphine oxide 38.2g, the rate of recovery 75.3% with 300g toluene recrystallization.
Embodiment 6:
In the 1L four-hole bottle, add 50.0g(0.152 mol) compound (III), 50g1,2-ethylene dichloride, the 20 ℃ of lower dichloro triphenylphosphine solution that make by embodiment 2 methods, insulation reaction 1.5h of dripping.Be cooled to 0 ℃, pass into HCl gas to saturated, insulated and stirred 1h.Add the 400g sherwood oil, stir 30min.Suction filtration, filter cake vacuum-drying obtains compound (IV) 36.0g, yield 71.7%.Mother liquor steams and desolventizes, and solid reclaims triphenylphosphine oxide 39.7g, the rate of recovery 78.4% with 300g toluene recrystallization.
(3) preparation of aztreonam
Embodiment 7:
With compound (II) 30g(0.167 mol) be suspended in 500g acetonitrile, the mixed solvent of quality than 9:1, under 0 ~ 5 ℃, drip 64g(0.634 mol) triethylamine.Fully molten clear after, add compound (IV) 90.7g(0.250 mol).Insulation reaction 1h adds 100 g water, filters, and filtrate is left standstill growing the grain 2h with 10wt% salt acid for adjusting pH to 1.5.Suction filtration, vacuum-drying obtains the about 72.1g(water-content of aztreonam: 14 ~ 18%), and about 85.7% (molar yield of giving money as a gift) of yield, HPLC surveys purity 99.25%.
Embodiment 8:
With compound (II) 30g(0.167 mol) be suspended in 500g acetonitrile, the mixed solvent of quality than 9:1, under 0 ~ 5 ℃, drip 64g(0.634 mol) triethylamine.Fully molten clear after, add compound (IV) 121.3g(0.334 mol).Insulation reaction 1h adds 100 g water, filters, and filtrate is left standstill growing the grain 2h with 10 wt % salt acid for adjusting pH to 2.0.Suction filtration, vacuum-drying obtains the about 73.3g(water-content of aztreonam: 14～18%), and about 86.9% (molar yield of giving money as a gift) of yield, HPLC surveys purity 99.12%.
Embodiment 9:
With compound (II) 30g(0.167 mol) be suspended in 500g acetone, the mixed solvent of quality than 9:1, under 0 ~ 5 ℃, drip 64g(0.634 mol) triethylamine.Fully molten clear after, add compound (IV) 90.7g(0.250 mol).Insulation reaction 1h adds 100 g water, filters, and filtrate is left standstill growing the grain 2h with 10wt% salt acid for adjusting pH to 1.5.Suction filtration, vacuum-drying obtains the about 74.5g(water-content of aztreonam: 14～18%), and about 88.4% (molar yield of giving money as a gift) of yield, HPLC surveys purity 99.35%.
Embodiment 10:
With compound (II) 30g(0.167 mol) be suspended in 500g acetone, the mixed solvent of quality than 9:1, under 0 ~ 5 ℃, drip 64g(0.634 mol) triethylamine.Fully molten clear after, add compound (IV) 121.3g(0.334 mol).Insulation reaction 1h adds 100 g water, filters, and filtrate is left standstill growing the grain 2h with 10 wt % salt acid for adjusting pH to 2.0.Suction filtration, vacuum-drying obtains the about 73.6g(water-content of aztreonam: 14～18%), and about 87.3% (molar yield of giving money as a gift) of yield, HPLC surveys purity 99.27%.
Embodiment 11:
With compound (II) 30g(0.167 mol) be suspended in 500g acetonitrile, the mixed solvent of quality than 9:1, under 0 ~ 5 ℃, drip 60g 25 wt % ammoniacal liquor.Fully molten clear after, add compound (IV) 90.7g(0.250 mol).Insulation reaction 1h adds 100 g water, filters, and filtrate is left standstill growing the grain 2h with 10 wt % salt acid for adjusting pH to 1.5.Suction filtration, vacuum-drying obtains the about 73.4g(water-content of aztreonam: 14～18%), and about 87.1% (molar yield of giving money as a gift) of yield, HPLC surveys purity 99.26%.
Embodiment 12:
With compound (II) 30g(0.167 mol) be suspended in 500g acetonitrile, the mixed solvent of quality than 9:1, under 0 ~ 5 ℃, drip 60g 25 wt % ammoniacal liquor.Fully molten clear after, add compound (IV) 121.3g(0.334 mol).Insulation reaction 1h adds 100 g water, filters, and filtrate is left standstill growing the grain 2h with 10 wt % salt acid for adjusting pH to 2.0.Suction filtration, vacuum-drying obtains the about 73.6g(water-content of aztreonam: 14～18%), and about 87.2% (molar yield of giving money as a gift) of yield, HPLC surveys purity 99.35%.
Embodiment 13:
With compound (II) 30g(0.167 mol) be suspended in 500mL acetone, the mixed solvent of quality than 9:1, under 0 ~ 5 ℃, drip 60g 25 wt % ammoniacal liquor.Fully molten clear after, add compound (IV) 90.7g(0.250 mol).Insulation reaction 1h adds 100 g water, filters, and filtrate is left standstill growing the grain 2h with 10 wt % salt acid for adjusting pH to 1.5.Suction filtration, vacuum-drying obtains the about 72.0g(water-content of aztreonam: 14～18%), and yield 85.7% (molar yield of giving money as a gift), HPLC surveys purity 99.12%.
Embodiment 14:
With compound (II) 30g(0.167 mol) be suspended in 500mL acetone, the mixed solvent of quality than 9:1, under 0 ~ 5 ℃, drip 60g 25 wt % ammoniacal liquor.Fully molten clear after, add compound (IV) 121.3g(0.334 mol).Insulation reaction 1h adds 100 g water, filters, and filtrate is left standstill growing the grain 2h with 10 wt % salt acid for adjusting pH to 2.0.Suction filtration, vacuum-drying obtains the about 74.4g(water-content of aztreonam: 14～18%), and about 88.2% (molar yield of giving money as a gift) of yield, HPLC surveys purity 99.11%.
Claims (10)
1. the synthetic method of an aztreonam as shown in the formula (I) is characterized in that described method comprises the steps:
(1) as shown in the formula (III) (thiazolamine-4 base)-2-(special butoxy carbonyl)-isopropyl oxygen imino acetic acid is in organic solvent A, in-30 ~ 30 ℃ of lower solution that contain the dichloro triphenylphosphine that drip ,-30 ~ 30 ℃ of lower reaction 1 ~ 10h after dropwising; Then in reaction system, pass into HCl gas to saturated, behind-30 ~ 30 ℃ of lower insulated and stirred 0.5 ~ 2h, add low polar solvent B toward reaction system, crystallize out after stirring, suction filtration obtains filter cake A and filtrate A, and filter cake A drying obtains suc as formula the 2-[[(Z shown in (IV))-1-(2-amino-4-thiazolyl)-2-chloro-2-oxo ethylidene] amino] oxygen-2 Methylpropionic acid hydrochloride; The described solution that contains the dichloro triphenylphosphine is to react the solution that makes by triphenylphosphine oxide and two (trichloromethyl) carbonic ether in organic solvent D; Described organic solvent D and organic solvent A are identical solvents; Described (thiazolamine-4 base)-2-(special butoxy carbonyl)-isopropyl oxygen imino acetic acid, the molar ratio of dichloro triphenylphosphine as shown in the formula (III) is 1.0: 1.0 ~ 1.5; The amount of substance of described dichloro triphenylphosphine measures with the amount of substance of triphenylphosphine oxide;
(2) as shown in the formula (II) aztreonam parent nucleus mixes with organic solvent C, water, adding alkaline matter makes reaction solution become clarification,-25 ~ 25 ℃ lower add step (1) gained suc as formula the 2-[[(Z shown in (IV))-1-(2-amino-4-thiazolyl)-2-chloro-2-oxo ethylidene] amino] oxygen-2 Methylpropionic acid hydrochloride ,-25 ~ 25 ℃ of lower insulated and stirred reaction 0.5 ~ 5h; Reaction finishes afterreaction liquid and obtains as shown in the formula (I) aztreonam through separation and purification; Described as shown in the formula (II) the aztreonam parent nucleus, suc as formula the 2-[[(Z shown in (IV))-1-(2-amino-4-thiazolyl)-2-chloro-2-oxo ethylidene] amino] molar ratio of oxygen-2 Methylpropionic acid hydrochloride and alkaline matter is 1.0: 1.0 ~ 2.0: 3.0 ~ 6.0.
2. the method for claim 1, it is characterized in that the described solution that contains the dichloro triphenylphosphine be by triphenylphosphine oxide and two (trichloromethyl) carbonic ethers in organic solvent D, react under the room temperature and made in 2 ~ 3 hours, described triphenylphosphine oxide is 1:0.335 ~ 0.5 with the ratio of the amount of substance of two (trichloromethyl) carbonic ethers.
3. the method for claim 1, it is characterized in that described organic solvent A is following one or more mixture: methylene dichloride, 1,2-ethylene dichloride, trichloromethane, acetone, ethyl acetate, acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran, DMF, dimethyl sulfoxide (DMSO).
4. the method for claim 1 is characterized in that described low polar solvent B is following one or more mixture: sherwood oil, normal hexane, hexanaphthene, Skellysolve A, pentamethylene, benzene,toluene,xylene.
5. the method for claim 1, it is characterized in that in the described step (2), described organic solvent C is following one or more mixture: acetone, acetonitrile, methyl alcohol, ethanol, DMF, N,N-dimethylacetamide, tetrahydrofuran (THF); The mass ratio of described organic solvent C and water is 0.05 ~ 30: 1.
6. the method for claim 1, it is characterized in that described alkaline matter is following one or more mixing: triethylamine, Tri-n-Propylamine, tri-isopropyl amine, quadrol, quinoline, pyridine, 2-picoline, 3-picoline, 4-picoline, 2,6-lutidine, ammoniacal liquor.
7. the method for claim 1, it is characterized in that in the described step (2), described reaction solution separation purification method is: after reaction finishes, reaction solution adds water, filtration, liquor B is 1.0 ~ 3.0 with the diluted mineral acid adjust pH, have crystal to separate out, leave standstill suction filtration behind 1 ~ 3h, filter cake C drying obtains aztreonam as shown in the formula (I).
8. method as claimed in claim 7 is characterized in that described diluted mineral acid is the mineral acid of mass percentage concentration 5 ~ 20%, and described mineral acid is following one or more mixing: hydrochloric acid, sulfuric acid, phosphoric acid.
9. the method for claim 1 is characterized in that in the described step (1), and after described filtrate A concentrating under reduced pressure reclaimed solvent, residuum obtained triphenylphosphine oxide with the toluene recrystallization, reclaims to be used for preparing the dichloro triphenylphosphine with two (trichloromethyl) carbonic ether.
10. synthetic method as claimed in claim 1, the temperature of reaction that it is characterized in that described step (1) is-15 ~-5 ℃; The temperature of reaction of described step (2) is 0 ~ 5 ℃.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105085511A (en) * | 2015-05-29 | 2015-11-25 | 石药集团中诺药业（石家庄）有限公司 | Novel aztreonam compound |
| CN105085511B (en) * | 2015-05-29 | 2018-04-06 | 石药集团中诺药业（石家庄）有限公司 | A kind of new aztreonam compound |
| CN105001215A (en) * | 2015-08-03 | 2015-10-28 | 青岛蓝盛洋医药生物科技有限责任公司 | Aztreonam compound serving as sterilization medicine and preparation method thereof |
| CN107011252A (en) * | 2017-06-09 | 2017-08-04 | 浙江工业大学 | The method for drawing azole intermediate and medicine is prepared using the green technology for substituting the poisonous and harmful substances such as phosgene, thionyl chloride |
| CN107011252B (en) * | 2017-06-09 | 2018-06-08 | 浙江工业大学 | The method for drawing azole intermediate and drug is prepared using the green technology for substituting the poisonous and harmful substances such as phosgene, thionyl chloride |
| CN113754651A (en) * | 2020-06-02 | 2021-12-07 | 中国医学科学院医药生物技术研究所 | Beta-lactam compound, application and preparation method thereof |
| CN113754651B (en) * | 2020-06-02 | 2023-04-18 | 中国医学科学院医药生物技术研究所 | Beta-lactam compound, application and preparation method thereof |
| CN111909088A (en) * | 2020-08-04 | 2020-11-10 | 浙江工业大学 | Utilizing BTC/Ph3Method for preparing isoquinoline hydrochloride intermediate and Rho kinase inhibitor by PO chloro system |
| CN111909088B (en) * | 2020-08-04 | 2022-03-01 | 浙江工业大学 | Method for preparing isoquinoline hydrochloride intermediate and Rho kinase inhibitor by using BTC/Ph3PO chloro-system |
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