CN102603772A - Method for preparing sterile cefmenoxime hydrochloride compound - Google Patents

Abstract

The invention discloses a method for preparing sterile cefmenoxime hydrochloride compound. The method includes: using 7-ACT.HCL which can be easily purchased at market as initial raw materials to be in condensation reaction with AE (activity ester) to generate 7-[alpha-(2-aminothianole-4-thiazolyl)-Z-2-methoxy-iminoacetamido]-3-(1-methyl-1H-5-tetrazolyl-sulfur methyl)-3-cephem-4-carboxylic acid (namely cefmenoxime sodium salt) which is further in action with 10% hydrochloric acid to generate cefmenoxime hydrochloride. The method is simple in operation, high in yield, cost-saving and stable in quality.

Description

A kind of method for preparing aseptic cefmenoxime hydrochloride compound

Technical field

The present invention relates to a kind of method for preparing aseptic cefmenoxime hydrochloride compound and purifying, belong to medical technical field.

Background technology

Cefmenoxime; English by name: Cefmenoxime; Molecular formula is: C16H17N9O5S2, and chemical name is:: (6R, 7R)-7-[2-(2-amino-4-thiazolyl) (methoxyimino) kharophen]-3-[[1-methyl isophthalic acid H-tetrazolium-5-yl]]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid; Belonging to third generation cephalosporin is the semisynthetic cephalosporins Broad spectrum antibiotics of the third generation, reaches germicidal action through the biosynthesizing that suppresses bacteria cell wall.In vitro tests shows that these article all have effect to gram-positive microorganism and negative bacterium.It is because the permeability of its pair cell adventitia is good and stable to β-Nei Xiananmei that these article have strong anti-microbial effect to Gram-negative bacteria; And to penicillium mould the organogenetic period of rat, rabbit and monkey the medicine-feeding test result show; Dead or the miscarriage of doe all appears in each administration group of rabbit, but various animal does not all see teratogenesis.The general reproductive toxicity test of rat, perinatal period, reproductive toxicity test was not all seen obviously unusual.Its conjugated protein (PBPs) 1A, 1B and 3 avidity are strong, thereby pair cell wall mucopeptide is cross-linked to form and has stronger inhibition.Cefmenoxime is prepared into hydrochloride usually when medical, its structural formula is:

（I）

Cefmenoxime Hemihydrochloride is the semi-synthetic Broad spectrum antibiotics by the exploitation of Japanese Takede Chemical Industries Ltd, production, entering Chinese market in 1996.It all has anti-microbial effect to Gram-negative and male aerophil and anerobes.In the Gram-negative bacteria; Anti-microbial effect to intestinal bacteria, pneumobacillus is stronger slightly than cefotiam; And obviously be better than the Kefzol of the first-generation; The anti-microbial effect of influenza being bitten blood bacillus, Bacillus proteus, serratia marcesens, Citrobacter, enterobacter is also more intense, and Bacteroides is also had very strong anti-microbial effect.In gram-positive microorganism, also stronger to micrococcus scarlatinae, pneumococcal anti-microbial effect.Peptococcus, Peptostreptococcus also there is the strong antibiotic effect.Stable to β-Nei Xiananmei.Quiet notes 1g, blood medicine peak value 99.4ug/ml, intramuscular injection 0.5g, blood medicine peak value is 10.8ug/ml, serum T 1/2 is about 1 hour.Metabolism hardly in vivo is mainly through renal excretion.Serum proteins combination rate 85%.These article are good to bile transport, and are higher at body fluid such as sputum, tonsilla, csf, hydrothorax, peritoneal exudate, kidney, bladder wall, uterus, uterine tube, ovary, pelvic cavity transudate, Cord blood, amniotic fluid and tissue distribution concentration.But transhipment seldom in milk.Be applicable to responsive microbial septicemia, meningitis, respiratory tract infection, pyothorax, liver and courage infection, peritonitis, urinary tract infection, genital system infection and burn and surgical wound infection etc.These article are since nineteen eighty-three listing, and clinical application constantly enlarges, and sales volume rises year by year, and are written into state's latest edition pharmacopeia such as Japan and the United States.

The synthetic route bibliographical information of Cefmenoxime Hemihydrochloride has a lot, as: European patent DE27132, U.S. Pat 3262932, Japanese Patent: 80-38349 and 84-53492 and Chen Fener chief editor's versions in 1999 " organic drug synthesis method " (first roll) etc.But the Cefmenoxime Hemihydrochloride purity that above-mentioned preparation method obtains is low, does not meet medical requirement.

Use the aluminum oxide chromatographic column in the U.S. Pat 5336673 preparation cefmenoxime processes and purify, with 80% acetonitrile wash-out, it is low to obtain product yield, and impurity is many.Other patent for example Chinese patent 200910007469.7 is used activated carbon decolorizing mostly, and its product yield is on the low side.

In order to overcome the deficiency of above-mentioned prior art, we have designed one and have produced route through discovering in earnest for a long time, have the route weak point, and reaction conditions is gentle, and easy and simple to handle, cost is low, the product purity advantages of higher.

Summary of the invention

The invention discloses a kind of method for preparing aseptic cefmenoxime hydrochloride compound; With 7ACT.HCL is starting raw material; In the presence of basifier, carry out condensation reaction with the AE active ester and generate (6R, 7R) – 7-[(Z) – 2 – (2-amino-4-thiazolyl)-2-methoxyimino kharophen]-3-[[(1-methyl isophthalic acid H-tetrazolium-5-yl)-sulphur] methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-sodium formiate (II).Compare with existing compound method, in the process of preparation (II), mix decolouring after washing filtering layer and get into the aseptic crystallization jar, transfer pH to make Cefmenoxime Hemihydrochloride (I) with 1mo l/L hydrochloric acid through sterile filtration with gac and aluminum oxide.

Concrete, Cefmenoxime Hemihydrochloride preparing method's provided by the invention technical scheme is following:

The compound method of the cefmenoxime hydrochloride compound shown in a kind of formula (I),

（I）

Comprise following three synthesis steps:

Step 1: with 7ACT.HCl is starting raw material; In the presence of basifier, carry out condensation reaction with the AE active ester and generate (6R, 7R) – 7-[(Z) – 2 – (2-amino-4-thiazolyl)-2-methoxyimino kharophen]-3-[[(1-methyl isophthalic acid H-tetrazolium-5-yl)-sulphur] methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-sodium formiate (II);

Step 2: stir down, add equivalent basifier room temperature reaction, extracting in water merges water, with gac and aluminum oxide decolouring;

Step 3: the aqueous solution sterile filtration that will pass through decolouring is gone in the lass lining crystallizer, washes the charcoal layer, and diafiltration liquid merges, and transfers pH with 1.0mol/L hydrochloric acid, and growing the grain leaches crystal with washing, in 40 ℃ of vacuum-dryings, gets Cefmenoxime Hemihydrochloride.

Wherein, gac and alumina weight proportioning are 1:2-12 in the said step 2, and preferred gac and alumina weight proportioning are 1:6-8;

Gac and aluminum oxide bleaching time are 10-30 minute in the said step 2, are preferably 20 minutes;

Use 1.0mol/L hydrochloric acid to transfer pH to be 1.0-3.0 in the said step 3, be preferably 2.0;

Rearing crystal time is 0.5-2 hour in the said step 3, is preferably 1 hour.

Midbody 7ACT.HCl is

;

Intermediate A E active ester is

.

Further, the compound method of the cefmenoxime hydrochloride compound of said structure provided by the invention comprises the steps:

(1) in glass-lined reactor, add methylene dichloride successively, 7-ACTHCl, the AE active ester stirs down, adds equivalent basifier room temperature reaction 3h, and extracting in water merges water, uses weight ratio to decolour 20 minutes as gac and the aluminum oxide of 1:8;

(2) aqueous solution sterile filtration that will pass through decolouring is gone in the lass lining crystallizer, washes the charcoal layer, and diafiltration liquid merges, and transfers pH to 2.0 with 1.0mol/L hydrochloric acid, and growing the grain 1h leaches crystal with washing, in 40 ℃ of vacuum-dryings, gets Cefmenoxime Hemihydrochloride.

Cefmenoxime Hemihydrochloride preparation method operation steps provided by the invention is short, and yield significantly improves, and cost is low, is fit to industrialized production.The existing compound method purity of products obtained therefrom quality is high, the look level is good.

Wherein, we find in a large amount of tests pleasantly surprisedly, use the gac and the aluminum oxide of proper ratio can effectively reduce impurity as discoloring agent, improve product gas purity greatly.Especially gac and aluminum oxide mix use according to specified proportion, and only with just obtaining highly purified product on a small quantity, the minimizing of discoloring agent consumption causes the finished product loss to reduce, and has improved yield effectively.Quality product is improved simultaneously, and purity can reach more than 99.60%, yield 130%, and the look level can reach below the 3#.Greatly improve the not high shortcoming of Cefmenoxime Hemihydrochloride purity, thereby satisfied its pharmaceutical grade purity requirement.

Below be with using gac separately, aluminum oxide and merge and use gac and aluminum oxide products obtained therefrom yield and quality simultaneous test, specifically data are following:

Table 1: use different ratios gac and aluminum oxide products obtained therefrom yield and quality simultaneous test

The decolouring thing	Consumption	Purity	Yield	The look level	Single impurity
						Gac	4kg	99.0%	92.8%	4#	0.14
Aluminum oxide	36kg	99.4%	120%	3#	0.13
						Gac adds aluminum oxide	2kg adds 16kg	99.6%	130%	2#	0.06
Gac adds aluminum oxide	2kg adds 14kg	99.5	130.4%%	2#	0.10
						Gac adds aluminum oxide	2kg adds 12kg	99.6	130.6%	3#	0.11

In addition, use the hydrochloric acid of suitable concn to transfer pH, growing the grain only needs 1 hour.The result is that rearing crystal time shortens, and has saved the production cycle greatly, has reduced production cost.

Embodiment

Below come further to explain or explanation content of the present invention through embodiment.But the embodiment that is provided should not be understood that protection domain of the present invention is constituted restriction.

Embodiment 1: cefmenoxime sodium salt synthetic

In the 1000L glass-lined reactor, add methylene dichloride 364.5L successively; 7-ACTHCl 36.45kg; AE active ester 42.00kg stirs down, adds equivalent basifier room temperature reaction 3h; Adding water 4 * 100L extracts; Merge water, decoloured 20 minutes, generate 7-[α-(thiazolamine-4-yl)-Z-2-methoxyimino acetamido]-3-(1-methyl isophthalic acid H-5-tetrazyl-thiomethyl)-3-cephem-4-carboxylic acid sodium salt solution (being the cefmenoxime sodium salt) (compound I I) with gac 2kg and aluminum oxide 16kg.

Embodiment 2: the preparation of Cefmenoxime Hemihydrochloride

To pass through the aqueous solution sterile filtration of decolouring and go in the 1000L lass lining crystallizer, washing charcoal layer, diafiltration liquid merges; Transfer pH to 2.0 with 1.0mol/L hydrochloric acid, growing the grain 1h leaches crystal with washing; In 40 ℃ of vacuum-dryings; Get Cefmenoxime Hemihydrochloride 47.39kg, yield 130%), HPLC purity 99.60%.

Claims (10)

1. the compound method of the cefmenoxime hydrochloride compound shown in the formula (I),

（I）

It is characterized in that comprising following three synthesis steps:

Step 1: with 7ACT.HCl is starting raw material; In the presence of basifier, carry out condensation reaction with the AE active ester and generate (6R, 7R) – 7-[(Z) – 2 – (2-amino-4-thiazolyl)-2-methoxyimino kharophen]-3-[[(1-methyl isophthalic acid H-tetrazolium-5-yl)-sulphur] methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-sodium formiate (II);

Step 2: stir down, add equivalent basifier room temperature reaction, extracting in water merges water, with gac and aluminum oxide decolouring;

Step 3: the aqueous solution sterile filtration that will pass through decolouring is gone in the lass lining crystallizer, washes the charcoal layer, and diafiltration liquid merges, and transfers pH with 1.0mol/L hydrochloric acid, and growing the grain leaches crystal with washing, in 40 ℃ of vacuum-dryings, gets Cefmenoxime Hemihydrochloride.

2. compound method according to claim 1, gac and alumina weight proportioning are 1:2-12 in the said step 2.

3. compound method according to claim 1, gac and alumina weight proportioning are 1:6-8 in the said step 2.

4. compound method according to claim 1, gac and aluminum oxide bleaching time are 10-30 minute in the said step 2.

5. compound method according to claim 1, gac and aluminum oxide bleaching time are 20 minutes in the said step 2.

6. compound method according to claim 1 uses 1.0mol/L hydrochloric acid to transfer pH to be 1.0-3.0 in the said step 3.

7. compound method according to claim 1, using 1.0mol/L hydrochloric acid to transfer pH in the said step 3 is 2.0.

8. compound method according to claim 1, rearing crystal time is 0.5-2 hour in the said step 3.

9. compound method according to claim 1, rearing crystal time is 1 hour in the said step 3.

10. compound method according to claim 1, it further comprises the steps:

(1) in glass-lined reactor, add methylene dichloride successively, 7-ACTHCl, the AE active ester stirs down, adds equivalent basifier room temperature reaction 3h, and extracting in water merges water, uses weight ratio to decolour 20 minutes as gac and the aluminum oxide of 1:8;

(2) aqueous solution sterile filtration that will pass through decolouring is gone in the lass lining crystallizer, washes the charcoal layer, and diafiltration liquid merges, and transfers pH to 2.0 with 1.0mol/L hydrochloric acid, and growing the grain 1h leaches crystal with washing, in 40 ℃ of vacuum-dryings, gets Cefmenoxime Hemihydrochloride.