CN106317075B - A kind of preparation method of cephalo sulphur benzyl pyridine acid - Google Patents
A kind of preparation method of cephalo sulphur benzyl pyridine acid Download PDFInfo
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- CN106317075B CN106317075B CN201610711102.3A CN201610711102A CN106317075B CN 106317075 B CN106317075 B CN 106317075B CN 201610711102 A CN201610711102 A CN 201610711102A CN 106317075 B CN106317075 B CN 106317075B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/48—Methylene radicals, substituted by hetero rings
- C07D501/54—Methylene radicals, substituted by hetero rings with the 7-amino radical acylated by an araliphatic carboxylic acid, which is substituted on the aliphatic radical by hetero atoms
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Abstract
The invention discloses a kind of preparation methods of cephalo sulphur benzyl pyridine acid, comprising the following steps: mixed acid anhydride is made in intermediate D- sulphur phenylacetic acid or its salt and acylation reaction；Key intermediate 7-PACA, which is dissolved in solvent under certain temperature under the action of organic base or inorganic base, obtains 7-PACA solution；Mixed acid anhydride solution is added dropwise in 7-PACA solution, sufficiently reaction, post-processing obtains cephalo sulphur benzyl pyridine acid.The present invention carries out 7- condensation reactions with mixed anhydride method using new synthetic route, mild condition, process stabilizing, it is easily operated, because prepared by sulphur phenyllacetyl chloride difficulty when solving existing method synthesis cephalo sulphur benzyl pyridine, perhaps acyl chlorides is unstable or intermediate unstable problem unstable so as to cause technique in subsequent reactions.
Description
Technical field
The invention belongs to technical field of medicine synthesis, specifically, being related to a kind of preparation method of cephalo sulphur benzyl pyridine acid.
Background technique
1964, first cephalosporin --- cefoxitin listing, henceforth, cephalosporins medicine was flourished,
Have more than 60 so far to sell in worldwide production.Cephalo sulphur benzyl pyridine belongs to third generation cephalosporin analog antibiotic, English name
Cefsulodine also known as cefsulodin, Cefsulodine Sodium, Cefsulodine Sodium etc. are developed by Japanese military field drug company,
Belong to first anti Bacillus pyocyaneu Flugge injection cephalosporin analog antibiotic.Clinically it is mainly used for the various sepsis as caused by Pseudomonas aeruginosa
Disease, pneumonia, bronchitis, bronchiectasis complication, pyelonephritis, cystitis, peritonitis, the secondary sexuality of wound or burn
Dye, it is curative for effect.Medicinal forms are sodium salt, i.e. cephalo sulphur benzyl pyridine sodium, chemical name are as follows: (6R, 7R) -3- [1- (4- carbamyl
Yl pyridines)-methyl] -8- oxo -7- [(2R) -2- phenyl -2- sodium sulfonate acetamido] -5- thia -1- azabicyclo
[4.2.0] oct-2-ene -2- carboxylic acid monosodium salt, molecular formula: C22H19N4NaO8S2, molecular weight: 554.53, CA accession number: 52152-
93-9, structural formula are as follows:
Cephalo sulphur benzyl pyridine is a kind of semi-synthetic cephalosporin analog antibiotic, using 7-ACA as parent nucleus.The medicine is mostly with 7-ACA, D-
Sulphur phenyllacetyl chloride carries out acylation reaction, then quaternary ammoniated obtained with Pyrazinamide again.Or 7-ACA elder generation and Pyrazinamide are at 3-
The quaternary ammoniated obtained key intermediate 7-PACA of amine is carried out, then carries out acylation reaction with sulphur phenyllacetyl chloride and the benzyl pyridine of cephalo sulphur is made, is turned
Sodium salt obtains cephalo sulphur benzyl pyridine sodium.Since perhaps acyl chlorides is unstable or intermediate is in subsequent reactions for the preparation of sulphur phenyllacetyl chloride difficulty
In it is unstable, and to equipment have corrosivity, leading to current technique, there are many deficiencies.
Summary of the invention
In view of this, the present invention is directed to above-mentioned problem, a kind of preparation method of cephalo sulphur benzyl pyridine acid is provided, technique is steady
It is fixed, easy industrialization.
In order to solve the above-mentioned technical problem, the invention discloses a kind of preparation method of cephalo sulphur benzyl pyridine acid, including it is following
Step: mixed acid anhydride is made in intermediate D- sulphur phenylacetic acid or its salt (I) and acylation reaction；Key intermediate 7-PACA (II) exists
It is dissolved under certain temperature under the action of alkali in solvent and obtains 7-PACA solution；Mixed acid anhydride solution is added dropwise to 7-PACA solution
In, sufficiently reaction, post-processing obtains cephalo sulphur benzyl pyridine acid；
Wherein, R1For H, Li, Na, K, Mg or Ca；R2For trimethylamine, triethylamine, diisopropylethylamine or N-methylmorpholine；
R3- Cl are as follows: methylchloroformate, ethyl chloroformate, isopropyl chlorocarbonate, butyl chlorocarbonate, pivaloyl chloride, methane sulfonyl chloride, benzene
Sulfonic acid chloride, p-methyl benzene sulfonic chloride.
Further, the preparation method of the cephalo sulphur benzyl pyridine acid specifically:
Step 1, D- sulphur phenylacetic acid or its salt are added in organic solvent, are cooled to -15 DEG C to -20 DEG C, and alkali, temperature control is added
To -10 DEG C hereinafter, acylating agent is added, insulated and stirred 1-3h obtains mixed acid anhydride solution；
Step 2,7-PACA is added in solvent, -30 DEG C~30 DEG C addition alkali, temperature control is dissolved to -10 DEG C or less 7-PACA
Obtain 7-PACA solution；
Step 3, the mixed acid anhydride solution is added dropwise in the 7-PACA solution, organic base maintains pH4.5-8.5, temperature
Degree maintains -30 DEG C~30 DEG C, and sufficiently reaction makes 7-PACA content≤3% in reaction solution；Purified water stirring is sufficiently added after reaction,
Split-phase washs filter cake, organic solvent is added, is adjusted with acid pH to 1.3-1.5 to filtering after water phase decoloration, after growing the grain 4h by
Filter, wash, drying and to obtain cephalo sulphur benzyl pyridine acid.
Further, the salt of D- sulphur phenylacetic acid is lithium salts, sodium salt, sylvite, triethylamine salt, front three amine salt, N-methylmorpholine
Salt, diisopropylethylamine salt, calcium salt or magnesium salts.
Further, acylating agent is methylchloroformate, ethyl chloroformate, isopropyl chlorocarbonate, chloro-carbonic acid in the step 1
Isobutyl ester, methane sulfonyl chloride, paratoluensulfonyl chloride, benzene sulfonyl chloride or pivaloyl chloride.
Further, the solvent of D- sulphur phenylacetic acid or its salt and acylation reaction is selected from chloroform, methylene chloride, N, N-
Dimethyl acetamide, N, dinethylformamide, methyl iso-butyl ketone (MIBK), acetone, any one or more compositions in acetonitrile
Mixed solvent.
Further, the key intermediate 7-PACA is free inner salt, or is the salt that itself and acid are formed, it is described with
The salt that acid is formed is hydrochloride, hydrobromate, hydriodate, nitrate, sulfate, phosphate, formates or acetate.
Further, alkali is organic base or inorganic base in the step 1, and the organic base is triethylamine, pyridine, N- methyl
Morpholine, diisopropylethylamine or 4- picoline, the inorganic base are potassium carbonate, sodium carbonate, sodium methoxide or sodium ethoxide；Step 2
Middle alkali is organic base or inorganic base, and the organic base is selected from triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, 4- methyl
Pyridine, diethylamine, tetramethylguanidine, sodium methoxide or sodium ethoxide, the inorganic base are selected from potassium carbonate or sodium carbonate.
Further, the solvent for dissolving 7-PACA is the mixed solvent of organic solvent or water and organic solvent；It is described organic
Solvent is selected from methanol, ethyl alcohol, isopropanol, acetone, tetrahydrofuran, N, N- dimethyl acetamide, N, dinethylformamide, acetonitrile
In any one or more compositions mixed solvent.
Further, mixed acid anhydride solution and the pH value of 7-PACA solution reaction system are tieed up with organic base in the step 3
It holds in 4.5-8.5；The organic base is triethylamine, diethylamine, trimethylamine or tetramethylguanidine.
Further, the molar ratio of the D- sulphur phenylacetic acid or its salt (I) and acylating agent is 1 ︰ 0.9-2.0；D- sulphur benzene second
Acid and the molar ratio of alkali are 1 ︰ 2-2.5, and the molar ratio of D- sulphur phenylacetate and alkali is 1 ︰ 0.1-1.5；7-PACA (II) and D-
The molar ratio of sulphur phenylacetic acid or its salt (I) is 1:1-5；The molar ratio of 7-PACA (II) and alkali is 1:2-5.
Compared with prior art, the present invention can be obtained including following technical effect:
(1) present invention will be mixed by the way that mixed acid anhydride is made in intermediate D- sulphur phenylacetic acid or its salt and acylation reaction
Anhydride solution is added in 7-PACA solution, and sufficiently reaction, post-processing obtains cephalo sulphur benzyl pyridine acid；It is used using new synthetic route mixed
It closes acid anhydrides method and carries out 7- condensation reactions, mild condition, process stabilizing is easily operated, solves existing method synthesis cephalo sulphur
Since perhaps acyl chlorides is unstable or intermediate is unstable to lead in subsequent reactions for the preparation of sulphur phenyllacetyl chloride difficulty when benzyl pyridine
The problem for causing technique unstable；
(2) the method for the present invention process stabilizing is feasible, and industrial industrialization easy to accomplish, product yield is high, high-quality.
Certainly, it implements any of the products of the present invention it is not absolutely required to while reaching all the above technical effect.
Specific embodiment
Carry out the embodiment that the present invention will be described in detail below in conjunction with embodiment, whereby to the present invention how application technology hand
Section solves technical problem and reaches the realization process of technical effect to fully understand and implement.
A kind of preparation method of cephalo sulphur benzyl pyridine acid of the present invention, comprising the following steps: intermediate D- sulphur phenylacetic acid or its salt
(I) mixed acid anhydride is made with acylation reaction；Key intermediate 7-PACA (II) dissolves under certain temperature in the presence of alkali
7-PACA solution is obtained in solvent；Mixed acid anhydride solution is added dropwise in 7-PACA solution, sufficiently reaction, post-processing obtains cephalo
Sulphur benzyl pyridine acid；
Wherein, R1For H, Li, Na, K, Mg or Ca；R2For trimethylamine, triethylamine, diisopropylethylamine or N-methylmorpholine；
R3- Cl are as follows: methylchloroformate, ethyl chloroformate, isopropyl chlorocarbonate, butyl chlorocarbonate, pivaloyl chloride, methane sulfonyl chloride, benzene
Sulfonic acid chloride, p-methyl benzene sulfonic chloride.
Further, the preparation method of the cephalo sulphur benzyl pyridine acid specifically:
Step 1, the preparation of D- sulphur phenylacetic acid mixed acid anhydride
D- sulphur phenylacetic acid or its salt are added in organic solvent, are cooled to -15 DEG C to -20 DEG C, alkali are added, temperature control is to -10 DEG C
Hereinafter, acylating agent is added, insulated and stirred 1-3h obtains mixed acid anhydride solution；
Wherein, the molar ratio of D- sulphur phenylacetic acid or its salt (I) and acylating agent is 1 ︰ 0.9-2.0, preferably 1 ︰ 1.3.D- sulphur benzene
The molar ratio of acetic acid and alkali is 1 ︰ 2-2.5, and the molar ratio of D- sulphur phenylacetate and alkali is 1 ︰ 0.1-1.5.
Step 2, the preparation of 7-PACA solution
7-PACA is added in solvent, -30 DEG C~30 DEG C addition alkali, 7-PACA dissolves to obtain 7-PACA solution；
Wherein, the molar ratio of 7-PACA (II) and D- sulphur phenylacetic acid or its salt (I) is 1:1-5, preferably 1:2.5-3.5.
The molar ratio of 7-PACA (II) and alkali is 1:2-5, preferably 1:2.5-3.5.
Step 3, the preparation of cephalo sulphur benzyl pyridine acid
The mixed acid anhydride solution is added dropwise in the 7-PACA solution, organic base maintains pH4.5-8.5, temperature dimension
- 30 DEG C~30 DEG C are held, sufficiently reaction makes 7-PACA content≤3% in reaction solution；Purified water stirring is sufficiently added after reaction, point
Phase washs filter cake, organic solvent is added to filtering after water phase decoloration, is adjusted with acid pH to 1.3-1.5, filtered after growing the grain 4h,
It washs, dry to obtain cephalo sulphur benzyl pyridine acid.
Further, the salt of D- sulphur phenylacetic acid is lithium salts, sodium salt, sylvite, triethylamine salt, front three amine salt, N- first in step 1
Base alkylbenzyldimethylasaltsum saltsum, diisopropylethylamine salt, calcium salt or magnesium salts, particular certain cancers, sylvite, triethylamine salt.
Further, acylating agent is different selected from methylchloroformate, ethyl chloroformate, isopropyl chlorocarbonate, chloro-carbonic acid in step 1
Butyl ester, methane sulfonyl chloride, paratoluensulfonyl chloride, benzene sulfonyl chloride or pivaloyl chloride, optimization methane sulfonic acid chloride and pivaloyl chloride.
Further, alkali is organic base or inorganic base in step 1, and the organic base is triethylamine, pyridine, N- methyl
Quinoline, diisopropylethylamine or 4- picoline, the inorganic base are potassium carbonate, sodium carbonate, sodium methoxide or sodium ethoxide.
Further, the solvent of D- sulphur phenylacetic acid or its salt and acylation reaction is selected from chloroform, dichloromethane in step 1
It is alkane, N, N- dimethyl acetamide, N, dinethylformamide, methyl iso-butyl ketone (MIBK), acetone, any one or more in acetonitrile
The mixed solvent of composition, the preferably mixed solvent of methylene chloride and N, N- dimethyl acetamide.
Further, key intermediate 7-PACA is free inner salt in step 2, or is the salt of itself and acid formation, such as
Hydrochloride, hydrobromate, hydriodate, nitrate, sulfate, phosphate, formates, acetate etc., preferably hydrochloride.
Further, alkali is organic base or inorganic base in step 2, and the organic base is selected from triethylamine, pyridine, N- methyl
Quinoline, diisopropylethylamine, 4- picoline, diethylamine, tetramethylguanidine, sodium methoxide or sodium ethoxide, the inorganic base are selected from carbonic acid
Potassium or sodium carbonate.
Further, the temperature that 7-PACA is dissolved in step 2 is controlled at -30 DEG C~30 DEG C, preferably -20 DEG C~-10 DEG C.
Further, the solvent that 7-PACA is dissolved in step 2 is the mixing of organic solvent or water and water-miscible organic solvent
Solvent；The organic solvent be selected from methanol, ethyl alcohol, isopropanol, acetonitrile, acetone, tetrahydrofuran, N, N- dimethyl acetamide, N,
The mixed solvent of any one or more compositions in dinethylformamide, the preferably mixed solvent of acetone and water.
Further, mixed acid anhydride solution and the pH value of 7-PACA solution reaction system are maintained with organic base in step 3
4.5-8.5 preferably 6.0-7.0；The organic base is selected from triethylamine, diethylamine, N-methylmorpholine or tetramethylguanidine, preferably three second
Amine.
Embodiment 1
Step 1, the preparation of D- sulphur phenylacetic acid mixed acid anhydride
165.2 grams of sodium salt of D- sulphur phenylacetic acid (0.6937mol) is added in 800mL methylene chloride and 80mL DMF, be cooled to-
It 15 DEG C, is added dropwise triethylamine 19.2mL (0.1338mol), temperature control is to -10 DEG C hereinafter, 76.8mL pivaloyl chloride is added dropwise
(0.6243mol), insulated and stirred 3h obtain the mixed acid anhydride solution of D- sulphur phenylacetic acid；
Step 2, the preparation of 7-PACA solution
310.8 grams of (0.6937mol) 7-PACA are added to the in the mixed solvent of purified water 1500mL and acetone 1500mL, drop
Temperature to 0 DEG C hereinafter, be added 175.5 grams of triethylamine (1.734mol), temperature control 0 DEG C hereinafter, 7-PACA dissolve 7-PACA is molten
Liquid；
Step 3, the preparation of cephalo sulphur benzyl pyridine acid
The mixed acid anhydride solution of D- sulphur phenylacetic acid is added in 7-PACA solution, 60min is reacted, in the process, with three second
Amine maintains pH6-7, and sufficiently reaction makes 7-PACA content≤3% in reaction solution；Purified water 500ml is added, stirs liquid separation, organic layer
Purified water 100ml extraction is added, water phase is merged, is filtered after active carbon decoloring is added, acetone is added in a small amount of water washing filter cake
300ml is filtered, water/acetone (1/1), acetone washing, in 30 DEG C after growing the grain 4h with the salt acid for adjusting pH of 4mol/L to 1.3-1.5
It is dried in vacuo 6h, obtains 142.0 grams of acid of the pyridine of cephalo sulphur benzyl, purity 96.1%.
Embodiment 2
Step 1, the preparation of D- sulphur phenylacetic acid mixed acid anhydride
800mL methylene chloride/80mL N, N- dimethylacetamide is added in 177.2 grams of sylvite of D- sulphur phenylacetic acid (0.6937mol)
In amine, -15 DEG C are cooled to, 82.3 grams of pyridine (1.04mol) is added dropwise, temperature control is to -10 DEG C hereinafter, being added dropwise 181.1 grams of mesyl chloride
(1.3874mol), insulated and stirred 1h obtain the mixed acid anhydride solution of D- sulphur phenylacetic acid；
Step 2, the preparation of 7-PACA solution
103.5 grams of (0.2312mol) 7-PACA are added in 300 milliliters of N, N- dimethyl acetamides, -20 DEG C is cooled to and adds
Enter 144.7 milliliters of tetramethylguanidine (1.156mol), temperature controls -10 DEG C hereinafter, 7-PACA dissolves to obtain 7-PACA solution；
Step 3, the preparation of cephalo sulphur benzyl pyridine acid
The mixed acid anhydride solution of D- sulphur phenylacetic acid is added in 7-PACA solution, reaction 60min uses tetramethyl in the process
Base guanidine maintains pH6-7, and sufficiently reaction makes 7-PACA content≤3% in reaction solution；Purified water 500ml is added, stirs liquid separation, it is organic
Layer adds purified water 100ml extraction, merges water phase, filters after active carbon decoloring is added, and ethyl alcohol is added in a small amount of water washing filter cake
300ml is filtered, water/ethyl alcohol (1/1), ethanol washing, in 30 DEG C after growing the grain 4h with the salt acid for adjusting pH of 4mol/L to 1.3-1.5
It is dried in vacuo 6h, obtains 71.5 grams of acid of the pyridine of cephalo sulphur benzyl, purity 97.9%.
Embodiment 3
Step 1, the preparation of D- sulphur phenylacetic acid mixed acid anhydride
220 grams of triethylamine salt of D- sulphur phenylacetic acid (0.6937moL) is added in 1000 milliliters of chloroform/100 milliliter DMF,
- 15 DEG C are cooled to, 92.0 milliliters of N-methylmorpholine (0.6937mol) is added dropwise, temperature control is to -10 DEG C hereinafter, methylchloroformate is added dropwise
86.3 grams (0.9131mol), insulated and stirred 3h obtains the mixed acid anhydride solution of D- sulphur phenylacetic acid；
Step 2, the preparation of 7-PACA solution
100 grams of (0.2232mol) 7-PACA are added in methanol, -10 DEG C of 98.0 milliliters of addition tetramethylguanidine are cooled to
(0.7829mol), temperature control -20 DEG C hereinafter, 7-PACA dissolves to obtain 7-PACA solution；
Step 3, the preparation of cephalo sulphur benzyl pyridine acid
The mixed acid anhydride solution of D- sulphur phenylacetic acid is added in 7-PACA solution, reaction 60min uses tetramethyl in the process
Base guanidine maintains pH6-7, and sufficiently reaction makes 7-PACA content≤3% in reaction solution；Purified water 500ml is added, stirs liquid separation, it is organic
Layer adds purified water 100ml extraction, merges water phase, filters after active carbon decoloring is added, and methanol is added in a small amount of water washing filter cake
300ml is filtered, water/methanol (1/1), methanol washing, in 30 DEG C after growing the grain 4h with the salt acid for adjusting pH of 4mol/L to 1.3-1.5
It is dried in vacuo 6h, obtains 74.5 grams of acid of the pyridine of cephalo sulphur benzyl, purity 98.1%.
Embodiment 4
Step 1, the preparation of D- sulphur phenylacetic acid mixed acid anhydride
178 grams of calcium salt of D- sulphur phenylacetic acid (0.6937mol) is added in 850 milliliters of methyl iso-butyl ketone (MIBK)/85 milliliter DMF, drop
To -15 DEG C 13.06 grams of picoline (0.1388mol) is added dropwise, temperature control is to -10 DEG C hereinafter, isopropyl chlorocarbonate 112 is added dropwise in temperature
Gram (0.91mol), insulated and stirred 2h obtain the mixed acid anhydride solution of D- sulphur phenylacetic acid；
Step 2, the preparation of 7-PACA solution
By in 100 grams of (0.2232mol) 7-PACA additions, 100 milliliters of N, dinethylformamide/300 milliliter water, cool down
To 0 DEG C of 53.7 grams of diethylamine of addition (0.74mol), temperature controls -30 DEG C hereinafter, 7-PACA dissolves to obtain 7-PACA solution；
Step 3, the preparation of cephalo sulphur benzyl pyridine acid
The mixed acid anhydride solution of D- sulphur phenylacetic acid is added in 7-PACA solution, 60min is reacted, diethylamine maintains pH7-
8.5, -10 DEG C of sufficiently reactions make 7-PACA content≤3% in reaction solution；Purified water 500ml is added, stirs liquid separation, organic layer is again
Purified water 100ml is added, liquid separation merges water phase, filters after active carbon decoloring is added, and isopropanol is added in a small amount of water washing filter cake,
With the salt acid for adjusting pH of 4mol/L to 1.3-1.5, filtered after growing the grain 4h, water/isopropanol (1/1), isopropanol washing are true in 30 DEG C
The dry 6h of sky obtains 70.5 grams of acid of the pyridine of cephalo sulphur benzyl, purity 97.6%.
Embodiment 5
Step 1, the preparation of D- sulphur phenylacetic acid mixed acid anhydride
100mL N, dinethylformamide/700mL dichloro is added in 154.7 grams of lithium salts of D- sulphur phenylacetic acid (0.6937mol)
In methane, -15 DEG C are cooled to, is added dropwise triethylamine 19.2mL (0.1388mol), temperature control is to -10 DEG C hereinafter, ethyl chloroformate is added dropwise
99.0 grams (0.91mol), insulated and stirred 3h obtains the mixed acid anhydride solution of D- sulphur phenylacetic acid；
Step 2, the preparation of 7-PACA solution
155.4 grams of (0.3469mol) 7-PACA are added in 300ml tetrahydrofuran/300ml water, 0 DEG C is cooled to and is added three
Ethamine 155.8ml (1.1184mol), temperature control -20 DEG C hereinafter, 7-PACA dissolves to obtain 7-PACA solution；
Step 3, the preparation of cephalo sulphur benzyl pyridine acid
The mixed acid anhydride solution of D- sulphur phenylacetic acid is added in 7-PACA solution, 60min is reacted, triethylamine maintains pH7-
8.5, -10 DEG C of sufficiently reactions make 7-PACA content≤3% in reaction solution；Purified water 500ml is added, stirs liquid separation, organic layer is again
Purified water 100ml is added, liquid separation merges water phase, filters after active carbon decoloring is added, and isopropanol is added in a small amount of water washing filter cake,
With the salt acid for adjusting pH of 4mol/L to 1.3-1.5, filtered after growing the grain 4h, water/isopropanol (1/1), isopropanol washing are true in 30 DEG C
The dry 6h of sky obtains 102.0 grams of acid of the pyridine of cephalo sulphur benzyl, purity 97.9%.
Embodiment 6
Step 1, the preparation of D- sulphur phenylacetic acid mixed acid anhydride
The mixed of 400ml methyl iso-butyl ketone (MIBK) and 400ml acetone is added in 165.2 grams of magnesium salts of D- sulphur phenylacetic acid (0.6937moL)
In bonding solvent, -15 DEG C are cooled to, 17.94 grams of (0.1388mol) temperature controls of diisopropylethylamine are added dropwise to -10 DEG C hereinafter, benzene is added dropwise
160.7 grams of sulfonic acid chloride (0.912mol), insulated and stirred 3h obtains the mixed acid anhydride solution of D- sulphur phenylacetic acid；
Step 2, the preparation of 7-PACA solution
100 grams of (0.2232mol) 7-PACA are added in 100ml purified water and the in the mixed solvent of 400ml ethyl alcohol, -20
DEG C be added triethylamine 77.9ml (0.5592mol), temperature control 0 DEG C hereinafter, 7-PACA dissolves to obtain 7-PACA solution；
Step 3, the preparation of cephalo sulphur benzyl pyridine acid
The mixed acid anhydride solution of D- sulphur phenylacetic acid is added in 7-PACA solution, 60min is reacted, triethylamine maintains pH7-
8.5, -10 DEG C of sufficiently reactions make 7-PACA content≤3% in reaction solution；Purified water 500ml is added, stirs liquid separation, organic layer is again
Purified water 100ml is added, liquid separation merges water phase, filters after active carbon decoloring is added, and ethyl alcohol is added in a small amount of water washing filter cake, uses
The salt acid for adjusting pH of 4mol/L is filtered, water/ethyl alcohol (1/1), ethanol washing after growing the grain 4h to 1.3-1.5, is dried in vacuo in 30 DEG C
6h obtains 70.0 grams of acid of the pyridine of cephalo sulphur benzyl, purity 97.8%.
Embodiment 7
Step 1, the preparation of D- sulphur phenylacetic acid mixed acid anhydride
The in the mixed solvent of 200mlDMF and 600ml methylene chloride is added in 173.9 grams of D- sulphur phenylacetic acid (0.6937moL),
- 15 DEG C are cooled to, 153.6 grams of triethylamine (1.517mol) is added dropwise, temperature control is to -10 DEG C hereinafter, being added dropwise 110.3 grams of pivaloyl chloride
(0.9121mol), insulated and stirred 30min obtain the mixed acid anhydride solution of D- sulphur phenylacetic acid；
Step 2, the preparation of 7-PACA solution
100 grams of (0.2232mol) 7-PACA are added in 100ml purified water and the in the mixed solvent of 400ml ethyl alcohol, 0 DEG C
It is added triethylamine 77.9ml (0.5592mol), temperature controls 0 DEG C hereinafter, 7-PACA dissolves to obtain 7-PACA solution；
Step 3, the preparation of cephalo sulphur benzyl pyridine acid
The mixed acid anhydride solution of D- sulphur phenylacetic acid is added in 7-PACA solution, 60min is reacted, triethylamine maintains pH7-
8.5, -10 DEG C of sufficiently reactions make 7-PACA content≤3% in reaction solution；Purified water 500ml is added, stirs liquid separation, organic layer is again
Purified water 100ml is added, liquid separation merges water phase, filters after active carbon decoloring is added, and ethyl alcohol is added in a small amount of water washing filter cake, uses
The salt acid for adjusting pH of 4mol/L is filtered, water/ethyl alcohol (1/1), ethanol washing after growing the grain 4h to 1.3-1.5, is dried in vacuo in 30 DEG C
6h obtains 75.0 grams of acid of the pyridine of cephalo sulphur benzyl, purity 98.8%.
Reference example
Cephalo sulphur benzyl pyridine acid prepared by the present invention and reaction of sodium bicarbonate are prepared into cephalo sulphur benzyl pyridine sodium:
11 grams of sodium bicarbonates are dissolved in 400 grams of purified waters, 70g cephalo sulphur benzyl pyridine acid is added, active carbon 1.5g is added,
It is filtered after stirring 30min, and with 30 grams of purifying water washing filter cakes；The addition ethyl alcohol about 1000ml into filtrate, growing the grain 1 hour, then
Addition 480ml ethyl alcohol, 0 DEG C of cooling, growing the grain 2 hours；Then it filters, and washs filter cake twice with cold acetone；Finally it is dried in vacuo 6
Hour, obtain about 52 grams of sodium of cephalo sulphur benzyl pyridine.Non-sterile cephalo sulphur benzyl pyridine sodium meets Japanese Pharmacopoeia mark in addition to sterile continuous item
It is quasi-.
The characterization of cephalo sulphur benzyl pyridine sodium:
Hydrogen nuclear magnetic resonance spectrum analysis: HNMR (D2O, 400M, TMS are internal standard): δ 3.12 (1H, d, J=18Hz), 3.64
(1H, d, J=18Hz), 5.10 (1H, s), 5.21 (1H, d, J=5Hz), 5.40 (1H, d, J=15Hz), 5.65 (1H, d, J=
15Hz), 5.73 (1H, d, J=5Hz), 7.41~7.65 (5H, m), 8.25 (2H, d, J=6.5Hz), 9.03 (2H, d, J=
6.5Hz)。
Infrared spectrum analysis: IR (KBr) cm-1: 3330 (CH, NH), 3200 (OH, broad), 1760 (C=O, β-
Lactam), 1685 (- CONH -), 1615 (- COO -), 1555 (- NH2, deformation), 1455,1395 (C=C,
SO2), 1200 (SO2, broad), 1120,1040 (- SO3—)。
It is feasible using above method synthesis cephalo sulphur benzyl pyridine acid and cephalo sulphur benzyl pyridine sodium process stabilizing, it is industrial easy to accomplish
Industrialization, product yield is high, high-quality.
As used some vocabulary in the specification and claims to censure special component or method.Art technology
Personnel are, it is to be appreciated that different regions may call the same ingredient with different nouns.This specification and claims are not
In such a way that the difference of title is as ingredient is distinguished.As the "comprising" mentioned by throughout the specification and claims is
One open language, therefore should be construed to " including but not limited to "." substantially " refer within the acceptable error range, this field
Technical staff can solve the technical problem within a certain error range, basically reach the technical effect.Specification is subsequent
It is described as implementing better embodiment of the invention, so the description is for the purpose of illustrating rule of the invention, not
To limit the scope of the invention.Protection scope of the present invention is as defined by the appended claims.
It should also be noted that, the terms "include", "comprise" or its any other variant are intended to nonexcludability
Include, so that commodity or system including a series of elements not only include those elements, but also including not clear
The other element listed, or further include for this commodity or the intrinsic element of system.In the feelings not limited more
Under condition, the element that is limited by sentence "including a ...", it is not excluded that in the commodity or system for including the element also
There are other identical elements.
Above description has shown and described several preferred embodiments of invention, but as previously described, it should be understood that invention is not
It is confined to form disclosed herein, should not be regarded as an exclusion of other examples, and can be used for various other combinations, modification
And environment, and can be carried out within that scope of the inventive concept describe herein by the above teachings or related fields of technology or knowledge
Change.And changes and modifications made by those skilled in the art do not depart from the spirit and scope of invention, then it all should be in the appended power of invention
In the protection scope that benefit requires.
Claims (8)
1. a kind of preparation method of cephalo sulphur benzyl pyridine acid, which comprises the following steps: intermediate D- sulphur phenylacetic acid or its
Mixed acid anhydride is made in salt (I) and acylation reaction；Key intermediate 7-PACA (II) is molten under certain temperature in the presence of alkali
Solution obtains 7-PACA solution in solvent；Mixed acid anhydride solution is added dropwise in 7-PACA solution, sufficiently reacts, post-process to the end
Spore sulphur benzyl pyridine acid；
Wherein, R1For H, Li, Na, K, Mg or Ca；R2For trimethylamine, triethylamine, diisopropylethylamine or N-methylmorpholine；R3-Cl
Are as follows: methylchloroformate, ethyl chloroformate, isopropyl chlorocarbonate, butyl chlorocarbonate, pivaloyl chloride, methane sulfonyl chloride, benzene sulfonyl
Chlorine, p-methyl benzene sulfonic chloride；
The preparation method of the cephalo sulphur benzyl pyridine acid specifically:
Step 1, D- sulphur phenylacetic acid or its salt are added in organic solvent, are cooled to -15 DEG C to -20 DEG C, and alkali, temperature control to -10 is added
DEG C hereinafter, acylating agent is added, insulated and stirred 1-3h obtains mixed acid anhydride solution；
Step 2,7-PACA is added in solvent, -30 DEG C~30 DEG C addition alkali, temperature control dissolves to obtain 7- to -10 DEG C or less 7-PACA
PACA solution；
Step 3, the mixed acid anhydride solution is added dropwise in the 7-PACA solution, organic base maintains pH4.5-8.5, temperature dimension
- 30 DEG C~30 DEG C are held, sufficiently reaction makes 7-PACA content≤3% in reaction solution；Purified water stirring is sufficiently added after reaction, point
Phase washs filter cake, organic solvent is added to filtering after water phase decoloration, is adjusted with acid pH to 1.3-1.5, filtered after growing the grain 4h,
It washs, dry to obtain cephalo sulphur benzyl pyridine acid.
2. a kind of preparation method of cephalo sulphur benzyl pyridine acid as described in claim 1, which is characterized in that acylated in the step 1
Agent be methylchloroformate, ethyl chloroformate, isopropyl chlorocarbonate, isobutyl chlorocarbonate, methane sulfonyl chloride, paratoluensulfonyl chloride,
Benzene sulfonyl chloride or pivaloyl chloride.
3. a kind of preparation method of cephalo sulphur benzyl pyridine acid as described in claim 1, which is characterized in that D- sulphur phenylacetic acid or its salt
Chloroform, methylene chloride, N, N- dimethyl acetamide, N, dinethylformamide, first are selected from the solvent of acylation reaction
Base isobutyl ketone, acetone, in acetonitrile any one or more compositions mixed solvent.
4. a kind of preparation method of cephalo sulphur benzyl pyridine acid as described in claim 1, which is characterized in that the key intermediate 7-
PACA is free inner salt, or the salt formed for it with acid, and the salt with sour formation is hydrochloride, hydrobromate, hydrogen iodine
Hydrochlorate, nitrate, sulfate, phosphate, formates or acetate.
5. a kind of preparation method of cephalo sulphur benzyl pyridine acid as described in claim 1, which is characterized in that alkali is in the step 1
Organic base or inorganic base, the organic base are triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine or 4- picoline, institute
Stating inorganic base is potassium carbonate or sodium carbonate；In step 2 alkali be organic base or inorganic base, the organic base be selected from triethylamine, pyridine,
N-methylmorpholine, diisopropylethylamine, 4- picoline, diethylamine, tetramethylguanidine, sodium methoxide or sodium ethoxide, the inorganic base
Selected from potassium carbonate or sodium carbonate.
6. a kind of preparation method of cephalo sulphur benzyl pyridine acid as described in claim 1, which is characterized in that dissolve the solvent of 7-PACA
For organic solvent or the mixed solvent of water and organic solvent；The organic solvent is selected from methanol, ethyl alcohol, isopropanol, acetone, tetrahydro
Furans, N, N- dimethyl acetamide, N, dinethylformamide, in acetonitrile any one or more compositions mixed solvent.
7. a kind of preparation method of cephalo sulphur benzyl pyridine acid as described in claim 1, which is characterized in that mixed in the step 3
The pH value of anhydride solution and 7-PACA solution reaction system maintains 4.5-8.5 with organic base；The organic base is triethylamine, two
Ethamine, trimethylamine or tetramethylguanidine.
8. a kind of preparation method of cephalo sulphur benzyl pyridine acid as described in claim 1, which is characterized in that the D- sulphur phenylacetic acid or
The molar ratio of its salt (I) and acylating agent is 1 ︰ 0.9-2.0；The molar ratio of D- sulphur phenylacetic acid and alkali is 1 ︰ 2-2.5, D- sulphur benzene second
The molar ratio of hydrochlorate and alkali is 1 ︰ 0.1-1.5；The molar ratio of 7-PACA (II) and D- sulphur phenylacetic acid or its salt (I) is 1:1-5；
The molar ratio of 7-PACA (II) and alkali is 1:2-5.
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| EP2116545A1 (en) * | 2008-05-07 | 2009-11-11 | Idexx Laboratories, Inc. | Process for preparing cefsulodin sodium |
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| EP2116545A1 (en) * | 2008-05-07 | 2009-11-11 | Idexx Laboratories, Inc. | Process for preparing cefsulodin sodium |
| CN101891755A (en) * | 2010-07-27 | 2010-11-24 | 海南永田药物研究院有限公司 | Cefsulodin sodium compound and novel preparation method thereof |
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