CN1282652C - Method for producing crystal of 3-chloromethyl-3-cephem derivative - Google Patents
Method for producing crystal of 3-chloromethyl-3-cephem derivative Download PDFInfo
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- CN1282652C CN1282652C CN 03150030 CN03150030A CN1282652C CN 1282652 C CN1282652 C CN 1282652C CN 03150030 CN03150030 CN 03150030 CN 03150030 A CN03150030 A CN 03150030A CN 1282652 C CN1282652 C CN 1282652C
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Abstract
To provide a method for producing crystals of 3-chloromethyl-3-cephem derivative, capable of immediately producing the crystals with a high purity in a high yield by a reaction. This method for producing the crystals of the 3-chloromethyl-3-cephem derivative expressed by general formula (2) comprises reacting a chlorinated azetidinone derivative expressed by general formula (1) (R<SB>1</SB>is a substituted or unsubstituted aryl or heterocyclic residue; and R<SB>2</SB>and R<SB>3</SB>are each a substituted or unsubstituted hydrocarbon residue) with an alcoholate in a solvent containing an alcohol and an ether under a condition of <=pH 8. (C)2004,JPO.
Description
Technical field
The present invention relates to 3-chloromethyl-3-Cephem Derivative crystalline manufacture method, particularly can access can be used as 3-chloromethyl-3-cephem be various antibiotic synthetic intermediate, with the 3-chloromethyl-3-Cephem Derivative crystalline manufacture method of following general formula (2) expression.
(in the formula, R
2, R
3Replace or the unsubstituted aromatic hydrocarbyl of expression).
Background technology
Known 3-chloromethyl-3-Cephem Derivative by above-mentioned general formula (2) expression is a kind of compound that can be used as the synthetic intermediate of synthetic cephalosporin antibiotics (spy open clear 59-172493 communique, spy open clear 58-72591 communique, spy open clear 60-255796 communique, spy and open that clear 61-5084 communique, spy are opened flat 1-156984 communique, the spy opens flat 1-308287 communique, No. 99/10352 communique of international publication number WO, No. 98/58932 communique of international publication number WO etc.).
Past, manufacture method with the 3-chloromethyl-3-Cephem Derivative of above-mentioned general formula (2) expression, for example, proposed to make the acetoxyl group of 3 acetoxy-methyls of 3-acetoxy-methyl cephalosporins derivatives in the presence of Lewis such as boron trichloride acid, to carry out halogenated method (Tetradedronlett., 3991p.1974), will be after the electrolytic reaction chlorination by the azetidinone derivative of penicillin G preparation, form the method (Tetradedronlett. of Cephem Derivative by the alkaline purification closed loop, 23,2187p, 1982) method, according to following reaction formula (1)
Reaction formula (1)
In the presence of alkaline earth metal carbonate, the method (spy opens flat 4-66584 communique) that 7-substituted-amino-3-methylol-3-cephem-4-carboxylicesters (compound (3)) and chlorination reagent are reacted; According to following reaction formula (2),
In the presence of alkali, the method (spy opens clear 58-74689 communique) that azetidinone derivative (compound (1a)) is reacted in organic solvent.
Wherein, it is the method for making oily 3-chloromethyl-3-Cephem Derivative that the spy opens clear 58-74689 communique, this method is that raw material azetidinone derivative (compound (1a)) is dissolved in the N as reaction solvent with resultant of reaction 3-chloromethyl-3-Cephem Derivative, in the dinethylformamide, weakly alkaline ammonia or ammoniacal liquor are used as alkali, when preventing the resultant of reaction decomposition, react, obtain the method for buttery 3-chloromethyl-3-Cephem Derivative.
In addition, open in the clear 58-74689 communique the spy, can enumerate methyl alcohol as reaction solvent, ethanol, alcohol such as Virahol, can enumerate alkaline sodium hydroxide as alkali, metal hydroxidess such as potassium hydroxide, but because alcohol can not dissolve the 3-chloromethyl-3-Cephem Derivative as resultant of reaction, thereby can not obtain oily matter, and because if these pure and mild alkali reactions generate water, make in this water and be dissolved with alkali, thereby the pH value that makes reaction system raises and is alkalescence, resultant of reaction 3-chloromethyl-3-Cephem Derivative is decomposed, thereby reduced yield.
And, the active very high chlorine atom owing in the molecule of 3-chloromethyl-3-Cephem Derivative, respond, unstable under the state of oily matter, can discharge hydrochloric acid when for example at room temperature preserving and promote self-decomposition, cause quality to reduce, so people wish can obtain having the product of long period stability under the condition of gentleness.
Therefore, just proposed to make the method that crystallization obtains 3-chloromethyl-3-Cephem Derivative from oily matter.
For example, in international publication number WO99/10352 communique, proposed the N of the oily matter of a kind of 3-of making chloromethyl-3-Cephem Derivative, the crystallization in refrigerative alcohol or pure water of dinethylformamide solution is separated out, and obtains the method for the crystallisate of 3-chloromethyl-3-Cephem Derivative.
But, according to No. 99/10352 communique of WO,, must separate out such complicated procedures of forming through crystallization again in case synthesized the oily matter of 3-chloromethyl-3-Cephem Derivative, be unfavorable for industrial production.
Summary of the invention
Therefore, the purpose of this invention is to provide a kind of can by reaction continuously with high yield and high purity obtain can be used as cynnematin system various antibiotic synthetic intermediates 3-chloromethyl-3-Cephem Derivative crystalline, help industrial 3-chloromethyl-3-Cephem Derivative crystalline manufacture method.
In view of above-mentioned problem, the inventor etc. are to obtaining the accumulation results that the 3-chloromethyl-3-Cephem Derivative crystalline method is studied with keen determination incessantly by reaction, found the combination of raw material chlorination azetidinone derivative and alcohol, and found can not to dissolve the combination of the ether of the 3-chloromethyl-pure and mild solubilized raw material of 3-Cephem Derivative crystalline chlorination azetidinone derivative and byproduct of reaction impurity, with as reaction solvent.According to this reaction system, if under anhydrous state, the carrying out of control reaction under the pH of specified range value, just can be by reaction, obtain to high incessantly yield and high purity the 3-chloromethyl as object-3-Cephem Derivative crystallization, thereby finish the present invention by above-mentioned general formula (2) expression.
That is, the present invention is the 3-chloromethyl-3-Cephem Derivative crystalline manufacture method shown in following general formula (2), it is characterized in that, in containing alcoholic solvent, pH under the condition below 8, makes as following general formula (1)
(in the formula, R
1Expression replaces or unsubstituted aryl or replacement or unsubstituted heterocycle residue, R
2And R
3Expression replaces or unsubstituted aromatic hydrocarbyl.)
(in the formula, R
2And R
3Expression replaces or unsubstituted aromatic hydrocarbyl.)
Shown chlorination azetidinone derivative and alkoxide react.
And, the invention provides a kind of 3-chloromethyl-3-Cephem Derivative crystalline manufacture method shown in following general formula (2), it is characterized in that, in containing the solvent of pure and mild ether, the pH value is under the condition below 8, chlorination azetidinone derivative and alkoxide shown in following general formula (1) to be reacted.
(in the formula, R
1Expression replaces or unsubstituted aryl or replacement or unsubstituted heterocycle residue, R
2And R
3Expression replaces or unsubstituted aromatic hydrocarbyl);
(in the formula, R
2And R
3Expression replaces or unsubstituted aromatic hydrocarbyl).
In the present invention, be preferably and contain the above-mentioned chlorination azetidinone derivative solution (A) in the ether solvents and be dissolved in the alkoxide solution (B) that contains in the alcoholic solvent, add in the alcoholic solution (C) and react being dissolved in.
Preferably in above-mentioned alcoholic solution (C), add as a part that is dissolved in the chlorination azetidinone derivative solution (A) that contains in the ether solvents, contain the equivalent that responds be 5～30mol% chlorination azetidinone derivative solution (A) afterwards, with remaining solution (A) that contains chlorination azetidinone derivative be dissolved in the alkoxide solution (B) that contains in the alcoholic solvent and join simultaneously in the above-mentioned alcoholic solution (C) and react.
The reaction of above-mentioned chlorination azetidinone derivative and alkoxide, the chlorination azetidinone derivative that is preferably with 1mol reacts the ratio of 0.8～1.5mol alkoxide.
Above-mentioned alcohol is preferably, and is selected from least a in methyl alcohol or the ethanol.
Above-mentioned ether is preferably diox.
Above-mentioned alkoxide is preferably sodium methylate or sodium ethylate.
Above-mentioned reaction is preferably being carried out below 5 ℃.
The above-mentioned solution (A) that contains chlorination azetidinone derivative is preferably chlorination azetidinone derivative is dissolved in the solution that forms in diox or the alcohol.
The above-mentioned solution (B) that contains alkoxide is preferably alkoxide is dissolved in the solution that alcohol forms.
Above-mentioned alcoholic solution (C) is preferably the mixed solvent of pure and mild diox.
Be preferably by dripping and add above-mentioned solution (A) and solution (B) to react.
Above-mentioned reaction is preferably under anhydrous state to be carried out.
Embodiment
Explain the present invention below.
The invention provides the 3-chloromethyl-3-Cephem Derivative crystalline manufacture method shown in following general formula (2), it is characterized in that, will be dissolved in the chlorination azetidinone derivative solution (A) shown in following general formula (1) (following note is made " solution (A) that contains chlorination azetidinone derivative ") that contains in the ether solvents; Be dissolved in the alkoxide solution (B) that contains in the alcoholic solvent (following note is made " solution (B) that contains alkoxide ") and be added drop-wise in the alcoholic solution (C), under pH is condition below 8, react.
(in the formula, R
1Expression replaces or unsubstituted aryl or replacement or unsubstituted heterocycle residue, R
2And R
3Expression replaces or unsubstituted aromatic hydrocarbyl.)
And, contain the solution (A) of chlorination azetidinone derivative and contain the dripping quantity of the solution (B) of alkoxide, be preferably in above-mentioned solution (A) that contains chlorination azetidinone derivative and the above-mentioned solution (B) that contains alkoxide, with respect to the chlorination azetidinone of 1mol, the mol ratio of alkoxide is 0.8～1.5 times of mol.
And dripping quantity is preferably, and when dripping end, pure content is 30～95 weight % in the reaction solvent.
And, above-mentioned reaction is preferably and is mixed with the solution (A) that contains with the chlorination azetidinone derivative of above-mentioned general formula (1) expression, the reaction equivalent that the makes chlorination azetidinone derivative earlier solution (A) that to be 5～30mol% ground contain above-mentioned chlorination azetidinone derivative with a part is added drop-wise to and contains in the alcoholic solvent, remaining is contained solution (A) with the chlorination azetidinone derivative of above-mentioned general formula (1) expression again and is added drop-wise to alcoholic solution (C) simultaneously with the solution (B) that contains alkoxide and reacts middlely.
And the above-mentioned solution (A) that contains chlorination azetidinone derivative preferably dissolves the solution that chlorination azetidinone derivative obtains by the mixed solvent of diox and alcohol.
And the above-mentioned solution (B) that contains alkoxide preferably is dissolved in the solution that alcohol forms by alkoxide.
And above-mentioned alcoholic solution (C) is the mixed solvent of pure and mild diox preferably.
The reaction formula of representing 3-chloromethyl of the present invention-3-Cephem Derivative process for producing crystal below.
Above-mentioned solution (A)～(C) used in the manufacture method of the present invention is described then.
＜contain the solution (A) of chlorination azetidinone derivative 〉
R as the chlorination azetidinone derivative that is used for raw material of the present invention (following also note is done " chlorination azetidinone derivative (compound (1)) ") with above-mentioned general formula (1) expression
1Expression replaces or unsubstituted aryl or replacement or unsubstituted heterocycle residue.As aryl, specifically can enumerate phenyl, p-aminomethyl phenyl, p-p-methoxy-phenyl, p-nitrophenyl, p-chloro-phenyl-, five chlorophenyl etc.And, can enumerate 2-pyridyl, 2-[4-morpholinodithio base, 1,3 as that replace or unsubstituted heterocycle residue, 4-thiadiazoles-5-base, 2-methyl isophthalic acid, 3,4-thiadiazoles-5-base, 1,2,3,4-tetrazolium-5-base, 1-methyl isophthalic acid, 2,3,4-tetrazolium-5-base, 1-phenyl-1,2,3,4-tetrazolium-5-base etc.
And R
2And R
3Replace or the unsubstituted aromatic hydrocarbyl of expression.Specifically can enumerate benzyl, p-methoxy-benzyl, phenyl, p-tolyl etc., R
2And R
3Can be identical, also can be different.
By the chlorination azetidinone derivative of above-mentioned general formula (1) expression, for example R in general formula (1)
2Be phenyl, R
3Being the compound of p-methoxy-benzyl, can thiazoline azetidinone derivative be raw material, makes (with reference to special fair 5-9425 communique) by the 2 steps reaction of reaction formula as follows (3) and reaction formula (4).
Reaction formula (3)
Reaction formula (4)
(in the formula, R
1Has identical meaning with the front).
＜contain the solution (A) of chlorination azetidinone derivative 〉
The solution that the resultant of reaction chlorination azetidinone derivative that obtains according to above-mentioned reaction formula (4) can be dissolved in solvent is used as the solution (A) that contains chlorination azetidinone derivative of the present invention after adjusting.
And,, can use with the above-mentioned chlorination azetidinone of dissolution with solvents derivative (compound (1a)) and be adjusted to solution behind the predetermined concentration as being used for the solution (A) that contains chlorination azetidinone derivative of the present invention.
The solution (A) that contains chlorination azetidinone derivative is to use with the above-mentioned chlorination azetidinone of dissolution with solvents derivative (compound (1)) and is adjusted to the solution of predetermined concentration.
As the solvent of solubilized chlorination azetidinone derivative, can enumerate for example ester classes such as methyl-formiate, ethyl formate, methyl acetate, ethyl acetate, butylacetate, ethyl propionate; Halohydrocarbon such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, ethylene dibromide, chlorobenzene; Ethers such as diethyl ether, dibutyl ether, diox, tetrahydrofuran (THF); Nitrile such as acetonitrile, butyronitrile; Hydro carbons such as pentane, hexane, hexanaphthene, these solvents can use one or more (below be called " solvent orange 2 A ").Wherein be preferably diox.
The content of these solvents is 50～500 weight parts with respect to the chlorination azetidinone derivative (compound (1)) of 100 weight parts, preferred 100～500 weight parts.
Such solution former state that is dissolved with behind the chlorination azetidinone derivative can be used, but because such soltion viscosity is very high, therefore the preferred alcohol (being called " solvent orange 2 A 2 " below) that adds solubilized chlorination azetidinone derivative in such solution reduces viscosity, so that the operation when dripping.With regard to operable alcohol, for example can use in the lower alcohols such as methyl alcohol, ethanol, Virahol, n-propyl alcohol one or more.Wherein as used lower alcohol, if when using methyl alcohol or ethanol under following reaction conditions, to react, because can with high yield and high purity obtain 3-chloromethyl-3-Cephem Derivative crystallization with above-mentioned general formula (2) expression, so be particularly preferred.
At this moment, the proportional quantity of alcohol (A2 solvent) is preferably chlorination azetidinone derivative (compound (1)) with respect to 100 weight parts at 100～500 weight parts, more preferably in the scope of 200～300 weight parts.
The solution that contains such chlorination azetidinone derivative, the content of its chlorination azetidinone derivative (compound (1)) is 0.05～1mol/L, is preferably 0.1～0.5mol/L.
＜contain the solution (B) of alkoxide 〉
The present invention is characterized as: use alkoxide in crystallization reaction.
Can be used for alkoxide general formula R of the present invention
4-OM represents.R in the formula
4Be the low alkyl group of the straight or branched of carbonatoms 1～4, for example can enumerate alkyl such as methyl, ethyl, sec.-propyl, normal-butyl.M in the formula represents basic metal such as lithium, sodium, potassium.
As alkoxide cpd, can enumerate for example sodium methylate, sodium ethylate, potassium methylate, potassium ethylate, lithium methoxide, lithium ethoxide, t-butanols potassium etc. particularly, can use in these alkoxide one or more.
Wherein, as alkoxide, preferably use sodium methylate or sodium ethylate.
The solution (B) that contains alkoxide is to use the above-mentioned alkoxide of dissolution with solvents and is adjusted to the solution of predetermined concentration.
As the solvent (being called " solvent B1 " below) of the above-mentioned alkoxide of dissolving, the preferred alcohol that uses specifically can be enumerated methyl alcohol, ethanol, Virahol, propyl carbinol etc., can use wherein one or more.Wherein preferably use methyl alcohol or ethanol.
＜alcoholic solution (C) 〉
Alcoholic solution will use the alcohol independent solvent of (being called " solvent C 1 " below) at least, perhaps with other solvent mixed solvent of (being called " solvent C 2 " below).As available alcohol, can enumerate lower alcohols such as methyl alcohol, ethanol, Virahol, propyl carbinol, can use in these alcohol one or more.Wherein, preferably use methyl alcohol or ethanol as alcohol.
The alcohol solubilized is with the raw material chlorination azetidinone derivative of general formula (1) expression, but for the resultant of reaction 3-chloromethyl-3-Cephem Derivative of unlikely dissolving with general formula (2) expression, the reaction solvent that preferred use can make resultant of reaction reclaim as direct crystallization.
And since with alcohol other solvent of (solvent C 1) blended (solvent C 2) solubilized raw material chlorination azetidinone derivative (compound (1)), and solubilized reaction becomes impurity such as the unreacting material chlorination azetidinone derivative of impurity or byproduct of reaction when finishing, so can reclaim 3-chloromethyl-3-Cephem Derivative crystallization with above-mentioned general formula (2) expression by high purity ground in the reaction solution.As such solvent, can enumerate for example ester classes such as methyl-formiate, ethyl formate, methyl acetate, ethyl acetate, butylacetate, ethyl propionate; Halohydrocarbon such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, ethylene dibromide, chlorobenzene; Ethers such as diethyl ether, dibutyl ether, diox, tetrahydrofuran (THF); Nitrile such as acetonitrile, butyronitrile; Hydro carbons such as benzene, hexane, hexanaphthene can use in these solvents one or more.Wherein preferably use diox.
If alcohol (solvent C 1) and other solvent (solvent C 2), with alcohol (solvent C 1) with respect to 100 weight parts, other solvent (solvent C 2) is 10～30 weight parts, the blending ratio of preferred 10～20 weight parts, react under the following conditions, just can obtain 3-chloromethyl-3-Cephem Derivative crystal with high yield and high purity with above-mentioned general formula (2) expression, therefore be preferred, on the other hand, when other solvent (solvent C 2) during less than 10 weight parts, carrying out along with reaction, 3-chloromethyl-3-Cephem Derivative the crystallization that generates will be when crystallization and impurity such as byproduct of reaction form bulk, thereby can not obtain 3-chloromethyl-3-Cephem Derivative crystallization with high purity and high yield, when surpassing 30 weight parts, owing to the 3-chloromethyl that generates-3-Cephem Derivative crystallization dissolving causes yield to reduce, therefore will not adopt.
The consumption of alcoholic solution (C), chlorination azetidinone derivative with respect to 100 weight parts with above-mentioned general formula (1) expression, preferred 300～2000 weight parts that use, more preferably 500～1000 weight parts, when less than 500 weight parts, reaction is difficult to carry out, raw material that simultaneously can remained unreacted, and when surpassing 1000 weight parts owing to will use solvent more than necessary amount, industrial be disadvantageous.
＜reaction conditions 〉
3-chloromethyl-3-Cephem Derivative crystalline manufacture method with above-mentioned general formula (2) expression of the present invention, it is characterized in that, to contain with the solution (A) of the chlorination azetidinone derivative of above-mentioned general formula (1) expression and the solution (B) that contains above-mentioned alkoxide and be added drop-wise in the alcoholic solution (C), under pH is condition below 8, react.
In the present invention, in pH value below 8, preferably react in pH value 6～8.The reason that pH value in the reaction is fixed on this scope is because resultant of reaction 3-chloromethyl-3-Cephem Derivative crystallization is extremely unstable to alkali, when pH value 8 is above, in reaction process, will decompose, and can not obtain object 3-chloromethyl-3-Cephem Derivative crystallization with high purity and high yield, therefore will not select for use.
Because reaction is carried out very soon, the mensuration of pH value is preferably in the reaction, for example by taking out reaction solution in the reaction system to litmus paper, drips water in the above and measures, or take a small amount of reaction solution, behind the water of interpolation twice, is measured by pH meter etc.Because the unreacted alkoxide is represented the weakly alkaline group, thus the rising of the pH value in the reaction, and tend to alkalescence more.
Therefore, reaction in the present invention, the solution (B) that preferably will contain the solution (A) of chlorination azetidinone derivative (compound (1)) and contain alkoxide in the scope of above-mentioned pH value is added drop-wise in the alcoholic solution (C).
And, contain with the solution (A) of the chlorination azetidinone derivative of above-mentioned general formula (1) expression and contain the dripping quantity of the solution (B) of above-mentioned alkoxide, if with the mol ratio with respect to the alkoxide in the solution that contains alkoxide (B) of the chlorination azetidinone derivative in the solution that contains chlorination azetidinone derivative (A) (compound (1)) is 0.8～1.5 times of mol, the ratio of preferred 1.1～1.2 times of mol drips, owing to can reduce the residual quantity of unreacting material chlorination azetidinone derivative (compound (1)), the just 3-chloromethyl-3-Cephem Derivative crystallization that can obtain generating with high purity and high yield, so be preferred, and less than 0.8 times of mol the time, the residual quantity of unreacting material chlorination azetidinone derivative (compound (1)) is more than essential value, if and when surpassing 1.5 times of mol, the pH value of reaction solution will be alkalescence above 8, the 3-chloromethyl that generates-3-Cephem Derivative crystallization meeting is decomposed, and therefore will not select for use.
In addition, contain the solution (A) of above-mentioned chlorination azetidinone derivative and contain the dripping quantity of the solution (B) of above-mentioned alkoxide, be preferably and make that the pure content (solvent orange 2 A 2+ solvent B1+ solvent C 1) of (solvent orange 2 A 1+ solvent orange 2 A 2+ solvent B1+ solvent C 1+ solvent C 2) is 30～95 weight % in the total overall reaction solvent of their solution (A)～solution (C) when drip finishing, be preferably 60～90 weight %.If drip when pure content is less than 30 weight % in the reaction solvent when finishing, the alkoxide of reaction raw materials is difficult to be dissolved in the reaction solution, and can cause 3-chloromethyl-3-Cephem Derivative crystallization dissolving and reduce yield, on the other hand, if react according to the ratio that surpasses 95 weight %, owing to can not dissolve the 3-chloromethyl-impurity such as byproduct of reaction of 3-Cephem Derivative crystallization when crystallization of generation, make these impurity form bulk, so just can not obtain 3-chloromethyl-3-Cephem Derivative crystallization, therefore will not select for use with high purity and high yield.
Particularly in the present invention, if for the solution (A) that contains chlorination azetidinone derivative (compound (1)), solvent as solubilized chlorination azetidinone derivative, use the mixed solvent of diox (solvent orange 2 A 1) and methyl alcohol and/or ethanol (solvent orange 2 A 2), as the solution that contains alkoxide (B), methyl alcohol and/or ethanol (solvent B1) have been used, and, used methyl alcohol and/or ethanol (solvent C 1) is Yu the mixed solvent of diox (solvent C 2) as containing alcoholic solvent (C), methyl alcohol and/or alcoholic acid content in the reaction solvent (solvent orange 2 A 1+ solvent orange 2 A 2+ solvent B1+ solvent C 1+ solvent C 2) when dripping end are 20～60 weight %, be preferably 30～50 weight %, just can obtain 3-chloromethyl-3-Cephem Derivative crystallization with above-mentioned general formula (2) expression with high yield and high purity, be particularly preferred therefore.
The solution (B) that will contain the solution (A) of above-mentioned chlorination azetidinone derivative (compound (1)) and contain above-mentioned alkoxide is added drop-wise to the method in the alcoholic solution (C), can enumerate as described below 1～2 dropping method.
1. prepare solution (solution A) that contains the chlorination azetidinone derivative of representing with above-mentioned general formula (1) and the solution (B) that contains above-mentioned alkoxide, the solution (B) that contains above-mentioned alkoxide in dropping before, dropping contains the solution (A) of above-mentioned chlorination azetidinone derivative, be added drop-wise to continuously or intermittently in the alcoholic solution (C) with solution (A) with (B), make the pH value of reaction system be in the interior method (hereinafter referred to as " dropping method 1 " of above-mentioned scope.)。
2. preparation contains the solution (A) with the chlorination azetidinone derivative of above-mentioned general formula (1) expression, at first make the reaction equivalent of chlorination azetidinone derivative be 5～30mol%, be preferably 10～20mol% ground above-mentioned solution (A) is added drop-wise in the alcoholic solution (C), then with the solution (A) and the solution (B) that contains alkoxide of containing of rest part with the chlorination azetidinone derivative of above-mentioned general formula (1) expression, be added drop-wise to simultaneously in the alcoholic solution (C), make the pH value of reaction system be in the interior method (hereinafter referred to as " dropping method 2 " of above-mentioned scope.)。
Above-mentioned dropping method 1 is suitably to regulate the solution (A) that contains chlorination azetidinone derivative and the dropping of the solution (B) that contains alkoxide order, makes pH value in the reaction system always be in the interior solution (A) that will contain above-mentioned chlorination azetidinone derivative of above-mentioned scope and the solution (B) that contains alkoxide is added drop-wise to method in the alcoholic solution (C).And dropping method 2, be the solution that contains chlorination azetidinone derivative (A) that in alcoholic solution (C), drips predetermined amount in advance, reaction system is in the acid range (for example the pH value is 4), the solution (B) that this moment remaining is contained the solution (A) of chlorination azetidinone derivative and contain alkoxide almost side by side is added drop-wise in the alcoholic solution (C) continuously, makes the pH value in the reaction system always be in the interior dropping method of above-mentioned scope.
In addition, in 3-chloromethyl of the present invention-3-Cephem Derivative crystalline manufacture method, also can be when preparation alcoholic solution (C), be 5～30mol% with content earlier, the above-mentioned chlorination azetidinone derivative of preferred 10～30mol% joins in the alcoholic solution (C), then according to dropping method 2 identical operations, in alcoholic solution (C), drip the solution and the solution that contains alkoxide of the chlorination azetidinone derivative that contains the aequum that responds again simultaneously, the pH value in the reaction system is always remained in the above-mentioned scope.
In reaction of the present invention, resultant of reaction 3-chloromethyl-3-Cephem Derivative crystallization is extremely unstable to alkali, when the pH value 8 when above, in reaction, can decompose, if the solution (B) that will contain the solution (A) of chlorination azetidinone derivative from the beginning and contain alkoxide is added drop-wise in the alcoholic solution (C) simultaneously, owing to can alkalitropism one side move, so shown in above-mentioned dropping method 1,2, be preferably and earlier continuously add chlorination azetidinone derivative (compound (1)), and pH value is no more than and is alkaline 8 when reaction is carried out.In addition, solution (A) the pH value that contains chlorination azetidinone derivative approximately is 4, and the solution (B) that contains alkoxide by interpolation rises the pH value of reaction system.
In the present invention, in above-mentioned dropping method 1,2, see that dropping method 2 is at industrial particularly advantageous on the calm pH value this point easy to control.
And, in the present invention, after the solution (A) that will contain raw material chlorination azetidinone derivative all adds alcoholic solution (C), the solution (B) that dropping contains alkoxide is when reacting below 8 at pH, along with reaction is carried out, might contain impurity in the resultant of reaction 3-chloromethyl of generation-3-Cephem Derivative crystallization, thereby cause quality to reduce, but owing to can obtain crystallization incessantly, although increased the burden of back refining step, reaction can be carried out with simple operation.
In the present invention, the solution of the chlorination azetidinone derivative that the chlorination reaction by the azetidinone derivative in the operation that obtains before the raw material chlorination azetidinone derivative can be obtained is as the material solution (A) that contains the chlorination azetidinone.This solution can be enumerated, and for example uses the method described in the special fair 5-9425, the solution of the azetidinone derivative of being made by the chlorination reaction of azetidinone derivative.If use such solution, the raw material azetidinone derivative of one manufacturing process begins in the past, obtains object 3-chloromethyl of the present invention-3-Cephem Derivative crystallization by the successive operation.
In manufacture method of the present invention, the solution (A) that contains raw material chlorination azetidinone derivative, the preferred chlorination azetidinone derivative that uses is dissolved in De dioxane solution in the diox, because De diox fusing point is 11 ℃ in the dioxane solution, under the situation of under the temperature of reaction below 10 ℃ for example, reacting, might cause soltion viscosity to rise, even solidify, for anti-phenomenon here, can dilute by adding alcohol such as the methyl alcohol can dissolve chlorination azetidinone derivative or ethanol, reduce the viscosity of solution, make to drip to be easy to carry out.
And, in manufacture method of the present invention, preferably react by containing as the reaction system of reaction solvent De diox, if the content of diox is few, because along with reaction is carried out, the impurity such as byproduct of reaction when the resultant of reaction 3-chloromethyl-3-Cephem Derivative crystallization of generation and crystallization can be combined into dough, so, the content of reaction system Zhong diox, with respect to chlorination azetidinone derivative, the scope that maintains 10～30 weight parts is preferred.
And, because in manufacture method of the present invention, be reflected in the reaction solvent and carry out, in reaction, can not generate water yet, be under anhydrous state, to react, so just have: does not produce the effect of alkali, be easy to prevent the advantage of 3-chloromethyl-3-Cephem Derivative crystalline decomposition of causing by alkali because of alkoxide is water-soluble.
Why in manufacture method of the present invention is preferred, be because above-mentioned reaction is to carry out under the temperature of reaction below 5 ℃, this has just suppressed the formation of by product, thereby can obtain the 3-chloromethyl-3-Cephem Derivative crystallization with above-mentioned general formula (2) expression as object with high yield.On the other hand, can separate out owing to be lower than under-20 ℃ the situation raw material, impurity, thus-20～5 ℃, preferably under-10～5 ℃, react.
Like this, by crystallization reaction with the 3-chloromethyl-3-Cephem Derivative of above-mentioned general formula (2) expression as object, by reaction solution bleach, muddy and can judge at any time that crystallization separates out, after reaction finishes, through neutralization, filter, dry and obtain crystallization.Also can make with extra care if necessary by clean, recrystallization.
As the solvent that can be used for clean and recrystallization, can suitably select for example alcohol such as methyl alcohol, ethanol, Virahol, propyl carbinol; Nitrile such as acetonitrile, butyronitrile; Ketone such as acetone, methylethylketone; In the middle of the amides such as dimethyl formamide, diethylformamide etc. one or more.
And, according to the 3-chloromethyl-3-Cephem Derivative crystalline manufacture method with above-mentioned general formula (2) expression of the present invention, react according to following reaction formula (5) by for example chlorination azetidinone derivative (compound (1a)) and alkoxide (compound (7))
Reaction formula (5)
(in the formula, R
1Expression replaces or unsubstituted aromatic hydrocarbyl, R
4The expression organic group, M represents basic metal).
In the 3-chloromethyl-3-Cephem Derivative crystallization (compound (2a)) that generates as object, also have metal organic sulfonate (compound (8)) by product to generate.For example, reclaim 3-chloromethyl-3-Cephem Derivative crystallization, make the metal organic sulfonate crystallization separate out (compound (8)) by the mother liquor after reclaiming, make then this metal organic sulfonate of separating out in solvent with bromine reaction, obtain sulfuryl bromide, the manufacturing raw material that can be used as the thiazoline azetidinone derivative (compound (4)) of for example above-mentioned reaction formula (3) utilizes again.
The 3-chloromethyl-3-Cephem Derivative crystallization by above-mentioned general formula (2) expression with manufacture method of the present invention obtains has excellent permanent stability under the condition of gentleness, for example,
According to following reaction formula (6),
Reaction formula (6)
Just can derive to can be used as various cynnematins is antibiotic 7-amino-3-chloromethyl-3-Cephem Derivative (compound (9)).
Embodiment
Explain the present invention according to embodiment below, but the present invention is not limited only to this.
Embodiment 1
With 68.6g (0.052mol) contain 47.7 weight % with following compound (10)
(compound (10)) De dioxane solution adds with in the dropping funnel of nitrogen replacement the chlorination azetidinone derivative of expression, adds 50g anhydrous methanol (Northeast chemistry reagent) dilution as A liquid.
The methanol solution (1 grade of reagent) that 13.5g (0.060mol) is contained 24 weight % sodium methylates is mixed with the methanol solution that contains 4 weight % sodium methylates, as B liquid with the dilution of 67.2g anhydrous methanol.
With in the flask, add the 13g diox in reaction, add the 160mL dehydrated alcohol, be cooled to-2～2 ℃.Have in the four-hole boiling flask of refrigerative reaction solvent in adding, 1/8 (the pH value is 4) of above-mentioned A liquid total amount joined in the above-mentioned reaction solvent for preparing.
Then, on one side with the temperature maintenance of reaction system between-2～2 ℃, drip above-mentioned A liquid and B liquid on one side simultaneously.After having dripped about 1/8 B liquid, reaction solution begins to occur white casse, becomes the slurries that contain white crystals.One side between-2～2 ℃, Yi Bian drip above-mentioned A liquid and B liquid simultaneously, approximately dropwised (the pH value is 7～8) with the temperature maintenance of reaction system through 4 hours then.Drip after the end, stir down at 0 ℃ again and reacted in 0.25 hour.
After reaction finishes, add 0.48g acetic acid in the reaction solution after reaction finishes and neutralize.PH value of reaction system after the neutralization is 4～5.After neutralizing treatment, stir down at-2～2 ℃ more like this and carried out slaking in 0.5 hour.
Then, after slaking finishes, filter with the 3G glass filter, with the filter cake that 18g obtains with ice-cooled methyl alcohol drip washing, the methanol solution with 36g moisture 30% carries out the drip washing second time again, carries out drip washing for the third time with 18g with ice-cooled methyl alcohol.
To put into moisture eliminator through the filter cake of carrying out washing treatment, at room temperature place a night, use the vacuum pump drying, obtain 3-chloromethyl-3-Cephem Derivative crystallization (general formula (2a)) (purity 94.1%, yield 85.1%) of 22.9g.
(authentication data)
1H-NMR(δ，CDCl
3)
3.41(1H，d，j＝18.5)，3.59(1H，d，j＝18.5)，4.92(1H，d，j＝4.9)，5.82(1H，d，d，j＝4.9，9.3)，6.12(1H，d，j＝9.3)，3.58(1H，d，j＝16.1)，3.67(1H，d，j＝16.1)，7.40～7.28(5H，m)，4.39(1H，d，j＝11.9)，4.50(1H，d，j＝11.9)，5.20(2H，s)，7.32(2H，d，j＝8.6)，6.88(2H，d，j＝8.6)，3.80(3H，s)
FT-IR(cm
-1，KBr)
3499cm
-1、3271cm
-1、1778cm
-1、1703cm
-1、1645cm
-1、1251cm
-1
FAB-MS
M+1：487m/z
Re-use the X-ray diffraction device RINT2400 that Co., Ltd. of science makes, utilize copper ray, X-ray diffraction analysis is carried out in the 3-chloromethyl-3-Cephem Derivative crystallization that is obtained by embodiment 1 by λ=1.5418 of monochromatic filter.Its X-ray diffraction pattern is as shown in table 1.
Table 1
| d | I/I 0 |
| 12.91 | 0.81 |
| 11.67 | 0.64 |
| 6.45 | 0.39 |
| 6.32 | 0.29 |
| 5.80 | 0.48 |
| 4.94 | 0.31 |
| 4.72 | 0.65 |
| 4.65 | 0.89 |
| 4.50 | 0.71 |
| 4.44 | 0.33 |
| 4.28 | 0.58 |
| 4.16 | 1.00 |
| d | I/I 0 |
| 4.04 | 0.13 |
| 3.97 | 0.15 |
| 3.85 | 0.71 |
| 3.77 | 0.50 |
| 3.70 | 0.11 |
| 3.45 | 0.46 |
| 3.37 | 0.20 |
| 3.20 | 0.13 |
| 3.16 | 0.18 |
| 3.09 | 0.12 |
| 2.90 | 0.13 |
D in (notes) table 1 is the lattice plane spacing; I/I
0It is relative intensity with respect to the d=4.17 diffraction peak
Embodiment 2
68.6g (0.052mol) is contained the chlorination azetidinone derivative of 47.7 weight %, and (compound (10)) De dioxane solution joins with in the dropping funnel of nitrogen replacement, adds 50g anhydrous methanol (Northeast chemistry reagent) and dilutes the liquid as A.
With 103g dissolve with methanol 4.46g (0.063mol) sodium ethylate, be mixed with the methanol solution that contains 4 weight % sodium ethylates, as B liquid.
With adding the 13g diox in the flask, add the 160mL dehydrated alcohol in reaction, be cooled to-2～2 ℃.In the four-hole boiling flask that has added the refrigerative reaction solvent, 1/8 of above-mentioned A liquid total amount is joined (the pH value is 4) in the above-mentioned reaction solvent for preparing.
Then, on one side with the temperature maintenance of reaction system between-2～2 ℃, drip above-mentioned A liquid and B liquid on one side simultaneously.After the B drop had added about 1/5, reaction solution began to occur white casse, became the slurries that contain white crystals.One side between-2～2 ℃, Yi Bian drip above-mentioned A liquid and B liquid simultaneously, approximately dropwised (the pH value is 7～8) with the temperature maintenance of reaction system through 4 hours then.Drip after the end, stir down at 0 ℃ again and reacted in 0.25 hour.
After reaction finishes, add 0.44g acetic acid in the reaction solution after reaction finishes and neutralize.In addition, the pH value with the afterreaction system in is 4～5.After neutralizing treatment, stir down at-2～2 ℃ same as before again and carried out slaking in 0.5 hour.
Then, after slaking finishes, filter with the 3G glass filter, with the filter cake that 18g obtains with ice-cooled methyl alcohol drip washing, the methanol solution with 36g moisture 30% carries out the drip washing second time again, carries out drip washing for the third time with 18g with ice-cooled methyl alcohol.
To put into moisture eliminator through the filter cake of carrying out washing treatment, at room temperature place a night, use the vacuum pump drying, obtain 3-chloromethyl-3-Cephem Derivative crystallization (general formula (2a)) (purity 94.3%, yield 81.2%) of 21.8g.
(authentication data)
1H-NMR(δ，CDCl
3)
3.41(1H，d，j＝18.5)，3.59(1H，d，j＝18.5)，4.92(1H，d，j＝4.9)，5.82(1H，d，d，j＝4.9，9.3)，6.12(1H，d，j＝9.3)，3.58(1H，d，j＝16.1)，3.67(1H，d，j＝16.1)，7.40～7.28(5H，m)，4.39(1H，d，j＝11.9)，4.50(1H，d，j＝11.9)，5.20(2H，s)，7.32(2H，d，j＝8.6)，6.88(2H，d，j＝8.6)，3.80(3H，s)
FT-IR(cm
-1，KBr)
3449cm
-1、3271cm
-1、1778cm
-1、1251cm
-1
FAB-MS
M+1：487m/z
Then, X-ray diffraction analysis is carried out in the 3-chloromethyl-3-Cephem Derivative crystallization that is obtained by embodiment 2, demonstrate X-ray diffraction pattern similarly to Example 1 by method similarly to Example 1.
Embodiment 3
69.75g (0.052mol) is contained the chlorination azetidinone derivative of 46.9 weight %, and (compound (10)) De dioxane solution joins with in the dropping funnel of nitrogen replacement, adds 50g anhydrous methanol (Northeast chemistry reagent) and dilutes the liquid as A.
With 103g anhydrous alcohol solution 4.46g (0.063mol) sodium ethylate, be mixed with the ethanolic soln that contains 4 weight % sodium ethylates, as B liquid.
In reaction flask, add the 13g diox, add the 160mL dehydrated alcohol, be cooled to-2～2 ℃.Having added the refrigerative reaction, 1/8 of above-mentioned A liquid total amount is joined (pH value 4) in the above-mentioned reaction solvent for preparing with in the four-hole boiling flask of solvent.
Then, on one side with the temperature maintenance of reaction system between-2～2 ℃, drip above-mentioned A liquid and B liquid on one side simultaneously.After the B drop had added about 1/4, reaction solution began to occur white casse, became the slurries that contain white crystals.Then on one side with the temperature maintenance of reaction system between-2～2 ℃, Yi Bian drip above-mentioned A liquid and B liquid simultaneously, dropwised in about 4 hours (the pH value is 7～8).Drip after the end, stir down at 0 ℃ again and reacted in 0.25 hour.
After reaction finishes, add 0.43g acetic acid in the reaction solution after reaction finishes and neutralize.In and the pH value of afterreaction system be 4～5.After neutralizing treatment, stir down at-2～2 ℃ more like this and carried out slaking in 0.5 hour.
Then, after slaking finishes, filter with the 3G glass filter, with the filter cake that 18g obtains with ice-cooled methyl alcohol drip washing, the methanol solution with 36g moisture 30% carries out the drip washing second time again, carries out drip washing for the third time with 18g with ice-cooled methyl alcohol.
To put into moisture eliminator through the filter cake of carrying out washing treatment, at room temperature place a night, use the vacuum pump drying, obtain 3-chloromethyl-3-Cephem Derivative crystallization (general formula (2a)) (purity 91.6%, yield 84.2%) of 23.28g.
(authentication data)
1H-NMR(δ，CDCl
3)
3.41(1H，d，j＝18.5)，3.59(1H，d，j＝18.5)，4.92(1H，d，j＝4.9)，5.82(1H，d，d，j＝4.9，9.3)，6.12(1H，d，j＝9.3)，3.58(1H，d，j＝16.1)，3.67(1H，d，j＝16.1)，7.40～7.28(5H，m)，4.39(1H，d，j＝11.9)，4.50(1H，d，j＝11.9)，5.20(2H，s)，7.32(2H，d，j＝8.6)，6.88(2H，d，j＝8.6)，3.80(3H，s)
FT-IR(cm
-1，KBr)
3449cm
-1、3271cm
-1、1778cm
-1、1251cm
-1
FAB-MS
M+1：487m/z
And, according to the method identical X-ray diffraction analysis is carried out in the 3-chloromethyl-3-Cephem Derivative crystallization that is obtained by embodiment 3 with embodiment 1, demonstrate X-ray diffraction pattern similarly to Example 1.
Embodiment 4
64.55g (0.052mol) is contained the chlorination azetidinone derivative of 50.6 weight %, and (compound (10)) De dioxane solution joins with in the dropping funnel of nitrogen replacement, adds 50g anhydrous methanol (Northeast chemistry reagent) and dilutes the liquid as A.
Dilute the methanol solution (reagent one-level) that 13.5g contains 24 weight % sodium methylates with the 67.2g anhydrous methanol, be mixed with the methanol solution that contains 4 weight % sodium methylates (0.060mol), as B liquid.
In reaction flask, add the 13g diox, add the 160mL dehydrated alcohol, be cooled to-2～2 ℃.Having added the refrigerative reaction, 1/8 of above-mentioned A liquid total amount is joined (pH value 4) in the above-mentioned reaction solvent for preparing with in the four-hole boiling flask of solvent.
Then, on one side with the temperature maintenance of reaction system between-2～2 ℃, drip above-mentioned A liquid and B liquid on one side simultaneously.After the B drop had added about 1/4, reaction solution began to occur white casse, became the slurries that contain white crystals.One side between-2～2 ℃, Yi Bian drip above-mentioned A liquid and B liquid simultaneously, approximately dropwised (the pH value is 7～8) with the temperature maintenance of reaction system through 2 hours then.Drip after the end, stir down at 0 ℃ again and reacted in 0.25 hour.
After reaction finishes, add 0.48g acetic acid in the reaction solution after reaction finishes and neutralize.In addition, the pH value with the afterreaction system in is 4～5.After neutralizing treatment, stir down at-2～2 ℃ more like this and carried out slaking in 0.5 hour.
Then, after slaking finishes, filter with the 3G glass filter, with the filter cake that 18g obtains with ice-cooled methyl alcohol drip washing, the methanol solution with 36g moisture 30% carries out the drip washing second time again, carries out drip washing for the third time with 18g with ice-cooled methyl alcohol.
To put into moisture eliminator through the filter cake of carrying out washing treatment, at room temperature place a night, use the vacuum pump drying, obtain 3-chloromethyl-3-Cephem Derivative crystallization (general formula (2a)) (purity 94.4%, yield 84.2%) of 22.58g.
(authentication data)
1H-NMR(δ，CDCl
3)
3.41(1H，d，j＝18.5)，3.59(1H，d，j＝18.5)，4.92(1H，d，j＝4.9)，5.82(1H，d，d，j＝4.9，9.3)，6.12(1H，d，j＝9.3)，3.58(1H，d，j＝16.1)，3.67(1H，d，j＝16.1)，7.40～7.28(5H，m)，4.39(1H，d，j＝11.9)，4.50(1H，d，j＝11.9)，5.20(2H，s)，7.32(2H，d，j＝8.6)，6.88(2H，d，j＝8.6)，3.80(3H，s)
FT-IR(cm
-1，KBr)
3449cm
-1、3271cm
-1、1778cm
-1、1251cm
-1
FAB-MS
M+1：487m/z
In addition, X-ray diffraction analysis is carried out in the 3-chloromethyl-3-Cephem Derivative crystallization that is obtained by embodiment 4, demonstrate X-ray diffraction pattern similarly to Example 1 according to method similarly to Example 1.
Embodiment 5
57.4g (0.052mol) is contained the chlorination azetidinone derivative of 57.6 weight %, and (compound (10)) De dioxane solution joins with in the dropping funnel of nitrogen replacement, adds 50g anhydrous methanol (Northeast chemistry reagent) dilution as A liquid.
Dilute the methanol solution (reagent one-level) that 13.5g contains 24 weight % sodium methylates with the 67.0g anhydrous methanol, be mixed with the methanol solution that contains 4 weight % sodium methylates (0.060mol), as B liquid.
Use adding 12.9g diox in the flask with the reaction of nitrogen replacement, add the 160mL dehydrated alcohol, be cooled to-2～2 ℃.Whole above-mentioned A liquid are joined (pH value 4) in the reaction solvent in the four-hole boiling flask of solvent having added refrigerative reaction.
Then, on one side with the temperature maintenance of reaction system between-2～2 ℃, on one side with about 2 hours dropping B liquid.After the B drop had added about 1/3, reaction solution began to occur white casse, became the slurries that contain white crystals.Drip when finishing, the pH value is 8.Drip after the end, stir down at 0 ℃ again and reacted in 0.25 hour.
After reaction finishes, add 0.40g acetic acid in the reaction solution after reaction finishes and neutralize.In and the pH value of afterreaction system be 4～5.After neutralizing treatment, stir down at-2～2 ℃ more like this and carried out slaking in 0.5 hour.
Then, after slaking finishes, filter with the 3G glass filter, with the filter cake that 18g obtains with ice-cooled methyl alcohol drip washing, the methanol solution with 36g moisture 30% carries out the drip washing second time again, carries out drip washing for the third time with 18g with ice-cooled methyl alcohol.
To put into moisture eliminator through the filter cake of carrying out washing treatment, at room temperature place a night, use the vacuum pump drying, obtain 3-chloromethyl-3-Cephem Derivative crystallization (general formula (2a)) (purity 92.0%, yield 74.5%) of 20.50g.
(authentication data)
1H-NMR(δ，CDCl
3)
3.41(1H，d，j＝18.5)，3.59(1H，d，j＝18.5)，4.92(1H，d，j＝4.9)，5.82(1H，d，d，j＝4.9，9.3)，6.12(1H，d，j＝9.3)，3.58(1H，d，j＝16.1)，3.67(1H，d，j＝16.1)，7.40～7.28(5H，m)，4.39(1H，d，j＝11.9)，4.50(1H，d，j＝11.9)，5.20(2H，s)，7.32(2H，d，j＝8.6)，6.88(2H，d，j＝8.6)，3.80(3H，s)
FT-IR(cm
-1，KBr)
3449cm
-1、3271cm
-1、1778cm
-1、1251cm
-1
FAB-MS
M+1：487m/z
Comparative example 1
65.8g (0.052mol) is contained the chlorination azetidinone derivative of 49.7 weight %, and (compound (10)) De dioxane solution joins with in the dropping funnel of nitrogen replacement, adds 50g anhydrous methanol (Northeast chemistry reagent) and dilutes the liquid as A.
Dilute the methanol solution (reagent one-level) that 17.0g contains 24 weight % sodium methylates with the 85.0g anhydrous methanol, be mixed with the methanol solution that contains 4 weight % sodium methylates (0.076mol), as B liquid.
With adding the 13g diox in the flask, add the 160mL dehydrated alcohol in reaction, be cooled to-2～2 ℃.In adding has the four-hole boiling flask of refrigerative reaction solvent, 1/8 of above-mentioned A liquid total amount is joined (pH value 4) in the above-mentioned reaction solvent for preparing.
Then, on one side with the temperature maintenance of reaction system between-2～2 ℃, drip A liquid and B liquid on one side simultaneously.After the B drop had added about 1/5, reaction solution began to occur white casse, became the slurries that contain white crystals.Drip A liquid and B liquid then simultaneously, continue to drip about 4 hours, add to the A drop finish (the pH value is 7～8).This moment, the dripping quantity of B liquid was 80.4g, and the pH value is 7～8.Needed again the B drop of remaining total amount 20g is added in 30 minutes.The reaction solution of this moment is to have red brown.PH value when finishing to drip is 10.Stir down at 0 ℃ again and reacted in 0.25 hour.
After reaction finishes, add 0.64g acetic acid in the reaction solution after reaction finishes and neutralize.In and the pH value of afterreaction system be 4～5.After neutralizing treatment, stir down at-2～2 ℃ more like this and carried out slaking in 0.5 hour.
Then, after slaking finishes, filter with the 3G glass filter, with the filter cake that 18g obtains with ice-cooled methyl alcohol drip washing, the methanol solution with 36g moisture 30% carries out the drip washing second time again, carries out drip washing for the third time with 18g with ice-cooled methyl alcohol.
To put into moisture eliminator through the filter cake of carrying out washing treatment, at room temperature place a night, use the vacuum pump drying, obtain 3-chloromethyl-3-Cephem Derivative crystallization (general formula (2a)) (purity 85.9%, yield 61.3%) of 18.07g.
Comparative example 2
Chlorination azetidinone derivative (compound (10)) with 71.48g (0.104mol) under nitrogen environment is dissolved in the 640mL dry DMF, is cooled to-30 ℃.Under-30～-20 ℃, drip 28%17.76g ammoniacal liquor (0.292mol is equivalent to 2.8 times of mol) then very slightly at every turn.Drip the back-30～-20 ℃ of following slakings 1 hour.
After reaction finishes, in reaction solution, add 5% hydrochloric acid, the pH value is adjusted to 4～5, and then add 1.92L acetic acid, separate organic layer down at 0 ℃.Use the isolated organic layer twice of saturated common salt water washing then, then, in organic layer, add anhydrous sodium sulphate and dewater.
Organic layer after under reduced pressure concentrated then this dehydration obtains 38.0g (purity 93.3%, yield 70.0%) buttery 3-chloromethyl-3-Cephem Derivative (general formula (2a)).
(authentication data)
1H-NMR(δ，CDCl
3)
3.41(1H，d，j＝18.5)，3.59(1H，d，j＝18.5)，4.92(1H，d，j＝4.9)，5.82(1H，d，d，j＝4.9，9.3)，6.12(1H，d，j＝9.3)，3.58(1H，d，j＝16.1)，3.67(1H，d，j＝16.1)，7.40～7.28(5H，m)，4.39(1H，d，j＝11.9)，4.50(1H，d，j＝11.9)，5.20(2H，s)，7.32(2H，d，j＝8.6)，6.88(2H，d，j＝8.6)，3.80(3H，s)
FT-IR(cm
-1，KBr)
3449cm
-1、3271cm
-1、1778cm
-1、1251cm
-1
FAB-MS
M+1：487m/z
Comparative example 3
3-chloromethyl-3-Cephem Derivative (general formula (2a)) that 10.0g is obtained by comparative example 2 is dissolved in the 28mL dry DMF.
At 3 ℃ of refrigerative methyl alcohol of preparing 400mL down,, separate out 3-chloromethyl-3-Cephem Derivative crystallization in addition in this refrigerative methyl alcohol, slowly dripping the above-mentioned DMF solution that is dissolved with oily 3-chloromethyl-3-Cephem Derivative under 3～5 ℃ the temperature.
After the solid-liquid separation, with 3-chloromethyl-3-Cephem Derivative crystallization that methyl alcohol drip washing is reclaimed, drying under reduced pressure obtains 8.62g (purity 94.0% then, yield 86.2%, the yield of being tried to achieve by comparative example 2 is 60.3%) 3-chloromethyl-3-Cephem Derivative crystallization.
(authentication data)
1H-NMR(δ，CDCl
3)
3.41(1H，d，j＝18.5)，3.59(1H，d，j＝18.5)，4.92(1H，d，j＝4.9)，5.82(1H，d，d，j＝4.9，9.3)，6.12(1H，d，j＝9.3)，3.58(1H，d，j＝16.1)，3.67(1H，d，j＝16.1)，7.40～7.28(5H，m)，4.39(1H，d，j＝11.9)，4.50(1H，d，j＝11.9)，5.20(2H，s)，7.32(2H，d，j＝8.6)，6.88(2H，d，j＝8.6)，3.80(3H，s)
FT-IR(cm
-1，KBr)
3449cm
-1、3271cm
-1、1778cm
-1、1251cm
-1
FAB-MS
M+1：487m/z
Then, according to the method identical with embodiment 1 X-ray diffraction analysis is carried out in the 3-chloromethyl-3-Cephem Derivative crystallization that is obtained by comparative example 3, its X-ray diffraction pattern is shown in Table 2.
Table 2
| d | I/I 0 |
| 12.95 | 0.61 |
| 11.68 | 0.51 |
| 9.91 | 0.10 |
| 6.47 | 0.63 |
| 6.33 | 0.24 |
| 5.81 | 0.62 |
| 4.96 | 0.47 |
| 4.73 | 0.70 |
| 4.66 | 0.72 |
| 4.51 | 0.67 |
| 4.44 | 0.31 |
| 4.29 | 0.56 |
| 4.17 | 1.00 |
| 4.05 | 0.25 |
| 3.98 | 0.17 |
| 3.86 | 0.74 |
| 3.78 | 0.47 |
| d | I/I 0 |
| 3.70 | 0.14 |
| 3.56 | 0.07 |
| 3.54 | 0.06 |
| 3.45 | 0.54 |
| 3.37 | 0.20 |
| 3.29 | 0.14 |
| 3.22 | 0.20 |
| 3.20 | 0.15 |
| 3.16 | 0.20 |
| 3.09 | 0.18 |
| 2.90 | 0.22 |
| 2.85 | 0.10 |
| 2.68 | 0.14 |
| 2.60 | 0.16 |
| 2.58 | 0.11 |
| 2.50 | 0.10 |
| 2.49 | 0.13 |
D in (notes) table 2 is the lattice plane spacing; I/I
0It is relative intensity with respect to the d=4.17 diffraction peak.
Comparative example 4
Chlorination azetidinone derivative (compound (10)) with 35.74g (0.052mol) under nitrogen environment dilutes in 135g methyl alcohol, and is cooled to-5 ℃.Under-5～-2 ℃, with 30 minutes, the solution that at every turn slightly 35.0g (0.078mol, 1.5 times of mol) is contained 20% aqueous ethanol of 12.5% Ke Xingjia dripped then.Drip the back-2～0 ℃ of following slaking 1 hour.PH value after the slaking is 9.After slaking is finished, add acetic acid the pH value is adjusted to 4～5, stir down at-2～2 ℃ then like this and carried out slaking in 0.5 hour.After slaking is finished, filter with the 3G glass funnel then, with the filter cake that 18g obtains with ice-cooled methyl alcohol drip washing, the methyl alcohol with 36g moisture 30% carries out the drip washing second time again, carries out drip washing for the third time with ice-cooled methyl alcohol.To put into moisture eliminator through the filter cake of carrying out washing treatment, at room temperature place a night, use the vacuum pump drying, obtain filemot 3-chloromethyl-3-Cephem Derivative (general formula (2a)) crystallization of 15.15g (purity 51.3%, yield 30.7%).
＜stability test 〉
To put into airtight beaker by each 5g of 3-chloromethyl-3 Cephem Derivative that embodiment 1～5 and comparative example 1～4 obtain, and be set in temperature 25 ℃ the thermostatic chamber and placed 30 days.
Again each 3-chloromethyl-3-Cephem Derivative was carried out purity testing later in 30 days placing, its result is as shown in the table 3.
Table 3
| Purity (%) before placing | Purity after the placement (%) | |
| Embodiment 1 | 94.1 | 94.1 |
| Embodiment 2 | 94.3 | 94.3 |
| Embodiment 3 | 91.6 | 91.6 |
| Embodiment 4 | 94.4 | 94.4 |
| Embodiment 5 | 92.0 | 92.0 |
| Comparative example 1 | 85.9 | 85.9 |
| Comparative example 2 | 93.3 | 89.9 |
| Comparative example 3 | 94.0 | 94.0 |
| Comparative example 4 | 51.3 | 46.5 |
The effect of invention
Can be found out by the above results, according to manufacture method of the present invention, can be by in industrial favourable method, produce the 3-chloromethyl of the synthetic intermediate of the various antibiotic that can be used as cynnematin system-3-Cephem Derivative crystallization with high receipts rate and high-purity incessantly. And the 3-chloromethyl that is obtained by manufacture method of the present invention-3-Cephem Derivative crystallization has excellent long-time stability under the condition of gentleness.
Claims (14)
1. the 3-chloromethyl shown in the general formula (2)-3-Cephem Derivative crystalline manufacture method is characterized in that, in containing alcoholic solvent, the pH value is under the condition below 8, chlorination azetidinone derivative and the alkoxide shown in the general formula (1) to be reacted:
In the formula, R
1Expression replaces or unsubstituted aryl or replacement or unsubstituted heterocycle residue, R
2And R
3Expression replaces or unsubstituted aromatic hydrocarbyl;
In the formula, R
2And R
3Expression replaces or unsubstituted aromatic hydrocarbyl.
2. 3-chloromethyl as claimed in claim 1-3-Cephem Derivative crystalline manufacture method is characterized in that, in containing the solvent of pure and mild ether, the pH value is under the condition below 8, chlorination azetidinone derivative and the alkoxide shown in the general formula (1) to be reacted:
In the formula, R
1Expression replaces or unsubstituted aryl or replacement or unsubstituted heterocycle residue, R
2And R
3Expression replaces or unsubstituted aromatic hydrocarbyl;
In the formula, R
2And R
3Expression replaces or unsubstituted aromatic hydrocarbyl.
3. 3-chloromethyl as claimed in claim 2-3-Cephem Derivative crystalline manufacture method, it is characterized in that, contain the described chlorination azetidinone derivative solution (A) in the ether solvents with being dissolved in and be dissolved in the alkoxide solution (B) that contains in the alcoholic solvent and join in the alcoholic solution (C) and react.
4. 3-chloromethyl as claimed in claim 3-3-Cephem Derivative crystalline manufacture method, it is characterized in that, in described alcoholic solution (C), add as a part that is dissolved in the chlorination azetidinone derivative solution (A) that contains in the ether solvents, contain the equivalent that responds be 5～30mol% chlorination azetidinone derivative solution (A) afterwards, with remaining solution (A) that contains chlorination azetidinone derivative be dissolved in the alkoxide solution (B) that contains in the alcoholic solvent and join simultaneously in the described alcoholic solution (C) and react.
5. as each described 3-chloromethyl-3-Cephem Derivative crystalline manufacture method in the claim 1～4, it is characterized in that, described chlorination azetidinone derivative and alkoxide react the ratio of 0.8～1.5mol alkoxide with 1mol chlorination azetidinone derivative.
6. as each described 3-chloromethyl-3-Cephem Derivative crystalline manufacture method in the claim 1～4, it is characterized in that described alcohol is selected from least a in methyl alcohol or the ethanol.
7. as claim 2 or 3 described 3-chloromethyls-3-Cephem Derivative crystalline manufacture method, it is characterized in that described ether is diox.
8. as each described 3-chloromethyl-3-Cephem Derivative crystalline manufacture method in the claim 1～4, it is characterized in that described alkoxide is sodium methylate or sodium ethylate.
9. as each described 3-chloromethyl-3-Cephem Derivative crystalline manufacture method in the claim 1～4, it is characterized in that described being reflected at below 5 ℃ carried out.
10. want 3 or 4 described 3-chloromethyls-3-Cephem Derivative crystalline manufacture method as right, it is characterized in that, described solution (A) is that the chlorination azetidinone is dissolved in the solution that forms in the mixed solvent of diox and alcohol.
11., it is characterized in that described solution (B) is that alkoxide is dissolved in the solution that forms in the alcohol as claim 3 or 4 described 3-chloromethyls-3-Cephem Derivative crystalline manufacture method.
12., it is characterized in that described solution (C) is the mixed solvent of pure and mild diox as claim 3 or 4 described 3-chloromethyls-3-Cephem Derivative crystalline manufacture method.
13. as claim 3 or 4 described 3-chloromethyls-3-Cephem Derivative crystalline manufacture method, it is characterized in that, by dripping described solution (A) and solution (B) reacts.
14., it is characterized in that described being reflected under the anhydrous state carried out as claim 3 or 4 described 3-chloromethyls-3-Cephem Derivative crystalline manufacture method.
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|---|---|---|---|
| JP2002119038 | 2002-04-22 | ||
| JP2002119038 | 2002-04-22 | ||
| JP2003046421 | 2003-02-24 | ||
| JP2003046421 | 2003-02-24 |
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| CN107033162B (en) * | 2016-02-03 | 2020-05-01 | 湖北凌晟药业有限公司 | Preparation of 7-phenylacetamide-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester |
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Assignee: CSPC CENWAY (TIANJIN) PHARMACEUTICALS CO.,LTD. Assignor: NIPPON CHEMICAL INDUSTRIAL Co.,Ltd. Contract record no.: 2011120000169 Denomination of invention: Method for producing crystal of 3-chloromethyl-3-cephem derivative Granted publication date: 20061101 License type: Exclusive License Open date: 20041027 Record date: 20110825 |
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