JPS6150953B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to an improved method for acylating amino-β-lactam carboxylic acids. More specifically, the present invention provides a method of protecting at least the carboxyl group of the compound by treating it with a silylating agent in an inert organic solvent prior to acylating 7-aminocephalosporanic acid or its 3-substituted product. , relates to methods of using certain secondary amines. 7-Aminocephalosporanic acid or 3
A method has been proposed in which the substituted product is reacted with a silylating agent in the presence or absence of a tertiary amine such as triethylamine to protect and acylate the carboxyl group and/or amino group of the raw material. . However, these methods require the use of a considerable excess of silylating agent, and have the drawback of requiring heat and time to form a solution. Therefore, for example, in 7-aminocephalosporanic acid or its 3-substituted derivatives, some double bond movement (△ ³ → △ ² ) is observed, which may reduce the antibacterial potency, purity, and yield of the target product. It happened. Under these circumstances, the inventors of the present invention investigated conditions for dissolving various amino-β-lactam carboxylic acids in inert organic solvents, and found that the pKb is 3.20 or less and the total number of carbon atoms is 4. It has been found that very good results are obtained using secondary amines having .about.16 and at least one branched carbon chain. The present invention, which was made based on this knowledge, has various advantages over known methods as described below, and is considered to be industrially superior as a method for producing cephalosporins. That is, (i) the secondary amine according to the present invention can solubilize amino-β-lactam carboxylic acids in organic solvents by using only a small excess amount. (ii) In particular, when secondary amines are used as raw materials for cephalosporins, because the amount used is small and a solution can be obtained in a short time even at a low temperature of about 0°C, double bonds are removed during dissolution. It is hardly accompanied by movement or epimerization. (iii) Since only a slight excess of the secondary amine is used, there is no adverse effect of the excess amine on the β-lactam ring, and there is no need to remove the excess amine except in special cases, so the removal step can be omitted and It is economical because there is no adverse effect on the purity or yield of the target product that may occur during the removal process. (iv) As the secondary amine, a sterically hindered and bulky one is used, so even if an excessive amount is present during the acylation reaction, it is difficult to react with the acylating agent such as an acid halide, and the acylating agent is Waste is avoided. (v) In this invention, amino-β-
Protection of the carboxy groups (and amino groups) of lactam carboxylic acids can be easily performed at low temperatures. Furthermore, the amount of silylating agent used can be reduced, and the desired cephalosporin can be obtained with high purity and high yield. Thus, the present invention is based on the general formula () [Wherein, Y is a hydrogen atom or an alkoxy group such as a methoxy group; Q is a hydrogen atom, a halogen atom,
Methyl group, methoxymethyl group, azidomethyl group,
It represents a lower acyloxymethyl group, a carpamoyloxymethyl group, or a heterocyclic thiomethyl group with or without a substituent. ] When reacting the amino-β-lactam carboxylic acid represented by with a silylating agent in an inert organic solvent and treating the resulting product with an acylating agent to obtain an acylamide compound, the compound of general formula () is A method for producing an acylamide compound, characterized in that a secondary amine having a pKb of 3.20 or less, a total carbon number of 4 to 16, and at least one branched carbon chain is used for dissolution in an active organic solvent. . In the above general formula (), representative examples of the heterocycle in the heterocycle thiomethyl group in the symbol Q are:
The following can be mentioned: That is, 1,3,4-thiadiazol-2-yl group, 5-methyl-1,3,4-thiadiazol-2-yl group, 1,2,3-triazol-4-
yl group, 1,2,4-triazol-3-yl group, 3-methyl-1,2,3-triazol-4
-yl group, 5-methyl-1,2,4-triazol-3-yl group, 4-methyl-1,2,4-triazol-3-yl group, 4,5-dimethyl-1.
2,4-triazol-3-yl group, 1-methyl-1H-1,2,3,4-tetrazol-5-yl group, 1,3,4-oxadiazol-2-yl group, 5-methyl -1,3,4-oxadiazol-2-yl group, 5-methyl-1,2-oxazol-4-yl group, 5-methyl-1,2-thiazol-4-yl group, and the like. In addition to the amino-β-lactam carboxylic acid derivatives () as explained above, it should be understood that all of the amines of the present invention described below that are soluble in organic solvents are included as raw materials of the present invention. It is. The silylating agent in this invention may be any of those currently known to be usable in the field and those that will be found to be used for similar purposes in the future. Tri-substituted halogenosilanes such as trialkylhalogenosilanes, trialkoxyhalogenosilanes, trialkylhalogenosilanes, dialkyl(alkoxy)halogenosilanes, dialkoxy(alkyl)silanes; disilazane such as hexaalkyldisilazane, hexaaryldisilazane di-substituted dihalogenosilanes such as dialkyldihalogenosilanes, alkylalkoxydisyhalogenosilanes, dialkoxydihalogenosilanes, and alkylenedioxydihalogenosilanes. Specific names of more preferred compounds among these include trimethylchlorosilane, dimethyl(methoxy)chlorosilane, methyldimethoxychlorosilane, trimethoxychlorosilane, and dimethyldichlorosilane, methylmethoxydichlorosilane, dimethoxydichlorosilane. , dichloropropylenedioxysilane, etc. The raw acid to be the acylating agent that can be used in this invention can be represented by the following general formula (). R-COOH () where R is an organic residue. One class of specific raw acid acids is represented by the following general formula (). In the formula, R ¹ is an optionally substituted alkyl group,
Aryl group, aralkyl group, aryloxy group,
Cycloalkenyl group, cycloalkyl group, heterocyclic residue, heterocyclic thio group, cyano group, or halogenoalkylthio group; R ² is a hydrogen atom, a carboxy group, or a group convertible thereto (e.g., an esterified carboxy group, a salt) carboxy group),
a sulfo group or a group convertible thereto (for example, an esterified sulfo group), an acyloxy group,
Aryl group, aryloxy group, formyloxy group, substituted or unsubstituted carbamoyloxy group, hydroxy group, alkoxy group, alkylthio group, arylcarbonyl group, heterocyclic carbonyl group, amino group, protected with an easily removable protecting group. means an amino group, an acylamino group, a formylamino group, a mono(or di)alkylamino group, a mono(or di)arylamino group, an azido group, or a halogen atom. A more interesting starting acid included in the general formula () is represented by the following general formula (). R3 ^- _CH2 -COOH () In the formula, ^R3 means a halogen atom, a trihalogenomethylthio group, a heterocyclic residue, a heterocyclic thio group, or a cyano group. Another interesting starting acid included in the general formula () is represented by the following general formula (). In the formula, R ⁴ is a phenyl group, a hydroxy-substituted phenyl group, a hydroxy-alkoxy-substituted phenyl group,
It represents a hydroxy-alkyl-substituted phenyl group, a hydroxy-halogen-substituted phenyl group, a phenyl group substituted with a carboxy group or a group convertible thereto, a heterocyclic residue, or a cycloalkenyl group, and R ⁵ is a protecting group that can be easily removed. means an amino group protected by In the general formula (), the hydroxy group, carboxy group, or a group convertible thereto as a substituent on the phenyl group is at the 3-position or 4-position.
Preferably, it is present in the position. Furthermore, other classes of specific raw acid acids are represented by the following general formula (). R ⁶ —CO—COOH () In the formula, R ⁶ means an optionally substituted aryl group or a heterocyclic residue. Other classes of specific raw acid acids are represented by the following general formula (). R ⁷ —COOH () In the formula, R ⁷ means a 3-(halogen-substituted or unsubstituted phenyl)-5-methylisoxazol-4-yl group. The heterocycle of the heterocycle residue or heterocycle thio group in general formulas () to () refers to 2-thienyl, 3
Preferred examples include -thienyl, tetrazol-1-yl, pyridin-4-yl, and furyl. Specific examples of raw acids for such acylating agents include phenylacetic acid, α-phenooxyacetic acid, α-phenooxypropionic acid, α-phenooxybutyric acid, diphenooxyacetic acid, diphenylacetic acid, naphthyl acetic acid, naphthoxyacetic acid, α -aminophenyl acetic acid, α-chlorophenylacetic acid, α-
Bromophenyl acetic acid, α-azidophenyl acetic acid,
Mandelic acid, α-acyloxyphenylacetic acid, α
-Methylthiophenyl acetic acid, α-ethoxycarbonyl phenylacetic acid, α-aryloxycarbonyl phenylacetic acid, thienyl acetic acid, furyl acetic acid,
(1,2,4-triazol-3-yl)acetic acid,
(1H-1.2.3.4-tetrazol-1-yl)acetic acid, α-oxofrylacetic acid, α-oxothienyl acetic acid, α-hydroxythienyl acetic acid, α
-Formyloxythienyl acetic acid, α-formyloxyphenylacetic acid, α-oxycarbonylphenyl acetic acid, α-sulfophenyl acetic acid, α-amino-
(2,5-cyclohexadien-2-yl)acetic acid, α-chloromethoxycarbonylamino-p-
Hydroxyphenylacetic acid, α-N-(4-oxo-4H-pyran-3-yl-carbonylamino)-
p-hydroxyphenylacetic acid, α-N-(4-oxo-4H-thiopyran-3-yl-carbonylamino)-p-hydroxyphenylacetic acid, α-N
-(4-oxo-4H-thiopyran-3-yl-carbonylamino)-phenylacetic acid, α-N-(4-
hydroxynicotinoylamino)-p-hydroxyphenylacetic acid, α-N-(4-hydroxynicotinoylamino)phenylacetic acid, α-(formylamino)-p-hydroxyphenylacetic acid, α-formylaminophenylacetic acid, Examples include α-formylamino-(2,5-cyclohexadien-2-yl)acetic acid. These raw acids are usually mixed acid anhydrides, acid halides, acid activated esters, acid azides, acid cyanides,
It is used as an acylating agent in the form of reactive derivatives such as acid-activated amides. Preferred acylating agents include acid chlorides and mixed acid anhydrides. Furthermore, examples of mixed acid anhydrides include mixed acid anhydrides with substituted acetic acids, alkyl carbonates, aryl carbonates, and aralkyl carbonates. Examples of the active ester include cyanomethyl ester, substituted phenyl ester, substituted benzyl ester, and substituted thienyl ester. In addition, examples of the acid-active amide include N-acylsactucalin,
Examples include N-acylimidazole, N-acylbenzoylamide, N·N-dicyclohexyl-N-acylurea, and N-acylsulfonamide. A suitable example of a protecting group for an amino group protected with an easily removable protecting group is 1-N.
N-dimethylcarbamoylpropen-2-yl,
1-morpholinocarbonylpropen-2-yl,
1-methoxycarbonylpropen-2-yl, 1
-ethoxycarbamoylpropen-2-yl, 1
-acetyl-propen-2-yl, 2.2.2-
Examples include trichloroethoxycarbonyl, t-butoxycarbonyl, chloroacetyl, bromoacetyl, formyl, and the like. Next, the secondary aminone used in this invention, which has a pKb of 3.20 or less, has a total carbon number of 4 to 16, and has at least one branched carbon, is an important substance that should form the basis of this invention. The term "branched carbon chain" as used herein means a branched carbon chain in, for example, an isopropyl group or a cyclohexyl group. The amine may be a symmetrical amine or a hybrid amine. Specific examples include diisopropylamine,
Di-sec-butylamine, di-t-butylamine, di-(1-methylbutyl)amine, di-t-
Amylamine, diisoamylamine, dineopentylamine, dioctylamine, dicyclohexylamine, methyl-isopropylamine, methyl-isoamylamine, ethyl-isobutylamine, ethyl-isoamylamine, propyl-isobutylamine, propyl-isoamylamine, butyl-isobutyl Examples include amines. Among these, particularly preferred are dicyclohexylamine, diisopropylamine, di-sec-butylamine or dioctylamine. The above amount of amine used is amino-β-
For 1 mole of lactam carboxylic acids (),
Preferably it is from 1.05 to 3 mol, especially from 1.1 to 2.0 mol. The amount used allows the compound () to be dissolved in an inert organic solvent as described below, and the solution is sufficient to achieve the purpose of forming a mixed acid anhydride with the silylating agent and the subsequent acylation reaction. Can be used. Although there is a slight excess of amine here,
This will serve as an acid acceptor for the acylating agent. Inert organic solvents include methylene chloride, ethylene chloride, propylene chloride, trimethylene chloride,
Chloroform, tetrachloroethane, trichlorethylene, tetrachlorethylene, dioxane,
Examples include tetrahydrofuran, ethylene glycol dimethyl ether, ethyl acetate, acetonitrile, and chlorobenzene. These organic solvents include, for example, methylene chloride and tetrahydrofuran,
A mixed system such as a combination of chloroform and dioxane may also be used. Further, these organic solvents are used in an anhydrous state. Furthermore, the amount of organic solvent used varies depending on the type of amino-β-lactam carboxylic acid () and the type of the amine according to the present invention, but is usually 10 to 50 times the volume of () to achieve the purpose of the present invention. can be reached. In the reaction of the present invention, amino-β-lactam carboxylic acids () are preferably ground into fine powder and dried, and the above-mentioned organic solvent and a predetermined amount of amine are added thereto and stirred in the cold to form a solution. and this solution is directly reacted with a silylating agent. However, for amino-β-lactam carboxylic acids (), this solution may be used by removing the solvent under reduced pressure to form a salt between the compound () and the amine, and redissolving it in the desired organic solvent. . Solubilization at room temperature,
Preferably it is carried out at a temperature of 0 to 20°C, more preferably 0 to 10°C, and the reaction time is 10 to 30 minutes. The solution of the salt of compound () thus obtained is reacted with a silica gelling agent at room temperature or under ice cooling, preferably at a temperature of -20 to 30°C. This reaction is preferably carried out in a stream of dry nitrogen. The amount of silylating agent used varies somewhat depending on the type of acylating agent. When the acylating agent is an acid halide, the amount of tri-substituted halogenosilanes is 1.2 to 1 mole of the raw material compound ().
~3.0 moles, preferably 1.3 to 1.8 moles, with the disubstituted dihalogenosilanes in half the molar ratio. In the case of acid anhydrides, tri-substituted halogenosilanes are used.
The amount is 1.8 to 3.0 mol, preferably 2.0 to 2.5 mol, and the disubstituted dihalogenosilanes is half the amount. On the other hand, acylating agents are often prepared by converting a raw material carboxylic acid into a reactive derivative as described above immediately before use. In this case, it is convenient to prepare the acylating agent using the above-mentioned organic solvent and use it as it is in the acylation reaction. The acylation reaction of this invention is -
1-6 at a temperature of 40-40℃, preferably -30-30℃
Time is done. This acylation reaction is preferably carried out with the addition of an acid binder. Examples include pyridine and its homologs, N.N-dimethylaniline and its homologues, quinoline and its homologues, and the like. The above reaction must be carried out under anhydrous conditions. Next, water or alcohols such as methyl alcohol, ethyl alcohol, propyl alcohol, butanol, etc. are added to this at room temperature or under cooling to decompose the silyl group, thereby obtaining the desired target product in high yield. can. If this product has, for example, a protected amino group, the protecting group can be removed by a method known per se to lead to a compound having a free amino group. In addition, for example, compounds in which the substituent on the phenyl group of the raw material carboxylic acid is an easily decomposable esterified carboxy group, compounds in which the substituent at the 2-position of the carboxylic acid are an easily decomposable acyloxy group, etc. The ester and acyl moieties can be removed by methods known in the art. Depending on the type of cephalosporin, after the reaction of the present invention, it can be subjected to, for example, a substitution reaction at the 3-position to form a useful compound. Furthermore, the target product obtained by this invention can be converted into a corresponding salt, particularly a pharmaceutically acceptable salt, by a conventional method. The method of the present invention as explained above has advantages such as the target product can be obtained in high yield, the reagents used are relatively inexpensive, and post-reaction post-treatment is simple, and it is suitable for industrial use. This is considered to be an extremely valuable method. Representative cephalosporins obtainable according to the method of this invention include, for example, cephalothin, cefazoline, cefatridine, cefacetril, cefapirin, cefamandole, O-
Examples include formyl-cefamandole, cefuroxime, cefrazine, cephalexin, cefoxitin, and cefanone. Next, the method of the present invention will be explained using reference examples and examples. Reference example Dry fine powder of 7-aminocephalosporanic acid (7-ACA), 7-aminodeacetoxycephalosporanic acid (7-ACA) and 7-amino-
3-(5-methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-3-cephem-4-
One millimol of each carboxylic acid (7-AMTCA) was suspended in 5 ml of freshly purified methylene chloride, stirred with a typical base using a magnetic stirrer, and the time required for dissolution was measured. The results are shown in Table 1. However, 7-ACA, 7-ADCA and 7-AMTCA were carried out at 0°C. Note that triethylamine was used as a base for comparison.

【table】

[Table] Example 1 1.09 g (4 mmol) of dried fine powder of 7-aminocephalosporanic acid (purity 98%) was suspended in 30 ml of methylene chloride, and diisopropylamine was added under ice cooling.
0.65 g (6.4 mmol) was added and stirred to form a solution. To this, 0.58 g (4.8 mmol) of dimethylaniline was added, and then 0.69 g of trimethylchlorosilane was added.
A solution of 5 ml of methylene chloride containing g (6.4 mmol) was added dropwise thereto and stirred for about 1 hour under ice cooling to obtain a substantially homogeneous solution. Add to this 0.71g of 2-thienylacetyl chloride.
A solution of 10 ml of methylene chloride containing (4.4 mmol) was added dropwise at 0°C for 30 minutes, then the temperature was gradually raised to 20°C.
Stirred at ~30°C for about 3 hours. The progress of the reaction was monitored by thin layer chromatography (butanol:acetic acid:water=4:1:1, azide iodide solution sprayed and then heated). After the reaction, most of the solvent was distilled off under reduced pressure, 20ml of ethyl acetate was added, and the pH was adjusted to 2.0 with 2N hydrochloric acid.
Adjusted to. The organic layer was separated, and the aqueous layer was extracted several times with ethyl acetate. The organic layers were combined, washed several times with small amounts of brine, and dried. This solution was concentrated under reduced pressure to about 1/5 volume. Add sodium acetate to the residual liquid.
A concentrated aqueous solution containing 0.33 g (4 mmol) was added and stirred to precipitate white crystals. The crystals were collected and recrystallized from aqueous acetone in a conventional manner to obtain 1.61 g (96% )
I got it. This free acid had a mp of 156°C (decomposed), and its infrared and ultraviolet absorption spectra were consistent with the standard. Almost the same results were obtained when anhydrous chloroform was used in place of methylene chloride in the above reaction. Example 2 Trimethylchlorosilane 0.69 in Example 1
(6.4 mmol), the following reagents were used and the reaction and treatment were carried out according to Example 1. The yield of sodium salt of cephalothin is shown in the table below.

[Table] Example 3 In place of 6.4 mmol (0.65 g) of diisopropylamine in Example 1, the same mmol of dicyclohexylamine (1.16 g) and diisooctylamine (1.54 g) were used, and the reaction was carried out according to Example 1. I processed it. The yields of sodium salt of cephalothin were 94% and 85%, respectively. Example 4 7-Amino-3-(5-methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-3-cephem-4-carboxylic acid 1.38 in dry fine powder
g was suspended in 30 ml of methylene chloride, 0.61 g of diisopropylamine was added, and the mixture was stirred under ice cooling. 0.58 g of N·N-dimethylaniline and 0.69 g of trimethylchlorosilane were added to the obtained solution, and the mixture was heated at 0°C for 20 minutes.
Then, the mixture was stirred at room temperature for about 30 minutes to obtain a substantially uniform solution. This solution was cooled on ice, and 0.64 g of (1H-1.2.3.4-tetrazol-1-yl)acetyl chloride was added.
Add a solution of 5 ml of methylene chloride containing
The mixture was stirred at room temperature for about 2 hours. The progress of the reaction was monitored by thin layer chromatography in the same manner as in Example 1. The reaction-completed solution was ice-cooled, most of the solvent was distilled off under reduced pressure, 30 ml of ethyl acetate was added, and the pH was adjusted to 2.0 with 2N hydrochloric acid while stirring under ice-cooling. The organic layer was separated, and the aqueous layer was extracted several times with ethyl acetate.
The organic layers were combined, washed with a small amount of brine, and dried. Distill the solvent under reduced pressure to reduce the solution volume to about 1/2.
To this was added a concentrated aqueous solution containing 0.33 g of sodium acetate, and upon stirring, crystals precipitated. The precipitated crystals were recrystallized from aqueous acetone to obtain 7-
[(1H-1.2.3.4-tetrazol-1-yl)-acetamide]-3-(5-methyl-1.3.
4-thiadiazol-2-yl-thiomethyl)-
3-Cefem-4-carboxylic acid (cefazoline)
1.81 g (95%) of the sodium salt was obtained. This free acid had a temperature of 178°C (decomposed), and its infrared and ultraviolet absorption spectra and thin layer chromatogram were consistent with the standard. Example 5 0.86 g of dried fine powder of 7-amino deacetoxycephalosporanic acid (purity 99%) was suspended in 20 ml of methylene chloride, and diisopropylamine was added under ice cooling.
1.00 g was added, stirred to dissolve, and the solvent was distilled off under reduced pressure. The residue was redissolved in methylene chloride under ice cooling, and 0.20 g of diisopropylamine and 0.58 g of N.N-dimethylaniline were added. A solution of 5 ml of methylene chloride containing 0.74 g of trimethylchlorosilane was added dropwise to the mixture, and the mixture was stirred for 20 minutes under ice cooling and then for 30 minutes at room temperature to obtain a substantially uniform solution. A solution of 5 ml of methylene chloride containing 0.71 g of phenylacetyl chloride was added dropwise to this solution while stirring under ice cooling. The reaction was carried out under ice cooling for 30 minutes, then gradually heated and stirred at room temperature for about 2 hours. The reaction progress was followed by thin layer chromatography. To the reaction completed solution, 10 ml of ice water and 20 ml of ethyl acetate were added, the pH was adjusted to 2.0 with 6N hydrochloric acid, and the organic layer was separated. The aqueous layer was extracted several times with methylene chloride. The organic layers were combined, washed with brine, dried, and the solvent was distilled off under reduced pressure to obtain a solid. This product was dissolved in 5 ml of ethyl acetate, and a concentrated aqueous solution containing 0.33 g of sodium acetate was added and stirred to precipitate white crystals. This was recrystallized from aqueous acetone and 7-phenylacetamide-3-methyl-3-
Sodium salt of cefem-4-carboxylic acid 1.26g
(95%). This thing's free acid is mp191-193℃ (decomposition)
The thin layer chromatogram and infrared and ultraviolet absorption spectra were consistent with the standard. When 0.46 g of dimethyldichlorosilane was used in place of 0.74 g of trimethylchlorosilane in the above reaction, the yield was 93%. Example 6 7-Aminodeacetoxycephalosporanic acid
Diisopropylamine salt derived from 0.86 g was dissolved in 30 ml of methylene chloride under ice cooling, and 0.97 g of N.N-dimethylaniline and 0.70 g of trimethylsilyl chloride were dissolved.
g was added thereto, and a solution was prepared in a conventional manner. Add to this newly purified finely powdered D-α-amino-phenylacetyl chloride hydrochloride (98% purity).
0.91 g was added at once and reacted at 0°C for 20 minutes, then gradually raised the temperature to 20-30°C for about 2 hours. The reaction was followed by thin layer chromatography. After the reaction is complete, cool on ice and add 20 methanol under stirring.
ml was added, and the pH was adjusted to 2.3 with 6N hydrochloric acid. The solvent was concentrated to about 1/3 volume under mild vacuum. Insoluble matter was removed, the pH was adjusted to 5.0 with triethylamine, and the mixture was placed in an ice chamber overnight. The precipitated solid was collected, washed with methanol and then acetone, and dried to obtain 1.36 g (93%) of crude crystals of cephalexin monohydrate. This product was dissolved in methanol using hydrochloric acid, purified by precipitation with triethylamine, and 1.23 g (84
%) was obtained. The thin layer chromatogram and infrared and ultraviolet absorption spectra of this product were consistent with the standard. All the mother liquors were collected, 20 ml of water was added, most of the organic solvent was distilled off under reduced pressure, the pH was adjusted to 4.0 with 6N hydrochloric acid, a small amount of acetone and 0.15 g of quinoline were added, and the mixture was stirred under ice cooling. The precipitated crystals were collected, washed with aqueous acetone and then acetone, and dried to give 0.23 g (1:1) of quinoline adduct of cephalexin (1:1).
%) was obtained. The total yield was 96%. Example 7 D-α-amino-
1,4-Cyclohexadienyl acetyl chloride hydrochloride was reacted and treated according to Example 6 to give 7-(D-α-amino-1,4-cyclohexadienyl acetamide)-3-methyl. -3-Cefem-4-carboxylic acid (cefrazine) yield 81
%, quinoline adduct 14%, total yield 95%. The thin layer chromatogram, infrared and ultraviolet absorption spectra of this product matched those of the standard product. Example 8 7-Aminodeacetoxycephalosporanic acid
0.86g with 0.93g of diisopropylamine and N・N-
30 ml of methylene chloride with 0.24 g of dimethylaniline
and stirred under ice cooling to form a solution. A solution of 1.00 g of trimethylchlorosilane dissolved in 5 ml of methylene chloride was added dropwise to this while stirring.
Stirring was performed at 0°C for 10 minutes and then at 20-30°C for about 30 minutes to obtain a nearly homogeneous solution. Meanwhile, dried fine powder D-N-(N'-morpholino-carbonyl-propen-2-yl)-α-
1.43 g of sodium salt of aminophenylacetic acid was suspended in 20 ml of methylene chloride, cooled to -40°C, and then
- Two drops of methylmorpholine were added, followed by a solution of 0.48 g of ethyl chlorocarbonate in 5 ml of methylene chloride. The mixture was further stirred at the same temperature for 90 minutes to prepare a mixed acid anhydride. The above-prepared solution was added dropwise to this solution. −
The reaction was carried out at 40 to -30°C for 3 hours and then at -30 to -20°C for 30 minutes with stirring. Add 20 ml of methanol containing 0.60 g of triethylamine to this and -20℃
The mixture was stirred for about 30 minutes. The precipitated crystals were collected and washed with a small amount of methanol.
The intermediate was suspended in 15 ml of methanol and stirred for 30 minutes while adjusting the pH to 2.0 using 6N hydrochloric acid under ice cooling. After removing insoluble matter and adjusting the isoelectric point with triethylamine, 1.14 g of cephalexin monohydrate (yield 78
%) was obtained. Example 9 Dry fine powder of 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-3-cephem-4-carboxylic acid 1.38
g was suspended in 20 ml of methylene chloride under ice-cooling, and 0.89 g of diisopropylamine and N/N-dimethylaniline were added.
0.24g was added and stirred to form a solution. A solution of 5 ml of methylene chloride containing 1.00 g of trimethylchlorosilane was added to this, and the mixture was allowed to react at 0° C. for 20 minutes and then at room temperature for about 30 minutes to obtain a substantially homogeneous solution. On the other hand, D-α-(4-oxo-4H-thiapyran-
1.22 g of 3-yl-carbonylamino)-p-hydroxyphenylacetic acid was dissolved in 30 ml of tetrahydrofuran, and 0.44 g of N-methylmorpholine was added and stirred. Cool this to -10°C and use ethyl chlorocarbonate.
Add dropwise a solution of 5 ml of methylene chloride containing 0.46 g,
Stir at -10℃ for 90 minutes to make mixed acid anhydride -40
Cooled to ℃. Add the solution of the silyl compound to this solution,
The reaction was stirred at -40°C for 2 hours and then at -30 to -20°C for 1 hour. The progress of the reaction was followed by thin layer chromatography. After the reaction was completed, the solvent was distilled off under reduced pressure, 20 ml of ethyl acetate and 10 ml of ice water were added to the residue, and the pH was adjusted to 2.0 with 5N hydrochloric acid while stirring. The organic layer was separated, washed with brine, and dried. The solvent was distilled off under reduced pressure, and 7-[D
-α-(4-oxo-4H-thiapyran-3-yl-carbonylamino)-p-hydroxyphenylacetamide]-3-(5-methyl-1,3,4-thiadiazol-2-yl-thiomethyl 2.32 g (92%) of crude crystals of )-3-cephem-4-carboxylic acid
I got it. Infrared absorption spectrum of this product: 1775cm ^-1 (β-lactam), ultraviolet absorption spectrum λmax 284mμ
(ethanol). Example 10 7-Aminodeacetoxycephalosporanic acid
0.86g and diisopropylamine in methylene chloride
The mixture was added to 20 ml and stirred under ice cooling to form a solution. Add 0.65g of hexamethyldisilazane to this and cool on ice for 1 hour.
After stirring for an hour, the mixture was concentrated under reduced pressure. N.N-dimethylaniline and 20 ml of methylene chloride were added to the residue and mixed under ice cooling to form a solution. A solution of phenylacetyl chloride in 5 ml of methylene chloride was added dropwise to this solution while stirring. The reaction was carried out at 0°C for 20 minutes and at room temperature for about 2 hours. Thereafter, treatment was carried out according to a conventional method to obtain sodium salt of 7-phenylacetamide-3-methyl-3-cephem-4-carboxylic acid in a yield of 94%. Example 11 7-Aminodeacetoxycephalosporanic acid
0.86 g (4 mmol), 0.79 g (5.2 mmol) of N.N-dimethylaniline, and 0.52 g (5.2 mmol) of diisopropylamine were stirred in 20 ml of methylene chloride under ice cooling in a stream of dry nitrogen gas for about 20 minutes. Add this to 0.70g of trimethylsilyl chloride.
(6.4 mmol) in methylene chloride was added, and the temperature was gradually increased for 10 minutes under ice-cooling.
At the end, the solution was briefly stirred at 40°C to obtain a homogeneous solution. While cooling the reaction solution on ice and stirring, add 0.91 g (4.4 g) of D-α-amino-phenylacetyl chloride hydrochloride
(mmol) was added at once, and then the temperature was raised and the reaction was carried out at room temperature (20 to 30°C) for about 2 hours. The entire process was carried out in a nitrogen gas stream. Follow the reaction with thin layer chromatography. After the reaction was completed, the reaction solution was treated according to a conventional method to obtain crude crystals of cephalexin.
This was purified by a conventional method to obtain 1.24 g (85%) of cephalexin monohydrate. All crystal mother liquors were collected and recovered as quinoline adduct. Yield 11% Total yield 96%. In the above reaction, trimethylsilyl chloride (6.4
When dimethylsilyl dichloride (3.3 mmol) was used instead of cephalexin monohydrate (3.3 mmol), cephalexin monohydrate was obtained in a yield of 84%, and a quinoline adduct was obtained in a yield of 11%.

Claims (1)

[Claims] 1 General formula (): [In the formula, Y is a hydrogen atom or an alkoxy group such as a methoxy group; Q is a hydrogen atom, a halogen atom, a methyl group, a methoxymethyl group, an azidomethyl group, a lower acyloxymethyl group, a carbamoyloxymethyl group, or a substituent. The amino-β-lactam carboxylic acid represented by [representing a heterocyclic thiomethyl group with or without] is reacted with a silylating agent in an inert organic solvent, and the resulting product is treated with an acylating agent to form an acylamide compound. In order to dissolve the compound of general formula () in an inert organic solvent, use a secondary amine having a pKb of 3.20 or less, a total carbon number of 4 to 16, and at least one branched carbon chain. A method for producing an acylamide compound, characterized by: 2 The secondary amine is diisopropylamine, di-
sec-butylamine, di-t-butylamine, di-(1-methylbutyl)amine, di-t-amylamine, diisoamylamine, dineopentylamine, dioctylamine, dicyclohexylamine, methyl-isopropylamine, methyl-isoamylamine, 2. The method of claim 1, wherein ethyl-isobutylamine, ethyl-isoamylamine, propyl-isobutylamine, propyl-isoamylamine or butyl-isobutylamine is used. 3. The method of claim 2, wherein the secondary amine is dicyclohexylamine, diisopropylamine, di-sec-butylamine or dioctylamine. 4 The acylating agent has the general formula () [In the formula, R ¹ is an optionally substituted alkyl group, aryl group, aralkyl group, aryloxy group, cycloalkenyl group, cycloalkyl group, heterocyclic residue, heterocyclic thio group, cyano group or halogenoalkylthio group; R ² is a hydrogen atom, a carboxy group or a group convertible thereto (e.g., an esterified carboxy group, a salted carboxy group), a sulfo group or a group convertible thereto (e.g., an esterified sulfo group), an acyloxy group , aryl group, aryloxy group, formyloxy group, substituted or unsubstituted carbamoyloxy group, hydroxy group, alkoxy group, alkylthio group, arylcarbonyl group, heterocyclic carbonyl group, amino group, protected with an easily removable protecting group [representing an amino group, an acylamino group, a formylamino group, a mono(or di)alkylamino group, or a mono(or di)arylamino group, an azide group, or a halogen atom] Claim 1 or the method described in paragraph 2. 5 A reaction in which the acylating agent has the general formula () R ³ -CH ₂ -COOH () (in the formula, R ³ represents a halogen atom, a trihalogenomethylthio group, a heterocyclic residue, a heterocyclic thio group, or a cyano group) The method according to claim 4, which is a sexual derivative. 6 The acylating agent has the general formula () (In the formula, R ⁴ is a phenyl group, a hydroxy-substituted phenyl group, a hydroxy-alkoxy-substituted phenyl group,
It represents a hydroxy-alkyl-substituted phenyl group, a hydroxy-halogen-substituted phenyl group, a phenyl group substituted with a carboxy group or a group convertible thereto, a heterocyclic residue, or a cycloalkenyl group, and R ⁵ is a protecting group that can be easily removed. indicates a protected amino group. ) The method according to claim 4, wherein the method is a reactive derivative of 7. A patent claim in which the acylating agent is a reactive derivative of the general formula () R ⁶ -CO-COOH () (wherein R ⁶ represents an optionally substituted aryl group or heterocyclic residue) The method according to scope 1 or 2. 8 The reactivity of the acylating agent with the general formula () R ₇ -COOH () (wherein R ⁷ represents a 3-(halogen-substituted or unsubstituted phenyl)-5-methylisoxazol-4-yl group) The method according to claim 1 or 2, which is a derivative. 9 As an organic solvent, use methylene chloride, ethylene chloride, propylene chloride, trimethylene chloride, chloroform, tetrachloroethane, trichlorethylene, tetrachlorethylene, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethyl acetate, acetonitrile, chlorobenzene, or a mixed solvent thereof. The method according to any one of claims 1 to 8 for use.