JPH0826038B2 - Process for producing hydroxycepham carboxylic acid ester - Google Patents

Description

Detailed Description of the Invention

[0001]

OBJECT OF THE INVENTION This invention is a 3-hydroxycepham-4.
-Carboxylic acid aralkyl ester to 3-Sefmu 4
-It relates to an improved method for producing a carboxylic acid aralkyl ester.

[0002]

DETAILED DESCRIPTION OF THE INVENTION The method of the present invention comprises elimination of 3-hydroxy group, reaction of acylating 3-hydroxy, deacylation of 3-acylated 7-amide, elimination of 3-acyloxy group and combinations thereof. Consists of.

I. Elimination reaction of hydroxy group 7-amido-3ξ-hydroxycepham-4-carboxylic acid aralkyl ester is an aprotic organic solvent 5 to 20.
In a volume part, 1 to 3 equivalents of (alkane or aryl) sulfonyl halide and 1 to 10 equivalents of trialkylamine in the presence of a elimination reaction agent are reacted at + 30 ° C to -60 ° C for 5 hours or less. 70% of 3-Chem compound
Give in ~ 90% yield.

II. 3-O-acylation reaction Further, the reaction of the above II is 7-amide-3ξ- which is a raw material.
Hydroxycepham-4-carboxylic acid aralkyl ester acylated 3-hydroxy group 7-amide-3ξ
It is also possible to use -acyloxycephum-4-carboxylic acid aralkyl esters. This reaction can be carried out by a conventional method. When a trialkylamine is used as the acid scavenger, the elimination reaction of the acyloxy group occurs simultaneously, so an aromatic base such as pyridine is more suitable.

III. 7-Deamidation Reaction 7-amido-3ξ-hydroxycepham-4-carboxylic acid aralkyl ester or 7-amide-3ξ-acyloxycepham-4-carboxylic acid aralkyl ester is reacted with phosphorus pentachloride-aromatic base. A new compound, 7-amino-3ξ, is obtained by amide lysis under acidic conditions according to a conventional method such as imino chloride, which is reacted with alcohol to form imino ether and then reacted with acid.
-(Hydroxy or protected hydroxy) cepham-4-
It can also be a carboxylic acid aralkyl ester. At this stage, absorption at 260 nm due to 3-cem-4-carboxylate is not observed in the reaction solution.

IV. 3-Deacyloxylation reaction 7-amido-3ξ-acyloxycepham-4-carboxylic acid aralkyl ester undergoes an acyloxy group elimination reaction when an acid scavenger such as trialkylamine is allowed to act by a conventional method.

V. Reaction conditions Unless otherwise specified, each reaction is usually -80 ° C to +3.
At a temperature of 0 ° C (especially -50 ° C to -30 ° C) for 10 minutes
It is possible to react for 10 hours. These are carried out in a solvent, preferably under stirring or anhydrous conditions. Any other conventional method can be applied.

The reaction solvent includes hydrocarbons (pentane, hexane, octane, benzene, toluene, xylene, etc.), halogenated hydrocarbons (dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, chlorobenzene, etc.), ether. (Diethyl ether
Ter, methyl isobutyl ether, anisole, dioxane, tetrahydrofuran, etc.), ester (ethyl acetate, isobutyl acetate, methyl benzoate, etc.), nitrile (acetonitrile, benzonitrile, etc.), amide (formamide, acetamide, dimethylformamide, etc.) Dimethylacetamide, hexamethylphosphorotriamide, etc.), carboxylic acids (formic acid, acetic acid, propionic acid, etc.), organic bases (diethylamine, triethylamine,
Pyridine, picoline, collidine, quinoline, etc.), alcohols (methanol, ethanol, propanol, hexanole, octanole, benzyl alcohol, etc.),
Industrial solvents belonging to other series or mixtures thereof can be adopted.

Each target product is obtained by extracting, evaporating and washing impurities such as unreacted raw materials, by-products and solvents from the reaction solution.
After removal by a conventional method such as concentration, precipitation, filtration, or drying, it can be isolated by a combination of conventional post-treatment methods such as adsorption, elution, distillation, precipitation, precipitation, and chromatography. .

[0010]

[Effect] 7-amido-3ξ is obtained by reacting 7-amino-3ξ- (hydroxy or protected hydroxy) cepham-4-carboxylic acid aralkyl ester with a reactive derivative of carboxylic acid such as chloride or anhydride for amidation. −
(Hydroxy or protected hydroxy) cepham-4-carboxylic acid aralkyl ester is obtained. If a double bond is introduced by the elimination reaction as described above, the corresponding 7-
It becomes an amide-3-unsubstituted-3-cem-4-carboxylic acid aralkyl ester. Can be manufactured in this way 3
ξ-Hydroxycepham-4-carboxylic acid ester is a synthetic intermediate for various 3-unsubstituted cephalosporins. When a method such as JP-A-52-106891 using a Lewis acid and a cation trapping agent is applied to the aralkyl ester of these compounds to deesterify them into carboxylic acids,
A cefalosporin agent having excellent antibacterial properties can be produced.

[0011]

EXAMPLES The embodiments of the present invention will be described below with reference to examples. The amount of the reagent is expressed in parts (parts by weight) and equivalents (molar equivalents) relative to the beta-lactam raw material. Concentration is performed under reduced pressure, and sodium sulfate is used to dry the solution. Before deacyloxylation, wet the reaction system before starting the reaction.
Check with test paper and add triethylamine until pH = 9. The abbreviations used are as follows. BOC = t-butoxycarbonyl. Bz = benzyl. Bu-t = t-butyl. Cbz = carbobenzoxy.
Ph = phenyl.

Example 1 (3-hydroxy elimination reaction)

Embedded image 1) 3ξ-Hydroxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester was suspended in 13 parts of dichloromethane, cooled to −10 ° C. under N ₂ and added with 4 equivalents of triethylamine, and then methane. 2.0 equivalents of sulfonic acid chloride are added over 7 minutes at -10 ° C. After reacting the produced methanesulphonic acid ester at about -10 ° C for 30 minutes, 20 parts of methylene chloride is added. The reaction solution is washed with water, 5% sulfuric acid and water, dried over sodium sulfate and concentrated. When 4 parts of methanol was added to the residue for crystallization, 7β-phenylacetylamino-3-
Cefem-4-carboxylic acid diphenyl ester is obtained. Yield: 75.4%.

2) 3ξ-Hydroxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester was added to dimethylformamide (more-cylinder).
(Dry dried sheave) dissolved in 9.5 parts, cooled to -50 ° C under N ₂ , added 4 equivalents of triethylamine, and then added 2 equivalents of methanesulfonic acid chloride at -52 to -45 ° C for 3 minutes. And added dropwise, and reacted at −55 to −45 ° C. for 2.5 hours to generate methanesulfonic acid ester, and then −15 to −15
Incubate at -12 ° C for 50 minutes. The reaction mixture is extracted with ethyl acetate, washed with water, 5% hydrochloric acid and water, dried over sodium sulfate and concentrated. The residue was crystallized from 4 parts of methanol to give 7β-phenylacetylamino-3-cefm-.
4-Carboxylic acid diphenylmethyl ester is obtained. Yield: 81.53%. mp. 166 ° C (decomposition). IR (Nujol) ν: 3250, 1775, 1710, 1645 1625 cm ^-1 .NMR (CDCl ₃ ) δ: 3.30 to 3.43 (m, 2H), 3.63 (s, 2H),
4.90 (d, J = 4.5Hz, 1H), 5.93 (dd, J ₁ = 4.5Hz, J ₂ = 9Hz, 1
H), 6.45 ~ 6.67 (m, 2H). 6.90 (s, 1H), 7.30 (m, 15H), p
pm.

Example 2 (3-O-acylation reaction)

Embedded image a: R ¹ = CH ₃ CO- b: R ¹ = PCl ₄ -c: R ¹ = CH ₃ SO ₂ -d:
R ¹ = p-CH ₃ C ₆ H ₄ SO _2-

A. R ¹ = CH ₃ CO- ₃ ξ-hydroxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester was added to 13 parts of dichloromethane, and pyridine 6 was added under ice cooling.
Equivalents and 6 equivalents of acetic anhydride are added and kept at 0-5 ° C for 14 hours. The reaction mixture is diluted with ice water, the organic layer is collected, washed with hydrochloric acid, aqueous sodium hydrogencarbonate and water, dried and concentrated. 3 if the residue was crystallized from a dichloromethane-hexane mixture
ξ-acetoxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester (3a) is obtained. Yield: 98.1%. mp.187-188 ° C (decomposition). IR (Nujol) ν: 3350, 1780, 1740, 1738, 1665 cm ^-1 .NMR (CDCl ₃ ) δ: 1.63 (s, 3H), 2.61 (m, 1H), 3.20
(m, 1H), 3.60 (s, 2H), 4.95 (m, 2H), 5.20 (d, J = 5Hz, 1
H), 5.55 (dd, J ₁ = 5Hz, J ₂ = 9Hz, 1H), 6.50 (d, J = 9Hz, 1
H), 6.83 (s, 1H), 7.27 (m, 15H) ppm.

B. R ¹ = PCl ₄ 3ξ-Hydroxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester was added to 13 parts of dichloromethane, and 0 to 0 in a nitrogen gas.
Add 3 equivalents of pyridine at -5 ° C. This is -20 to -2
After cooling to 5 ° C, 2.7 equivalents of phosphorus pentachloride was added, -1
A solution of 7- (2-phenyl-2-chloromethylideneamino-3-tetrachlorophosphonyloxycepham-4ξ-carboxylic acid diphenylmethyl ester (3b) is obtained by stirring at 0 to -15 ° C for 4 hours. .

C. R ¹ = CH ₃ SO ₂ -3 ξ-hydroxy-7β-phenylacetylaminocepham-4 ξ-carboxylic acid diphenylmethyl ester was suspended in 18 parts of dichloromethane, cooled to -30 ° C, and 6 equivalents of methanesulfonyl chloride were added. And 6 equivalents of pyridine are added dropwise. The mixture is allowed to react for 17 hours at 0-5 ° C. The reaction solution is diluted with ice water, the organic layer is taken, washed with hydrochloric acid and water, dried and concentrated. The residue was crystallized from ethyl acetate-hexane to give 3ξ-mesyloxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester (3c). Yield: 96.5%. mp.
151-152 ° C (decomposition). IR (Nujol) ν: 3300, 1765, 1720, 1660, 1350, 1180
cm ^-1 .NMR (CDCl ₃ ) δ: 2.65 (s, 3H), 2.83 (m, 1H), 3.40
(m, 1H), 3.57 (s, 2H), 4.9 ~ 5.1 (m, 2H), 5.20 (d, J = 5H
z, 1H), 5.50 (dd, J ₁ = 5Hz, J ₂ = 9Hz, 1H), 6.43 (d, J = 9H
z, 1H), 6.87 (s, 1H), 7.32 (s, 15H) ppm.

D. R ¹ = p-CH ₃ C ₆ H ₄ SO ₂ -3 ξ-Hydroxy-7β-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester was added to 9 parts of dichloromethane under ice cooling. 6 equivalents of pyridine and toluenesulfonyl chloride are added and reacted at 0 to 5 ° C for 105 hours. The reaction solution is diluted with ice water, the organic layer is taken, washed with hydrochloric acid and water, dried and concentrated. The residue was crystallized from ethyl acetate-hexane to give 3ξ-p-toluenesulfonyloxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester.
Get (3d). Yield: 84.7%. mp.133-136 ℃
(Disassembly). IR (Nujol) ν: 3300, 1760, 1730, 1640, 1310, 1180 c
m ^-1 .NMR (CDCl ₃ ) δ: 2.43 (s, 3H), 2.70 (m, 1H), 3.33 (m,
1H), 3.60 (s, 2H), 4.53 ~ 4.90 (m, 2H), 5.20 (d, J = 4.
5Hz, 1H), 5.53 (dd, J ₁ = 4.5Hz, J ₂ = 9Hz, 1H), 6.16 (d,
J = 9Hz, 1H), 6.83 (s, 1H), 7.32 (m, 17H), 7.63 (d, J = 8
Hz, 2H) ppm.

Example 3 (7-deamidation reaction)

Embedded image a: R ¹ = CH ₃ CO- b: R ¹ = PCl ₄ -c: R ¹ = CH ₃ SO ₂ -d:
R ¹ = p-CH ₃ C ₆ H ₄ SO _2-

A. R ¹ = CH ₃ CO- ₃ ξ-acetoxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester (3a)
Is dissolved in 7 parts of dichloromethane, cooled to -20 to 25 ° C, 2 equivalents of pyridine and 1.7 equivalents of phosphorus pentachloride are added in a nitrogen atmosphere, and the mixture is stirred at -10 to -15 ° C for 4 hours. 12 parts of methanol at -30 ° C was added to the reaction solution, and 3.5 at -30 ° C.
Stir for 2 hours at 0-5 ° C for 2 hours. The reaction solution is concentrated,
After diluting with dichloromethane-water and stirring at 0-5 ° C for 20 minutes, the organic layer is taken, washed with aqueous sodium hydrogen carbonate solution and water, dried and concentrated. The residue is dissolved in a small amount of dichloromethane and ether is added for crystallization. The crystals are filtered off,
When dissolved in methanol-water, neutralized with sodium hydrogen carbonate water, and crystallized by adding water, 3ξ-acetoxy-7β-
Aminocepham-4ξ-carboxylic acid diphenylmethyl ester (4a) is obtained. Yield: 80.2%. mp.155-1
56 ° C (decomposition). IR (Nujol) ν: 3350, 3300, 1760, 1750, 1735 cm
^-1 . NMR (CDCl ₃ ) δ: 1.60 (s, 3H), 1.77 (m, 2H), 2.70
(m, 1H), 3.27 (m, 1H), 4.40 (m, 1H), 5.13 (m, 3H), 6.9
0 (s, 1H), 7.23 (s, 10H) ppm.

B. R ¹ = PCl _{4 To} a solution of 7- (2-phenyl-2-chloromethylideneamino-3-tetrachlorophosphonyloxycepham-4ξ-carboxylic acid diphenylmethyl ester obtained in Example 2B, methanol 20 Parts or isobutanol 10
Parts, and stir at 0-5 ° C for 2-3 hours. The reaction solution is cooled to -20 to -25 ° C, 14 equivalents of triethylamine is added dropwise, and the mixture is stirred at 0 to 5 ° C for 15 hours. -5 to this
Add 20 parts of water at ~ -10 ° C, stir for 10 minutes, and extract with dichloromethane. The extract is hydrochloric acid, water, 5
Wash with% sodium bicarbonate water and water, dry and concentrate. The residue was crystallized from ethyl acetate to give 7-amino-3.
-Chem-4-carboxylic acid diphenylmethyl ester is obtained. Yield: 47.3% (from methanol); 37.2% (from isobutanol). mp. 159-160 ° C (decomposition).

C. R ¹ = CH ₃ SO ₂ -3 ξ-mesyloxy-7β-phenylacetylaminocepham-4 ξ-carboxylic acid diphenylmethyl ester (3
c) is dissolved in 7 parts of dichloromethane, cooled to -20 to -25 ° C, 2 equivalents of pyridine and 1.7 equivalents of phosphorus pentachloride are added in a nitrogen atmosphere, and the mixture is stirred at -10 to -15 ° C for 4 hours. To the reaction solution was added 11 parts of methanol at -25 to -30 ° C, and -3
Stir at 0 ° C for 30 minutes and at -5 to 0 ° C for 2.5 hours. Dilute the reaction mixture with dichloromethane-ice water, 0-5 ° C.
After stirring for 20 minutes, the organic layer is taken, washed with water, dried and concentrated. The residue is dissolved in a small amount of dichloromethane and ether is added for crystallization. The crystals are collected by filtration, dissolved in methanol-water, neutralized with aqueous sodium hydrogen carbonate, and crystallized by adding water to give 3ξ-mesyloxy-7β-aminocepham-4ξ-carboxylic acid diphenylmethyl ester (4c). obtain. Yield: 55.7%. mp.145-147
° C (decomposition). IR (Nujol) ν: 3350, 3300, 1760, 1735, 1340, 11
70 cm ^-1 NMR (CDCl ₃ ) δ: 1.77 (s, 2H), 2.67 (s, 3H), 2.87
(m, 1H), 3.50 (m, 1H), 4.46 (d, J = 4Hz, 1H), 5.13 (m, 2
H), 5.20 (d, J = 4Hz, 1H), 6.90 (s, 1H), 7.33 (s, 10H)
ppm.

D. R ¹ = p-CH ₃ C ₆ H ₄ SO ₂ -3ξ-p-toluenesulfonyloxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester (3d) was dissolved in 7 parts of dichloromethane, and −
The mixture is cooled to 20 to -25 ° C, 2 equivalents of pyridine and 1.7 equivalents of phosphorus pentachloride are added in nitrogen gas, and the mixture is stirred at -10 to -15 ° C for 4 hours. 12 parts of methanol at -30 ° C is added to the reaction solution, and the mixture is stirred at -25 to -30 ° C for 30 minutes and at 0 to 5 ° C for 2 hours. Dilute the reaction mixture with ice water and dichloromethane, and
After stirring at ~ 5 ° C for 20 minutes, the organic layer is taken, washed with water, dried and concentrated. The residue is dichloromethane-
Crystallization from tellurium gives 3ξ-p-toluenesulfonyloxy-7β-aminocepham-4ξ-carboxylic acid diphenylmethyl ester (4d) tosylate. mp. 190-194 ° C (decomposition). IR (Nujol) ν: 1780, 1750, 1360, 1180 cm ^-1 . Elemental _{analysis: C 34 H 34 N 2 O} 9 S 3 · H 2 O Calculated (%):. C, 56.73 ; H, 4.90; N, 3.89; S, 13.36 Found (%): C, 56.90; H, 4.78; N, 3.97; S, 13.20.

Example 4 (Deacyloxylation reaction)

[Chemical 4] a: R ¹ = CH ₃ CO- b: R ¹ = PCl ₄ -c: R ¹ = CH ₃ SO ₂ -d:
R ¹ = p-CH ₃ C ₆ H ₄ SO _2-

A. R ¹ ═CH ₃ CO- ₃ ξ-acetoxy-7β-aminocepham-4ξ-carboxylic acid diphenylmethyl ester (4a) was dissolved in dichloromethane, and triethylamine 1 to 3 was added at -20 to -25 ° C.
An equivalent amount is added, the temperature is gradually raised to 0 to 5 ° C, and the mixture is left standing overnight. 20 parts of ice water is added to this, and the mixture is stirred for 20 minutes and then extracted with dichloromethane. The extract is hydrochloric acid, water, 7
Washed with 5% sodium hydrogen carbonate solution and 5% saline solution, dried,
Concentrate. The residue is crystallized from ethyl acetate to give 7β-amino-3-ceph-4-carboxylic acid diphenylmethyl ester. Yield: (1) to 61.0%. mp. 159-160 ° C (decomposition). IR (Nujol) ν: 3350, 3300, 1770, 1720, 1630 cm ^-1 .NMR (CDCl ₃ ) δ: 2.76 (s, 2H), 3.43 (m, 2H), 4.83
(m, 2H), 6.57 (m, 1H), 6.90 (s, 1H), 7.30 (s, 10H) pp
m.

Similarly, the products of Examples 3A to 4D are treated with 1 to 3 equivalents of triethylamine in dichloromethane at 0 to 5 ° C. for 2 to 15 hours to obtain the same products.

Example 5

Embedded image If the corresponding 3ξ-mesyloxy-7-acylaminocephem-4ξ-carboxylic acid diphenylmethyl ester was reacted with 1 to 3 equivalents of triethylamine in dichloromethane at room temperature for 1 to 6 hours under the same conditions as in Example 4. , The compounds of Table 2 are obtained.

Example 6 (Acylation of 7-amino)

[Chemical 6] 7-Amino-3-acetoxycepham-4-carboxylic acid diphenylmethyl ester was dissolved in 7 parts of dichloromethane and cooled to -30 to -10 ° C, and 1.7 equivalents of pyridine and phenylacetic acid chloride were added thereto. Add 1 equivalent 3
Stir for 0 minutes. 1 to 9 equivalents of triethylamine is added to the reaction solution, and the mixture is stirred at 0 to 5 ° C for 24 hours, diluted with ice water, and the organic layer is taken, washed with hydrochloric acid and water, dried, and concentrated. The residue is crystallized from ethyl acetate-ether to give 7β-phenylacetylamino-3-cefm-4-carboxylic acid diphenylmethyl ester. Yield: 7
0.0%. mp. 170-171 ° C (decomposition).

Under the same conditions as above, 7-amino-3-acyloxycepham-4-carboxylic acid diphenylmethyl ester was dissolved in 3-10 parts of dichloromethane to give -4
Cool to 0--5 ° C and add 1-2 equivalents of pyridine and 7 each
Add 1 to 2 equivalents of carboxylic acid chloride corresponding to the side chain and stir for 1 to 24 hours. The reaction solution is washed with hydrochloric acid and water, dried and concentrated. The compounds shown in Table 1 can be synthesized by crystallizing the residue from ethyl acetate-ether.

Example 7 (elimination of 3-acyloxy and 3-acyl)

[Chemical 7] a: R ¹ = CH ₃ CO- c: R ¹ = CH ₃ SO ₂ -d: R ¹ = p-CH ₃ C ₆ H ₄ SO
₂ -e: R ¹ = H

A. R ¹ = CH ₃ CO-1) 3ξ-acetoxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester
Dissolve (3a) in 13 parts of dichloromethane, and in a nitrogen atmosphere, -5
Cool to ~ 0 ° C, add 2 equivalents of pyridine and add -20 to -2.
After cooling to 5 ° C. and adding 1.7 equivalents of phosphorus pentachloride, -1
Stir for 4 hours at 5-10 ° C. -40 to-in the reaction solution
20 parts of methanol at 30 ° C. and 5 parts of dichloromethane are added, and the mixture is stirred at −25 to −30 ° C. for 3.5 hours. The reaction solution was brought to -20 to -25 ° C, and triethylamine 1 was added thereto.
0.9 eq is added dropwise and left overnight at 0-5 ° C. The reaction solution is diluted with 20 parts of ice water and stirred for 20 minutes, and then the organic layer is taken, washed with hydrochloric acid, water and aqueous sodium hydrogen carbonate solution and water, dried and concentrated. The residue is crystallized from ethyl acetate to give 7β-amino-3-cephem-4-carboxylic acid diphenylmethyl ester. Yield: 60.2%.

2) The starting material (3a) was added to dichloromethane 1
Melt in 3 parts, cool to −5 to 0 ° C. in a nitrogen atmosphere, add 2 equivalents of pyridine, cool to −30 to −25 ° C., add 1.7 equivalents of phosphorus pentachloride, and then add −15 to −−. Stir at 10 ° C for 4 hours. The reaction solution is cooled to -25 to -30 ° C, 10 parts of isobutanol at -30 to -20 ° C in nitrogen gas is added thereto, and the mixture is left to stand at 0 to 5 ° C overnight. The reaction solution is -20 to -25
C., 10.9 equivalents of triethylamine are added dropwise thereto, and the mixture is left standing at 0-5.degree. C. overnight. The reaction solution is diluted with 20 parts of dichloromethane and 20 parts of ice water and stirred for 20 minutes. The organic layer is taken, washed with hydrochloric acid, water, aqueous sodium hydrogen carbonate solution and water, dried and concentrated. The residue is crystallized from ethyl acetate to give 7β-amino-3-cephem-4-carboxylic acid diphenylmethyl ester. Yield: 6
0.8%.

C. R ¹ = CH ₃ SO ₂ -3 ξ-mesyloxy-7β-phenylacetylaminocepham-4 ξ-carboxylic acid diphenylmethyl ester (3
c) is dissolved in 7 parts of dichloromethane and in a nitrogen atmosphere, -20 to
Cool to −25 ° C., 2 equivalents of pyridine and 1.7 of phosphorus pentachloride.
After adding an equivalent amount, the mixture is stirred at -15 to -10 ° C for 4 hours. 12 parts of methanol at -40 to -30 ° C is added to the reaction solution, and the mixture is stirred at -30 ° C for 30 minutes and at 0 to 5 ° C for 2.5 hours. The reaction solution is brought to -30 ° C, 8.1 equivalents of triethylamine is added dropwise thereto, and the mixture is left at 0-5 ° C overnight. The reaction solution is diluted with ice water and dichloromethane and stirred at 0 to 5 ° C for 20 minutes. The organic layer is collected, washed with hydrochloric acid, water, aqueous sodium hydrogen carbonate solution and water, dried and concentrated. The residue is crystallized from ethyl acetate to give 7β-amino-3-cephem-4-carboxylic acid diphenylmethyl ester. Yield: 55.7%.

D. R ¹ = p-CH ₃ C ₆ H ₄ SO ₂ -3ξ-p-tosyloxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester (3d) was dissolved in 7 parts of dichloromethane to give -10. -15
After cooling to ℃, add 2 equivalents of pyridine and 1.7 equivalents of phosphorus pentachloride, and stir at -15 to -10 ° C for 4 hours. To the reaction solution was added 12 parts of methanol at -40 to -30 ° C, and -3
Stir at 0 ° C for 30 minutes and 0-5 ° C for 2.5 hours. The reaction solution is brought to -30 to -40 ° C, 8 equivalents of triethylamine is added dropwise thereto, and the mixture is stirred at 0 to 5 ° C for 2 hours and then left overnight. Dilute the reaction mixture with ice water and dichloromethane, and
After stirring at -5 ° C for 20 minutes, the organic layer is taken, washed with hydrochloric acid, water, aqueous sodium hydrogen carbonate and water, dried and concentrated. If the residue was crystallized from ethyl acetate, 7β-
Amino-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained. Yield: 57.9%.

E. R ¹ = H 1) 3ξ-hydroxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester (3e) was suspended in 13 parts of dichloromethane and cooled to −5 to 0 ° C. in a nitrogen atmosphere, Add 3 equivalents of pyridine,
After cooling to 20 to -25 ° C and adding 2.7 equivalents of phosphorus pentachloride, the mixture is stirred at -15 to -10 ° C for 4 hours. To the reaction solution, 20 parts of methanol at -40 to -30 ° C was added, and -10 to
Stir at -15 ° C for 3 hours. The reaction solution is -20 to -25
12 ° C of triethylamine was added dropwise to 0 ° C,
Leave overnight at 5 ° C. Dilute the reaction mixture with 20 parts of ice water, and
After stirring at -5 ° C for 20 minutes, the organic layer is taken, washed with hydrochloric acid, water, aqueous sodium hydrogen carbonate and water, dried and concentrated. If the residue was crystallized from ethyl acetate, 7β-
Amino-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained. Yield: 47.3%.

2) The starting material (3e) was added to dichloromethane 1
Melt in 3 parts, cool to −5 to 0 ° C. in a nitrogen atmosphere, add 3 equivalents of pyridine, cool to −20 to −25 ° C., add 2.7 equivalents of phosphorus pentachloride, and then −15 to − Stir at 10 ° C for 4 hours. To the reaction solution was added 11 parts of isobutanol at -40 to -30 ° C, and the mixture was stirred at 0 to 5 ° C for 2 hours, then 0 to
Leave overnight at 5 ° C. The reaction solution was set at -20 to -25 ° C,
To this, 14 equivalents of triethylamine was added dropwise, and the mixture was left at 0 to 5 ° C overnight. The reaction mixture was diluted with ice water and dichloromethane and stirred for 20 minutes, then the organic layer was collected, hydrochloric acid,
Wash with water, aqueous sodium hydrogen carbonate and water, dry and concentrate. The residue is crystallized from ethyl acetate to give 7β-amino-3-cephem-4-carboxylic acid diphenylmethyl ester. Yield: 37.2%.

[0037]

[Reference Example] 7-Amino-3-cephem-4-carboxylic acid diphenylmethyl ester (R = H) in Table 1 was dissolved in 7 parts of dichloromethane and the carboxylic acid corresponding to each 7-position side chain was added at 0 ° C. Acid chloride 1-2 equivalents and pyridine 1-2
Add equivalent amount and stir for 1 to 5 hours. The reaction solution is washed with hydrochloric acid and water, dried and concentrated. The residue was washed with ethyl acetate
The compound shown in Table 1 (R = predetermined acyl) can be synthesized by crystallization from tellurium.

Table 1

Embedded image

[Table 1]

[Table 2]

Claims (1)

[Claims] 1. 3ξ-Hydroxy-7β-acylamino
Cefam-4ξ-carboxylic acid aralkyl ester
In the presence of an aromatic base as a trapping agent, a carboxylic acid or
The sulfonic acid chloride or anhydride is allowed to act on the 3- (
Acyl rubonate or acyl sulfonate) oxy-7β
-Acylaminocepham-4ξ-carboxylic acid aralkyl
A method for producing an ester.