JPS61155388A - Production of hydroxycephamcarboxylic acid ester - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a synthetic intermediate for 3-unsubstituted cephalosporin, in high yield, by reducing 3-oxocepham-4- carboxylic acid aralkyl ester, etc. with alkali metal borohydride under specific condition. CONSTITUTION:The objective 3xsi-hydroxycephem-4-carboxylic acid aralkyl ester can be produced by (1) dissolving preferably 7-amido-3-oxocepham-4-carboxylic acid aralkyl ester or its enol compound in 3-30pts.vol of a mixture of prefer ably a halohydrocarbon and an anhydrous lower alkanol or N,N- dialkylalkanamide, (2) cooling the solution to <=-20 deg.C, especially to -30--80 deg.C, and (3) adding 1-20 equivalent, especially 1-5 equivalent of an alkali metal borohydride to the solution and reacting for 10min-20hr, espe cially for 30min-10hr.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention reduces 3-oxocepham-4-carboxylic acid aralkyl ester or its enol form with an alkali metal borohydride to produce 3-hydroxycepham-4-carboxylic acid aralkyl ester. This invention relates to an improved method for producing 3-cephem-4-carboxylic acid aralkyl ester.

The method of this invention includes (1) reduction reaction of reducing 3-oxocepham-4-carboxylic acid aralkyl ester to 3-hydroxycepham-4-carboxylic acid aralkyl ester, (2) elimination of 3-hydroxy group, 0) It consists of a reaction to acylate 3-hydroxy, (4) deacylation of 3-acylated product 7-amide, (elimination of 93-acyloxy group, etc.), and combinations thereof.

1. Reduction reaction This reaction itself is known from JP-A-49-49989, etc., but when the present inventor reduced an aralkyl ester under known hydrous conditions, he discovered that the starting carboxylic acid (hereinafter referred to as the blank) Completed the invention.

In other words, this invention reduces a 3-year-old xocepham 4-carboxylic acid aralkyl ester alcohol with an alkali metal borohydride in an anhydrous organic solvent at -20°C or lower to obtain the corresponding 3-hydroxycefam-4- This is a method for producing aralkyl carboxylic acid ester.

The raw material 3-oxocepham-4-carboxylic acid aralkyl ester or its enol may have an amide side chain at its 7-position.

Here, as the 7-amide side chain, among the amine side chains and their analogs known for penicillins, cephalosporins, and their synthetic intermediates, those that do not cause any unfavorable changes under these reaction conditions are used. can.

Aralkyl esters include benzyl esters, methoxybenzyl esters, and methoxybenzyl esters that have highly nucleophilic ester groups.
Diphenyl methyl ester and the like are suitable.

Solvents include methanol, ethanol, propatool,
Lower alcohols such as butanol and substantially anhydrous polar organic solvents such as dialkylamides are preferred. Inert solvents such as halohydrocarbons and ethers can also be used in this reaction.

The alkali metal in the alkali metal borohydride is preferably lithium, sodium, or potassium.

According to the present invention, 7-amido-3-oxocepham-4-carboxylic acid aralkyl ester or its enol form is preferably used as a mixture of a halohydrocarbon and an anhydrous lower alkanol or as a N,N-dialkylalkanamide 3 After dissolving to ~30 parts by volume and cooling to -20°C or below (especially -30°C to -80°C), add 1 to 20 equivalents (especially 1 to 5 equivalents) of alkali metal borohydride for 10 minutes. The reaction is carried out for 20 hours (especially 30 minutes to 10 hours) to produce the desired 3ξ-hydroxycepham-4-carboxylic acid aralkyl ester in a yield of 99%.

If necessary, a reaction accelerator such as acetic acid, an inert gas such as nitrogen,
Conventional methods for smoothing the reaction, such as stirring, can also be employed.

The target product can be collected by applying conventional post-treatments to the reaction solution, such as vacuum distillation of low-boiling substances, extraction, washing, drying, and crystallization.

■． Hydroxy group elimination reaction! 7-amide-3ξ-hydroxycephalic acid produced by
The 4-carboxylic acid aralkyl ester contains 1 to 3 equivalents of (alkane or aryl)sulfonyl halide and 1 part of trialkylamine in 5 to 20 parts by volume of an aprotic organic solvent.
+30°C to -60°C in the presence of an elimination reactant such as ~10 equivalents
When the reaction is carried out at .degree. C., the desired 3-cephem compound is obtained in a yield of 70 to 90% within 5 hours.

1,3-0-Acylation Reaction The above reaction (1) is a 7-amide-3ξ- acylation of the 3-hydroxy group of the raw material 7-amide-3ξ-hydroxycepham-4-carboxylic acid aralkyl ester.
Acyloxycepham-4=carboxylic acid aralkyl esters can also be used. This reaction can be carried out using conventional methods. When trialkylamine is used as an acid scavenger,
Since the elimination reaction of the acyloxy group also occurs, aromatic bases such as pyridine are more suitable.

IV, 7-Mode Amidation Reaction 7-Amido-3ξ-hydroxycepham-4-carboxylic acid aralkyl ester -3ξ-acyloxycepham-4-carboxylic acid aralkyl ester is reacted with phosphorus pentachloride-pyridine to form iminochloride. The new compound 7-
It can also be an amino-3ξ-(hydroxy or protected hydroxy) cepham-4-carboxylic acid aralkyl ester. At this stage, the reaction solution contains 3-cephem-4-
No absorption of 260th+a due to carboxylate was observed.

V. 3- Theory Acyloxylation Reaction 7-Amido-3ξ-acyloxycepham-4-carboxylic acid aralkyl ester undergoes an elimination reaction of the acyloxy group when treated with an acid scavenger such as trialkylamine in a conventional manner.

■． Application 7-Amino-3ξ-(hydroxy or protected hydroxy)cepham-4-carboxylic acid aralkyl ester is amidated with a reactive derivative of carboxylic acid, such as a chloride or anhydride, to form 7-amide-3ξ-( Hydroxy or protected hydroxy)cepham-4-carboxylic acid aralkyl esters are obtained. In this case, if a double bond is introduced by an elimination reaction such as ① or ①, the corresponding 7-
It becomes amido-3-unsubstituted-3-cephem-4-carboxylic acid aralkyl ester.

3ξ-Hydroxycefam which can be produced in this way
4-carboxylic acid esters are intermediates in the synthesis of various 3-unsubstituted cephalosborins.

If the aralkyl esters of these compounds are deesterified into carboxylic acids by applying the method of JP-A-52-106891 using a Lewis acid or the like and a cation scavenger, a cephalosporin agent with excellent antibacterial properties can be obtained. Can be manufactured.

■． Reaction conditions Unless otherwise specified, each reaction is usually carried out at -80°C to +
10 at a temperature of 30°C (especially -50°C to -30°C)
The reaction can be carried out over a period of minutes to 10 hours. These are carried out in a solvent, preferably under stirring or anhydrous conditions. Any other conventional law may be applied.

Hydrocarbons (pentane, hexane,
octane, benzene, toluene, xylene, etc.), halogenated hydrocarbons (dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, chlorobenzene, etc.), ethers (diethyl ether, methyl isobutyl ether, anisole, dioxane, tetrahydrofuran, etc.), esters ( ethyl acetate, inbutyl acetate, methyl benzoate, etc.), nitriles (acetonitrile, benzonitrile, etc.), amides (formamide, acetamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, etc.), carvone* (formic acid, acetic acid, propionic acid, etc.) ), organic bases (diethylamine, triethylamine, pyridine, picoline, frizine, quinoline, etc.), alfurs (methanol, ethanol, propatool, hexanol, octatool, benzyl alcohol, etc.), and other industrial solvents or mixtures thereof. can be adopted.

Each desired product is produced by extracting impurities such as unreacted raw materials, by-products, and solvents from the reaction solution, evaporating, washing, concentrating, precipitating,
After removal by conventional methods such as filtration and drying, it can be isolated by combining conventional post-treatment methods such as adsorption, elution, distillation, precipitation, precipitation, and chromatography.

The present invention will be explained in detail below using Examples.

The amount of 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. During deacyloxylation, the reaction system was checked with a wet pH test paper before the reaction started, and triethylamine was added until the pH reached 9.

The abbreviations used are as follows.

BOC-t-butoxycarbonyl.

Bz - benzyl.

But-t = t-butyl.

Cbz bound carbobenzoxy.

Ph Zen phenyl.

(Left below) Example 1 (Reduction reaction) 1) 3-year-old xo-7β-phenylacetylamine cepham-4ξ-carboxylic acid diphenylmethyl ester (1)
Alternatively, the enol is dissolved in a mixture of 6.5 parts of dichloromethane and 4 parts of methanol, cooled to -53°C in a nitrogen atmosphere, and 4 equivalents of sodium borohydride are dissolved at -53 to -57°C.
It takes 7 minutes to add the liquid. After reacting at the same temperature for 30 minutes, 1.4 parts of glacial acetic acid was slowly added at the same temperature, followed by 10 parts of water. The reaction solution was extracted with dichloromethane, washed with 5% sodium hydrogen suboxide and water, and sulfuric acid was added. Dry with sodium and concentrate. The residue was crystallized from a mixture of 4 parts of dichloromethane and 1.7 parts of n-hexane to give 3
Diphenylmethyl ξ-hydroxy-7β-phenylacetylaminocepham-4ξ-carboxylate (2) is obtained. Yield: 89.7%.

2) The above reaction was performed using ethanol-chloroform (yield near B) instead of methanol-dichloromethane as the reaction solvent.
%), ethanol-dichloromethane (yield: 81%) or methanol-ethanol-dichloromethane (yield:
96%) at -35 to -80°C, Compound (1) can also be obtained.

3) 3-Hydroxy-7β-phenylacetylamine-
3-cephem-4-carboxylic acid diphenylmethyl ester (1) was dissolved in 9.5 parts of dimethylformamide (dried with molecular sieves), cooled to -so"c under N2, and 4 equivalents of sodium borohydride were dissolved in -53 to - 3 at 48℃
Insert in minutes. After reacting at the same temperature for 30 minutes, 1.4 parts of glacial acetic acid was slowly added at the same temperature, followed by 10 parts of water. The reaction solution was extracted with ethyl acetate, washed with 5% sodium bicarbonate and water, dried over sodium sulfate, and concentrated. The residue was dissolved in 4 parts of dichloromethane and 1.7 parts of n-hexane.
crystallized from a mixture with 3ξ-hydroxy-7
β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester (2) is obtained. Yield, 76.3
%.

trrp, 196-198°C (decomposition).

I R (Nujol) V: 3450.3300.
1765.1740°1645 c+a-'.

NMR(CDsSOCD=)δ: 2.8-3.
2 (m, 2H), 3.37 (s, LH), 3.
57 (s, 2H), 4.13 (m, IH),
4.77 (d.

J=6Hz, IH), 5.13(d, J=4.5
Hz, LH>, 5.40 (dd.

J+=4.5Hz, J==9Hz, LH), 6.1
0(d, J'9Hz, LH>.

6.80 (s, IH), 7.23-7.33 (m,
151) ppm.

Elemental analysis: C= a Hl # N * Os S calculated value (X): C, 66,92; H, 5, 2CN, 5
．． 57; S, 6.38 experimental value C%): C, 66,8
2: H, 5,19iN, 5.70; S, 6.35 (blank below) Actual mH2 (3-hydroxy elimination reaction) 1) 3ξ-hydroxy-7β-phenylacederamide, Nocefamu 4
ξ-Carboxylic acid diphenylmethyl ester ■ was suspended in 13 parts of dichloromethane, cooled to -10°C under Nz, 4 equivalents of triethylamine was added, and then 2.0 equivalents of methanesulfonic acid chloride was added at 10°C for 7 minutes. Add as needed.

The methanesulfonic acid ester (3) produced at -10°
After reacting for 30 minutes near C, 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. Adding 4 parts of methanol to the residue and crystallizing it gives 7β-phenylacetylamino-3-cephem-4-carboxylic acid diphenyl ester (6).
Yield: 7s, 4%.

2) 3ξ-hydroxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester ■ was dissolved in 9.5 parts of dimethylformamide (dried with molecular sieves), cooled to -50°C under N2, and 4 equivalents of triethylamine were dissolved. Then, 2 equivalents of methanesulfonic acid chloride were added dropwise at -52 to -45°C over 3 minutes.
React at -55 to -45°C for 2.5 hours to produce methanesulfonic acid ester, then at -15 to -12°C.
The reaction mixture was extracted with ethyl acetate, washed with water, 5% hydrochloric acid and water, and dried over sodium sulfate.
Concentrate. When the residue is crystallized from 4 parts of methanol, 7
β-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester (2) is obtained. Yield, 81
．． 53%.

mp, 166°C (decomposed).

I R (Nujol) v i 3250.1775.
1710.16451625 cm river.

NMR(CDCIs) δ: 3.30-3.4
3 (m, 2H), 3.63 (s, 2H),
4.90 (d, J=4.5Hz, LH),
5.93 (dd, J, = 4.5Hz, J, = 9
Hz, 18), 6.45=6.67(m,
2H), 6.90(s, LH>, 7.30(
m, 15H), ppm.

Example 3 (3-0-acylation reaction) a' R”CH
sCO-b'R"PCl3-c:R'=cuSso
t-d: R'-p-CHsCsHaSOt-A,
Rl-CHsCO- 3ξ-hydroxy-7β-phenylacetylamine cepham-4ξ-carboxylic acid diphenylmethyl ester (RI was suspended in 13 parts of dichloromethane, and 6 equivalents of pyridine and 6 equivalents of acetic anhydride were added under cooling with water to give a solution of 0 to 5 9 The reaction solution kept at ℃ for 14 hours is diluted with ice water, the organic layer is taken, washed with hydrochloric acid, then with sodium hydrogen aqueous solution and water, dried, and concentrated.The residue is crystallized from a dichloromethane-hexane mixture to give 3.
ξ-acetoxy-7β-phenylacetylamine cepham-4ξ-carboxylic acid diphenylmethyl ester (3a
). Yield, 98.1%-ff1p, 187-1
88°C (decomposition).

I R (Nujol) 'v: 3350.1780
．． 1740.1738.1665Qm-'.

NMR (CDC1,) 8: 1.63 (
s, 3H), 2.61 (m.

18), 3.20 (m, LH), 3.60 (s,
2H), 4.95 (m, 2H).

5.20(d, J=5Hz, 1N>, 5.55(
dd, J, = 5H2, J*: 9Hz.

IH), 6.50 (d, J=9Hz, LH),
6.83 (s, LH), 7.27 (m, 15H)
ppm.

B, R’ Sue PCI.

3ξ-Hydroxy-7β-phenylacetylaminocephalic acid diphenylmethyl ester (4ξ-carboxylic acid) was suspended in 13 parts of dichloromethane and added to 0.0
Add 3 equivalents of pyridine at ~-5°C. This is -20～-
After cooling to 25°C, 2.7 equivalents of phosphorus pentachloride were added,
7-(2-) if stirred at -10~-15℃ for 4 hours
An m solution of di-2-2-chloromethylideneamino 3-tetrachlorophosphonyloxycepham-4ξ-carboxylic acid diphenylmethyl ester (3b) is obtained.

C,R14CHsSO*- 3ξ-hydroxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester (ri) was suspended in 18 parts of dichloromethane, cooled to -30°C, and 6 equivalents of methanesulfonyl chloride Then, 6 equivalents of pyridine are added dropwise.The mixture is reacted at 0 to 5°C for 17 hours.The reaction solution is diluted with ice water, and the organic layer is taken, washed with hydrochloric acid and water, dried, and concentrated.The residue is Crystallization from ethyl acetate-hexane gives 3ξ-mesyloxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester (3c).

Yield, 96.5%, mp, 151-152°C (decomposition).

I R (Nujol) v: 3300. 176
5. 1720. 1660°1350.1180c
m-'.

NMR (CDC1,) δ: 2.65 (s
, 3H), 2.83 (m.

LH>, 3.40 (m, LH>, 3.57
(s, 2H), 4.9=5.1(m.

2H), 5.20 (d, J=5Hz, IH), 5.50
(dd, J, = 5Hz, J* = 9Hz, I
H), 6.43 (d, J=9Hz, IH)
, 6.87 (s, LH).

7.32 (s, 15H) ppta.

D, R' proverb p<HsC*HaSO*- 3ξ-Hydroxy-7β-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester ■ was suspended in 9 parts of dichloromethane, and 6 equivalents of pyridine was added to this while cooling with water. Add toluenesulfonyl chloride and heat to 0-5°C
The reaction mixture was diluted with ice water, and the organic layer was taken, washed with hydrochloric acid and water, dried, and concentrated. Crystallization of the residue from ethyl acetate-hexane gives 3ξ-P-toluenesulfonyloxy-7β-phenylacetylaminocephalic acid diphenylmethyl ester (3d). Yield: 84.7%.

mp, 133-136°C (decomposed).

I R (Nujol) ν: 3300.1760.17
30.1640.1310°1180 a1'.

NMR(CDCIs>8:2.43(s, 38),
2.70 (m, IH).

3.33 (m, LH), 3.60 (s, 28),
4.53-4.90 (m, 2H).

5.20 (d, J=4.5Hz, LH), 5.53 (
dd, J, = 4.5Hz + J-9Hz, IH)
, 6.16 (d, J=9Hz, 11)
, 6.83 (s, LH).

7.32 (m, 17H), 7.63 (d, J=
8Hz, 2H) ppm.

Example 4 (7-hypothesis amidation reaction) a'R"CHsCO-b'R'=PC1a-c:
R'=CH5SOa-d:R'=p-CHsC*Ha
SOm-A, R'■CH,C0- 3ξ-acetoxy-7β-phenylacederaminocepham-4ξ-carboxylic acid diphenylmethyl ester (3
Dissolve a) in 7 parts of dichloromethane, cool to -20 to 25°C, add 2 equivalents of pyridine and 1.7 equivalents of phosphorus pentachloride in a nitrogen atmosphere, and stir at -10 to -15°C for 4 hours. Add 12 parts of methanol at -30°C to the reaction solution and stir at -30°C for 3.5 hours and at 0-5°C for 2 hours.Concentrate the reaction solution, dilute with dichloromethane-water, and stir at 0-5°C for 20 minutes. After stirring, remove the organic layer, wash with sodium bicarbonate and water, dry, and concentrate. Dissolve the residue in a small amount of dichloromethane and add ether to crystallize. If the crystals are collected by filtration, dissolved in methanol and water, neutralized with sodium bicarbonate water, and crystallized by adding water, 3ξ-acetoxy-
7β-aminocepham-4ξ-carboxylic acid diphenylmethyl ester ~156°C (decomposition).

I R (Nujol) l/: 3350. 3
300. 1760. 1750.

1735 am"'.

NMR (CDCIs) 8: 1.60 (s,
3H), 1.77 (m.

2H), 2.70(m, 11(), 3.2
7 (m, LH), 4.40 (m, LH).

5.13 (m, 3H), 6.90 (s, I
H), 7.23 (s, 10H) ppm.

B, R1mPCl4 To a solution of 7-(2-phenyl-2-chloromethylideneamino-3-tetrachlorophosphonyloxysepam-4ξ-carboxylic acid diphenylmethyl ester obtained in B of Example 3) was added 20 parts of methanol or in butanol 10
9. Cool the reaction solution to -20 to -25°C, add 14 equivalents of triethylamine dropwise, and stir at 0 to 5°C for 15 hours. To this-
Add 20 parts of water at 5 to -10°C, stir for 10 minutes, and then extract with dichloromethane. Add the extract to hydrochloric acid, water, 5
% sodium bicarbonate and water, dry, and concentrate. Crystallization of the residue from ethyl acetate yields 7-amino-3-
Cephem-4-carboxylic acid diphenylmethyl ester (
Get 9.

Yield: 47.3% (from methanol), 37.2% (from imbutanol).

mp, 159-160°C (decomposed).

C, R' 糟CH, So I - 3ξ-Mesyloxy-7β-phenylacetylamine cepham-4ξ-carboxylic acid diphenyl mefl ester (
3C) in 7 parts of dichloromethane, -20 to -25
Cool to ℃ and add 2 equivalents of pyridine and 1.
Add 7 equivalents and stir at -10 to -15℃ for 4 hours.
Add 11 parts of methanol at -25 to -30°C to the reaction solution,
Stir at -30°C for 30 minutes and at -5 to 0°C for 2.5 hours. Dilute the reaction solution with dichloromethane-ice water,
After stirring for 20 minutes at °C, remove the organic layer, wash with water, dry and concentrate. The residue is dissolved in a small amount of dichloromethane and crystallized by adding ether. The crystals were collected by filtration, dissolved in methanol-water, and neutralized with sodium bicarbonate water.
Crystallization by adding water yields 3ξ-mesyloxy-7β-aminocepham-4ξ-carboxylic acid diphenylmethyl ester (4c). Yield: 55.7%, mp, 145
~147°C (decomposed).

I R (Nujol) ν: 3350.3300.1
760.1735°1340.1170 cm-'.

NMR (CDC1,) ε: 1.77 (s, 21)
, 2.67 (s.

3H), 2.87 (n+, IH), 3.50 (m
, IH), 4°46 (d, J=4Hz, l), 5.13 (m, 21), 5.20 (d, J=
4Hz, IH).

6.90(s, 1)1), 7:33(s,
10H) ppm.

D, R'=p-CHsC*HaSOm-3ξ-p
-Toluenesulfonyloxy-7β-puenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester (3d) was dissolved in 7 parts of dichloromethane, and -20
Cool to -25°C, add 2 equivalents of pyridine and 1.7 equivalents of phosphorus pentachloride in a nitrogen atmosphere, and stir at -10 to -15°C for 4 hours. Add 12 parts of methanol at 30°C to the reaction solution.
Stir at 25 to -30°C for 30 minutes and at 0 to 5°C for 2 hours. Dilute the reaction solution with ice water and dichloromethane, and stir at 0 to -30°C for 2 hours.
After stirring for 20 minutes at 5°C, remove the organic layer, wash with water, dry, and concentrate. Crystallization of the residue from dichloromethane-ether gives 3ξ-p-toluenesulfonyloxy-7β-aminocephalic acid diphenylmethyl ester (4d) tosylate.

mp, 190-194°C (decomposed).

I R (Nujol) ν: 1780.1750.1
360°1180 am-'.

Elemental analysis: C,, Hs, N, O*Ss-) (to and L
-C calculated value (X): c, 56.73; tt, 4.
90; N, 3.89+5, 13.36° Experimental value (X): C, 56,90i H, 4,78; N
, 3.97; S, 13.20° Example 5 (Deacyloxylation reaction) a: R'=CH1CO-1): R'=PCI-
-C'R"CH+5(11-d'R"p-CHsC
J4SOt-A, R'-CHICo- 3ξ-acetoxy-7β-aminocepham-4ξ-carboxylic acid diphenylmethyl ester Dissolved in dichloromethane, added 1 to 3 equivalents of triethylamine at -20 to -25 °C, and gradually heated to 0 to 5 °C. Raise the temperature to -100 mL and set it up overnight. Add 20 parts of ice water to this, stir for 20 minutes, and then extract with dichloromethane. Wash the extract with hydrochloric acid, water, 7% aqueous sodium bicarbonate, and 5% brine, dry, and concentrate. Crystallization of the residue from ethyl acetate yields 7β-amino-3
-cephem-4-carboxylic acid diphenylmethyl ester (9 obtained. Yield: 61 from (1), 0%, mp.15
9-160°C (decomposition).

I R (Nujol): 3350. 330
0. 1770. 1720.

1630cm-'.

NMR (CDC1.) δ: 2.76 (s, 2H)
, 3.43 (m, 2H).

4,83 (m. 28), 6.57 (m. IH),
6.90 (s. LH>, 7.30 (s. 108
) ppm.

Similarly, 1 to 3 equivalents of triethylamine were added to the products of Examples 4A to 4D in dichloromethane at 0 to 5°C to form 2 to 15
The same product is obtained if allowed to act for a longer period of time.

Example 6 Under similar conditions as in Example 5, the corresponding 3ξ-mesyloxy-7-acylaminocephem-4ξ-carboxylic acid diphenylmethyl ester (3) was treated with 1 to 3 equivalents of triethylamine in dichloromethane at room temperature for 1 to 6 hours. When allowed to act, the compound (■) in Table 2 is obtained.

Example 7 (Acylation of 7-amino) 7-Amino-3-acetoxycepham-4-carboxylic acid diphenylmethyl ester (9 was dissolved in 7 parts of dichloromethane, cooled to -30 to -10°C, Add 1.7 equivalents of pyridine and 1.1 equivalents of phenylacetic acid chloride,
Stir for 0 minutes.

Add 1-g equivalent of triethylamine to the reaction solution and heat at 0-5°
Stir at C for 24 hours, dilute with ice water, remove the organic layer,
Wash with hydrochloric acid and water, dry and concentrate.

If the residue is crystallized from ethyl acetate-ether, 7β-
Phenylacetylamine-3-cephem-4-carboxylic acid diphenylmethyl ester (■ is obtained. Yield near 0.
0%, mp. 170-171°C (decomposition).

Under the same conditions as above, 7-amino-3-acyloxycepham-4-carboxylic acid diphenylmethyl ester (9
Dissolve in 3 to 10 parts of dichloromethane and heat to -40 to -5°C.
1 to 2 equivalents of pyridine and 1 to 2 equivalents of carboxylic acid chloride corresponding to each 7-position side chain were added to the
Stir the time. Add 1 to 3 equivalents of triethylamine to the reaction solution, and allow to stand at 0 to 5°C for 12 hours, then wash with hydrochloric acid, water, and rehydrated sodium hydrogen aqueous solution, dry, and concentrate. Compound (6) shown in Table 2 can be synthesized by crystallizing the residue from ethyl acetate-ether.

(Left below) Example 8 (Elimination of 3-acyloxy and 7-acyl) a'
R1=CH5CO-c' R12CHsSO*-d:
R'=p-CHsCsl(tSOt-e: R'=H
A, R'-CH, C0- 1) 3ξ-acetoxy-7β-phenylacetylamine cepham-4ξ-carboxylic acid diphenylmethyl ester (3a) was dissolved in 13 parts of dichloromethane, and in a nitrogen atmosphere,
Cool to -5~θ℃, add 2 equivalents of pyridine,
After cooling to -25 °C and adding 1.7 equivalents of phosphorus pentachloride, stir at -15 to -10 °C for 4 hours.
Add 20 parts of methanol at 0 to -30°C and 5 parts of dichloromethane and stir at -25 to -30°C for 3.5 hours. The reaction solution is brought to -20 to -25°C, and 100 g equivalent of triethylamine is added dropwise to this. Leave overnight at 0-5°C0
The reaction solution was diluted with 20 parts of ice water and stirred for 20 minutes, then the organic layer was taken, washed with hydrochloric acid, water, aqueous sodium bicarbonate and water, dried and concentrated. The residue is crystallized from ethyl acetate to give 7β-amino-3-cephem-4-carboxylic acid diphenylmethyl ester (9. Yield: 60.
2%.

2) The raw material (3a) was dissolved in 13 parts of dichloromethane, cooled to -5 to 0°C in a nitrogen atmosphere, added 2 equivalents of pyridine, cooled to -30 to -25°C, and dissolved in 1.7 parts of phosphorus pentachloride.
After adding an equivalent amount, stir at -15 to -10°C for 4 hours. Cool the reaction solution to -25 to -30°C, and add 10 parts of inbutanol at -30 to -20°C in a nitrogen atmosphere. ,
The reaction solution was left overnight at 0 to 5°C and the temperature was brought to -20 to -25°C, and 109 g equivalent of triethylamine was added dropwise to it.
Leave the reaction solution at ~5°C overnight in dichloromethane 20°C.
After stirring for 20 minutes, remove the organic layer, wash with hydrochloric acid, water, sodium bicarbonate and water, dry and concentrate. Crystallization of the residue from ethyl acetate gives 7β-amino-3-cephem-4-carboxylic acid diphenylmethyl ester (9. Yield: 60.8
%.

C, R'-CHl5OI- 3ξ-mesyloxy-7β-phenylacetylamine cepham-4ξ-carboxylic acid diphenylmethyl ester (
3c) was dissolved in 7 parts of dichloromethane, and -2
Cool to 0 to -25°C, add 2 equivalents of pyridine and 1 phosphorus pentachloride.
．． After adding 7 equivalents, stir at -15 to -10°C for 4 hours. Add 12 parts of methanol at -40 to -30°C to the reaction solution, and stir at -30°C for 30 minutes and 0 to 5°C for 2.5 hours. The temperature of the stirred reaction solution is -30°C, 8.1 equivalents of triethylamine are added dropwise thereto, and the mixture is left at 0 to 5°C overnight.

Dilute the reaction solution with ice water and dichloromethane, and heat at 0 to 5℃ for 2 hours.
After stirring for 0 minutes, remove the organic layer, wash with hydrochloric acid, water, sodium bicarbonate and water, dry and concentrate. Crystallization of the residue from ethyl acetate yields 7β-amino-3-
Cephem-4-carboxylic acid diphenylmethyl ester (
Get 9. Yield: 55.7%.

D, R' gastric p-CHsCsHaSO*-3ξ-p-tosyloxy-7β-phenylacetylamine cepham-4
ξ-Carboxylic acid diphenylmethyl ester (3d) was dissolved in 7 parts of dichloromethane, cooled to -10 to -15°C, and 2 equivalents of pyridine and 1.7 equivalents of phosphorus pentachloride were added.
Stir the reaction solution for 4 hours at -15 to -10 °C.
Add 12 parts of methanol at 0 to -30°C and stir at -30°C for 30 minutes and at 0 to 5°C for 2.5 hours. Bring the reaction solution to -30 to -40°C, and add 8 equivalents of triethylamine dropwise to this. , Stir at 0-5℃ for 2 hours, then leave overnight.Dilute the reaction solution with ice water and dichloromethane, and stir at 0-5℃.
After stirring for 20 minutes, remove the organic layer and add hydrochloric acid, water,
Wash with sodium bicarbonate and water, dry, and concentrate.

Crystallization of the residue from ethyl acetate yields 7β-amino-
3-cephem-4-carboxylic acid diphenylmethyl ester (9 is obtained. Yield: 57.9%.

E, R'-H ■) 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, -2
After cooling to 0 to -25°C and adding 2.7 equivalents of phosphorus pentachloride, the reaction solution was stirred for 4 hours at -15 to -10°C.
Add 20 parts of methanol at 40 to -30°C, -10 to -
Stir 1 reaction solution at 15℃ for 3 hours at -20~-25℃
To this, 12 equivalents of triethylamine was added dropwise, 0 to 5
The 0 reaction solution left overnight at °C was diluted with 20 parts of ice water.
After stirring at ~5°C for 20 minutes, remove the organic layer, wash with hydrochloric acid, water, hydrogen carbonate solution, and water, dry, and concentrate. Crystallization of the residue from ethyl acetate gives 7β-amino-3-cephem-4-carboxylic acid diphenylmethyl ester (9. Yield: 47.3%.

2) Suspend the raw material (3e) in 13 parts of dichloromethane, cool to -5 to 0°C in a nitrogen atmosphere, add 3 equivalents of pyridine, cool to -20 to -25°C, and dissolve 2 parts of phosphorus pentachloride. After adding .7 equivalents of inbutanol at -40 to -30°C to the reaction solution, stir at -15 to -10°C for 4 hours.
After adding 1 part and stirring at 0 to 5°C for 2 hours,
The temperature of the reaction solution left overnight at 5°C is set to -20 to -25°C,
14 equivalents of triethylamine were added dropwise to this, and the mixture was left overnight at 0 to 5°C. The reaction solution was diluted with ice water and dichloromethane, stirred for 20 minutes, and then the organic layer was removed, and hydrochloric acid, water,
Wash with sodium bicarbonate and water, dry, and concentrate.

Crystallization of the residue from ethyl acetate yields 7β-amino-
3-cephem-4-carboxylic acid diphenylmethyl ester (9 is obtained. Yield, 37.2%.

Reference Example 7-Amino-3-cephem-4-carboxylic acid diphenylmethyl ester (9 was dissolved in 7 parts of dichloromethane, 0
This was followed by the chloride 1 of the carboxylic acid corresponding to each 7-position side chain at °C.
Add ~2 equivalents and 1-2 equivalents of pyridine and stir for 1-5 hours. Wash the reaction with hydrochloric acid and water, dry, and concentrate.

Compound (6) in Table 2 can be synthesized by crystallizing the residue from ethyl acetate-ether.

(Margins below) Procedural official document (spontaneous) May 29, 1985 1. Indication of the case 1982 Patent Application No. 275709 2. Title of the invention and method for producing droxycepham carboxylic acid ester 3. Amendment Patent applicant 4, agent address: 5-12-4 Sagisu, Fukushima-ku, Osaka 553 Shionogi & Co., Ltd. Patent Department Scope column and Detailed description of the invention column 7, Contents of amendment (1) The claims on page 1 of the specification are corrected as shown in the attached sheet.

(1 pyridine on page 7, line 7 of the same book) is 1 aromatic base.
I am corrected.

0) Insert "" from Table 1, Table 2, in front of 17-amino on page 36, line 19.

(4) Compounds (e
, is corrected as "corresponding carboxy compound j.

(In the structural formula of the compound (υ and (ri) on page 38 of 9), 3
The position substituent 'CI' is corrected to 'OH4.

8. List of attached documents At least 1 copy of paper (attachment) 3-oxocepham-4-carboxylic acid aralkyl ester or its enol form in an anhydrous organic solvent at -20
1. A method for producing a hydroxycepham carboxylic acid ester, which comprises reducing with an alkali metal borohydride at a temperature below °C to produce the corresponding aralkyl 3-hydroxycepham-4-carboxylic acid ester.

Dish 3ξ-Hydroxy-7β-acylaminocephalic acid
A 4ξ-carboxylic acid ester is reacted with a chloride or anhydride of a carboxylic acid or a sulfonic acid in the presence of an aromatic base as an acid scavenger to obtain 3-(acyl carboxylate or acyl sulfonate)oxy-7β-acyl. A method for producing aminocefam-4ξ-carboxylic acid ester.

Claims (2)

[Claims] (1) 3-oxocepham-4-carboxylic acid aralkyl ester or its enol form in an anhydrous organic solvent, -2
A method for producing a hydroxycefam carboxylic acid ester, which comprises reducing the corresponding 3-hydroxycefam-4-carboxylic acid aralkyl ester by reducing the borohydride with an alkali metal hydride at 0°C or lower. (2) 3ξ-Hydroxy-7β-acylaminocepham-4ξ-carboxylic acid ester is reacted with a chloride or anhydride of a carboxylic acid or sulfonic acid in the presence of an aromatic base as an acid scavenger. A method for producing (acyl carboxylate or acyl sulfonate) oxy-7β-acylaminocepham-4ξ-carboxylic acid ester.