JPS6133832B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for cleaving ester groups. According to the method of the present invention, the ester group of Δ ³ -cephalosporanic acid p-nitrobenzyl ester can be cleaved to produce the corresponding cephalosporanic acid derivative. This cleavage reaction is carried out by reacting the cephalosporanic acid ester with dithionite under basic conditions. A process has been developed for converting penicillin sulfoxide esters to desacetoxycephalosporanic acid esters, and improvements have been made to the process to produce certain esters of penicillin starting materials and the resulting desacetoxycephalosporin esters. With the discovery of a method to easily cleave certain esters of
Recently, methods for the semisynthesis of 7-acylamidodesacetoxycephalosporin antibiotics from penicillin starting materials have become important. The discovery that certain solvents can be used to specifically direct the thermal rearrangement of penicillin sulfoxide esters to form the corresponding desacetoxycephalosporin esters and to permit processing at relatively low temperatures has been made. The result was a further improvement of the method. It has been recognized that certain 7-acylamidodesacetoxycephalosporanic acid compounds have unique properties as antibiotics in their own right. For example, cephalexin, 7-[D-α-aminophenylacetamide]-3-methyl-Δ ³ -cephem-4
- Oral administration of carboxylic acid zwitterionic forms and their pharmacologically acceptable cationic and anionic salts for the control of infections caused by penicillin-resistant bacteria such as Staphylothucus aureus and many other Gram-positive and Gram-negative bacteria. It is useful as an antibiotic. The reaction in the ring expansion method described above can be represented by the following chemical formula: [In the formula, R _a represents an acylamide residue, and R represents an ester-forming alcohol residue. ] As is clear from the above formula, both the starting material and the product are in the form of esters. An example of a preferred ester used in such a ring expansion method is p-nitrobenzyl ester. However, since the ester form has little or no antibiotic activity, the production of desacetoxycephalosporin antibiotics requires cleavage of the ester group to form the corresponding acid. Currently, cleavage of p-nitrobenzyl esters of Δ ³ -desacetoxycephalosporins uses metallic zinc or hydrogen under acidic conditions. However, such known p-
In the nitrobenzyl ester cleavage method, the desired Δ ³
- The by-product of insoluble substances is unavoidable, which complicates the isolation and recovery of desacetoxycephalosporanic acid. It is therefore an object of the present invention to provide a new and improved process for converting the p-nitrobenzyl esters of Δ ³ -cephalosporins into the corresponding acids, while avoiding the formation of unnecessary by-products, as well as for the conversion of p-nitrobenzyl esters of Δ ³ -cephalosporin acids into the corresponding acids. - To provide a new and improved method for cleaving nitrobenzyl esters to form the corresponding acids in high purity. That is, according to the invention, Δ ³ -desacetoxycephalosporanic acid, Δ ³ -cephalosporanic acid 3-alkylthiomethyl ester or Δ ³
- By reacting p-nitrobenzyl ester of cephalosporanic acid 3-alkoxymethyl ester with dithionite under basic conditions,
The p-nitrobenzyl ester group can be cleaved to generate the corresponding acid. The use of dithionite allows the cleavage reaction to occur effectively without the by-product of insoluble organic matter as occurs when using zinc or hydrogen. As the dithionite, it is preferable to use an alkali metal salt such as sodium dithionite, potassium dithionite, or lithium dithionite, but various other dithionite salts may also be used. . As mentioned above, this reaction is carried out under basic conditions, that is, at a pH of 7 or higher. Any base may be used to adjust the pH of the reaction mixture as long as it does not substantially react with the reaction reagent. Representative examples of suitable bases include:
Alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, lithium hydroxide) and ammonium hydroxide, as well as organic bases such as secondary and tertiary amines (e.g. triethylamine, diethylamine, tripropylamine, dipropylamine, pyridine, morpholine, piperidine), etc. Although the reaction is preferably carried out in an inert solvent, it may sometimes be desirable to use an organic base as a solvent. Examples of solvents include water, alkanols (e.g. methanol, ethanol,
isopropanol), aliphatic ketones (e.g. acetone, methyl ethyl ketone), chlorinated hydrocarbons (e.g. chloroform, methylene chloride, carbon tetrachloride, dichloroethane), aliphatic nitriles (e.g. acetonitrile), and various other solvents. can be used. In addition, these may be used as a mixture. Although the reaction temperature is not critical and can be varied within a wide range, the best results are usually obtained when the reaction temperature is -20 to 100°C, preferably 0 to 50°C. Similarly, there are no particular restrictions on the amount of dithionite used, but generally at least 1 mole of dithionite is used per mole of cephalosporanate in the reaction mixture. The best results are obtained when using a ratio of 3 to 6 moles of dithionite per mole of ester, the presence of excess dithionite being preferred to drive the reaction to completion. As the p-nitrobenzyl ester of Δ ³ -cephalosporic acid, it is preferable to use a compound represented by the following formula: [In the formula, R ₁ is a hydrogen atom or an acyl group, R ₆ is a hydrogen atom, an alkylthio group having 1 to 6 carbon atoms (for example, methylthio, ethylthio, isopropylthio, butylthio) or an alkoxy group having 1 to 6 carbon atoms (for example, methoxy , ethoxy, propoxy). In the practice of this invention, various acyls described in the literature regarding penicillin and cephalosporin antibiotics can be used since the various R ₁ groups do not essentially participate in the reaction. Representative examples of acyl groups that may be present in the starting material are as follows. (1) [In the formula, n is 0 or an integer of 1 to 6, and _R2 is an organic group such as a substituted or unsubstituted aryl having 6 to 14 carbon atoms. ] Suitable aryl groups are those derived from benzene or naphthalene and are represented by the following formula:

[Formula] or

[Formula] [wherein Q is a hydrogen atom or one or more substituents (e.g. C ₁ -C ₃ alkyl (e.g. methyl, ethyl, propyl, isopropyl), C ₁ -C ₃ alkoxy (e.g. methoxy,
ethoxy, propoxy), cyano, nitro, hydroxy, halogen (e.g. chlorine, fluorine, bromine, iodine), trifluoromethyl, carboxy, amino, C1 _{- C4} carboxyalkyl, carboxyamidoalkyl [ _H2N -C(0 )-alkyl] (e.g. carboxyamidomethyl,
carboxyamidoethyl), etc. )] Therefore, specific examples of the above acyl group include the following: benzoyl, phenylacetyl, β-phenylpropionyl, naphthoyl, naphthylacetyl, γ-phenylbutyryl, p-methylbenzoyl, 2,4- Dimethylphenylacetyl, 5-methoxynaphthylacetyl, p-cyanophenylacetyl, 4-nitronaphthoyl, 3-nitrobenzoyl, 3.5
-dicyanonaphthylacetyl, β-(3-nitrophenyl)propionyl, p-hydroxybenzoyl, 4-hydroxyphenylacetyl,
p-chlorophenylacetyl, m-bromobenzoyl, 3-trifluoromethylphenylacetyl, 0-carboxyphenylacetyl, m-
Carboxymethylphenylacetyl, m-carboxyamidomethylphenylacetyl, β-
(5-carboxamidomethylnaphthyl)propionyl, aminobenzoyl, aminophenylacetyl, etc. R ₂ can also be cycloalkyl having 4 to 8 carbon atoms, and examples thereof include cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Furthermore, R ₂ can also be a cycloalkyl group substituted with one or more of the above Q substituents. Therefore, specific examples of the acyl group in such cases include cyclopentanoyl, cyclohexanoyl, 3-methylcyclohexanoyl, cyclobutylcarbonyl, 2-methoxycyclohexanoyl, 3-chlorocyclohexylacetyl,
Cyclopentyl acetyl, β-cyclopentylpropionyl, 3-methoxycyclohexylacetyl, 2-cyanocyclopentyl acetyl,
Examples include 3-nitrocyclohexanoyl, 3-carboxycyclohexylacetyl, 3-carboxamidomethylcyclohexylacetyl, and the like. R ₂ can also be a heterocyclic ring in which the heteroatom is O, S, N or a combination thereof;
Examples include dioxanyl, 2-furyl, 3-
Furyl, imidazolyl, isoxazolyl, morpholinyl, oxazolyl, pyranyl, pyrazinyl, pyrazolyl, N-pyridyl, 2-pyridyl, 3-pyridyl, pyrimidyl, N-pyryl,
2-pyryl, 3-pyryl, thiazolyl, 2-thienyl, 3-thienyl, 2-benzothienyl,
3-benzothienyl, triazinyl, triazolyl, etc. or partially or fully hydrogenated tetrahydrofuryl, imidazolinyl, imidazolidyl, piperidyl, tetrahydropyrimidyl, pyrrolidyl, etc. or substituted with one or more Q substituents as described above. Groups of the above, such as picolyl, methylfuryl, methylthienyl, nitrofuryl, cyanofuryl, nitrobenzothienyl, nitropyridyl, cyanopyridyl, methoxypyrimidyl, bromopyridyl,
Examples include trifluoromethylpyridyl. Therefore, specific examples of the acyl group when R ₂ is a heterocyclic group include dioxanylacetyl, 2
-furylcarbonyl, β-pyrazinylpropionyl, 2-pyridylacetyl, 3-pyridylcarbonyl, 2-thienylacetyl, 3-benzothienylcarbonyl, piperidylacetyl, pyrrolidylcarbonyl, nitrobenzothienylacetyl, β-(nitrophenyl)- Examples include propionyl and cyanopyridylcarbonyl. (2) [In the formula, R ₃ is an alkyl group having 1 to 8 carbon atoms (for example, methyl, ethyl, isopropyl, n-butyl, t-butyl, hexyl, isooctyl) or an alkenyl group having 2 to 8 carbon atoms (for example, vinyl, allyl, 2-butenyl, 3-hexenyl). R ₃ may also be an alkyl or alkenyl group as described above with one or more substituents such as amino, cyano, nitro, hydroxy, halogen (e.g. chlorine, fluorine, bromine). ,iodine),
carboxy, carboxamide

Examples include [Formula]. Therefore, examples of acyl groups in these cases include acetyl, propionyl, acrylic, crotoyl, 2
-aminoacetyl, 3-chloropropionyl,
Included are 6-heptenoyl, adipoyl, 3-hydroxypropionyl, 5-nitrohexanoyl, and the like. (3) [In the formula, n is the same as above, m is 0 or 1 to 5
, X is Q or S, R ₄ is R ₂ as above
(i.e. aryl, cycloalkyl or heterocyclic group; optionally substituted) or _R3 (i.e. _C1 - _C8 alkyl, _C2 - _C8 alkenyl, etc.; optionally substituted). It is. ] Therefore, typical examples of the acyl group in this case include:
t-butoxycarbonyl, t-butoxyacetyl, ethoxyacetyl, t-butylmercaptocarbonyl, t-butylmercaptoacetyl,
vinyloxyacetyl, allylmercaptoacetyl, 3-bromopropoxyacetyl, 3-hydroxypropylcarbonyl, 2-thienyloxyacetyl, piperidylmercaptoacetyl, 2-pyridyloxycarbonyl, phenoxyacetyl, naphthoxyacetyl, phenoxycarbonyl, Aminophenoxyacetyl, β-
Phenoxypropionyl, cyclohexyloxyacetyl, chlorocyclopentyloxyacetyl, benzyloxyacetyl, phenylmercaptoacetyl, phenylbutoxyacetyl,
Includes phenylethylmercaptopropionyl, phenylmercaptoacetyl, and the like. (Four) [Wherein, Y is an amino group, a protected amino group, a hydroxyl group, a _C1 - _C3 alkoxy group (e.g. methoxy, ethoxy), a carboxyl group, or a _C1 - _C3
Alkanoyloxy groups (e.g. acetoxy,
propionyloxy), R ₅ is R ₂ as described above
(i.e. aryl, heterocycle or cycloalkyl). ] Therefore, typical examples of the acyl group in this case include 2-phenyl-2-aminoacetyl, 2-
(p-methoxyphenyl)-2-aminoacetyl, 2-cyclohexyl-2-methoxyacetyl, 2-phenyl-2-acetoxyacetyl,
2-(2'-pyridyl)-2-hydroxyacetyl, 2-piperidyl-2-aminoacetyl, 2
-(2'-pyridyl)-2-hydroxyacetyl,
2-piperidyl-2-aminoacetyl, 2-
(2-thienyl)-2-acetoxyacetyl and the like are included. 7- with free amino group as starting material
When using a substance having a free amino group such as ADCA or 7-acylamidodesacetoxycephalosporanic acid ester, it is generally preferred to use the salt thereof. For this reason, it is preferable to use sulfonates such as tosylate and naphthalene sulfonate. Sulfonate salts are stable, convenient to handle, and easily dissolved in the reaction mixture at the beginning of the reaction. Note that R ₁ may be various acyl groups other than those mentioned above, and specific examples thereof include phenyl-α·α-dimethylacetyl and its Q-substituted product. Representative examples of suitable esters that can be converted to the corresponding 3-cephalosporic acids include the following compounds: 7-amino-Δ ³ -desacetoxycephalosporanic acid p-nitrobenzyl ester, 7-(allylmercaptomethylacetamide). ) ^-Δ3 -desacetoxycephalosporanic acid p-nitrobenzyl ester, 7-phenylacetamide- ^Δ3 -desacetoxycephalosporanic acid p-nitrobenzyl ester, 7-(γ-chlorocrotylmercaptoacetamide)- Δ ³ -desacetoxycephalosporanic acid p-nitrobenzyl ester, 7-
(n-butylmercaptoacetamide) -Δ ³ -
Desacetoxycephalosporanic acid p-nitrobenzyl ester, 7-(2',6'-dimethoxybenzamide) ^-Δ3 -desacetoxycephalosporanic acid p-nitrobenzyl ester, 7
-(cyclohexylacetamide- ^Δ3 -desacetoxycephalosporanic acid p-nitrobenzyl ester, 7-(cyclopentylbutyrylamide) ^-Δ3 -desacetoxycephalosporanic acid p-nitrobenzyl ester, 7-
(3'-Pyridylacetamide) ^-Δ3 -desacetoxycephalosporanic acid p-nitrobenzyl ester, 7-phenylmercaptoacetamide- ^Δ3 -desacetoxycephalosporanic acid p-nitrobenzyl ester, 7-benzyloxyacetamide -Δ ³ -desacetoxycephalosporanic acid p-nitrobenzyl ester,
7-(4'-methylphenylbutyramide)-Δ ³
-Desacetoxycephalosporanic acid p-nitrobenzyl ester, 7-(3'-isopropylbenzylmercaptoacetamide)-Δ ³ -Desacetoxycephalosporanic acid p-nitrobenzyl ester, 7-benzylmercaptopropionamide-Δ ³ - Desacetoxycephalosporanic acid p-nitrobenzyl ester, 7-
Phenylethyl mercaptopropionamide
Δ ³ -desacetoxycephalosporanic acid p-
nitrobenzyl ester, 7-phenylbutoxybutyrylamide-Δ ³ -desacetoxycephalosporanic acid p-nitrobenzyl ester,
7-(4'-Fluorophenoxyacetamide)-
Δ ³ -desacetoxycephalosporanic acid p-
Nitrobenzyl ester, 7-(3-bromophenylpropionamide)-Δ ³ -desacetoxycephalosporanic acid p-nitrobenzyl ester, 7-(phenyl-α・α-dimethylacetamide)-Δ ³ -desacetoxycef Allosporanic acid p-nitrobenzyl ester, 7-
(2′-phenyl-2′-aminoacetamide)-Δ
³ -desacetoxycephalosporanic acid p-nitrobenzyl ester, 7-(2'-thienylacetamide)-Δ ³ -desacetoxycephalosporanic acid p-nitrobenzyl ester, 7-
(2'-Nitrophenylmercaptoacetamide) ^-Δ3 -desacetoxycephalosporanic acid p-nitrobenzyl ester, 7-(4'-cyanophenylpropionamide) ^-Δ3 -desacetoxycephalosporanic acid p- Nitrobenzyl ester, 7-(4'-trifluoromethylphenylacetamide)-Δ ³ -desacetoxycephalosporanic acid p-nitrobenzyl ester, 7-amino-3-methylthiomethyl-Δ
³ -Cephalosporanic acid p-nitrobenzyl ester, 7-(2'-cyclohexylacetamide)-3-methoxymethyl-Δ ³ -Cephalosporanic acid p-nitrobenzyl ester, 7-
(3'-cyanophenylacetamide)-3-ethylthiomethyl-Δ ³ -cephalosporanic acid p-
such as nitrobenzyl ester. The starting material ester can be prepared in a number of ways. Penicillin sulfoxide p-nitrobenzyl ester is generally subjected to ring expansion to produce the desacetoxy starting material. As another method, 7-acylamido-Δ ³ -desacetoxycephalosporanic acid p-nitrobenzyl ester can be obtained by cleaving the 7-acylamido group.
-Amino- ^Δ3 -desacetoxycephalosporanic acid p-nitrobenzyl ester is acylated with a desired acylating agent according to a conventional method to produce 7-acylamide- ^Δ3 -desacetoxycephalosporanic acid p-nitrobenzyl ester. This may be subjected to ester cleavage according to the method of the present invention. The same applies to 3-alkylthiomethyl and 3-alkoxymethyl compounds. The 7-acyl group of the product produced by the process of the present invention may be cleaved by conventional treatments, and the resulting 7-amino compound can be re-acylated to give the desired compound by conventional methods. For example, penicillin V sulfoxide p-nitrobenzyl ester can be subjected to a ring expansion treatment to yield 7-phenoxyacetamidodesacetoxycephalosporanic acid p-nitrobenzyl ester, which can be treated according to the method of the invention. In this case, the corresponding acid is obtained, which can be deacylated and reacylated. An example of this is shown below: The enamine amino protecting group is removed by subjecting the product to a coordination treatment during the recovery operation. Product [XI] is the antibiotic 7-(2'-phenyl-2'-aminoacetamide)-Δ ³ -desacetoxycephalosporanic acid (cephalexin). Since the method of the present invention can be similarly applied to 7-amino-Δ ³ -desacetoxycephalosporanic acid p-nitrobenzyl ester, the above procedure initially
The corresponding 7 by cleaving the phenoxyacetamide group
-amino-Δ ³ -desacetoxycephalosporanic acid p-nitrobenzyl ester,
Deesterification and reacylation may then be carried out according to the method of the invention. In order to further clarify the basic concept of the method of the present invention, specific examples will be given and explained below, but this description does not limit the scope of the present invention in any way.
It should be understood that a wide variety of methods can be implemented within the scope of the invention. Example 1 5.39 g (10 mmol) of 7-amino-Δ ³ -desacetoxycephalosporanic acid p-nitrobenzyl ester tosylate salt was dissolved in 100 ml of an equal volume mixture of acetonitrile and water and IN sodium hydroxide was added. Adjust the pH of the solution to 7.5.
After addition of the sodium hydroxide, a portion of the solid ester precipitates to form a slurry. Add 45 ml of 1N sodium hydroxide to the resulting slurry.
Sodium dithionite 5.2g (30mmol)
Add over several minutes. During the addition, the temperature of the solution increases from 21°C to 31°C and the contained solids dissolve. After adding sodium dithionite, the mixture was stirred at room temperature for about 5 minutes and concentrated hydrochloric acid was added to adjust the pH of the solution.
Adjust to approximately 3.7. The mixture was stirred for 15 minutes while keeping the pH of the mixture at 3.7, and the solid formed was collected by filtration, washed with water, acetonitrile and acetone, and then dried under reduced pressure at 40°C. 1.89 g of 7-amino-Δ ³ -desacetoxycephalosporanic acid (purity 98
%). Melting point: 241-243°C (decomposed) Example 2 7-(2′-phenyl-2′-aminoacetamide)-Δ ³ -desacetoxycephalosporanic acid p-nitrobenzyl ester tosylate salt 3.75
(5 mmol) was stirred with 36 ml of methanol and the pH of the solution was adjusted by adding 0.7 ml of triethylamine.
Adjust to 7 or higher. Thereafter, 10 ml of water are added followed by a solution of 2.6 g (15 mmol) of sodium dithionite in 15 ml of 1N sodium hydroxide. During the addition of sodium dithionite, the temperature of the reaction mixture is
The temperature rises from 27℃ to 39℃, and the pH becomes 8.9 after addition. The mixture is then stirred and cooled to 5° C. to precipitate the inorganic solids, filtered off and washed with a cold mixture of methanol and water (3:2 by volume). Add hydrochloric acid to the filtrate to adjust the pH to 4.2, and remove methanol on a rotary evaporator. Acetonitrile 50
ml and add cephalexin seed crystals to the mixture. Add at least 50 ml of acetonitrile and cool the resulting mixture in the refrigerator for 2 hours. The solid thus obtained was collected by filtration, washed with a mixture of acetonitrile and water (4:1 by volume), and
The mixture was dried under reduced pressure at °C to obtain 0.48 g (purity: 86.4%) of 7(2'-phenyl-2'-aminoacetamide)-Δ ³ -desacetoxycephalosporanic acid. UV
(λmax): 260mμ (E=7560), NMR (D ₂ O/
pyridine): δ2.10 (s, 3H, CH ₃ ) 3.38 (d,
2H, 2-CH ₂ ), 5.17 (d, 1H, 6-H), 5.35
(s, 2H, NH ₂ ), 5.47 (s, 1H, benzene-
CHNH ₂ OH), 6.01 (d, 1H, 7-H), 7.53
(m, 3H, benzene-H), 7.80 (m, 2H, benzene-H) Example 3 7-phenylacetamido-Δ ³ -desacetoxycephalosporanic acid p-nitrobenzyl ester was stirred in methanol, Add piperidine to this mixture to adjust the pH to 7 or higher. Thereafter, a 1N potassium hydroxide solution of potassium dithionite is added to the mixture and the mixture is stirred for 15 minutes and cooled to about 5°C. The precipitated inorganic solid is filtered off, and concentrated hydrochloric acid is added to the filtrate to adjust the pH to about 3. Remove the methanol, add acetonitrile, and chill in the refrigerator for 1 hour. The solid produced is filtered, washed and dried. The product was identified as 7-phenyl-acetamido-Δ ³ -desacetoxycephalosporanic acid. Example 4 7-(2'-phenoxypropionamide) ^-Δ3
-Desacetoxycephalosporanic acid p-nitrobenzyl ester is dissolved in ethanol and triethylamine is added to the mixture to raise the pH and adjust it to basicity. Thereafter, a 1N sodium hydroxide solution of sodium dithionite is added over a period of about 5 minutes. During the addition the mixture temperature is approximately 25
It rises to ~32℃. The reaction mixture is then cooled to facilitate removal of inorganic solids, and the resulting supernatant is acidified with hydrochloric acid. The product was then isolated as described in Example 2. This product was identified as 7-(2'-phenoxypropionamide)-Δ ³ -desacetoxycephalosporanic acid. Example 5 7-(2′-thienylacetamide)-Δ ³ -desacetoxycephalosporanic acid p-nitrobenzyl ester is dissolved in a mixture of acetonitrile and water and sodium hydroxide is added to adjust the PH to 8.3. . . Thereafter, a sodium hydroxide solution of sodium dithionite is added. The mixture solution rises to about 37°C. The inorganic solids are separated, the filtrate is acidified, and the product is precipitated by the method described in Example 2. This product is 7-(2'-thienylacetamide)-Δ ³
-Identified as desacetoxycephalosporanic acid. UV (λmax): 2.37mμ (E=11600), 258
mμ (E = 7181); pKa = 5.5 Example 6 Procedure as described in Example 2 using 7-(allylmercaptomethylacetamide)-Δ ³ -desacetoxycephalosporanic acid p-nitrobenzyl ester as starting material Do this. By the same operation as above, the product is separated from the reaction mixture in good yield. This product was identified as 7-(allylmercaptomethylacetamide)-Δ ³ -desacetoxycephalosporanic acid. Example 7 The procedure described in Example 2 was carried out using 7-(2'-6'-dimethoxyphenoxyacetamide)-Δ ³ -desacetoxycephalosporanic acid p-nitrobenzyl ester as the starting material. The corresponding acid is obtained in good yield. Example 8 Using 7-(2'-cyclohexylpropionamide))-Δ ³ -desacetoxycephalosporanic acid p-nitrobenzyl ester as the starting material, the procedure described in Example 1 was carried out to obtain the corresponding acid i.e. 7-(2′-Cyclohexylpropionamide)-Δ ³ -desacetoxycephalosporanic acid is obtained in good yield. Example 9 7-Butyryl acetamide-Δ as starting material
Using ³ -desacetoxycephalosporanic acid p-nitrobenzyl ester and following the procedure described in Example 1, the corresponding acid is obtained in good yield. Example 10 By the procedure described in Example 2, 7-amino-
3-Methoxymethyl-Δ ³ -cephalosporanic acid p-nitrobenzyl ester is dissolved in methanol, and triethyleneamine is added to the resulting mixture to adjust the pH to 7 or higher. After that, potassium dithionite is added and the temperature of the reaction mixture reaches 25℃.
The temperature rises from 34℃ to 34℃. The mixture is then stirred, cooled to 5°C and the precipitated inorganic solids are filtered off. The filtrate was acidified and the product was separated according to the procedure described in Example 2, 7-
Amino-3-methoxymethyl-Δ ³ -cephalosporanic acid is obtained in good yield. NMR (DMSO- _d6 /
DCl): δ3.31 (s, 3H, 3- _CH2OCH3 ), _3.62
(s, 2H, 2-CH ₂ ), 4.24 (s, 2H, 3-
CH ₂ OCH ₃ ), 5.12 (d, 1H, 6-H), 5.24
(d, 1H, 7-H), 6.25 (broad, 2H,
NH ₂ ) Example 11 7-Phenoxyacetamide as starting material
Example 10 using 3-methylthiomethyl-Δ ³ -cephalosporanic acid p-nitrobenzyl ester
Perform the operations described in . Using sodium dithionite as the dithionite salt, 7 as the product
-Phenoxyacetamido-3-methylthiomethyl- ^Δ3 -cephalosporanic acid is obtained in good yield.
NMR ( _CDCl3 ): δ2.15(s, 3H, 3-
_CH2SCH3 ), _3.6 (s, 2H, 3-CH2 _{-SCH3 )} ,
3.7 (q, 2H, 2-CH ₂ ), 4.62 (s, 2H, benzene-OCH ₂ CONH), 5.15 (d, 1H, 6-H),
5.70 (q, 1H, 7-H), 7.3 (m, 5H, benzene-H), 7.6 (d, 1H, NH) Example 12 7-(2'-Thienylacetamido)-3-methoxymethyl as starting material - Δ ³ -cephalosporanic acid and the operation described in Example 10,
The corresponding acid is obtained in good yield. Melting point: 95-97°C Example 13 Using 7-phenylmercaptoacetamide-3-methylthiomethyl-Δ ³ -cephalosporanic acid p-nitrobenzyl ester as the starting material, the procedure described in Example 10 was carried out to prepare the corresponding acid. Obtained in yield. Example 14 7-(3′-Cyclohexylpropionamide)-3-methylthiomethyl-Δ ³ -cephalosporanic acid p-nitrobenzyl ester was reacted with sodium dithionite according to the procedure described in Example 10. The acid is obtained in good yield. Example 15 7-benzylmercaptopropionamido-3-methylthiomethyl Δ ³ -cephalosporanic acid p-nitrobenzyl ester as starting material is reacted with potassium dithionite by the procedure described in Example 10 to form the corresponding acid. Obtained in good yield. Example 16 7-(3′-pyridylpropionamide)-3-ethoxymethyl-
Δ ³ -cephalosporanic acid is reacted with potassium dithionite to give the corresponding acid in good yield.

Claims (1)

[Claims] 1 formula A method for cleaving an ester group, which comprises reacting the ester represented by the above with a dithionite at a pH of 7 or above to remove the p-nitrobenzyl ester group. [In the formula, R ₁ represents a hydrogen atom or an acyl group, and R ₆ represents a hydrogen atom, an alkylthio group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms. ].