JPH0134227B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 3-alkoxymethylcephalosporin. More specifically, the present invention relates to the general formula () [In the formula, R ₁ NH represents an amino group or a protected amino group. ] A general formula () characterized by reacting a compound represented by or a salt thereof with a lower alcohol in the presence of an iodine compound [In the formula, R ₁ NH has the same meaning as described above, and R ₂ represents a lower alkyl group. ] The present invention relates to a method for producing 3-alkoxymethylcephalosporin or a salt thereof.

Among the 3-alkoxymethylcephalosporin derivatives represented by the general formula () and their salts, there are known compounds that themselves exhibit strong antibacterial activity, as well as raw materials for cephalosporin antibiotics that have various antibacterial effects. It is important as such.

Methods for producing the 3-alkoxymethylcephalosporin derivative represented by the general formula () include: a) Reacting the 3-acetoxymethyl form with a lower alcohol (Japanese Patent Publication No. 10873/1983) b) Alkylating the 3-hydroxymethyl form (Special Publication No. 50-10873) c Method of reacting a 3-halomethyl compound with a lower alcohol (Special Publication No. 10872-1972) d Method of reacting a 3-haloacetoxymethyl compound with a lower alcohol (Special Publication No. 50-10872) No.) e Method of isomerizing Δ ² -3-halomethyl form to Δ ³ form after reaction with lower alcohol (J.Med.
Chem. 14 , 113 (1971)), but none of them are satisfactory as production methods on an industrial scale. That is, method a), as described in Example 1 of Japanese Patent Publication No. 10873/1987, has an extremely low yield and is difficult to separate and purify.

b) The method can be obtained in a good yield when diazomethane is reacted in the presence of boron trifluoride as an alkylating agent, but in this method, the 3-acetoxymethyl group must be changed into a 3-hydroxymethyl group; Problems include the need to protect the carboxyl group in position, and the use of large amounts of diazomethane poses problems in terms of toxicity and danger.

c) The process requires two steps to produce the 3-halomethyl compound, which is the raw material compound, from the industrially available 3-acetoxymethyl compound, as described in Japanese Patent Publication No. 10872/1987, page 218. Specifically, it requires three steps to protect the carboxyl group (see Patent Example 8), and the reaction yield between the 3-halomethyl compound and the alcohol is not necessarily good.

Similarly to method c), method d) requires 3 to 4 steps to produce the 3-haloacetoxymethyl compound as a raw material from the 3-acetoxymethyl compound, and the reaction yield with alcohol is poor.

e) The method is a step to increase the reactivity of the halogen in the halomethyl group and to synthesize the 3-methyl form by halogenating it, by first isomerizing the 3-cephem form to the 2-ceme form and then returning it to the 3-ceme form. is long.

Because of this situation, even if a useful compound is found among cephalosporins having an alkoxymethyl group at the 3-position, it is difficult to put it into practical use.

As a result of extensive research into this problem, the present inventors found that by reacting a solution of the raw material compound () or its salt with a lower alcohol in the presence of an iodine compound, the target compound () can be relatively produced in one step. They found that it can be produced with good yield, and after further studies on this reaction, they have completed the present invention.

When R ₁ NH represents an amino group (R ₁ is a hydrogen atom) in the starting compound (), 7-ACA (7-
It is a compound already widely known as aminocephalosporanic acid), and when R ₁ NH represents a protected amino group, it is not particularly limited as long as it is a protecting group that does not participate in this reaction, but it is usually an acylated amino group. An amino group that has formed a Schiff base or an acylated amino group is particularly preferred.

Examples of acyl groups include aliphatic acyl groups such as acetyl, propionyl, butyryl, glutaryl, adipoyl, and aminoadipoyl, aromatic acyl groups such as benzoyl, toluoyl, and phthaloyl, and phenylacetyl and phenoxyacetyl groups. Aliphatic acyl groups having an aromatic ring, heterocyclic acyl groups such as oxazolyl acetyl, thiazolyl acetyl, thienyl acetyl, etc., ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, trichloroethoxycarbonyl, etc. Examples include alkoxycarbonyl acyl groups such as. Furthermore, substituents such as an amino group, a hydroxyl group, a hydroxyimino group, an alkoxyimino group, an alkoxy group, a mercapto group, an alkylthio group, a cyano group, etc. may be present in these acyl moieties, and these substituents may be added as appropriate. may be protected with a group.

The amino group forming a Schiff base refers to a form such as a benzylidene amino group obtained by dehydration condensation of an aldehyde such as benzaldehyde or salicylaldehyde and an amino group.

Most of the starting compounds () are known compounds, but new compounds can also be easily produced by protecting the amino group of cephalosporin C or 7-aminocephalosporanic acid by a known method.

The raw material compound () and the salt of the compound () produced by the present invention are cephalosporin 4
A salt at the carboxyl group in position, usually with ammonia, a metal, or an organic base. Metals include alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, and the like. Examples of organic bases include triethylamine, dicyclohexylamine,
1-3 such as tertiary octylamine etc.
Examples include grade amines. In short, any salt can be used as long as it dissolves in the solvent during the reaction or is suitable for collecting the target product after the reaction, but sodium or potassium salts are usually suitable for the reaction, and the target product can be collected after the reaction. In addition to sodium salt and potassium salt, dicyclohexylamine salt is also suitable for collection.

The most important point in the method of the present invention is that the reaction is carried out in the presence of an iodine compound. In the absence of iodine compounds, the above-mentioned
As is clear from No. 10873 and experiments conducted by the present inventors, the reaction yield is extremely poor. On the other hand, it has been found that when the reaction is carried out in the presence of an iodine compound, the reaction proceeds smoothly and the reaction yield increases by 5 to 10 times or more.

The iodine compound used in this reaction is not particularly limited as long as it produces an iodine anion during the reaction, but examples of such compounds include lithium iodide, sodium iodide, potassium iodide, magnesium iodide, Metal iodides such as calcium iodide, quaternary ammoniums such as N-methylpyridinium iodide, N-methylquinolinium iodide, etc.
Examples include iodide. Among these, particularly preferred is sodium iodide.

The amount of iodine compound used varies depending on its type, reaction conditions, etc., but is usually used in an amount of 1 to 20 times the amount of the raw material compound.

The lower alcohol used in the method of the present invention includes 1 to 3 carbon atoms having 1 to 5 carbon atoms, such as methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, etc.
Grade alcohol can be given.

The reaction is usually carried out in a suitable solvent. As such a solvent, the lower alcohol used in the reaction can be used as is, and a polar solvent such as acetone, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, water, or a mixture thereof is suitable. .

There is no particular restriction on the reaction temperature, but it is usually preferable to heat the reaction to 40 to 80°C.

The reaction time varies depending on the reaction temperature, solvent, etc., but is usually carried out for 1 to 10 hours.

After completion of the reaction, the target compound is collected from the reaction mixture by a conventional method.

For example, when the organic solvent is distilled off from the reaction mixture and water is added, the pH is adjusted to 2 if the amino group is protected.
-3, if it is not protected, it can be collected by adjusting the pH to 6-7 and collecting the precipitate, or by extracting it with a suitable organic solvent. Furthermore, the target compound can also be isolated in the form of an ester, if necessary.

Next, the method of the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.

<Example 1> Method for producing 7-phenoxyacetamide-3-methoxymethyl-3-cepheme-4-carboxylic acid 5 g of 7-phenoxyacetamide-3-acetoxymethyl-3-cepheme-4-carboxylic acid sodium salt 490 mg of sodium bicarbonate and 50 mg of sodium iodide in 50 ml of 50% (V/V) methanol water
The mixture was heated and dissolved with g, and stirred at 63 to 65°C for 2 hours. The reaction solution was concentrated under reduced pressure to remove excess methanol, then 100 ml of ethyl acetate and 50 ml of 0.5% sodium bicarbonate were added and stirred, and the aqueous layer was separated. The ethyl acetate layer was washed once again with water, and the aqueous layers were combined and adjusted to pH 2-3 using hydrochloric acid. ethyl acetate 100ml
The extracts were combined and washed with 50 ml of 10% sodium thiosulfate water. Furthermore, after sequentially washing with water and saturated saline, it was dehydrated and dried over anhydrous magnesium sulfate, concentrated and dried under reduced pressure, and 7-phenoxyacetamide-3-methoxymethyl-3-cepheme-4
-3.87g of foamy solid containing carboxylic acid was obtained.

NMR spectrum (CDCl ₃ ) δppm 3.35 (3H, s, OCH ₃ ) 3.56 (2H, s, CH ₂ 2nd position) 4.39 (2H, s, CH ₂ 3rd position) 4.58 (2H, s) 5.02 (1H, d, J = 5Hz, 6th position) 5.88 (1H, dd, J = 5,9Hz, 7th position) 6.8-7.6 (6H, m, phenyl and NH) 9.18 (1H, s, COOH) IR spectrum (Nudiyol cm ^-1 ) 1790 β-Lactam (C=0) 1730 -COOH 1690 Amide (C=0) <Example 2> Method for producing 7-phenoxyacetamide-3-methoxymethyl-3-cephem-4-carboxylic acid dicyclohexylamine salt ( A) 20 g of 7-phenoxyacetamide-3-acetoxymethyl-3-cephem-4-carboxylic acid sodium salt was treated in the same manner as in Example 1 using 200 g of sodium iodide and 2 g of sodium bicarbonate in 50% methanol water. , 17.2 g of a solid containing 7-phenoxyacetamido-3-methoxymethyl-3-cephem-4-carboxylic acid was obtained. Dissolve this in 100ml of ethyl acetate, add 10ml of dicyclohexylamine and isopropyl alcohol.
100 ml was added and concentrated under reduced pressure to about half the volume. Crystals will start to precipitate, so after cooling them on ice for another 2 hours,
The residue was washed with isopropyl alcohol and dried to obtain 13.9 g of the title compound.

NMR spectrum (heavy DMSO, δppm) 0.8-2.3 (20H, m) 2.7-3.4 (2H, m) 3.18 (3H, s, OCH ₃ ) 3.38 (2H, 2nd position CH ₂ ) 4.19 (2H, s, 3rd position CH ₂ -O-) 4.60 (2H, s, CH ₂ ) 4.99 (1H, d, J = 5.5Hz, 6th place) 5.56 (1H, dd, J = 5.5, 9Hz, 7th place) 6.7~7.5 (5H, m, phenyl) 8.98 (1H, d, NH) IR spectrum (nudyol cm ^-1 ) 2350-2700 N ⁺ H ₂ 1770 C=0, β-lactam 1680 C=0, amide (B) 7-phenoxyacetamide 2 g of sodium salt of -3-acetoxymethyl-3-cephem-4-carboxylic acid was dissolved in 10 ml of methanol, 10 g of sodium iodide was added, and the mixture was heated to 60° C. and stirred for 4 hours. This was treated in the same manner as in Example 1, and 7
1.2 g of a solid containing -phenoxyacetamide-3-methoxymethyl-3-cephem-4-carboxylic acid was obtained. Add this to 10ml of ethyl acetate, remove the insoluble part, and add dicyclohexylamine to the liquid.
Added 0.6ml. Remove the reddish-brown precipitate that has formed,
20 ml of isopropyl alcohol was added to the mother liquor, and the mixture was concentrated to about half under reduced pressure, and when placed on ice, crystals were precipitated. This was taken, washed with isopropyl alcohol, and dried to obtain 830 mg of the title compound.

(C) After treatment of 500 mg of 7-phenoxyacetamide-3-acetoxymethyl-3-cepheme-4-carboxylic acid sodium salt with 5 g of calcium iodide tetrahydrate in 5 ml of methanol at 60°C for 2 hours, ( The mixture was treated in the same manner as in A) to obtain 130 mg of the title compound.

(D) After treatment of 500 mg of 7-phenoxyacetamide-3-acetoxymethyl-3-cephem-4-carboxylic acid sodium salt in 5 ml of methanol with 5 g of barium iodide dihydrate at 60°C for 2 hours (A) The mixture was treated in the same manner as above to obtain 88 mg of the title compound.

(E) After treatment of 500 mg of 7-phenoxyacetamide-3-acetoxymethyl-3-cepheme-4-carboxylic acid sodium salt with 5 g of magnesium iodide octahydrate in 5 ml of methanol at 60°C for 2 hours (A) The mixture was treated in the same manner as above to obtain 56 mg of the title compound.

<Example 3> Method for producing 7-phenoxyacetamide-3-ethoxymethyl-3-cepheme-4-carboxylic acid 1 g of 7-phenoxyacetamide-3-acetoxymethyl-3-cepheme-4-carboxylic acid sodium salt was dissolved in 10 ml of 50% ethanol water, 10 g of sodium iodide and 90 mg of sodium bicarbonate were added, and the mixture was heated to 65°C and stirred for 2 hours and 35 minutes. After cooling, 100 ml of ethyl acetate was added to the reaction solution, and the aqueous layer was acidified and extracted using an aqueous potassium bisulfate solution. 2 more
After extraction with 30 ml of ethyl acetate each time, these were combined, washed with 5% sodium thiosulfate water and saturated saline, dehydrated and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to dryness. Acetamide-3
550 mg of a solid containing -ethoxymethyl-3-cephem-4-carboxylic acid was obtained.

NMR spectrum (CDCl ₃ ) δppm 1.10 (3H, t, J=7Hz) 3.38 (2H, q, J=7Hz) 3.56 (2H, s, CH ₂ 2nd place) 4.40 (2H, s, CH ₂ 3rd place) 4.59 (2H, s) 5.00 (1H, d, J = 5Hz, 6th position) 5.84 (1H, dd, J = 5Hz, 9Hz, 7th position) 6.7-8 (7H, m) <Example 4> 7-phenyl Process for producing acetamido-3-methoxymethyl-3-cepheme-4-carboxylic acid 7-phenylacetamidocephalosporanic acid
A mixture of 19.5 g, 6.3 g of sodium bicarbonate, 190 g of sodium iodide, 100 ml of methanol and 100 ml of water was stirred at 65°C for 2.5 hours, then the methanol was distilled off and 200 ml of ethyl acetate was added. Adjust the pH to 2-3 with hydrochloric acid,
The ethyl acetate layer was separated and the aqueous layer was extracted three times with ethyl acetate. The extracts were combined and washed sequentially with 5% sodium thiosulfate, water, and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain about 10 g of crude product.

This was dissolved in a small amount of ethyl acetate and isopropanol, 6 ml of dicyclohexylamine was added, and the precipitated crystals were collected to obtain 9.2 g of the dicyclohexylamine salt of the title compound.

This was suspended in a mixture of ethyl acetate and water, adjusted to pH 2 with hydrochloric acid, and further extracted with ethyl acetate. The extract was washed with 5% hydrochloric acid and NaCl water, dried over magnesium sulfate, and the solvent was distilled off to obtain 5.3 g of 7-phenylacetamido-3-methoxymethyl-3-cephem-4-carboxylic acid as a pale yellow powder. Ta.

Melting point 158-160℃ (decomposed), recrystallized from ethyl acetate NMR spectrum (deuterated acetone) δppm 3.28 (3H, s, OCH ₃ ) 3.57 (2H, s, 2nd position CH ₂ ) 3.68 (2H, s, φ-CH ₂ ―) 4.29 (2H, s, 3rd place CH ₂ -O) 5.07 (1H, d, J=5Hz, 6th place H) 5.79 (1H, dd, J=5, J=9Hz, 7th place
H) 7.1 to 7.5 (5H, m, C ₆ H ₅ ) 8.03 (1H, d, J = 9Hz, NH) <Example 5> 7-[2-(2-formylaminothiazole-
4-yl)-(Z)-2-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid dicyclohexylamine salt 7-[2-(2-formylaminothiazole-
15 g of 4-yl)-(Z)-2-methoxyiminoacetamide]-3-acetoxymethyl-3-cephem-4-carboxylic acid and 150 ml of 50% methanol water
3.9 g of sodium bicarbonate, 150 g of sodium iodide
The mixture was heated and stirred at 63 to 65°C for 2 hours. The reaction solution was cooled and concentrated under reduced pressure to remove excess methanol, and then 200 ml of ethyl acetate and 100 ml of 0.5% aqueous sodium bicarbonate were added to separate the layers, and the aqueous layer was separated. After the ethyl acetate layer was further extracted twice with 50 ml of water, the aqueous layers were combined, the pH was adjusted to 2-3 with hydrochloric acid, and 500 ml of ethyl acetate was added and stirred. The resulting precipitate was removed, and the ethyl acetate layer was separated. 2 more
The aqueous layer was extracted twice using 100 ml of ethyl acetate, and these extracts were combined and added with 5% sodium thiosulfate aqueous solution.
Washed with saturated saline. After dehydration and drying over anhydrous magnesium sulfate, the residue was concentrated under reduced pressure to obtain 5.84 g of a yellow solid. Dissolve this in 50ml of methanol, add 2.55ml of dicyclohexylamine, and add 150ml of ethanol.
ml was added and concentrated under reduced pressure to about half the volume. Since crystals began to precipitate, the mixture was cooled on ice and allowed to stand for 5 hours to over-separate the crystals. After washing with cooled ethanol and drying, 3 g of the title compound was obtained.

NMR spectrum (heavy DMSO, δppm) 0.8-2.3 (20H, m) 2.7-3.4 (2H, m) 3.19 (3H, s, - OCH ₃ ) 3.35 (2H, 2nd CH ₂ ) 3.91 (3H, s, O -CH ₃ , methoxime) 4.20 (2H, s, 3rd place CH ₂ -O-) 5.03 (1H, d, J=5.5Hz, 6th place) 5.64 (1H, dd, J=5.5, 9Hz, 7th place) 6.3 ~8.7 (approximately 3H, COOH and NH, formamide) 7.39 (1H, s, thiazole ring 5th position) 8.52 (1H, s, formyl) 9.55 (1H, d, J = 9Hz, NH amide) <Example 6> 7 -(4-Phenoxyacetylaminoadipoylamide)-3-methoxymethyl-3-cephem-4-carboxylic acid production method 7-(4-Phenoxyacetylaminoadipoylamide)-3-acetoxymethyl -3-Cefem-4-carboxylic acid 1g to sodium bicarbonate 382
mg, dissolved in 10 ml of 50% methanol water with 13 g of sodium iodide, heated to 63-65°C, and stirred for 2 hours. Cool, add 50 ml of ethyl acetate, and wash by adding 20 ml of saturated potassium bisulfate. Extract the aqueous layer twice more with ethyl acetate, combine the extracts, and wash with 50 ml of 10% sodium thiosulfate water. After further washing with saturated saline, dehydration and drying over anhydrous magnesium sulfate,
Concentrate under reduced pressure to give 7-(4-phenoxyacetylaminoadipoylamide)-3-methoxymethyl-3
A solid containing -cefem-4-carboxylic acid was obtained.

NMR spectrum ( _D2O / _NaHCO3 ) δppm 1.0-2.6 (6H, m, _CH2 ) 3.35 (3H, s, _OCH3 ) 3.40 (2H, ABq, J=18Hz, _CH2 2nd position) 4.22 (2H, s, CH ₂ 3rd place) 4.3 (1H, CH) 4.67 (2H, s, CH ₂ ) 5.11 (1H, d, J=5Hz, 6th place) 5.66 (1H, d, J=5Hz, 7th place) 6.7~ 7.7 (5H, m, phenyl) Rf value 0.08 EtOAc−EtOH−H ₂ O=5:2:
1 (Silica gel TLC) 0.3 n-BuOH-AcOH-
H ₂ O = 4:1:1 This was dissolved in 10 ml of methanol, diphenyldiazomethane was added until it became colored, concentrated under reduced pressure, and chromatographed on a silica gel column using the solvent system n-hexane-ethyl acetate 1:2. . 204 mg of diphenyl methyl ester of the title compound was obtained as a colorless solid.

NMR spectrum (CDCl ₃ , δppm) 1.3-2.5 (6H, m) 3.13 (3H, s) 3.39 (2H) 4.14 (2H, s) 4.45 (2H, s) 4.65-4.95 (2H) 5.72 (1H, dd, J=5.5,9Hz) 6.7-7.8 (~29H, m) <Example 7> Method for producing 7-phenoxyacetamido-3-methoxymethyl-3-cephem-4-carboxylic acid 7-N-benzylideneamino-3 - Dissolve 2 g of acetoxymethyl-3-cefem-4-carboxylic acid sodium salt in 20 ml of 50% methanol water, add 20 g of sodium iodide and 450 mg of sodium bicarbonate.
The mixture was heated and stirred at 65°C for 3 hours, and the reaction solution was concentrated under reduced pressure to remove methanol. Add 5 ml of water and 10 ml of acetone to this, and add sodium bicarbonate.
After adding 900 mg, the mixture was stirred under ice cooling, and 890 mg of phenoxyacetyl chloride was added dropwise. After stirring for 30 minutes,
100 ml of ethyl acetate was added to the reaction solution, and a saturated aqueous potassium bisulfate solution was added to separate the layers. ethyl acetate 50ml
The aqueous layer was extracted once again, and these extracts were combined, washed with saturated brine, and then dehydrated and dried over anhydrous magnesium sulfate. Add to this 2 diphenyldiazomethane
g was added, and after standing for 30 minutes, it was concentrated under reduced pressure, and using 50 g of silica gel, the solvent system n-hexane-ethyl acetate 1:
1 was subjected to chromatography. Concentrate the eluate and extract the diphenyl methyl ester of the listed compound 169
I got mg.

NMR spectrum (CDCl ₃ , δppm) 3.20 (3H, s, 3rd position OCH ₃ ) 3.50 (2H, s, 2nd position CH ₂ ) 4.25 (2H, s, 3rd position CH ₂ ) 4.57 (2H, s, CH ₂ ) 5.00 (1H, d, J = 5.0Hz, 6th position) 5.87 (1H, dd, J = 5.0, 9.0Hz, 7th position) 6.7-7.6 (17H, m) <Example 8> 7-Amino-3-methoxy Method for producing methyl-3-cephalosporanic acid sodium salt 2 g of 7-aminocephalosporanic acid was dissolved in 20 ml of 50% methanol water using 1.23 g of sodium bicarbonate, and 20 g of sodium iodide was added thereto at 65°C. The mixture was stirred for 30 minutes. After concentrating the reaction solution under reduced pressure to remove methanol, add 50 ml of water and further add hydrochloric acid to adjust the pH.
It was set as 2. After removing the formed precipitate and adding sodium bicarbonate to adjust the pH to 7-8, Amberlite-XAD
-2 (1) was used to adsorb the target substance using water.
The product was washed with 1 portion of water, and then the target product was eluted with 50% methanol and concentrated under reduced pressure. Dissolve this in 20ml of water, add acetone, remove the resulting precipitate, and dry.
558 mg of the title compound was obtained.

NMR spectrum (D ₂ O) 3.27 (3H, s, 3rd position OCH ₃ ) 3.41 (2H, ABq, J=17Hz, 2nd position CH ₂ ) 4.15 (2H, s, 3rd position CH ₂ ) 5.05 (1H, d, J = 5 Hz, 6th position) 5.44 (1H, d, J = 5 Hz, 7th position) <Example 9> Process for producing 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid 7-aminocephalosporan 5 g of acid was dissolved in 50 ml of 50% methanol water along with 3.1 g of sodium bicarbonate, 50 g of sodium iodide was added, and the mixture was heated at 65° C. for 2 hours and 30 minutes. Methanol was removed by concentration under reduced pressure, and 50 ml of water and 50 ml of acetone were added, followed by stirring under ice cooling. Phenoxyacetyl chloride 3.1 to this
After stirring at the same temperature for 30 minutes, the mixture was concentrated under reduced pressure to remove acetone. 200 ml of ethyl acetate was added, and the aqueous layer was adjusted to pH 2-3 using hydrochloric acid and separated. After the aqueous layer was extracted again with a small amount of ethyl acetate, these layers were combined and washed successively with 5% aqueous sodium thiosulfate and brine. After dehydration and drying over anhydrous magnesium sulfate, the solvent was removed by concentration under reduced pressure. The solution was dissolved again in 20 ml of ethyl acetate, 800 mg of dicyclohexylamine was added, and 100 ml of isopropyl alcohol was further added and concentrated under reduced pressure to a total volume of about 30 ml.

Cool this on ice for 5 hours, let it stand, remove the resulting precipitate,
After washing and drying, 649 mg of the title compound was obtained.

It was confirmed by NMR spectrum and infrared absorption spectrum that this product was the same as the compound obtained in Example 2-(A).

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ NH represents an amino group or a protected amino group. ] A general formula characterized by reacting cephalosporanic acid or a salt thereof with a lower alcohol in the presence of an iodine compound. [In the formula, R ₁ NH has the same meaning as described above, and R ₂ represents a lower alkyl group. ] A method for producing 3-alkoxymethylcephalosporin or a salt thereof.