JPS63115887A - Production of 7-amino-3-alkoxymethylcephalosporins - Google Patents

Abstract

PURPOSE:To industrially and advantageously obtain the titled compound useful as a raw material for antibiotic substances having antimicrobial activity, by reacting aminocephalosporanic acids with a lower alcohol in the presence of a lower alcohol complex compound of boron trifluoride and halogenosulfonic acid or alkylsulfionic acid. CONSTITUTION:7-Aminocephalosporanic acids expressed by formula I [R1 is H or alkoxy; X is (substituted)acyloxy or carbamoyloxy] or derivatives or salts thereof at the carboxyl group are reacted with a lower alcohol, preferably 1-5C alcohol in the presence of a lower alcohol complex compound of boron trifluoride and a halogenosulfonic acid or, if necessary, alkylsulfonic acid, e.g. chlorosulfonic acid, etc., having a halogen as a substituent group in an organic solvent to afford the aimed compound expressed by formula II.

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention relates to a method for producing 7-amino-3-alkoxymethyl-5-cephem-4-carboxylic acids, more specifically, it relates to a method for producing 7-amino-3-alkoxymethyl-5-cephem-4-carboxylic acids, and more specifically, it relates to a method for producing 7-amino-3-alkoxymethyl-5-cephem-4-carboxylic acids. ) R1 OOH (wherein, R represents a hydrogen atom or an alkoxy group, and X represents an optionally substituted acyloxy or carbamoyloxy group.) Alternatively, a salt thereof is reacted with a lower alcohol in an organic solvent in the presence of a lower alcohol complex compound of boron trifluoride and a halogenosulfonic acid or an alkylsulfonic acid with or without a halogen tea group f: Characteristics 7-amino-3-alkoxymethyl-3-cephem-4-carboxylic acid represented by the general formula σDR 0OH (wherein, Rt is a hydrogen atom, and nine represents an alkoxy group, and -Fi represents a lower alkyl group). Ra and te relate to methods for producing derivatives or salts thereof at the carboxyl group.

7-amino-3-alkoxymethyl-3-cephem-4-carboxylic acids represented by the general formula (iii).

It is an important compound as a raw material for cephalosporin antibiotics that have extensive antibacterial activity.

(Prior Art) The following method is known as a method for producing 7-amino-3-alkoxymethyl-3-cephem-4-carboxylic acids represented by the general formula. For example, (I) a method of reacting a 5-acetoxymethyl compound with a lower alcohol (C% Kosho 5O-10873).

(2) Method for alkylating 3-hydroxymethyl compound (
Special public bean paste 5O-10872) R3) Δ! A method in which -6-halomethyl compound is reacted with a lower alcohol and then isomerized [
Journal of Medical Chemistry (J
, Med, Chem, ), 14. 115 (
I971)).

(Problems to be Solved by the Invention) The method (I) has an extremely low yield; (The method 21 requires protecting the 4-position carboxyl group and using a large amount of diazomethane; , method (3) is
The yield of the reaction with alcohol is low, the 4-position carboxyl group needs to be protected, and the process requires 5 steps, which are unsatisfactory as industrial production methods. Therefore, it has been desired to develop a method for industrially easily producing 7-amino-5-flucoxymether-3-cephem-4-carboxylic acids represented by the general formula.

(Means for Solving the Problems) Under the above-mentioned background, the present inventors produced 7-amino-3-alkoxymethyl-5-cephem-4-carboxylic acids, derivatives at the carboxyl group, or salts thereof. This is the result of intensive research into methods that can be easily carried out industrially.

CI)
([0 (R1, By reacting the compound of the general formula (I) with a lower alcohol in the presence of an alcohol complex compound and a halogenosulfonic acid or an alkylsulfonic acid with or without a halogen as a substituent, the compound of the general formula (I) is reacted with a lower alcohol in the -step. After discovering that the compound can be produced in good yield and conducting intensive studies on one more reaction, they finally completed their invention.

That is, the object of the present invention is compound 1- having the above formula 〇, which is an important intermediate for cephalosporin compounds having excellent antibacterial activity.

It is an object of the present invention to provide a method for obtaining a compound having the formula (I) with industrially easy operation and with high purity.

The present invention will be explained in detail below.

In the present invention, examples of the alkyloxy group for R8 include methoxy, nidoxy, propoxy, and butoxy groups.

Further, as the optionally substituted acyloxy and carbamoyloxy groups represented by X.

Examples include fulcaryloxy groups such as acetoxy, propionyloxy, and butyryloxy; carbamoyloxy groups, etc., and examples of substituents that may be substituted include halogen atoms, nitro groups, alkyl groups, alkoxy groups, and alkylthio groups. , an acyloxy group, an acylamino group, a hydroxy group, a carboxyl group, a sulfamoyl group, a carbamoyl group, a carbalkoxycarbamoyl group, and other substituents known as substituents for a 7-syloxy group and a carbamoyloxy group.

Examples of derivatives of the carboxyl group of the compounds of formulas (I) and 0 include the following. Esters include all esters that do not adversely affect the reaction. For example, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, tert-butyl ester, methoxymethyl ester, ethoxymethyl ester, phenodimethyl ester, methylthiomethyl ester, methylthioethyl ester, phenylthiomethyl ester.

Dimethylaminoethyl ester, diethylaminoethyl ester, morpholinoethyl ester, piperidinoethyl ester, acetylmethyl ester, phenacyl ester, acetogysimethyl ester, pivaloyloxymethyl ester, benzoyloxymethyl ester, methanesulfonylethyl ester, toluene Sulfonyl ethyl ester, bromomethyl ester, iodoethyl ester, )! Substituted friends such as J dichlorotyl ester and 7-talimitomethyl ester are unsubstituted alkyl esters; cycloalkyl esters such as cyclohexyl ester and cycloheptyl ester; phenyl ester, tolyl ester, xylyl varnish fk, t-phthyl ester, 1
p-nitrophenyl ester, 2. a-,) Nitro 7 ale ester, p-methoxyphenyl ester,)! J
Substituted or unsubstituted 7-aryl esters such as chloro 7-ethyl ester, 1p-methanesulfonylphenyl ester; benzyl ester, 7-enethyl ester, p-/loropenzyl ester% p-nitrobenzyl ester, p-
Substituted or unsubstituted alkyl esters such as methoxybenzyl ester, diphenylmethyl ester, and trityl ester; indanyl ester; and 7-thalidyl ester.

Other examples include anhydrides of carboxyl groups and N-hydroxysuccinimide, N-hydroxy 7-thallimide, dimethylhydroxylamine, diethylhydroxylamine, 1-hydroxypiperidine, oxime, and the like.

In addition, amides include acid amides,
Includes all N-substituted acid amides and N,N-disubstituted acid amides. For example, N-methyl acid amide.

N-alkyl acid amide such as N-ethylic acid amide; N-
ON-aryl amide such as phenyl amide; N,
N-dimethylamide, N,N-diethylamide, N
Examples thereof include ON, N-dialkyl acid amides such as -ethyl-N-methyl acid amide; acid amides with imidazole, 4-substituted imidazole, triazolopyridone, and the like. Also included are groups retaining carboxyl groups such as di- or trialkylsilyl or penthydryl.

The salts of the compounds represented by the above formulas 〇) and ① mean salts in the free carboxyl group or acid addition salts in the amine group, and examples of the salts in the carboxyl group include sodium, potassium, etc. Salts with alkali metals such as; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; triethylamine.

diethylamine, pyridine, N-methylpiperidine, N
-Me? Examples include salts with organic bases containing organic bases such as lumorpholine and N,N-dimethylaniline; salts with amine groups include acid addition salts with mineral acids such as hydrochloric acid and sulfuric acid;
Adding 0F11 with a carboxylic acid such as oxalic acid, formic acid, trichloroacetic acid, trifluoroacetic acid [; methanesulfonic acid,
Examples include salts with sulfonic acids such as toluenesulfonic acid and sulfonic acid.

As the lower alcohol used in the method of the present invention, primary to tertiary alcohols having 1 to 5 carbon atoms, such as methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, methyl alcohol, and substituted alcohols thereof are used. .

The reaction is usually carried out in a suitable solvent. As such a solvent, any organic solvent that does not adversely affect the reaction can be used.1 For example, the lower alcohol used in the reaction can be used as is, and acetonitrile, propionitrile, benzonitrile, malondinitrile, etc. Nitriles; Nitroalkanes such as nitromethane, nitroethane, and nitropropane; Aromatic hydrocarbons such as nitrobenzene; Organic carboxylic acids and their esters such as acetic acid, formic acid, propionic acid, and trifluoroacetic acid; Aceto/, methyl ethyl ketone, and methyl isobutyl ketones,
Alkyl ketones such as acetophenone; halogenated alkanes such as dichloromethane, chloroform, dichloroethane, carbon tetrachloride; halogenated alkenes such as dichloroethylene and trichlorethylene; acids such as formamide, dimethylformamide, acetamide, etc. Amides; ethers such as diethyl ether, tetrahydro7rane, ethylene glycol, dimethyl ether; and sulfolanes such as sulfolane, dimethyl sulfoxide, etc. These solvents can also be used in a mixture of 2'8i or more.

The amount of the complex compound of boron trifluoride and lower alcohol to be used is as long as the amount of boron trifluoride and lower alcohol is equal to or more than the equivalent mole of the compound of formula (I) or its carboxyl group derivative It based on their salts. However, it can also be used as a solvent.

Further, examples of the chlorosulfonic acid or the alkylsulfonic acid with or without a halogen as a substituent that can be used together with the lower alcohol complex compound of boron trifluoride include #-1, chlorosulfone e1, fluorosulfonic acid, etc. Genosulfonic acids such as trifluoromethanesulfonic acid, methanesulfonic acid, etc.; and alkylsulfonic acids with or without nitrogen as a substituent, such as trifluoromethanesulfonic acid and methanesulfonic acid. The amount of halogenosulfonic acid and alkylsulfonic acid with or without halogen as a substituent may be at least the equivalent molar amount of the compound of general formula (I) based on the carboxyl group derivative or salt thereof. Bye.

In general, depending on the solvent used, the lower alcohol complex compound of boron trifluoride used, and the amount of lower alcohol used, the amount of halogenosulfonic acid and alkylsulfonic acid with or without halogen as a substituent is as follows: It is desirable to increase or decrease the amount as appropriate depending on each individual case.

Since this reaction is preferably used in a substantially anhydrous state, a dehydrating agent may be added to the reaction system.

The reaction temperature is not limited to %, and usually the reaction temperature is -20 to 90%.
C, and the time required for the reaction mainly depends on the starting materials,
The reaction time varies depending on the amount of reagent, type of solvent used, reaction temperature, etc., and ranges from several minutes to several tens of hours.

After the reaction is completed, the target product is collected from the reaction mixture by a conventional method. For example, after adding ice water to one reaction mixture, the solution of one reaction mixture has a pH of 3 to 4 or 6 to 7 Kv4! I do.

Either collect the precipitated crystal tP or use FiXAD-II (
Organo Co., Ltd.), HP-20 (Mitsubishi Chemical Industries, Ltd.), etc. to elute the eluate, tpHf! II! L
, the precipitated crystals are collected in a furnace. In the case of derivatives of the carboxyl group of formula 0, those that can be easily eliminated can be eliminated to obtain the desired product as a free carboxylic acid or a salt thereof.

(Example) Next, the present invention 1 will be explained based on an example.
The invention is not limited to these examples.

Example 1 7-7 Minosephalosporan @ 7.20r, methanol 5.939 was clouded with nitromethane 1sttKR, boron trifluoride/methanol complex compound 42.7 t (containing 5191 boron trifluoride), fluorosulfonic acid 16 .5f
1 and reacted at 25C for 10 minutes. Cool the reaction solution and adjust the pH of the reaction solution to 5.5 using a saturated aqueous solution of hydrogen carbonate. Then acetone 1
After adding 801Rt and stirring for 1 hour under water cooling, the precipitated crystals t
-F taken, ice water 5.0 m.

If sequentially washed with 10 m of acetone, 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid 4.95
f (Yield 65.91) f: Obtain.

IR(nujol)crrl-'; 3160 (-
NH! ), 1800 (β-lactamid C20), 1
620 (-C0OHνC=0), 1100 (C%OC%) NMR (CF, C00D); 3.62 (3H; s; -
C horse OCH,) 3.77 (2H; s; C”-C
H,)4.86 (2H;s;-CH,QC horse]5.
43 (2H; S; C'-H, 0-H) Example 2 1.44 P of 7-amituse 7 allosboranic acid and 1.19 f of methanol were suspended in 3-nitromethane.

To this, boron trifluoride/methanol complex compound (containing 51% boron trifluoride) and 8.549% fluorosulfonic acid 3j If were sequentially added and stirred at 25C for 10 minutes (during this time, the reaction solution was completely dissolved). ). After cooling the reaction solution and distilling off nitromethane and methanol under reduced pressure, 10-5% of water was added.
Add saturated aqueous sodium hydrogen carbonate solution to adjust pH to 7.5. This liquid) IP-20C Mitsubishi Chemical Industries, Ltd.
(used water for elution), and the eluate was
% hydrochloric acid solution to adjust the pH to 5,5Kv4, and count the precipitated crystals.

Washing with 10 g of ice water and 10 g of cold methanol.

The target product 0.86 f (yield 63.2%) was obtained.

NMR and IR of this product were obtained in Example 1 and were consistent with the following.

Example 3 7-7minose7 allosborane acid 2.88? , methanol 1.1? f was suspended in 5rtl of nitromethane, and a boron trisulfide/methanol complex compound (boron trisulfide 5rtl) was suspended in 5rtl of nitromethane.
1%) 8.54f, fluorosulfonic acid 5.51
Add 9 in sequence and stir at 25C for 15 minutes. The reaction solution was cooled, nitromethane and methanol were distilled off under reduced pressure, and water 1
00- was added, and the solution was mixed with HP-20 [Mitsubishi Chemical Corporation (
Co., Ltd. column. Eluate containing the target substance t-p
After adjusting the temperature to 5.5, the precipitated crystals were collected by F and soaked in ice water (15m%).
When washed with cold methanol 5-, the target material is 1.50 f.
(yield: 55.8 cm).

Both NMR and IR of this product matched those obtained in Example 1.

Example 4 7-amituse 7 allosbodic acid 2.88? ,) 1.19 t of finol is suspended in methylene chloride 3- to form a boron trisulfide/methanol complex compound (boron trisulfate s 1)
% content) 8.54 t, fluorosulfonic acid Aj I
Add f sequentially and stir at 25C for 15 minutes. Cool the reaction solution, add 20ml of ice water, and leave.

The pH of the reaction solution was adjusted to 3.5 with aqueous ammonia (27%).
1 Ci! Ill arrange it. The precipitated crystals were separated and washed with 10 parts of ice water and 5 parts of methanol to obtain 1.6 of the desired product (yield: 57.5 parts).

The NMR and IRu of this product matched those obtained in Example 1.

Example 5 7-aminose7 allosborane lR2,88p, methanol 1.19fi was suspended in acetonitrile 3-, boron trifluoride/methanol complex compound (boron trifluoride 51
8.54 f, fluorosulfonic acid 3.31
Add F sequentially and react at 25 U for 15 minutes. After cooling the reaction solution and adding 20+ntt- of ice water, the pH of the reaction solution was adjusted to 5.5KllI4 with aqueous ammonia (271).
Arrange. Count the precipitated crystals, add 10 parts of ice water and 5 parts of methanol.
The target product was 1.481 (yield 55.5%
) obtained. NMR of this thing.

The IR was consistent with that obtained in Example 1.

Example 6 Fu 7 2.88f of minosephalosboranic acid and 2.579f of methanol to nitromethane 6-! @ Muddy.

Boron trifluoride/methanol complex compound (contains 51% boron trifluoride) 17.1? ,) Add 9.929 g of fluoromethanesulfonic acid one after another and stir for 130 minutes at 25C (during which time the reaction solution is completely dissolved). The reaction solution was cooled and analyzed by t-HPLC of a diluted solution containing 100 wtf of methanol. As a result, 7-amino-3-methoxymethyl-3-
It was confirmed that cephem-4-carboxylic acid was produced in a yield of 60.6%.

(Effect of the invention〕

Claims (1)

[Claims] General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 represents a hydrogen atom or an alkoxy group, and X represents an optionally substituted acyloxy or carbamoyloxy group. 7-aminocephalosporanic acids represented by the formula (7-aminocephalosporanic acids), or derivatives thereof at the carboxyl group, or salts thereof, in an organic solvent, with a lower alcohol complex compound of boron trifluoride and a halogenosulfonic acid or a halogen as a substituent. General formula (II), which is characterized by reacting with a lower alcohol in the presence of an alkyl sulfonic acid or not, includes numerical formulas, chemical formulas, tables, etc. , R_2
represents a lower alkyl group. ) A method for producing 7-amino-3-alkoxymethyl-3-cephem-4-carboxylic acids represented by the following, or derivatives at the carboxyl group thereof, or salts thereof.