JP3138760B2 - Method for producing iodine compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to an esterifying agent used for esterifying a carboxyl group, a sulfo group, or the like possessed in a molecule of cephalosporin, penicillin, a monocyclic β-lactam compound, etc. The present invention relates to a method for producing 1-alkyl iodide carbonate. These ester derivatives of cephalosporins, penicillins and monocyclic β-lactam compounds are particularly important as orally administrable antibiotics.

[0002]

2. Description of the Related Art As a method for synthesizing an alkyl iodide using an alkyl chloride or an alkyl bromide as a raw material, a conventional method involves reacting an alkyl chloride or an alkyl bromide with sodium iodide or potassium iodide in an organic solvent such as acetone. Halogen exchange reactions are common. But,
When trying to utilize this reaction in the synthesis of alkyl iodide carbonate, even if various reaction conditions are examined, the reaction raw materials and reaction products are unstable in the reaction system and decompose, resulting in low yields. It could not be an industrial manufacturing method.

Recently, JP-A-61-40246 and JP-A-62-273937 have been reported as methods for producing 1-alkyl iodide carbonates. JP 6
The production method in No. 1-40246 is a method in which a 1-halogenated alkyl carbonate is reacted with an iodinating agent in the presence of a perhalogenohydrocarbon or carbon disulfide and a Lewis acid to obtain a 1-alkylated alkyl carbonate. However, both perhalogeno hydrocarbons and carbon disulfide are toxic and are not suitable as industrial solvents. Further, under these reaction conditions, since the pH becomes strongly acidic, unstable raw materials and products are easily decomposed under acidic conditions, and the operation of isolating the products in high yield is extremely difficult. It is not advantageous in mass production.

The production method disclosed in Japanese Patent Application Laid-Open No. Sho 62-273937 is a method in which 1-chloroethyl-alkyl carbonate is reacted with an iodinating agent in the presence of a protonic acid and calcium phosphate to obtain 1-ethyl iodide-alkyl carbonate. However, in this method, a protonic acid is used as a raw material.
0.9 relative to -chloroethyl-alkyl carbonate
It is said that it is preferable to use up to 1.5 equivalents, so that the reaction system becomes strongly acidic, but under such conditions, decomposition of unstable raw materials and products occurs under acidic conditions as described above. It is not easy to isolate the resulting product in high yield and high quality without decomposing it, and the protonic acid itself is not easy to handle, so that it is not suitable as an industrial production method.

[0005]

Accordingly, the decomposition of the starting materials and products in the reaction system is unlikely to occur, no toxic solvents, difficult-to-handle reagents, expensive catalysts, etc. are not used, and the operation of isolating the products is difficult. Simple, excellent yield and quality 1-
An industrially advantageous method for producing an alkyl iodide carbonate has not been found yet, and its development has been demanded.

[0006]

Under these circumstances, the present inventors have conducted various studies and found that the expression

Embedded image [In the formula, X represents fluorine, chlorine or bromine, R ¹ represents a hydrogen atom or a hydrocarbon group, and R ² represents a hydrocarbon group. When the compound represented by the formula (I) is reacted with an iodinating agent in the presence of an alkaline earth metal halide, the conventional demand is unexpectedly satisfied,

Embedded image [Wherein, R ¹ and R ² have the same meanings as described above. ] Has been found that the compound represented by the formula (1) can be industrially advantageously produced in large quantities, and the present invention has been completed based on this. That is, the present invention employs the formula

Embedded image [In the formula, X represents fluorine, chlorine or bromine, R ¹ represents a hydrogen atom or a hydrocarbon group, and R ² represents a hydrocarbon group. Wherein the compound represented by the formula (I) is reacted with an iodinating agent in the presence of an alkaline earth metal halide.

Embedded image [Wherein, R ¹ and R ² have the same meanings as described above. (2) the method according to (1), wherein the alkaline earth metal halide is calcium chloride; and (3) the method (1), wherein the alkaline earth metal halide is magnesium chloride. (4) The production method according to (1), wherein the reaction is carried out in acetonitrile.

In the above formula, R ¹ represents a hydrogen atom or a hydrocarbon group. R ² represents a hydrocarbon group. Examples of the hydrocarbon group represented by R ¹ and R ² include an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, and an aryl group. The alkyl group preferably has 1 to 10 carbon atoms, the alkenyl group and the alkynyl group preferably have 2 to 10 carbon atoms, and they may be linear or branched. The cycloalkyl group and cycloalkenyl group preferably have 3 to 10 carbon atoms. The aryl group preferably has 6 to 10 carbon atoms. Examples of the alkyl group include methyl, ethyl, n-propyl, i
-Propyl, n-butyl, i-butyl, sec-butyl, ter
t-butyl, n-pentyl, i-pentyl, 2-methylbutyl, sec-pentyl, 1,2-dimethylpropyl, neo
-Pentyl, 1-ethylpropyl, 1,1-dimethylpropyl, hexyl, heptyl, octyl, nonyl, decyl and the like are used, and preferably, for example, methyl, ethyl,
n-propyl, i-propyl, n-butyl, i-butyl, se
An alkyl group having 1 to 6 carbon atoms such as c-butyl and tert-butyl, more preferably an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl and i-propyl is used. Examples of the alkenyl group include ethenyl, 1-
An alkenyl group having 2 to 10 carbon atoms such as propenyl, 2-propenyl, 1-methylethenyl, butenyl, pentenyl, hexenyl, heptenyl, and decenyl is used, and preferably, for example, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, An alkenyl group having 2 to 6 carbon atoms such as butenyl is more preferably ethenyl, 1-
An alkenyl group having 2 to 4 carbon atoms such as propenyl, 2-propenyl and 1-methylethenyl is used. Examples of the alkynyl group include alkynyl groups having 2 to 10 carbon atoms such as ethynyl, propynyl, butynyl, hexynyl, and decynyl, and preferably ethynyl, propynyl,
An alkynyl group having 2 to 6 carbon atoms such as butynyl, and more preferably an alkynyl group having 2 to 4 carbon atoms such as ethynyl and propynyl are used. As the cycloalkyl group, for example, a cycloalkyl group having 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl is used, and preferably, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , A cycloalkyl group having 3 to 8 carbon atoms such as cycloheptyl is more preferably a cycloalkyl group having 3 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
~ 6 cycloalkyl groups are used. As the cycloalkenyl group, for example, a cycloalkenyl group having 3 to 10 carbon atoms such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl and cyclodecenyl is used. A cycloalkenyl group having 3 to 8 carbon atoms such as cyclohexenyl and cyclohexadienyl is used, and a cycloalkenyl group having 3 to 6 carbon atoms such as cyclopropenyl, cyclopentenyl and cyclohexenyl is more preferably used. As the aryl group, an aryl group having 6 to 10 carbon atoms such as phenyl and naphthyl is used, preferably an aryl group having 6 to 8 carbon atoms such as phenyl, and more preferably phenyl is used. The above-mentioned alkyl group, alkenyl group, alkynyl group is, for example, the above-mentioned cycloalkyl group, cycloalkenyl group, aryl group and the like, and the above-mentioned cycloalkyl group, cycloalkenyl group is, for example, the above-mentioned alkyl group, alkenyl group, alkynyl group, aryl In the group, 1 to 4 aryl groups may be substituted with an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, or the like. R ¹ is a hydrogen atom or methyl, ethyl, n-
Propyl, i-propyl, n-butyl, i-butyl, sec-
Butyl, tert-butyl, n-pentyl, i-pentyl, 2
Alkyl groups having 1 to 10 carbon atoms such as -methylbutyl, sec-pentyl, 1,2-dimethylpropyl, neo-pentyl, 1-ethylpropyl, 1,1-dimethylpropyl, hexyl, heptyl, octyl, nonyl, decyl, etc. Is preferably used, for example, a hydrogen atom or methyl, ethyl,
n-propyl, i-propyl, n-butyl, i-butyl, se
An alkyl group having 1 to 6 carbon atoms such as c-butyl and tert-butyl, and more preferably an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl and i-propyl are used. R ² represents methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, 2-methylbutyl, sec-pentyl, , 2-Dimethylpropyl, neo-pentyl, 1-ethylpropyl, 1,1-dimethylpropyl, hexyl, heptyl, octyl, nonyl, nonyl, decyl, etc. alkyl groups having 1 to 10 carbon atoms or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl And cycloalkyl groups having 3 to 10 carbon atoms such as cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl are used, and preferably, for example, methyl, ethyl, n
-Propyl, i-propyl, n-butyl, i-butyl, sec
Alkyl groups having 1 to 6 carbon atoms such as -butyl and tert-butyl; and 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl
Is more preferably a group having 1 carbon atom such as methyl, ethyl, n-propyl, i-propyl and the like.
Or 4 alkyl groups or 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
And the like. X represents fluorine, chlorine or bromine. Preferred examples of X include, for example, chlorine and bromine, and more preferably, for example, chlorine and the like.

In the method of the present invention, the desired product [II] can be obtained by reacting the raw material [I] with the iodizing agent in the presence of an alkaline earth metal halide. As the alkaline earth metal halide used here, for example, C
a, Mg, Ba alkaline earth metal halides (eg, calcium chloride, magnesium chloride, barium chloride,
Calcium bromide, magnesium bromide, barium bromide, calcium fluoride, magnesium fluoride, barium fluoride, calcium iodide, magnesium iodide, barium iodide, etc.), and in particular, chlorides and bromides of Ca and Mg, Preferred are iodides (eg, calcium chloride, magnesium chloride, barium chloride, calcium bromide, magnesium bromide, barium bromide, calcium iodide, magnesium iodide, barium iodide, etc.), and these alkaline earth metal halides are You may use individually or in mixture of 2 or more types. Specifically, calcium chloride and magnesium chloride are particularly preferred from the economical and industrial viewpoints. Since the presence of water is not preferred in the halogen exchange reaction, it is preferable that these alkaline earth metal halides are as anhydrous as possible. The amount of the alkaline earth metal halide to be used is 0.01 to 1 mol per mol of the raw material [I].
1 mole, preferably 0.05 to 0.4 mole.

The iodinating agents used in the present invention include, for example, iodides of alkali metals such as Li, Na and K (for example, lithium iodide, sodium iodide, potassium iodide and the like),
Examples thereof include iodides of alkaline earth metals such as Ca and Mg (for example, calcium iodide, magnesium iodide and the like), and preferred are sodium iodide and potassium iodide. The amount of the iodinating agent to be used is generally 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of the raw material [I]. This reaction is performed in a solvent. Examples of the solvent used include ketones such as acetone, ethers such as tetrahydrofuran and diethyl ether, aliphatic hydrocarbons such as hexane and heptane, cycloaliphatic hydrocarbons such as cyclopentane and cyclohexane, benzene and toluene. Aromatic hydrocarbons, halogenated hydrocarbons such as methylene chloride and chloroform, esters such as ethyl acetate, nitriles such as acetonitrile, and amides such as dimethylformamide and dimethylacetamide are used alone or in combination. You may use with the above mixed solvent. In particular, ketones such as acetone, nitriles such as acetonitrile, and amides such as dimethylformamide are preferred solvents. The reaction temperature of this reaction is generally 0 to 100 ° C, preferably 30 to 100 ° C.
６０60 ° C. The reaction time is generally 15-360 minutes, preferably 30-240 minutes, more preferably 40-180 minutes. The reaction is usually advantageously carried out under stirring.

[0010] Thus, the reaction product obtained by this reaction is
Since it contains the target compound [II] with higher purity than known methods, it is purified by a simple method such as concentration, extraction, etc., and then esterified with cephalosporin, penicillin, monocyclic β-lactam, etc. It can be used as a raw material for a chemical reaction. However, it may be used after isolation and purification by known means such as distillation, crystallization, and column chromatography.

The 1-halogenated alkyl carbonate represented by the general formula [I] used in the present invention can be produced, for example, by a method described in JP-A-61-40246 or a method analogous thereto. it can.

[0012]

The target compound [II] obtained by the method of the present invention is an important raw material as an esterifying agent, for example, according to a method known per se as a raw material for an ester of cephalosporin and a penicillin compound or a method analogous thereto. Used (for example, JP-A-51-56487, JP-A-53
-21192, and methods described in JP-A-57-77690).

The cephalosporin ester compound and penicillin ester compound obtained from the target compound [II] as a raw material are rapidly absorbed from the gastrointestinal tract by oral administration. Decomposed to produce high blood levels of its non-ester form. Thus, these ester compounds are orally administered to human and mammalian bacteria (eg, Gram-positive bacteria, eg, Staphylococcus aureus) .
hyloccus aureus ), Gram-negative bacteria such as Esherichia coli , Klebsiella pneumoniae , Proteus
It is effective in treating infectious diseases caused by Bvlgaris ( Proteus vulgaris ), Proteus mirabilis ( Proteus mirabilis ), and Proteus morgani ( Proteusmorganii ).

The cephalosporin ester compound and the penicillin ester compound or salts thereof are known pharmaceutically acceptable excipients (eg, starch, lactose, calcium carbonate, etc.), binders (eg, starch, gum arabic, carboxymethyl). Cellulose, crystalline cellulose, etc.), lubricants (eg, magnesium stearate,
Talc) and disintegrants (eg, carboxymethyl calcium, talc, etc.) to give capsules, powders, fine granules, granules, and tablets in a conventional manner. The dose is 1 dose of cephalosporin ester compound and penicillin ester compound or a salt thereof to one adult.
A daily dose of 0.3 to 5 g, preferably 0.5 to 3 g, can be given in 3 to 4 divided doses.

[0015]

EXAMPLES The present invention will be described in more detail with reference to specific examples, but the present invention is not limited to these specific examples. The symbols used in the examples and comparative examples have the following meanings. NMR: nuclear magnetic resonance spectrum, g: gram, ml: milliliter, Hz: hertz ppm: chemical shift, CDCl ₃ : deuterated chloroform, d: doublet, t: triplet, q: quartet, m: multiplet, J: coupling constant ,%:
Weight percent

Example 1 Preparation of 1-iodoethyl cyclohexyl carbonate 51.7 g (0.25 mol) of 1-chloroethyl cyclohexyl carbonate was added to 200 ml of acetonitrile. Furthermore, 75 g (0.50 mol) of sodium iodide,
8.3 g (0.075 mol) of calcium chloride was added, stirred, and reacted at 45 ° C. for 60 minutes. Acetonitrile was concentrated and distilled off under reduced pressure. 500 ml of methylene chloride and 500 of cold water
ml was added for liquid separation. The organic layer was taken and washed with 200 ml of a 5% aqueous solution of sodium thiosulfate and 200 ml of cold water. The methylene chloride was distilled off under reduced pressure to give a colorless clear oily substance.
2.0 g were obtained. According to gas chromatography analysis, 68.6 g of the title compound was found in the product (yield: 92%).
%) Was included. NMR (CDCl ₃ ) δ (ppm): 1.1-2.1 (m, 10H), 2.15 (d, J = 7H
(z, 3H), 4.5-4.9 (m, 1H), 6.75 (q, J = 7 Hz, 1H) (Comparative Example) The reaction was carried out in the same manner as in Example 1 without adding calcium chloride. Was 40%.

Example 2 Preparation of 1-iodoethyl cyclohexyl carbonate To 200 ml of acetonitrile was added 51.7 g (0.25 mol) of 1-chloroethyl cyclohexyl carbonate. Further, 56 g (0.375 mol) of sodium iodide and 5.5 g (0.05 mol) of calcium chloride were added, stirred, and reacted at 45 ° C. for 90 minutes. Acetonitrile was concentrated and distilled off under reduced pressure. 500 ml of methylene chloride and 50 cold water
0 ml was added and the mixture was separated. The organic layer was taken and washed with 200 ml of a 5% aqueous solution of sodium thiosulfate and 200 ml of cold water. The methylene chloride was distilled off under reduced pressure to give a colorless clear oily substance of 6%.
9.1 g were obtained. According to gas chromatography analysis, 65.6 g (yield: 88) of the title compound was found in the product.
%) Was included. NMR (CDCl ₃ ) δ (ppm): 1.1-2.1 (m, 10H), 2.15 (d, J = 7H
(z, 3H), 4.5-4.9 (m, 1H), 6.75 (q, J = 7 Hz, 1H) (Comparative Example) When the reaction was carried out in the same manner as in Example 2 without adding calcium chloride, the yield of the title compound was obtained. Was 40%.

Example 3 Preparation of 1-iodoethyl cyclohexyl carbonate 51.7 g (0.25) of 1-chloroethyl cyclohexyl carbonate was added to 200 ml of acetone in the same manner as in Example 1.
Mol), 56 g (0.375 mol) of sodium iodide,
4.75 g (0.05 mol) of magnesium chloride were added,
The reaction was performed at 40 ° C. for 125 minutes. Thereafter, in the same manner as in Example 1, 70.3 g of a colorless clear oily substance was obtained. According to gas chromatography analysis, the title compound was 63.
4 g (yield; 85%) was contained. NMR (CDCl ₃ ) δ (ppm): 1.1-2.1 (m, 10H), 2.15 (d, J = 7H
(z, 3H), 4.5-4.9 (m, 1H), 6.75 (q, J = 7 Hz, 1H) (Comparative Example) The reaction was carried out in the same manner as in Example 3 without adding magnesium chloride to obtain the title compound. Was 48%.

Example 4 Preparation of 1-iodoethyl ethyl carbonate 7.63 g of 1-chloroethyl ethyl carbonate (0.6%)
Was dissolved in 50 ml of acetonitrile, and 15 g (0.10 mol) of sodium iodide and 1.7 g of calcium chloride were dissolved.
g (0.015 mol) was added and the mixture was stirred at 45 ° C for 60 minutes. After acetonitrile was concentrated and distilled off under reduced pressure, the same procedure as in Example 1 was performed. Gas chromatography analysis of the obtained oil (12.0 g) revealed that the desired title compound was found to be 11.3 g.
g (yield; 93%). NMR (CDCl ₃ ) δ (ppm): 1.36 (t, J = 7 Hz, 3H), 2.25 (d, J =
(6 Hz, 3H), 4.30 (q, J = 7 Hz, 2 H), 6.80 (q, J = 6 Hz, 1 H) (Comparative Example) In the same manner as in Example 4, when the reaction was carried out without adding calcium chloride, The yield was 58%.

Example 5 Production of 1-iodoethyl cyclohexyl carbonate To 200 ml of acetonitrile was added 51.7 g (0.25 mol) of 1-chloroethyl cyclohexyl carbonate. In addition, 48 g (0.32 mol) of sodium iodide,
8.3 g (0.075 mol) of calcium chloride was added, stirred, and reacted at 45 ° C. for 100 minutes. Acetonitrile was concentrated and distilled off under reduced pressure. 500 ml of methylene chloride and 50 cold water
0 ml was added and the mixture was separated. The organic layer was taken and washed with 200 ml of a 5% aqueous solution of sodium thiosulfate and 200 ml of cold water. The methylene chloride was distilled off under reduced pressure to give a colorless clear oily substance of 6%.
6.7 g were obtained. Gas chromatography analysis revealed that 63.4 g (yield: 85) of the title compound was found in this product.
%) Was included. NMR (CDCl ₃ ) δ (ppm): 1.1-2.1 (m, 10H), 2.15 (d, J = 7H
(z, 3H), 4.5-4.9 (m, 1H), 6.75 (q, J = 7 Hz, 1H) (Comparative Example) The reaction was carried out in the same manner as in Example 1 without adding calcium chloride. Was 35%.

[0021]

According to the method of the present invention, (1) the raw materials and products are hardly decomposed in the reaction system, (2) there is no need to use toxic solvents, difficult-to-handle reagents or expensive catalysts. The present invention provides an industrially advantageous method for producing 1-alkyl iodide carbonate, which is easy to isolate the product, and (4) is excellent in yield and quality.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-63-33352 (JP, A) JP-A-62-273937 (JP, A) JP-A-61-40246 (JP, A) (58) Field (Int. Cl. ⁷ , DB name) C07C 69/96 C07C 68/06

Claims (4)

(57) [Claims] (1) Formula (1) [In the formula, X represents fluorine, chlorine or bromine, R ¹ represents a hydrogen atom or a hydrocarbon group, and R ² represents a hydrocarbon group. Wherein the compound represented by the formula (I) is reacted with an iodinating agent in the presence of an alkaline earth metal halide. [Wherein, R ¹ and R ² have the same meanings as described above. ] The manufacturing method of the compound represented by this. 2. The method according to claim 1, wherein the alkaline earth metal halide is calcium chloride. 3. The method according to claim 1, wherein the alkaline earth metal halide is magnesium chloride. 4. The process according to claim 1, wherein the reaction is carried out in acetonitrile.