JPH0481579B2 - - Google Patents

Description

[Detailed description of the invention]

``Purpose of the Invention'' Industrial Field of Application The present invention relates to 1-alkyl iodide which is extremely useful as a raw material for esterifying pharmaceuticals having carboxyl groups, sulfo groups, etc. in the molecule, such as penicillin, cephalosporin, single β-lactam, etc. This invention relates to a method for improving the iodination reaction in the production of carbonic esters. Pharmaceutical products such as pinicillin, cephalosporin, and single β-lactams esterified using 1-iodinated alkyl carbonate esters are particularly important compounds as oral preparations. Conventional technology As an iodination reaction, the Finkelstein reaction has been known for a long time [H.Finkelstein,
Ber. 43 1528 (1910). ]. This reaction was expressed by the reaction formula RBr + NaI → RI + NaBr, and involved reacting alkyl bromide with sodium iodide in a solvent such as acetone to synthesize alkyl iodide. Subsequent research revealed that this reaction can be applied to cases where R is an alkyl group with a substituent, and by selecting a solvent, the desired iodide (RI) can be obtained even if chloride (RCl) is used as a raw material. This has been recognized as a general reaction with a wide range of applications. However, when this reaction was used for the synthesis of 1-iodinated alkyl carbonate esters, satisfactory results could not be obtained even after considering the selection of solvent, temperature conditions, reaction time, etc. 20287, page 14].
In fact, for example, when 1-chlorodiethyl carbonate is iodinated using the usual Finkelstein reaction or a modified method thereof, a large amount of by-products are produced and the yield is low, so that it cannot be an industrial production method. Generally, halides are often used for esterification, and iodide is particularly preferred because it has higher reactivity than the corresponding chlorides and bromides. In particular, when esterifying the carboxyl group at the 3-position of penicillin, the carboxyl group at the 4-position of cephalosporin, the sulfo group at the 1-position of a single β-lactam, etc. with a 1-halogenated alkyl carbonate, changes in the chemical bonds of the raw materials (double bond 1-alkyl iodide carbonate is preferable to chloride or bromide because it can be carried out under mild reaction conditions such as short reaction time and low reaction temperature, in order to suppress the reaction (migration, cleavage of the lactam ring, etc.). Therefore, it has been desired to develop a method for obtaining 1-iodinated alkyl carbonate in good yield on an industrial scale. Problems to be Solved by the Invention As described above, the present invention provides 1-
The object of the present invention is to provide an improved production method for synthesizing an alkyl iodide carbonate ester in a higher yield and more easily than before. That is, the present inventors conducted intensive studies on a method for producing 1-iodized alkyl carbonate using 1-halogenated alkyl carbonate, and found that in the presence of perhalogeno hydrocarbon or carbon disulfide and Lewis carbonate, The present invention was completed based on the discovery that when an iodination reaction is carried out, 1-iodination alkyl carbonate can be obtained in high yield and purity with very little by-product formation. "Structure of the invention" Means for solving the problem The reaction of the present invention is expressed by the general formula The raw material [] represents a 1-halogenated alkyl carbonate, and the product [] represents a 1-iodated alkyl carbonate. In raw materials [], X represents a halogen atom with an atomic weight of 100 or less, specifically fluorine, chlorine, and bromine;
Preferred are chlorine and bromine. Further, in the raw material [] and the product [], both R ₁ and R ₂ represent an optionally substituted hydrocarbon group. Hydrocarbon groups include alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, cycloalkenyl groups,
Examples include aryl groups. Here, an alkyl group, an alkenyl group, an alkynyl group are a cycloalkyl group, a cycloalkenyl group, an aryl group, a cycloalkyl group, a cycloalkenyl group is an alkyl group,
In the alkenyl group, alkynyl group, and aryl group, the aryl group may be substituted with an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, or a cycloalkenyl group, respectively. The alkyl group, alkenyl group, and alkynyl group preferably have 1 to 10 carbon atoms, and may be linear or branched. Specific examples of alkyl groups include methyl,
Ethyl, propyl (n-propyl, i-propyl), butyl (n-butyl, i-butyl, sec-butyl, tert-butyl), pentyl (n-pentyl,
i-pentyl, 2-methylbutyl, sec-pentyl, 1,2-dimethylpropyl, neo-pentyl, 1-ethylpropyl, 1,1-dimethylpropyl), hexyl, heptyl, octyl, nonyl,
Such as decile. Specific examples of alkenyl groups include ethenyl, propenyl (1-propenyl, 2-propenyl,
-propenyl, 2-methyl ester), butenyl,
These include pentenyl, hexenyl, heptenyl, and decenyl. Specific examples of alkynyl groups include ethynyl, propynyl, butynyl, hexynyl, and decynyl. The cycloalkyl group and cycloalkenyl group preferably have 3 to 7 carbon atoms. Specific examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Specific examples of cycloalkenyl groups include cyclopentenyl,
Cyclohexenyl, cyclohexadienyl, etc. The aryl group preferably has 6 to 10 carbon atoms, and specific examples include phenyl and naphthyl. The above hydrocarbon groups represented by R ₁ and R ₂ and those substituted with other hydrocarbon groups may further include a nitro group, a cyano group, an oxo group, a thioxo group, a C _1-6 alkoxy group, and a carboxyl group. ,
It may have a substituent such as a C _1-6 alkoxycarbonyl group. The product [ ] is obtained in high yield by reacting the raw material [ ] of the present invention with an iodinating agent in the presence of a perhalogeno hydrocarbon or carbon disulfide and a Lewis acid. Here, perhalogeno refers to a hydrocarbon in which all of the hydrocarbon atoms are replaced with the same type of halogen atoms or two or more different types of halogen atoms. Specifically, the halogen atoms constituting perhalogeno hydrocarbons are fluorine, chlorine, bromine, and iodine. The hydrocarbons forming the perhalogeno hydrocarbons in the present invention include aliphatic hydrocarbons and aromatic hydrocarbons, where the aliphatic hydrocarbons are aromatic hydrocarbon groups, and the aromatic hydrocarbons are aliphatic hydrocarbon groups, respectively. May be replaced. Aliphatic hydrocarbons mean acyclic hydrocarbons and alicyclic hydrocarbons, preferably linear or branched acyclic hydrocarbons having 1 to 6 carbon atoms or 3 carbon atoms, respectively.
~7 alicyclic hydrocarbons. Acyclic hydrocarbons mean alkanes, alkenes, and alkynes, and alicyclic hydrocarbons mean cycloalkanes and cycloalkenes, respectively. Therefore, preferred perhalogeno hydrocarbons in the present invention include perhalogeno C _1-6 alkanes, perhalogeno C _1-6 alkenes, perhalogeno C 1-6 alkynes, and perhalogeno C _1-6 alkynes.
C _3-7 cycloalkane, perhalogeno C _3-7 cycloalkene, perhalogenobenzene, perhalogenonaphthalene, perhalogeno (C _3-7 cycloalkyl
_C1-6 alkanes), perhalogeno (phenyl _C1-6 )
perhalogeno (C _1-6 alkyl C _3-7 cycloalkane), perhalogeno (C _1-6 alkylbenzene), etc. Preferred perhalogeno hydrocarbons are more specifically carbon tetrachloride, carbon tetrabromide, carbon tetraiodide, fluorotrichloromethane (Freon 11), bromotrichloromethane,
Difluorodichloromethane (Freon 12), dichlorodibromomethane, hexachloroethane, hexabromoethane, 1,1,2-trichloro-1,
2,2-trifluoroethane (Freon 113),
1,2-dichloro-1,1,2,2-tetrafluoroethane (Freon 114), 1,2-dibromo-
1,1,2,2-tetrafluoroethane, octafluoropropane, 1-iodo-1,1,2,
These include 2,3,3,3-heptafluoropropane, tetrachloroethylene, perchloro-1,3-butadiene, perfluorocyclobutane, hexachlorocyclopentadiene, hexachlorobenzene, hexabromobenzene, and the like. As one of the constituent elements of the present invention, one type of the above-mentioned perhalogeno hydrocarbon and carbon disulfide may be used, or a mixture of two or more types may be used. The compound or mixture of the group consisting of perhalogeno hydrocarbon and carbon disulfide is hereinafter abbreviated as "compound []". When the compound [] is a liquid, it may serve as a solvent or may be used after being dissolved in a solvent as described below. On the other hand, when the compound [] is fixed, it is used after being dissolved in a solvent. The amount of compound [] used is usually 2 to 20 times the amount of raw material [] (v/w for liquids, w/w for solids).
w), preferably 3 to 7 times the amount (v/w for liquids,
In solids, it is w/w). Examples of Lewis acids used in the present invention include Lewis acids used in Friedel-Crafts reactions, and specifically, aluminum chloride, aluminum bromide, zinc chloride, zinc bromide, copper chloride, and copper bromide. , tin chloride, ferric chloride, mercuric chloride, titanium chloride, boron trifluoride, etc.
Among these Lewis acids, zinc chloride and ferric chloride are preferred from the viewpoint of economy, ease of handling, high yield, etc. The amount of Lewis acid used is the raw material []
0.2 to 1.5 mol per mol, preferably 0.2 to 1.5 mol
It is 0.8 mole. The iodizing agent used in the present invention includes inorganic iodides, specifically alkali metal iodides such as lithium iodide, sodium iodide, and potassium iodide, and alkali metal iodides such as calcium iodide and magnesium iodide. Earth metal iodides and the like are used. Most preferred is sodium iodide. The amount of iodinating agent used is usually 1 to 4 mol, preferably 1 mol, per 1 mol of raw material [].
~2 moles. Since the reaction of the present invention is usually carried out in the form of a solution using a compound [] as a raw material [] and an iodide in the presence of a Lewis acid, a solvent may be used. That is, when the compound [] is a liquid, the compound [] may also serve as a solvent, or another solvent may be used. Also, if the compound [] is a solid, a solvent is used. The solvent used here may be any solvent as long as it does not participate in the reaction. Examples of such solvents include aliphatic hydrocarbons such as n-pentane, n-hexane, n-heptane, and cyclohexane; aromatic hydrocarbons such as benzene and toluene;
Examples include ethers such as diethyl ether, diisopropyl ether, dibutyl ether, dioxane, and tetrahydrofuran.
When using the above solvent, the amount of solvent should be an appropriate amount that allows the reaction to proceed in a solution state, usually 10 times the amount of the compound [] (if [] is a liquid, v/v, [] If is a solid, v/w) or less, preferably 5 times the amount (if [ ] is a liquid, v/v,
When [] is a solid, it is less than v/w). Next, reaction conditions for the reaction of the present invention will be described. The reaction temperature is usually -30 to 50℃, preferably 10 to 50℃.
It is 30℃. However, if the compound [] is a liquid with a low boiling point or a gas at room temperature, a temperature of -30 to 10°C tends to give better results. The reaction time is the reaction temperature,
It varies depending on the type and amount of solvent, but usually
The time period is 30 minutes to 5 hours, preferably 30 minutes to 3 hours.
The reaction is usually carried out under stirring, and after the completion of the reaction, the product [] may be isolated and purified, or may be used as it is for esterification without purification.
For example, after the reaction, the reaction solution is decomposed with water and the aqueous layer is removed, and then the organic layer containing the product [] can be immediately used for the esterification reaction as described below. Furthermore, after concentrating the organic layer containing the product [], it is also possible to isolate and purify it using a conventional purification means such as silica gel column chromatography or vacuum distillation. The 1-iodinated alkyl carbonate ester thus obtained is used as a raw material for esterifying, for example, penicillin, cephalosvorin, single β-8 lactam, etc., which have a carboxyl group or a sulfo group in the molecule. These esterification reactions will be described in detail in the "Effects" section. The 1-halogenated alkyl carbonate ester represented by the general formula [] used in the present invention can be produced by the method shown by the following reaction formula. In the above formula, X, R ₁ and R ₂ have the same meanings as above.
The reaction between compound [] and compound [] is usually carried out in a solvent. Suitable solvents include halogenated hydrocarbons such as cyclomethane and chloroform;
Nitriles such as acetonitrile and propionitrile, ethers such as diethyl ether, diisopropyl ether, dioxane, and tetrahydrofuran, N,N-dimethylformamide, N,N
-A solvent inert to the reaction of aminos such as dimethylacetamide is used. Since hydrochloric acid is produced in this reaction, examples of deoxidizing agents such as pyridine,
The reaction proceeds faster when a base such as an organic tertiary amine such as triethylamine is used. The reaction temperature is -20 to 100°C, preferably -10 to 40°C. The reaction is completed in about 1 to 5 hours. The obtained 1-halogenated alkyl carbonate ester can also be purified by conventional isolation and purification methods such as distillation and column treatment. The above-mentioned compound [], which is a raw material for the 1-halogenated alkyl carbonate [], can be easily produced by a known method or a method known per se. Effect The esterification reaction of cephalosporin and penicillin compounds can be carried out using methods known per se (for example, JP-A-Sho et al.
51-56487, JP 53-21192, JP 57-77690
It is carried out according to the method described in et al. For example, the cephalosporin compound 7β-
[2-(2-aminothiazol-4-yl)acetamide]-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thio]methyl]cef-3-em-4 -Carboxylic acid (Special Publication Act 1987)
-12913, hereinafter abbreviated as compound []) 4
Ester compound of carboxyl group in position [] and 1
-It is carried out by reacting an iodized alkyl carbonate ester, that is, a compound represented by the general formula [], in a solvent inert to the reaction, to give the corresponding ester []. The formula for this reaction is as follows. Suitable solvents for the esterification reaction include amides such as N,N-dimethylformamide, N,N-dimethylacetamide and hexamethylphosphorotriamide, halogenated hydrocarbons such as dichloromethane and chloroform, such as dimethylsulfoxide and sulfolane. Examples include sulfoxides such as dioxane, ethers such as tetrahydrofuran, ketones such as acetone and methyl ethyl ketone, nitriles such as acetonitrile, and liquefied anhydrous sulfite. Among these, particularly preferred solvents are N,N-dimethylformamide, N,N-dimethylacetamide,
These include hexamethylphosphorotriamide, acetone, acetonitrile, and liquefied anhydrous sulfite. This esterification reaction is generally carried out at a temperature of -20°C to 20°C and may not require a catalyst; however, a phase transfer catalyst such as 18-crown-6, tetrabutylammonium salt (chloride, bromide, iodide, etc.) Catalysts such as the following may also be used. When using liquefied anhydrous sulfite as a solvent,
Near the boiling point (-10℃) of this solvent, i.e. -10~-
Preferably it is carried out at 20°C. The time required for this reaction varies depending on the type of reactant and solvent, but is generally 5 minutes to 1 hour. Cephalosporin ester compounds (for example []) and penicillin ester compounds or salts thereof (for example, salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., such as maleic acid, acetic acid, citric acid, succinic acid, etc.) thus obtained. acids, salts with organic acids such as tartaric acid, malic acid, and ascorbic acid) can be purified by known isolation and purification means (eg, crystallization, recrystallization, chromatography, etc.). Cephalosporin ester compounds (for example [ ]) and penicillin ester compounds are rapidly absorbed from the gastrointestinal tract after oral administration, and after absorption, the ester moiety at position 4 is hydrolyzed by enzymes in the body, resulting in its non-ester form. (For example, when the above [ ] is orally administered, its non-ester form means [ ] or a salt thereof) resulting in a high blood concentration. Therefore, by oral administration, human and mammalian bacteria (such as Gram-positive bacteria such as Staphylococcus aureus, Gram-negative bacteria such as Esherichia coli, Klebsiella
Pneumoniae), Proteus vulgaris, Proteus mirabilis, Proteus morganii) infections. Cephalospolyester compounds and penicillin ester compounds or their salts may contain known pharmaceutically acceptable excipients (e.g. starch, lactose, calcium carbonate, etc.), binders (e.g. starch, gum arabic, carboxymethyl cellulose, crystalline cellulose). capsules, powders, etc.) by mixing with lubricants (e.g. magnesium stearate, talc, etc.) and disintegrants (e.g. carboxymethylcalcium, talc, etc.) and preparing capsules, powders, etc.
It can be made into fine granules, granules, and tablets. The dosage is 0.3 to 5 g of cephalosporin ester compound and penicillin ester compound or their salts per adult, preferably 0.5 g per day.
~3g can be given in 3 to 4 doses. The present invention will be explained in more detail below using specific examples, but the present invention is not limited to these specific examples. In addition, reference examples, working examples, comparative examples,
Symbols used in experimental examples have the following meanings. S: singlet, d: doublet, dd:
double doublet, t: triplet, q: quartet, ABq: AB type quartet, m: multiplet, quin: quintet, J: binding constant, b: broad, bp: boiling point, %: percent Example Example 1 1 -Manufacture of iododiethyl carbonate Dissolve 5 g of 1-chlorodiethyl carbonate in 25 ml of carbon disulfide and add 6.8 g of sodium iodide.
g (1.4 times the mole) and 0.25 g (0.56 times the mole) of anhydrous zinc chloride were added and stirred at 20°C for 2 hours. Ice water after reaction
In addition to 100 ml, the organic layer was separated. The aqueous layer was extracted twice with 25 ml each of carbon tetrachloride. The organic layers were combined, washed successively with 50 ml of a 5% aqueous sodium thiosulfate solution, 50 ml of a 5% aqueous sodium bicarbonate solution, and 50 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 7.5 g (oil) of the title compound. Yield 94% 1Rν liquid film maxcm ^-1 : 1760. NMR (CDCl ₃ ) δ: 1.37 (t, J = 7Hz, 3H),
2.25 (d, J = 6Hz, 3H), 4.30 (q, J = 7Hz,
2H), 6.82 (q, J=6Hz, 1H). When this product was subjected to gas chromatography, 1-chlorodiethyl carbonate was not observed, and only 1-iododiethyl carbonate, the target product, was observed as one peak. Examples 2-14 1-halogenated diethyl carbonate (X=
Using Cl, Br) as raw materials, an iodination reaction was carried out according to the method of Example 1, changing the compound [], solvent Lewis acid, and iodinating agent as appropriate. The results are summarized in Table 1 together with the yield of 1-iododiethyl carbonate obtained. (Example 1 is also listed with the results)

[Table] Example 15 Production of 1-iodoethyl cyclohexyl carbonate 5 g of 1-chloroethyl cyclohexyl carbonate was dissolved in 25 ml of carbon tetrachloride, and 5 g of sodium iodide (1.4 times the mole) and 0.25 g of anhydrous zinc chloride were dissolved in 25 ml of carbon tetrachloride.
g (0.76 times the mole) and stirred at 20°C for 2 hours. After the reaction, the mixture was added to 100 ml of ice water and the organic layer was separated.
The aqueous layer was extracted twice with 25 ml each of carbon tetrachloride. Combine the organic layers and add 50 ml of 5% sodium thiosulfate aqueous solution.
After sequentially washing with 50 ml of % sodium bicarbonate aqueous solution and 50 ml of water, it was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 6.6 g (oil) of the title compound. Yield: 92% This product was measured by gas chromatography, but no peaks other than those of the title compound were observed. 1Rν liquid film maxcm ^-1 : 1760. NMR (CDCl ₃ ) δ: 0.90 to 2.10 (m, 10H), 2.23
(d, J=6Hz, 3H), 4.30~5.00 (m, 1H),
6.76 (q, J=6Hz, 1H). The 1-chloroethyl cyclohexyl carbonate used was produced according to the following method. 17.6 g of cyclohexanol and 16.7 g of chloroformic acid 1-chloroethyl ester were dissolved in 50 ml of dichloromethane and cooled to 0°C. While stirring, 9.2 g of pyridine dissolved in 20 ml of dichloromethane was added dropwise and stirred for 30 minutes.
The deposited precipitate was filtered off, and the filtrate was washed twice with 200 ml of water each time, and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was distilled under reduced pressure to obtain 19 g of 1-chloroethyl cyclohexyl carbonate. bp107-111℃/10mmHg 1Rν liquid film maxcm ^-1 : 1755. NMR (CDCl ₃ ) δ: 0.80-2.40 (m, 14H), 4.40
~4.94 (m, 1H), 6.45 (q, J=6Hz, 1H). Example 16 In the iodination of 1-chloroethyl cyclohexyl carbonate shown in Example 15, carbon disulfide was used in place of the carbon tetrachloride used as the compound [], and the reaction was carried out in the same manner, yielding 6.3 g of 1-iodoethyl cyclohexyl carbonate. I got it.
Yield: 87% This product was found to be the title compound by 1R NMR. Comparative Example 1 1 g of 1-chloroethyl cyclohexyl carbonate was dissolved in 5 ml of carbon tetrachloride, and 1 g (1.4 times the mole) of sodium iodide was added thereto, followed by stirring at 20° C. for 4 hours. It was added to 20 ml of ice water and the organic layer was separated.
Gas chromatography of this organic layer revealed that the production of 1-iodoethyl cyclohexyl carbonate was 5% or less. Comparative Example 2 A reaction was carried out in the same manner as in Comparative Example 1 except that carbon disulfide was used in place of the carbon tetrachloride used in Comparative Example 1. The production of 1-iodoethyl cyclohexyl carbonate was less than 5%. Comparative Example 3 Dissolve 1 g of 1-chloroethyl cyclohexyl carbonate in 5 ml of acetonitrile and add 1 g of sodium iodide (1.4 times the mole) and anhydrous zinc chloride.
0.05g (0.76 times the mole) was added and stirred at 20°C for 2 hours. It was added to 20 ml of ice water and 5 ml of n-hexane, and the organic layer was separated. Gas chromatography of this organic layer revealed that the production of 1-iodoethyl cyclohexyl carbonate was less than 10%. Comparative Examples 4 to 16 Reactions similar to Comparative Example 3 were carried out in the same manner as in Comparative Example 3, except that the solvent was changed from acetonitrile to another solvent. The results in various solvents are summarized in Table 2. (The results of Examples 15 and 16 and Comparative Examples 1 to 3 are also listed.)

【table】

[Table] Example 17 Production of 1-iodoethyl 3-methylbutyl carbonate Dissolve 5 g of 1-chloroethyl 3-methylbutyl carbonate in 25 ml of carbon tetrachloride, add 5.3 g (1.4 times the mole) of sodium iodide, and 0.25 g of anhydrous zinc chloride.
g (0.72 times the mole) and stirred at 20°C for 2 hours. After the reaction, the mixture was added to 100 ml of ice water and the organic layer was separated.
The aqueous layer was extracted twice with 25 ml each of carbon tetrachloride. Combine the organic layers and add 50 ml of 5% sodium thiosulfate aqueous solution.
After sequentially washing with 50 ml of % sodium bicarbonate aqueous solution and 50 ml of water, it was dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure to obtain 6.5 g of the title compound (oil).
I got it. Yield 88% 1Rν liquid film maxcm ^-1 : 1760. NMR (CDCl ₃ ) δ: 0.94 (d, J=6Hz, 6H),
1.25-1.90 (m, 3H), 2.20 (d, J=6Hz,
3H), 4.23 (t, J = 7Hz, 2H), 6.75 (q, J
=6Hz, 1H). The 1-chloroethyl 3-methylbutyl carbonate used was produced according to the following method. 13 ml of 3-methyl-1-butanol and 17 g of 1-chloroethyl chloroformate were dissolved in 70 ml of dichloromethane and cooled to 0°C. 30ml dichloromethane under stirring
9.6 g of pyridine dissolved in was added dropwise and stirred for 30 minutes. The deposited precipitate was filtered off, and the filtrate was diluted with 200 ml of water each.
After washing twice, it was dried with anhydrous sodium sulfate.
After removing the solvent under reduced pressure, the residue was distilled under reduced pressure to obtain 12.5 g of 1-chloroethyl 3-methylbutyl carbonate. bp 120-122℃/30mmHg 1Rν liquid film maxcm ^-1 : 1760. NMR (CDCl ₃ ) δ: 0.94 (d, J=Hz, 6H), 1.25
~1.90 (m, 3H), 1.84 (d, J=6Hz, 3H),
4.23 (t, J=7Hz, 2H), 6.44 (q, J=6Hz,
1H). Example 18 The reaction of Example 17 was carried out using carbon disulfide instead of carbon tetrachloride used as the compound [].
The same procedure as in 17 was carried out to obtain 6.4 g of 1-iodoethyl-3-methylbutyl carbonate. Yield: 87% Examples 19-37 An iodination reaction was carried out in the same manner as in Example 17, except that the starting compound [] was changed from 1-chloroethyl 3-methylbutyl carbonate to another compound. The results for various raw materials [] are summarized in Tables 3 and 4. (The results of Examples 17 and 18 are also listed.)

【table】

[Table] Reference example 1 1-ethoxycarbonyloxyethyl 7β-[2
Production of -(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-methylcef-3-em-4-carboxylate 7β-[2-(2-aminothiazol-4-yl)
-2-Methoxyiminoacetamide]-3-methylceph-3-M-4-carboxylic acid potassium 12g
was dissolved in 120 ml of dimethylacetamide and cooled to 0°C. 1-iododiethyl carbonate under stirring
9.7g was added and reacted for 20 minutes. Pour the reaction solution into ice water at 250 ml.
ml and 200 ml of ethyl acetate, and the organic layer was separated. Furthermore, the aqueous layer was extracted with 100 ml of ethyl acetate.
The organic layers were combined and washed three times with 100 ml of ice water each time, then with 100 ml of saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the residue, and the resulting white powder was collected by filtration, washed with diisopropyl ether, and dried to obtain 6.9 g of the title compound. 1R (KBr) cm ^-1 : 1775, 1760, 1680 NMR (CDCl ₃ ) δ: 1.28 (t, J = 7Hz, 3H),
1.53 (d, J=6Hz, 3H), 2.13 (s, 3H),
3.24 and 3.48 (ABq, J=18Hz, 2H), 4.00 (s,
3H), 4,25 (q, J=7Hz, 2H) 5.05 (d,
J = 5Hz, 1H), 5.60-6.30 (m, 3H), 6.68
(s, 1H) 6.87 (q, J=6Hz, 1H), 8.22 (d,
J=9Hz, 1H). Elemental analysis value C ₁₉ H ₂₃ N ₅ O ₈ S ₂ Calculated value (%) C: 44.44, H: 4.51, N: 13.68 Actual value (%) C: 44.27, H: 4.57, N: 13.44 Reference example 2 1 -cyclohexyloxycarbonyloxyethyl 7β-[2-(2-aminothiazole-4-
Production of yl)acetamido]-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5yl]thio]methyl]cef-3-em-4-carboxylate dihydrochloride [a] 7β-[2-(2-aminothiazol-4-yl)
Acetamide]-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thio]methyl]cef-3-em-4-carboxylic acid[] 6.8 g of potassium salt was dissolved in dimethylacetamide.
It was dissolved in 110 ml and cooled to -10°C. 1- under stirring
Iodoethyl cyclohexyl carbonate 5.4
g was added and reacted for 10 minutes. To the reaction solution were added 24 ml of a solution of 3N hydrochloric acid in diisopropyl ether, and further 220 ml of diisopropyl ether. residue
Dissolve in 0.01N hydrochloric acid and add dichloromethane to this.
Added 150ml. After adjusting the pH to 7 with 10% ammonia water while maintaining the temperature at 5°C, the organic layer was separated. Furthermore, the aqueous layer was extracted with 100 ml of dichloromethane. The organic layers were combined, washed twice with 150 ml each of ice water, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the residue, and the extracted white precipitate was collected by filtration. Add the filtered precipitate to acetone.
The solution was dissolved in 150 ml, and 10 ml of a solution of 3N hydrochloric acid in diisopropyl ether was added thereto. The precipitate was collected by filtration, washed with acetone, and dried to obtain the title compound [a].
7.9g was obtained. 1R (KBr) cm ^-1 : 1780, 1760, 1680 NMR ( _d6 -DMSO) δ: 1.1-2.1 (m, 10H),
1.54 and 1.60 (d, J=6Hz, 3H), 2.84 (s,
6H), 3.64 (s, 2H), 3.65 (t, J=6Hz,
2H), 3.72 and 3.94 (ABq, J=18Hz, 2H), 4.26
-4.56 (m, 2H), 4,2-4.9 (m, 1H), 4.82
(t, J=6Hz, 2H), 5.13 and 5.18 (d, J=5
Hz, 1H), 5.70 and 5.75 (dd, J=5Hz and 8
Hz, 1H) 6.68 (s, 1H), 6.84 and 6.90 (d, J=
8Hz, 1H), 9.12 and 9.2 (d, J = 10Hz, 2H). Elemental analysis value C ₂₇ H ₃₇ N ₉ O ₇ S ₃・2HCl・2H ₂ O Calculated value (%) C: 40.30, H: 5.39, N: 15.66 Actual value (%) C: 40.91, H: 5.35, N : 15.44. Experimental example Ester compound [a] of Reference Example 2 was added to mouse 1.
100 mg/Kg (as the non-ester) was orally administered to mice, and the concentration of the non-ester [] in the plasma of the mice was measured 0.25, 0.5, 1.0, and 2.0 hours after administration using the cup method (as a test organism). (using Proteus mirabilis Eb313), and the area under the blood concentration curve (AUC) from 0 to 2 hours is calculated. Bioavailability is calculated by the following formula. Bioavailability (%) = AUC (oral administration) / AUC (subcutaneous administration) x 100 The results are as follows.

【table】

Claims (1)

[Claims] 1. A method for producing a 1-iodinated alkyl carbonate, which comprises reacting the 1-halogenated alkyl carbonate with an iodinating agent in the presence of a perhalogeno hydrocarbon or carbon disulfide and a Lewis acid.