JPS5932444B2 - Improved Arndt-Eistelt synthesis method - Google Patents

Description

[Detailed description of the invention] RC0Cl+2CH2N2----- Ag+ RCOCHN2+Y The diazomethane used in the reaction has a low boiling point, is a yellow toxic gas at room temperature, and is explosive, so the reaction is not carried out on an industrial scale because it is dangerous.

On the other hand, JournalofOrganicChemis
Try) 13, 763 (1948) discloses the synthesis of Arunthoeistelt using higher diazo hydrocarbons such as diazoethane and diazopropane. Arnto-Eistelt (Arn), which produces esters
dt-Eistert) synthesis method.

Arunto-eistelt synthesis involves rearranging a diazoketone obtained by reacting a carboxylic acid chloride with diazomethane together with an alcohol or an amine under a metal salt catalyst such as a silver salt to form an acid ester, an acid amide, or an acid ester with one more carbon atom. It is a reaction that produces acids, etc., and is expressed by the following formula, for example.

CCOCHN2+ CH3Cl+N2(1)H2COO
R'+N2(2)CH2CONHbi+N2(2)' However, this cannot be done if side chains such as methyl or ethyl groups are introduced in addition to carbon chain extension, and only the carbon main chain is desired to be extended. .

The purpose of the present invention is to solve these problems in the synthesis of Arunto-eistelt, and to extend one carbon chain from a carboxylic acid chloride without creating a side chain to produce acid esters, acids, etc. An object of the present invention is to provide an improved method for synthesizing Arndtau estert, which is a safe reaction.

The improved method for synthesizing Arunto'eistelt of the present invention is to react an intermediate product obtained by reacting a carboxylic acid chloride with trialkylsilyldiazomethane (hereinafter referred to as the first reaction) and an alcohol (hereinafter referred to as the second reaction). It is characterized by causing

The first reaction in the present invention, that is, the reaction between the carboxylic acid chloride and the trialkylsilyldiazomethane, is preferably carried out under anhydrous conditions, and the reaction temperature is preferably 50 to 30°C, preferably 20°C.
The reaction temperature is -10°C and is usually carried out in a solvent, and the reaction time is not particularly limited, but it is usually carried out for 0.5 to 60 hours. The amount of trialkylsilyldiazomethane used relative to the carboxylic acid chloride in the first reaction is 2 moles or more, the higher the amount, the faster the reaction, so the reaction time can be shortened, and when the amount is less than 2 moles, the reaction is faster. The reaction usually proceeds by adding a tertiary amine such as triethylamine. The amount of amine used is usually 1 to 2 equivalents relative to the carboxylic acid chloride. The trialkylsilyldiazomethane of the present invention has the general formula R2SiCHN2 [where RO has 1 to 1 carbon atoms]
four straight-chain or branched alkyl groups, each representing the same or different types of groups, such as trimethylsilyldiazomethane, triethylsilyldiazomethane, tripropylsilyldiazomethane, dimethylethylsilyldiazomethane, dimethyl t-butyl Examples include silyldiazomethane, and trimethylsilyldiazomethane is particularly preferred.

The carboxylic acid chloride of the present invention refers to chlorides of monocarboxylic acids, dicarboxylic acids, tricarboxylic acids, and the like.

For example, in the monocarboxylic acid chloride represented by the general formula RCOCl, R may include alkyl, aryl, aralkyl, cycloalkyl, thienyl, pyrrolidinyl, and the like. Examples of the solvent for the first reaction of the present invention include hydrocarbons such as benzenetoluene, ethers such as ethyl ether, tetrahydrofuran, and dimethoxyethane, acetals, nitriles such as acetonitrile, and mixed solvents selected from these. It will be done. Especially tetrahydrofuran-acetonitrile (1:1)
Mixed solvents are preferred. After the first reaction is completed, the solvent is distilled off using a method such as reduced pressure, and an intermediate product is obtained as a residue. Taking a monocarboxylic acid chloride as an example, this intermediate product is presumed to be a trialkylsilyl diazoketone obtained by the following reaction. The second reaction of the present invention involves reacting the intermediate product of the first reaction with an alcohol to produce a carboxylic acid ester in which the carbon chain of the carboxylic acid chloride is extended by one, and from the ester by a conventional method. Carboxylic acids etc. can be obtained.

The alcohol for the second reaction is not particularly limited, and any alcohol depending on the desired ester may be used, but if it is desired to further obtain a carboxylic acid from the resulting ester, benzyl alcohol is suitably used. The reaction temperature of the second reaction is 50 to 250°C, and when benzyl alcohol is used, 170 to 190°C is suitable. The reaction is usually carried out under normal pressure, but depending on the alcohol used, it may be carried out under pressure if necessary. In the second reaction, dimethylaniline, diethylaniline, 2,4,6-
The yield can be improved by using amines such as trimethylpyridine (γ-colicin), quinoline, isoquinoline, N-normalhexylpiperidine, triethanolamine, and methyldiethanolamine. Especially 2, 4, 6
- Preference is given to using trimethylpyridine, quinoline and the like. The amount of these amines used is 1 to 10 equivalents based on the carboxylic acid chloride. A feature of the improved method for synthesizing Arunto-eistelt of the present invention is that by using trialkylsilyldiazomethane, explosives such as diazomethane,
The danger of toxic gas accidents has been eliminated, and this has become a safe synthetic reaction that is industrially practical. In addition, conventionally, in this synthesis reaction, a higher diazo hydrocarbon was used to introduce a substituent (RS) at the α-position as shown in formula (4), but this has a drawback when only the carbon main chain is desired to be extended. was. By using the trialkylsilyldiazomethane of the present invention [RS is R2Sl-], only the carbon chain can be extended as shown in formula (5). Useful pharmaceuticals can be produced using the compounds obtained by the present invention as raw materials.

An example is shown below. Fuexamag, which is derived from 4-n-butyloxyphenylacetic acid benzyl ester, is useful as an anti-inflammatory agent.

Cephalothin of the formula derived from thiophene-2-acetic acid benzyl ester is useful as an antibiotic.

(S)-1-benzyloxycarbonyl-2 represented by the formula
- Clemastine of the formula derived from benzyl pyrrolidine acetate is useful as an antihistamine.

The present invention will be explained below with reference to Examples.

Since trimethylsilyldiazomethane in the examples contains hexamethyldisiloxane, the composition was determined from the integral value of nuclear magnetic resonance spectrum (NMR) and the amount thereof was calculated. The silica gel used for column chromatography was SilcARCC-7Sp manufactured by Mallinckrodt.
ecjal was used.

Preparative thin layer chromatography is Silica manufactured by Talc.
Gel6OF254Plate was used. In addition, (%*) of the pale yellow oily substance in the examples indicates the yield based on the carboxylic acid chloride. Example 1 In a 30 ml three-necked flask, 3 mmol of trimethylsilyldiazomethane and 30 mmol of triethylamine were added under anhydrous conditions.
Pour 10 ml of a tetrahydrofuran-acetonitrile (1:1 volume ratio) solution containing 3 mmol (3 mmol), and
337 mg (2.4 mmol) of benzoyl chloride was added at °C, and the mixture was stirred for 24 hours to carry out the first reaction.

After the reaction, the solvent was distilled off under reduced pressure to obtain an intermediate product. To this intermediate product, 2 ml of benzyl alcohol and 2 ml of 112.4.6-trimethylpyridine were added and stirred at 180-185° C. for 7 minutes to carry out a second reaction.

Anti after that? The liquid was cooled to room temperature, benzene was added thereto, washed successively with 10% citric acid, water, and saturated saline, dried over anhydrous magnesium sulfate, the solvent and unreacted benzyl alcohol were distilled off under reduced pressure, and the remaining oil was purified with silica gel. Purified by column chromatography (eluent: benzenelihexanelydiethyl ether 10:10:1) to obtain a pale yellow oil 33
57r19 (62.8%*) was obtained. Infrared spectrum of the obtained pale yellow oil (film, hereinafter abbreviated as R)
Is it 1738? -1 (C-0), and exhibits absorption at nuclear magnetic resonance spectrum (hereinafter abbreviated as NMR).

The signal δ (Ppm) of CDCl3 was 3.64 (
2H. s. CH2C0), 5.12 (2H..s,.0
CH2) was 6.80 to 7.28 (10 H.m, aromatic hydrogen). From the above results, it was confirmed that the obtained pale yellow oil was phenylacetic acid benzyl ester represented by the following formula.

Example 2 In Example 1, benzoyl chloride was changed to 420 W (2.4 mmol) of 4-chlorobenzoyl chloride, and chromatography was performed using preparative thin layer chromatography (developing solution: benzenelihexanelydiethyl ether). I did the same thing, except I changed it to 10:10:1).

A pale yellow oily substance 413 (66.0%*) was obtained. The obtained pale yellow oily substance R exhibits absorption at 1735CfL-1 (C-0), and the NMR δ (Ppm) value is 360 (2H.
s. CH2C0), 5.12 (2H, S.OCH2),
7.20 (4H.s, aromatic hydrogen), 7.28 (5H.s)
s, aromatic hydrogen). From the above results, it was confirmed that the obtained pale yellow oil was 4-chlorophenyl acetic acid benzyl ester represented by the following formula. Example 3 In Example 1, benzoyl chloride was replaced with naphthol chloride 4
The same procedure was carried out except that 58η (2.4 mmol) was used for 24 hours instead of 30 hours, and the eluent for chromatography was changed to (benzenlyhexanelydiethyl ether 10:20:1).

516 wa of light yellow oil (77.8%*) was obtained. The IR of the obtained pale yellow oil was 1730CTrL-1 (C-
0), and the NMR δ (Ppm) value is 4.1
2 (2H..s.CH2C0), 5.13 (2H- q
-0CHOY7.16-8,17 (12H-m, aromatic hydrogen). From the above results, it was confirmed that the obtained pale yellow oil was 1-naphthyl acetic acid benzyl ester represented by the following formula.

Example 4 In Example 1, the amount of trimethylsilyldiazomethane was changed to 3.6 mmol, benzoyl chloride was added to 410 methoxybenzoyl chloride (2.4 mmol) for 24 hours to 48 hours, and silica gel column chromatography was performed. The eluate (benzenelyhexanelychloroform-1:1:
The same procedure as in Example 1 was carried out except for changing to 1) to obtain a pale yellow oily substance 370% (60.2%*).

The IR of the obtained pale yellow oil was 1725CTIL-1 (
C-0), and the NMR δ (Ppm) value is 3.
．． 60 (2H..s..CH2C0), 3.76 (3H
1s, 0CH3), 5.12 (2H, .s.0CH2)
, 6.80 to 7.28 (9 H.m, aromatic hydrogen).

From the above results, it was confirmed that the obtained pale yellow oil was benzyl 4-methoxyphenyl acetate represented by the following formula.

Example 5 The 4-methoxybenzoyl chloride of Example 4 was mixed with 352 w (2.4 mmol) of thiophene-2-carbonyl chloride.
Then, chromatography was performed using preparative thin layer chromatography (developing solution: benzene, hexane, dichloroform, 1:1).
: The same procedure as in Example 4 was carried out except that the method was changed to 1).

A pale yellow oil 359T19 (64.4%*) was obtained. The obtained pale yellow oil had an IR of 1735(:Tfl-1(
C-0), and the NMR δ (Ppm) value is 3.
．． 88 (2H.s.CH2C0), 5.16 (2H.s.
．． 0CH2), 6.88-7.28 (3H, 9m, [,
J and 7.32 (5H.S, aromatic hydrogen).

From the above results, it was confirmed that the obtained pale yellow oil was benzyl thiophene-22-acetic acid ester represented by the following formula.

Example 6 The same procedure as in Example 4 was carried out except that 4-methoxybenzoyl chloride in Example 4 was changed to 510 m(2.4 mmol) of 4n-butoxybenzoyl chloride and the amount of trimethylsilyldiazomethane was changed to 4.8 mmol.

543 g (75.8%) of a pale yellow oil was obtained. IR of the obtained pale yellow oil shows absorption at 1735cTn-1 (C-0), and NMR δ (Ppm) value is 0.96 (3
H. ．． t. CH2Cdan. ), 1.16-1.88 (4H
．． m. CH2CH2) 3.60 (2H.s, CH2CO
), 3.92 (2H.t.CH2CH20), 5.10
(2H.s.0CH2Ph), 6.80-7.28 (9
H. m, aromatic hydrogen). As a result, it was confirmed that the obtained pale yellow oil was 4-n-butoxyphenyl acetic acid benzyl ester represented by the following formula.

Example 7 In Example 1, one triethylamine was not used, and the amount of trimethylsilyldiazotane was changed to 563 myropionyl.
05 w (2.4 mmol), the stirring time of the first reaction was changed to 4 hours, and the eluent of the silica gel column chromatography was changed to (benzenelyhexanelydiethyl ether-20:20:1). The same procedure as in Example 1 was carried out.

442 watts (72.4%) of a pale yellow oil was obtained. IR of the obtained pale yellow oil shows absorption at 1730C7n (C-0), and NMR δ (Ppm) value is 1.92 (2H.
．． g,. CH2C]12CH2), 2.36(2H.t
．． C1112C0), 2,64(2H.t, Cll2P
h), 5.12 (2H.s, 0CH2), 7.04-7
．． 36 (10H, .ml aromatic hydrogen).

As a result of the above, the obtained pale yellow oily substance is expressed by the following formula 4
- It was confirmed that it was phenylbutyric acid benzyl ester.

Example 8 In Example 7, 3-phenylpropionyl chloride was converted to cyclohexanecarboxylic acid chloride 352Tnfi! (
2.4 mmol), stirring time for the first reaction was 6 hours, and preparative thin layer chromatography (developing solution; benzenelyhexanelydiethyl ether = 2).
The same procedure as in Example 7 was carried out except that the ratio was changed to 0:20:1).

A light yellow oily substance 326 (58.5%*) was obtained. The R of the obtained pale yellow oil is 1735cTn-1 (C-0)
The NMR δ(Ppm) value is 0.72-
2.04(11H,.m,.be〉), 2.24(2
H. ．． d,. CH2C0), 5.12 (2H1s.0C
H2), 7.34 (5H.s, aromatic hydrogen).

From the above results, it was confirmed that the obtained pale yellow oil was cyclohexyl acetic acid benzyl ester represented by the following formula.

Example 9 A 30 ml three-necked flask was charged with 4 ml of a methylene chloride solution containing benzyloxycarbonyl-L-proane 598 (2.4 mmol) under anhydrous conditions, one drop of dimethylformamide was added, and then chlorinated at 0°C. After adding 0.3 ml (3.6 mmol) of oxalyl and stirring for 15 minutes, the temperature was returned to room temperature and the reaction was stirred for 1 hour.
The reaction solution was dried under reduced pressure to give benzyloxycarbonyl-L-
A crude product of proline acid chloride was obtained.

Tetrahydrofuran-acetonitrile (1
:1 volume ratio) was added thereto, and at 0° C., 5.3 mmol of trimethylsilyldiazomethane was added and stirred for 5 hours to carry out the first reaction.

After the reaction, the solvent was distilled off under reduced pressure to obtain an intermediate product. 2 ml of benzyl alcohol and 2 ml of 4,6-trimethylpyridine were added to this intermediate product, and the mixture was stirred at 180 to 185° C. for 7 minutes to carry out a second reaction. Thereafter, the reaction solution was cooled to room temperature, benzene was added, washed with 10% citric acid, water, and saturated brine, dried over anhydrous magnesium sulfate, and the solvent and unreacted benzyl alcohol were distilled off under reduced pressure. Preparative thin layer chromatography (developing solution: benzene-dichloroform-lysyl-diethyl ether 2:2:1)
to obtain a pale yellow oil 656Tf9 (77.4% from benzyloxycarbonyl L-proline).

The R of the obtained pale yellow oil is 1725cm-11695
? -1 shows absorption of (C=O), NMR δ(Ppm
) value is 1.60-2.38 (4H,.m1Cdan,CU
2-) 2.50-2.98 (2H,.m1Cdan, CO)
, 3.24-3.56 (2H.m,.CH.2N), 4
．． 08-4.36 (1H,.m,.CHN), 5.08
(2H.s.0CH2), 5.12 (2H.s, 0C
), 7.32 (10 H.s, aromatic hydrogen). From the above results, it was confirmed that the obtained pale yellow oil was (S)-1-benzyloxycarbonyl-2-pyrrolidine benzyl acetate ester represented by the following formula.

Claims (1)

[Claims] 1 Trialkylsilyldiazomethane (here, trialkyl consists of the same and/or different types selected from the group of linear or branched alkyl groups having 1 to 4 carbon atoms) to the carboxylic acid chloride. An improved method for Arndt-Eistert synthesis, characterized by reacting an intermediate product obtained by the reaction with an alcohol.