JP2009120599A - Method for producing etodolac ester - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide mainly a method for producing an etodolac ester which is an intermediate for producing etodolac. <P>SOLUTION: The method for producing etodolac methyl ester is to react 7-ethyl tryptophol with a 3-oxo-valerate ester in an acetonitrile solvent or a mixed solvent containing ≥50 vol% acetonitrile in the presence of an acid. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention provides (±) -1,8-diethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid (hereinafter referred to as “etodolac”) useful as a medicine. The present invention relates to a novel method for producing an ester of an etodolac (hereinafter referred to as “etodolac ester”).

  Etodolac is known as a non-steroidal anti-inflammatory agent having selective inhibitory activity on cyclooxygenase 2, and has already been sold in about 58 countries around the world (see, for example, Non-Patent Document 1). In Japan, chronic rheumatism, osteoarthritis and the like have been sold as indications since 1994.

  It is known that etodolac can be produced by hydrolyzing etodolac ester (see, for example, Patent Document 1). Such etodolac ester can be produced by reacting 7-ethyltryptohol and 3-oxovalerate in the presence of sulfuric acid, in a methanol solvent, or in the presence of hydrogen chloride gas in an alcohol solvent. (For example, refer to Patent Document 2 and Patent Document 3).

  However, in the above-described conventional method, it takes 7 to 12 hours for the condensation reaction between 7-ethyltryptohol and 3-oxovalerate to be completed. This is not satisfactory as a manufacturing method on an industrial scale.

In addition, since the conventional method requires a large amount of reaction solvent, a production facility equipped with a large-capacity reaction vessel is necessary, and there are problems in terms of infrastructure and cost.
Kawai S, et al, Inflamm Res. Supp12, 102-106 (1998) US Pat. No. 4,585,877 Chinese Patent No. 174174 US Pat. No. 6,331,638

  An object of the present invention is mainly to provide a production method capable of obtaining an etodolac ester, which is an etodolac production intermediate, in a short time and in a high yield.

  The present inventor made a high yield in a short time by reacting 7-ethyltryptohol and 3-oxovaleric ester in an acetonitrile solvent or a mixed solvent containing 50% by volume or more of acetonitrile in the presence of an acid. The present inventors have found that etodolac ester can be produced with this method.

As the present invention, for example, the following 1. And 2. Can be mentioned.
1. In the presence of an acid, 7-ethyltryptohol represented by the following structural formula (1) and 3-oxovaleric acid ester represented by the following general structural formula (2) are added in acetonitrile solvent or acetonitrile. A method for producing an etodolac ester represented by the following general structural formula (3), wherein the reaction is carried out in a mixed solvent containing 50% by volume or more.

In said general structural formula, R represents a C1-C8 alkyl.
2. A method for producing etodolac, comprising the following steps 1 and 2.
Step 1: In the presence of an acid, 7-ethyltryptohol represented by the following structural formula (1) and 3-oxovaleric acid ester represented by the following general structural formula (2) in an acetonitrile solvent or The process made to react in the mixed solvent containing 50 volume% or more of acetonitrile.

Step 2: A step of obtaining etodolac by hydrolyzing the etodolac ester represented by the following general structural formula (3) obtained in step 1.

In said general structural formula, R represents a C1-C8 alkyl.

  The present invention is described in detail below.

I. Etodolac ester production method Etodolac ester can be produced according to the following reaction formula.

  In the reaction formula, R represents an alkyl having 1 to 8 carbon atoms.

  In this reaction, the present invention is characterized by using acetonitrile or a mixed solvent containing 50% by volume or more of acetonitrile as a solvent. In particular, it is preferable to use acetonitrile as a solvent. The mixed solvent is composed of acetonitrile and one or more other solvents, and examples of the other solvents include toluene.

  Here, “volume%” is well known to those skilled in the art, but the value obtained by dividing the volume (mL) of acetonitrile used as the reaction solvent by the sum of the volumes (mL) of each solvent used as the reaction solvent was multiplied by 100. Value.

  Acetonitrile is not particularly limited as long as it is generally available as a reaction solvent. For example, acetonitrile is sold by Nacalai Tesque Co., Ltd. (Nacalai Standard Grade 1, JIS Standard Special Grade, etc.), and is sold by Kanto Chemical Co., Ltd. Can be listed (such as deer 1 grade, special grade) and those sold by Wako Pure Chemical Industries, Ltd.

  The proportion of acetonitrile in the mixed solvent is suitably 50% by volume or more, but preferably 70% by volume or more.

  The amount of the solvent that can be used in this reaction varies depending on the solvent used, the type of acid, and the like, but is not particularly limited as long as the reaction proceeds basically. For example, 1 g of 7-ethyltryptohol (1) An amount in the range of 1 to 10 mL is appropriate, and an amount in the range of 1.5 to 3 mL is preferable.

  The acid that can be used in this reaction is not particularly limited as long as the reaction proceeds. For example, one or two acids selected from sulfuric acid, methanesulfonic acid, toluenesulfonic acid, and the like are suitable. Of these, sulfuric acid and methanesulfonic acid are preferable.

  The amount of the acid varies depending on the solvent to be used, the type of acid, and the like. Within the range of ˜2 mol is preferred.

  The amount of 3-oxovaleric acid ester (2) used in this reaction is not particularly limited as long as this reaction proceeds, but for example, 1 to 2 with respect to 1 mol of 7-ethyltryptohol (1). The molar range is appropriate, and the range of 1.0 to 1.1 mol is preferable.

  In addition, 7-ethyltryptohol (1) and 3-oxovaleric acid ester (2) used in this reaction can be produced by a known method (for example, see US Pat. No. 3,939,178).

  The ester portion of 3-oxovaleric acid ester (2) is not particularly limited as long as this reaction proceeds, and examples thereof include linear or branched alkyl having 1 to 6 carbon atoms. it can. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. Especially, a C1-C4 alkyl is preferable and a C1-C2 alkyl is more preferable.

  This reaction can be carried out by a conventional method except that the specific solvent according to the present invention is used. For example, it can be carried out by stirring and mixing each raw material and acid in a solvent.

  The reaction temperature varies depending on the solvent used, the type of acid, and the like, but is suitably 30 ° C or lower, and preferably within a range of -20 ° C to 20 ° C.

  According to the present invention, a high yield of etodolac ester (3) can be obtained in a short time.

  In the present invention, “short time” means within 4 hours, preferably within 2 hours, and more preferably within 1 hour. “High yield” means 80% or more, preferably 90% or more.

  Whether or not the above reaction is complete can be confirmed, for example, by measuring the amount of 7-ethyltryptohol or 3-oxovalerate in the reaction solution.

After completion of this reaction, the product etodolac ester can be isolated and purified by a conventional method. For example, the etodolac ester can be isolated by filtering a precipitate in the reaction solution, or by subjecting the concentrated and dried product of the reaction solution to an extraction treatment or column chromatography.
II. Etodolac production method Etodolac can be obtained by hydrolyzing the etodolac ester obtained by the above method in the presence of a base by a conventional method. For example, etodolac can be obtained from etodolac ester by the method described in US Pat. No. 4,585,877. The obtained etodolac can be optically resolved as necessary, and optical isomers of etodolac can be obtained by such optical resolution.

Hereinafter, the present invention will be described in further detail with reference examples, examples and test examples. However, the present invention is not limited to these.
Reference Example 1 According to the method described in Patent Document 2, (±) -1,8-diethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid methyl ester (hereinafter, “ Etodolac methyl ester "))) 7-Ethyl tryptohol 10 g and methyl 3-oxovalerate 7.95 g were dissolved in 63 mL of methanol, and 2.73 g of sulfuric acid was slowly added dropwise thereto. Stir for 5 hours. After cooling the reaction solution, the precipitate in the reaction solution was collected by filtration, washed with 5 mL of methanol, and further washed with water until the washing solution became neutral. The obtained precipitate was dried under reduced pressure to obtain 10.15 g of etodolac methyl ester as white crystals.
Reference Example 2 Production of etodolac methyl ester by the method described in Patent Document 3 Dissolve 7 g of ethyl tryptohol and 9.10 g of methyl 3-oxovalerate in 50 mL of methanol, and add 50 mL of 10 wt% hydrochloric acid methanol solution thereto. Then, the mixture was stirred at 25 ° C. for 7 hours. After the precipitate in the reaction solution was collected by filtration, the precipitate was washed with 5 mL of methanol, and further washed with water until the washing solution became neutral. The obtained precipitate was dried under reduced pressure to obtain 5.78 g of etodolac methyl ester as white crystals.
Example 1 Preparation of etodolac methyl ester by the method of the present invention 20 g of 7-ethyltryptohol and 14.4 g of methyl 3-oxovalerate were dissolved in 40 mL of acetonitrile (Nacalai Tesque, EP, the same shall apply hereinafter). After slowly dropping 4 g, the mixture was stirred at 0 ° C. for 1 hour. After the precipitate in the reaction solution was collected by filtration, the precipitate was washed with 20 mL of acetonitrile, and further washed with water until the washing solution became neutral. The obtained precipitate was dried under reduced pressure to obtain 29.7 g of etodolac methyl ester as white crystals.
Example 2-6
Etodolac methyl ester was produced under the same conditions as in Example 1 except that the reaction solvent type / amount, acid type / amount, reaction time, and reaction temperature were changed. A list of reaction conditions including reference examples is shown in Table 1.

In Table 1, “amount of solvent (v / w)” represents the amount of solvent (mL) relative to 1 g of 7-ethyltryptohol, and “amount of acid (eq)” represents 1 mol of 7-ethyltryptohol. Represents the molar amount of acid relative to.

Test Example 1 Yield and Chemical Purity Table 2 shows the yield and chemical purity of etodolacmethyl ester obtained in Reference Examples 1 and 2 and Examples 1 to 6.

  The chemical purity of etodolacmethyl ester was measured by the HPLC method under the following conditions, and calculated from the area ratio of each peak.

  The column used was cosmosil AR-II (150 mm, manufactured by Nacalai Tesque), the column temperature was set to 40 ° C., the flow rate was set to 1 mL / min, and the detection was set to UV 280 nm. The mobile phase was liquid A (0.1% perchloric acid aqueous solution / acetonitrile = 60/40) and liquid B (0.1% perchloric acid aqueous solution / acetonitrile = 20/80). Used in conditions.

  As apparent from Tables 1 and 2, according to the production methods (Examples 1 to 6) according to the present invention, etodolacmethyl ester was obtained in a short time and in a high yield as compared with the conventional methods (Reference Examples 1 and 2). Can be manufactured. Further, according to the production method of the present invention, the amount of the reaction solvent can be reduced to about 1/3 to 1/4 as compared with the conventional method.

  According to the present invention, etodolac ester can be produced in a high yield in a short time, which is very useful as a production method on an industrial scale. Further, the present invention is an advantageous production method from the viewpoint of infrastructure and cost because the amount of the reaction solvent can be greatly reduced.

Claims (6)

In the presence of an acid, 7-ethyltryptohol represented by the following structural formula (1) and 3-oxovaleric acid ester represented by the following general structural formula (2) are added in acetonitrile solvent or acetonitrile. (±) -1,8-diethyl-1,3,4,9-tetrahydropyrano represented by the following general structural formula (3), characterized by reacting in a mixed solvent containing 50% by volume or more A method for producing [3,4-b] indole-1-acetic acid ester (hereinafter referred to as “etodolac ester”).

In said general structural formula, R represents a C1-C8 alkyl. The production method according to claim 1, wherein R is methyl. The manufacturing method in any one of Claim 1 or 2 whose quantity of the reaction solvent is 1-10 mL with respect to 1-g of 7-ethyltryptohol (1). (±) -1,8-diethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid (hereinafter referred to as “etodolac”) including the following steps 1 and 2. ) Manufacturing method.
Step 1: In the presence of an acid, 7-ethyltryptohol represented by the following structural formula (1) and 3-oxovaleric acid ester represented by the following general structural formula (2) in an acetonitrile solvent or The process made to react in the mixed solvent containing 50 volume% or more of acetonitrile.

Step 2: A step of obtaining etodolac by hydrolyzing the etodolac ester represented by the following general structural formula (3) obtained in step 1.

In said general structural formula, R represents a C1-C8 alkyl. The production method according to claim 5, wherein R is methyl. The manufacturing method in any one of Claim 4 or 5 whose quantity of the reaction solvent in the process 1 is 1-10 mL with respect to 1-g of 7-ethyltryptohol (1).