WO2006030892A1

WO2006030892A1 - Process for production of heterocyclic compounds

Info

Publication number: WO2006030892A1
Application number: PCT/JP2005/017137
Authority: WO
Inventors: Tetsuji Harabe; Masaru Tanaka
Original assignee: Nippon Shinyaku Co., Ltd.
Priority date: 2004-09-17
Filing date: 2005-09-16
Publication date: 2006-03-23

Abstract

The invention aims at providing a process for the production of NS-220 which is suitable for mass production on an industrial scale. The invention is constituted of (1) a process for the production of methyl cis-5-(4-chlorobutyl) -2-methyl-1,3-dioxane-2-carboxylate, characterized by hydrolyzing a cis/trans isomer mixture of methyl 5-(4- chlorobutyl)-2-methyl-1,3-dioxane-2-carboxylate in the presence of a base; (2) a process for the production of 4-methyl-N-(2-oxopropyl)benzamide, characterized by oxidizing 4-methyl-N-(2-hydroxypropyl)benzamide with 2,2,6,6-tetra- methyl-1-piperidinyloxyl radicals and sodium hypochlorite; and so on.

Description

Specification

Method for producing heterocyclic compound

Technical field

[0001] The present invention relates to 2-methyl-c-5- {4- [5-methyl-2- (4-methylphenol) -1,3-oxazole-4-yl] butyl} 1,3 dioxane useful as a medicine —R— 2 It relates to a method for producing rubonic acid (hereinafter NS-220).

[Chemical 1]

NS-220

Background art

NS-220 is a blood triglyceride lowering action and low density lipoprotein cholesterol.

(Hereinafter referred to as LDL-C), and also has a blood glucose-lowering effect, blood insulin lowering effect, or high-density lipoprotein cholesterol (hereinafter referred to as HDL-C) increasing effect or arteriosclerosis index [non- This is the ratio of high-density lipoprotein cholesterol to HDL-C, calculated as (total cholesterol value-HDL-C value) ZHDL-C value. ] Has a lowering effect. Therefore, it is useful as a preventive or therapeutic agent for coronary artery disease, cerebral infarction, hyperlipidemia, arteriosclerosis, diabetes, hypertension, or obesity (see, for example, Patent Document 1) o NS-220 is It is known that it can be produced by the following method (for example, see Patent Document 1). Bre

Me

, C0 ₂ Me One 6

HN

People o — 220

Since NS-220 is a cis isomer, the production intermediate methyl cis-5- (4 chlorobutyl) 2-methyl-1,3 dioxane 2 carboxylate (compound 4) is Compound 4) was produced by resolution by column chromatography. However, in this conventional method, an unnecessary transformer body has to be discarded, and there is a problem in terms of manufacturing efficiency. In addition, the use of a purification method based on column chromatography in large-scale synthesis on an industrial scale necessitates the use of a considerable amount of silica gel and solvent, resulting in a rise in production costs and the adverse effect of the used solvent on the environment. Giving and giving. Further, the operation process is complicated and difficult.

[0003] On the other hand, 4-methyl-N— (2oxopropyl) benzamide (Compound 6), which is a raw material for NS 220, is in accordance with the known method for producing N— (2oxopropyl) benzamide (Compound 6 ′). Can be manufactured. However, as described below, none of the known production methods are satisfactory on an industrial scale.

[0004] Known branching of compound 6 production method

(1) Manufacturing method A

In the above production method A (for example, see Non-Patent Documents 1 and 2), compound 9 as a raw material is very expensive, and the total yield is only 58%. Furthermore, in the production of compound 11, which is a production intermediate, a large amount of water and hydrochloric acid must be used for the post-treatment, and temperature adjustment is necessary when adding water or hydrochloric acid to the reaction solution. Is also cumbersome.

(2) Manufacturing method B

[Chemical 4]

HC1

13

In the above production method B (for example, see Non-Patent Document 3), the raw material compound 13 is chemically unstable, and the compound 13 is not commercially available, and it is necessary to carry out raw material synthesis (3 steps). There is.

(3) Manufacturing method C

[Chemical 5]

The above production method C (for example, see Non-Patent Document 4) has a total yield of 18% and is not strong (in the case of Compound 6 ′), and it is difficult to crystallize Compound 6 in the post-reaction treatment. .

(4) Manufacturing method D

[Chemical 6]

6

The above production method D (for example, see Non-Patent Document 5) has a total yield of only 15% (in the case of Compound 6).

(4) Manufacturing method E

[Chemical 7]

Since the above production method E (for example, see Non-Patent Documents 6 to 7) uses a metal such as chromium or ruthenium as a reagent, a separate disposal process is required, and the product may contain these metals. is there.

As mentioned above, the production method of compound 6, which is an important raw material for NS 220, is not satisfactory on an industrial scale.

[0009] Patent Document 1: International Publication No. 01Z90087 Pamphlet

Non-patent literature l: J. Chem. Soc, 1948, 310-315

Non-Patent Document 2: Tetrahedron Lett., 2000, 41, 8969-8972

Non-Patent Document 3: J. Am. Chem. Soc, 1991, 113, 2247-2253

Non-Patent Document 4: Chem. Lett., 1989, 449-452, 515-518, 569-572

Non-Patent Document 5: Chem. Pharm. Bull, 1979, 27, 1181-1185

Non-Patent Document 6: TetrahedronLett "1985, 26, 3433-3436

Non-Patent Document 7: Syn 丄 ett., 1999, 10, 1642-1644

Disclosure of the invention

Problems to be solved by the invention

[0010] The main object of the present invention is to provide a novel method for producing NS-220 suitable for mass synthesis on an industrial scale. Means for solving the problem

As a result of extensive research, the present inventors have found that methyl cis-5- (4 chlorobutyl) -2-methyl-1,3 dioxane-2 carboxylate (compound 4), methyl 5- (4 tert-butyl) -2-methyl-1,3-dioxane-2-carboxylate (compound 5) and methyl cis 2-methyl-5- {5-[(4 methylbenzoyl) amino] 6 -xoheptyl} 1,3 dioxane 2 carboxy An industrial production method capable of producing a high rate (compound 7) and an industrial production method of 4-methyl-N- (2oxopropyl) benzamide (compound 6), which is a raw material for producing NS-220 Was completed.

Examples of the present invention include the following methods.

(1) Methyl 5- (4-chlorobutyl) -2-methyl-1,3-dioxane 2 Carboxylate cis-trans mixture (compound 4 ') is characterized by hydrolysis in the presence of a base. — (4-chlorobutyl) 2-methyl 1,3 dioxane 1-2 carboxylate (compound 4) production method,

(2) It is characterized by hydrolyzing a cis-trans mixture (methyl compound 5 ') of methyl 5— (4 tert-butyl) -2-methyl-1,3-dioxane-2-carboxylate in the presence of a base. A process for producing methyl cis-5- (4-iodobutyl) -2-methyl-1,3 dioxane 2 carboxylate (compound 5),

(3) Hydrolysis of a cis-trans mixture (compound 7,) of methyl 2-methyl-5- {5-[(4 methylbenzoyl) amino] 6 oxoheptyl} 1,3 dioxane 2 carboxylate in the presence of a base Methyl cis-2-methyl-5- — [(4 methylbenzoyl) amino] 6 oxoheptyl} 1,3 dioxane 1-carboxylate (compound 7), and

(4) Acidify 4-methyl-N— (2 hydroxypropyl) benzamide (compound 20) with 2, 2, 6, 6-tetramethyl-1-piberidi-loxy radical and sodium hypochlorite. A process for producing 4-methyl N- (2-oxopropyl) benzamide (compound 6), characterized in that

BEST MODE FOR CARRYING OUT THE INVENTION 1¾ Method for L Compound 4

Compound 4 which is an important production intermediate of NS-220 can be produced by the following method.

[Chemical 8]

As shown in the test examples described later, compound 4 ′ is hydrolyzed in the presence of a base, so that the trans form is preferentially hydrolyzed (selective hydrolysis). Therefore, by adjusting the amount of the base used, The hydrolysis rate can be controlled, and the compound 4 having a cis Z-trans ratio of 9 Zl to 50 Zl can be easily produced.

In addition, 5- (4 chlorobutyl) -2-methyl-1,3 dioxane-2-strong rubonic acid (compound 21), which has a high proportion of trans form produced by this selective hydrolysis, must undergo ketal exchange. To regenerate compound 4 ′. Therefore, the compound 4 can be obtained again by the similar selective hydrolysis of the regenerated compound 4 ′.

Conventionally, only the cis isomer obtained by column chromatography was used and unnecessary trans isomers were discarded. However, in the method for producing Compound 4 by selective hydrolysis, unnecessary trans isomers must be reused. NS-220 can be synthesized efficiently.

The solvent that can be used for this selective hydrolysis reaction is not particularly limited as long as it can dissolve the substrate compound 4 ′, but acetonitrile, Ν, Ν dimethylformamide, toluene, tetrahydrofuran, Ν-methyl-2-pyrrolidone. 1,3 dimethyl-2-imidazolidinone, acetone, and methanol are suitable, and acetonitrile, Ν, dimethylformamide, and tetrahydrofuran are preferred.

The amount of the solvent used in this selective hydrolysis reaction is not particularly limited as long as it dissolves compound 4 ′ as a substrate, but 0.5 to L0 amount (volume) with respect to compound 4 ′ as a substrate. (mL) Z weight (g)) is suitable, and 1 to 5 times the amount is more preferable.

The base that can be used for this selective hydrolysis reaction is not particularly limited as long as it is a base used for a usual ester hydrolysis reaction, but sodium hydroxide, potassium hydroxide, lithium hydroxide, hydroxide salt, and the like. Cesium is suitable, and sodium hydroxide and potassium hydroxide are preferred. By controlling the amount of base used in this hydrolysis reaction, the hydrolysis rate of compound 4 ′ as a substrate can be controlled. When the hydrolysis rate is low, many unreacted trans isomers remain, and when the hydrolysis rate is high, the yield of compound 4 decreases. The amount of base used varies depending on the cis-Z trans ratio of compound 4 ′, the substrate used, and the type and amount of solvent used. Appropriate, 0.2 to 0.4 times the amount of mono-layered S girls, 0.25 to 0.35 mono-layered amounts of girls! / ヽ.

The reaction temperature of this hydrolysis reaction is not particularly limited as long as it is not higher than the boiling point of the solvent to be used. In general, the range of 0 to 60 ° C is preferable, and the range of 10 to 40 ° C is more preferable. A range of 30 ° C is more preferred.

The reaction time of this hydrolysis reaction depends on the concentration of the substrate in the reaction solution, but the range of 30 minutes to 10 hours is preferred, and the range of 1 to 5 hours is more preferred.

This ketal exchange reaction is a general reaction and can be carried out by a known method. For example, it can be carried out by adding methyl pyruvate in the presence of boron trifluoride jetyl ether complex.

The solvent that can be used in this ketal exchange reaction is not particularly limited as long as it can dissolve compound 21 as a substrate, but toluene and acetonitrile are suitable, and toluene is preferable. Amount of solvent used in this ketal exchange reaction Is not particularly limited as long as it is an amount capable of dissolving compound 21 as a substrate, but 1 to L0 volume (volume (mL) Z weight (g)) is appropriate for compound 21 as substrate. 3 to 5 times the amount is preferable.

The reaction temperature of this ketal exchange reaction is not particularly limited as long as it is lower than the boiling point of the solvent to be used, but in general, the range of 0 to 60 ° C is preferred, and the range of 20 to 40 ° C is more preferred 2 5 A range of ˜35 ° C. is more preferable.

The reaction time of this ketal exchange reaction depends on the concentration of the substrate in the reaction solution. The range of 1S 30 minutes to 10 hours is preferred. The range of 1 to 5 hours is more preferred.

Thus, compound 4 can be produced by hydrolysis suitable for mass synthesis on an industrial scale, not by column chromatography. Furthermore, since unnecessary transformer bodies can be reused, the production efficiency can be improved.

II. Method for producing compound 5

Compound 5 which is an important production intermediate of NS 220 can be produced by the following method in the same manner as the production method of compound 4 described above.

[Chemical 9]

As shown in the test examples described below, compound 5 ′ is hydrolyzed in the presence of a base, whereby the trans form is preferentially hydrolyzed (selective hydrolysis). Therefore, by adjusting the amount of the base used, The hydrolysis rate can be controlled, and the compound 4 having a cis Z-trans ratio of 9 Zl to 50 Zl can be easily produced.

In addition, the trans-form produced by this selective hydrolysis is high in the proportion of 5- (4-iodobutyl) -2-methyl-1,3 dioxane-2-strong rubonic acid (Compound 22) should be ketal-exchanged. To regenerate compound 5 ′. Therefore, the compound 5 can be obtained again by the similar selective hydrolysis of the regenerated compound 5 ′.

Previously, only the cis form obtained by column chromatography was used, and the unnecessary trans form was discarded. However, the process for producing Compound 5 by selective hydrolysis involves reusing the unnecessary trans form. NS-220 can be synthesized efficiently.

The solvent, amount of solvent, base, amount of base, reaction temperature and reaction time that can be used for this selective hydrolysis reaction, and the amount of solvent, solvent, reaction temperature and reaction time that can be used for this ketal exchange reaction are as follows. This is the same as the production method of Compound 4.

In this way, compound 5 can be produced in large quantities on an industrial scale regardless of column chromatography. It can be produced by hydrolysis suitable for synthesis. Furthermore, since unnecessary transformer bodies can be reused, the production efficiency can be improved.

III. Method for producing Compound 7

Compound 7, which is an important production intermediate of NS-220, can also be produced in the same manner as compound 4.

[Chemical 10]

5 '6 7

The condensation reaction of compound 5 'and compound 6 can be carried out in the presence of a base, but as a by-product when an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide is used as the base. Since water is generated, hydrolysis reaction of the produced compound 7 ′ can be performed simultaneously by adding an excess base and carrying out this reaction.

As shown in the test examples described below, compound 7 ′ is also hydrolyzed in the presence of a base to preferentially hydrolyze the trans isomer (selective hydrolysis). Therefore, by adjusting the amount of base used, The hydrolysis rate can be controlled, and compound 7 having a cis Z-trans ratio of 9Zl to 50Z1 can be produced.

The solvent that can be used in this reaction is not particularly limited as long as it can dissolve the compounds 5 ′ and 6 as substrates, but N, N-dimethylformamide, N-methyl-2-pyrrolidone, 1,3-dimethyl- 2-Imidazolidinone is suitable, and N, N-dimethylformamide is preferred.

The amount of the solvent used in this reaction is not particularly limited as long as it dissolves the compound 5 ′ and the compound 6 as the substrate, but is 0.5 to L0 times the compound 5 ′ as the substrate. The amount (capacity (mL) Z weight (g)) is appropriate, and 1 to 5 times the amount is preferable.

The base that can be used in this reaction is not particularly limited as long as it is a base used for ordinary condensation reactions and ester hydrolysis reactions, but sodium hydroxide, potassium hydroxide, lithium hydroxide, hydroxide salt, and the like. Cesium and sodium hydride are suitable, sodium hydroxide, potassium hydroxide Um is preferred.

By controlling the amount of base used in this reaction, the hydrolysis rate of compound 7 ′ can be controlled. In addition, an equimolar amount of base is required for the condensation reaction of Compound 5 ′ and Compound 6. Therefore, the amount of base used in this reaction varies depending on the cis-Z trans ratio of compound 7 ′, which is the substrate used, and the type and amount of solvent used. 1. A 6-fold molar amount is appropriate, and 1.1 to 1.4-fold molar amount is preferred.

The reaction temperature of this reaction is not particularly limited as long as it is not higher than the boiling point of the solvent to be used. In general, the range of 0 to 60 ° C is suitable, and the range of 10 to 30 ° C is preferable.

Although the reaction time of this reaction depends on the concentration of the substrate in the reaction solution, the range of 30 minutes to 10 hours is appropriate, and the range of 1 to 5 hours is preferable.

Thus, compound 7 can also be produced by hydrolysis suitable for mass synthesis on an industrial scale. In addition, since this reaction can be carried out simultaneously with the condensation reaction of compound 5 ′ and compound 6, the production process of NS-220 can be reduced by one step, and the production efficiency can be improved. .

IV. Method of making compound 6

Compound 6, which is an important production raw material for NS-220, can be produced by the following method.

[Chemical 11]

Process 2 6 Acidify 4-methyl N- (2-hydroxypropyl) benzamide (compound 20) by using 2, 2, 6, 6-tetramethyl-1-piveridi-ruoxy radical (hereinafter referred to as TEMPO) and sodium hypochlorite Can be manufactured.

As shown in the test examples described later, since this production method uses TEMPO and sodium hypochlorite, the metal compound used in the conventional production method is not used. In addition, this production method has a high yield, the raw materials used are inexpensive and available, and thus the production cost can be reduced, and the post-treatment of each reaction, which requires only two steps, is very simple. Process 1

Step 1 is an amide formation reaction between an acid chloride and an amine and can be produced by a conventional method.

The solvent that can be used in the amide formation reaction is not particularly limited as long as it can dissolve the compound 18 as a substrate, but toluene, acetonitrile, N, N dimethylformamide, N-methyl-2-pyrrolidone, 1, 3 Dimethyl-2-imidazolidinone is suitable, and toluene and acetonitrile are preferred.

The amount of the solvent used in this amide formation reaction is not particularly limited as long as compound 18 as a substrate is dissolved, but it is 1 to 10 times the amount of compound 18 as a substrate (volume (mL) Z weight ( g)) is suitable, and 3 to 6 times the amount is preferred.

The reaction time of the present amide formation reaction depends on the concentration of the substrate in the reaction solution, but is suitably in the range of 30 minutes to 8 hours, preferably in the range of 1 to 4 hours.

The reaction temperature of the present amide formation reaction is not particularly limited as long as it is not higher than the boiling point of the solvent to be used. In general, the range of 20 to 60 ° C is appropriate, and the range of 0 to 40 ° C is preferable. The amount of 19 used in this amide formation reaction varies depending on the type and amount of the solvent used, the reaction temperature, and the reaction time, but a 1 to 10-fold molar amount relative to 18 is appropriate. The amount is good. Process 2

As a solvent that can be used in the acid-acid reaction in step 2, the compound 20 as a substrate may be partially used. Although it does not ask | require especially if it melt | dissolves, Acetonitrile, an ethyl acetate, isopropyl acetate, and toluene are suitable, Acetonitrile and an ethyl acetate are preferable.

The amount of solvent used in this oxidation reaction is not particularly limited as long as it partially dissolves the compound 20 as a substrate, but it is 1 to 40 times the amount of compound 20 as a substrate (volume (mL) Z Weight (g)) is suitable, 3 to 20 times the amount is preferred.

The amount of TEMPO used in this oxidation reaction varies depending on the type and amount of the solvent used, the reaction temperature, and the reaction time, but 0.001 to 2 times the molar amount is preferred with respect to the substrate. It is preferable to mass.

In general, the reaction temperature of the oxidation reaction in step 2 is suitably in the range of −20 to 30 ° C., preferably in the range of −10 to 20 ° C., more preferably in the range of 0 to 10 ° C.

The reaction time of the oxidation reaction in step 2 is preferably in the range of 30 minutes to 10 hours, more preferably in the range of 1 to 5 hours, although it depends on the concentration of the substrate in the reaction solution.

Example

Hereinafter, the present invention will be described in more detail with reference to test examples and examples according to the present invention. Test Example 1 Methyl cis 5- (4 chlorobutyl) 2 methyl 1.3 dioxane 2 carboxylate Debate

We investigated whether it is possible to efficiently synthesize Compound 4 which is a cis form by utilizing the difference in hydrolysis rate between the cis form and the trans form.

Specifically, compound 4 ′ synthesized by the method described in Patent Document 1 and having a cis / Z trans ratio of 3.4 / 1 is dissolved in an equal volume (volume (mL), Z weight (g)) of solvent. Then, various bases were added in a predetermined molar amount with respect to compound 4 ′, and a hydrolysis reaction was performed at 20 ° C. for 2 to 15 hours. Thereafter, the hydrolysis rate after the reaction and the cis-Z trans ratio of the hydrolyzed and complex compound 4 ′ were calculated by gas chromatography (GC). The results are shown in Table 1.

GC analysis conditions

Equipment: HP 6890 Series

Column: CBP1—S25—050 (Shimadzu Corporation)

Column oven temperature: 170 ° C Inlet temperature: 210 ° C

Detector temperature: 250 ° C

Carrier gas: Argon gas

Carrier gas flow:!: 2. OmLZ min

Detector: FID detector

[Table 1] Amount of base Hydrolysis rate

Unreacted compound 4 base type C compound 4 'to solvent type

(Molar amount with respect to cis Z trans ratio)

N a O H 0.30 D M F 2 8. 1 1 8 2 Z 1

N a O H 0.30 D M I 2 7. 2 1 7 9 1

N a O H 0.30 N P 2 7. 2 1 8 2/1

N a O H 0 .3 0 Aceton 2 8. 6 2 1 8/1

N a O H 0. 3 0 T H F 3 1. 1 2 9 4/1

N a O H 0.30 MeO H 2 9. 1 2 2 7 Z 1

N a O H 0 .3 5 MeC N 3 2 .5 4 9 7/1

N a O H 0 .3 0 Me C N 3 0 .6 2 1 8 Z 1 a O H 0 .3 0 卜 Luen 3 0 .6 1 5 9 Z 1

K O H 0. 3 5 D M F 3 3. 6 2 9 0 1

K O H 0. 4 0 Me C N 4 0. 8 8 6 3/1

K O H 0. 3 5 e C N 3 3. 2 3 Z 4/1

K O H 0. 2 0 Me C N 2 1. 8 1 0 0 Z 1

K O H 0, 40 卜 Luen 3 9. 3 4 4 2 Z 1

L i O H 0 .3 5 MeC N 3 3. 4 2 3 5/1 and i O H 0 .3 0 卜 3 2. 6 1 1 1/1

^{C s OH 0. 2 0 M} e CN 2 2 6 9. 0/1 As shown in Table 1, by increasing or decreasing the amount of base, it is possible you to control the hydrolysis rate of the compound 4 ' I found. In addition, the hydrolysis rate of the trans isomer is very fast compared to the cis isomerization rate of caro water, and the cis-Z trans ratio of the unreacted compound 4 ′ is 10 Zl when the hydrolysis rate is 21.8%. When the hydrolysis rate was 40.8%, the cis-trans ratio of the unreacted compound 4 was 86.3Z1.

If the cis-to-trans ratio is 9 or more (90% or more of the cis-isomer), the trans-isomer can be removed in the subsequent purification step in each reaction. Therefore, if the hydrolysis rate is controlled to 20% or more, it is possible to produce compound 4 without using conventional column chromatography.

This study is based on the power of cis-to-trans ratio 3.4 with compound 4 '. As described above, this production method is used regardless of the cis-to-trans ratio by controlling the hydrolysis rate. be able to.

[0017] Test Example 2 Methyl cis 5— (4-iodobutyl) 2 Methyl- 1.3 Dioxane

2 Discussion on the production method of carboxylate (compound 5)

We investigated whether it is possible to efficiently synthesize Compound 5 which is a cis form by utilizing the difference in hydrolysis rate between the cis form and the trans form.

Specifically, compound 5 ′ having a cis / Z trans ratio of 3.6 / 1 synthesized by the method described in Patent Document 1 is dissolved in an equal amount (volume (mL), Z weight (g)) of acetonitrile. Then, sodium hydroxide was added in a molar amount 0.4 times that of Compound 5 'and subjected to hydrolysis at 20 ° C for 2 hours. Thereafter, the hydrolysis rate after the reaction and the cis-Z trans ratio of the unhydrolyzed compound 4 ′ were calculated by gas chromatography (GC). The GC measurement conditions are the same as in Test Example 1. As a result, when the hydrolysis rate was 39.5%, the cis-Z trans ratio of the unreacted compound 4 ′ was 148.9Z1.

Therefore, the production method of Compound 5 using Compound 5 ′ is related to the cis-Z trans ratio by controlling the hydrolysis rate in the same manner as the production method of Compound 4 using Compound 4 ′ of Test Example 1. This manufacturing method can be used.

Test Example 3 Methyl 2 Methyl-5 1 “(4 Methylbenzoyl) amino 1 6-oxoheptyl 1 1.3 Dioxane 2 Carboxylate (Compound 7) The compound 7 was examined.

Specifically, compound 7 ′ synthesized by the method described in Patent Document 1 and having a cis-Z trans ratio of 3.5 / 1 is dissolved in a three-fold amount (volume (mL) Z weight (g)) of solvent. Then, various bases were added in a predetermined molar amount with respect to the compound 4 ′ and subjected to hydrolysis reaction at 10 to 20 ° C. for 2 hours. Thereafter, the hydrolysis rate after the reaction and the cis-Z trans ratio of the unhydrolyzed compound 7 ′ were calculated by HP LC. The results are shown in Table 2.

HPLC analysis conditions

Equipment: Shimadzu LC—10A

Column: COSMOSIL 5C-18-AR 150 X 4.6 mm (Nakarai Testa Co., Ltd.) Column temperature: 40 ° C

Moving layer: Acetonitrile Z water Z methanesulfonic acid = 550Z450Z1

Flow rate: 1. OmLZ min

Detector: UV detector

Measurement wavelength: 254nm

[Table 2]

As shown in Table 2, the hydrolysis rate of compound 7 ′ can be controlled by increasing or decreasing the amount of base, as in the case of compound 4 ′ of Test Example 1, by hydrolysis of compound 7 ′. If the hydrolysis rate is controlled, it is possible to produce compound 7 without using conventional column chromatography.

Test Example 4 Review of production method of 4-methyl-N— (2oxopropyl) benzamide (Compound 6)

The production of Compound 6 was studied by applying various oxidizing agents to 4-methyl N- (2 hydroxypropyl) benzamide.

Specifically, 4-methyl-N- (2hydroxypropyl) benzamide was subjected to an acid-acid reaction using various oxidizing agents other than metal compounds, and the yield was calculated by HPLC. The results are shown in Table 3.

HPLC analysis conditions

Equipment: Shimadzu LC—10A

Column: COSMOSIL 5C-18-AR 150 X 4.6 mm (Nakarai Testa Co., Ltd.)

Column temperature: 40 ° C

Moving bed: Acetonitrile Z water Z methanesulfonic acid = 400Z600Zl

Flow rate: 0.6mLZ min Detector: UV detector

Measurement wavelength: 254nm

[Table 3]

As shown in Table 3, it was found that most of the oxidant combinations are superior in comparison with other oxidants, because only the combination of the power TEMPO and sodium hypochlorite, which does not allow the oxidation reaction to proceed sufficiently. TEMPO is a well-known oxidant and has a particularly superior combination of TEMPO and sodium hypochlorite in the oxidation of 4-methyl-N- (2-hydroxypropyl) benzamide. The discovery of a powerful oxidant that could not be conceived has made it possible to easily produce Compound 7 which is an important raw material for producing NS-220, which is useful as a medicine, in high yield.

Example 1 Production of NS-220 including the production process of obtaining compound 4 by selective hydrolysis (Step 1) Production of compound 4 by selective hydrolysis

Compound 4 ′ (cis Z trans = 3Zl) was produced by the method described in Patent Document 1. Such compounds 4 '

700 g was dissolved in 700 mL of caseinotrinole, and 195.8 g of sodium hydroxide aqueous solution (44.8 g of 99% sodium hydroxide, 151 g of water) was added thereto. After stirring at 20-30 ° C for 2 hours, 700 mL of toluene and 700 mL of water were added and the layers were separated. The organic layer was concentrated under reduced pressure to obtain 441.4 g of compound 4 (Scis Z trans = 98.4 / 1.6). The aqueous layer was used in Example 2. (Step 2) Production of Compound 5

To 441 g of the compound 4 obtained in step 1, 442 g of sodium iodide and 820 mL of acetone were added and refluxed for 15 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and 500 mL of water and 840 mL of toluene were added to the residue for separation and extraction. The organic layer is a salt solution

After washing with 420 mL, it was dried with 42 g of magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 559 g of an oily product of Compound 5.

To the oily lOOg, 500 mL of n-heptane was added and cooled to −26 ° C. with stirring. The precipitated crystals were filtered and dried under reduced pressure at room temperature to obtain 83.2 g of compound 5 as white crystals.

(Step 3) Production of Compound 7

While stirring Compound 4 14.0 g, Compound 6 9.39 g, and DMF 42 ml, 2.97 g of hydroxylated power lithium was added in portions at 0 ° C. or lower. After the addition, the mixture was stirred at 20 ° C for 2 hours, and then the reaction solution was partitioned with 84 ml of toluene and 84 ml of water, and the upper layer was washed with 29.8 g of 1% aqueous hydrochloric acid and 28. Og of 5% aqueous sodium chloride. The solution was prepared by concentration under reduced pressure to obtain 59.6 g of a toluene solution of compound 7.

(Step 4) Production of Compound 8

While stirring 69.6 g of the toluene solution of Compound 7 obtained in Step 3, 6.2 g of salted oxalyl was added dropwise. After stirring at 50 to 55 ° C. for 1.5 hours, 4. l ml of water and 45.9 g of a 15% potassium hydroxide aqueous solution were added and stirred for 2 hours. After separation, the upper layer was washed with 17 ml of water to obtain a toluene solution of compound 8.

(Process 5) Manufacture of NS-220

A solution obtained by dissolving 3.27 g of sodium hydroxide in 16 ml of water and 6.3 ml of methanol were added to the toluene solution of compound 8 obtained in Step 4. After stirring at 50 to 55 ° C for 3 hours, the layers were separated, 76 ml of toluene was added to the lower layer, neutralized with 8.2 g of concentrated hydrochloric acid, and extracted while hot. The upper layer was washed with 15 ml of water while hot, crystallized after cooling to 2 ° C, the precipitated crystals were filtered, dried under reduced pressure at 50 ° C, and 9.43 g of crude NS-220 (transformer 0.1%) Obtained. Powerful crude NS— 220 2. Dissolve Og in 30 ml of isopropyl acetate at 72 ° C, filter while hot, cool the filtrate from 72 ° C to 20 ° C over 1.4h, crystallize, filter the precipitated crystals by filtration After drying under reduced pressure at 50 ° C., 1.53 g of target NS-220 (0.1%) was obtained. The cis-Z trans ratio of NS-220 was calculated by HPLC.

HPLC analysis conditions

Equipment: Agilent 1100 Series

Column: Cadenza CD—C18 250 X 4.6 mm (Intertat Corporation) Column temperature: 40 ° C

Moving layer: Acetonitrile Z water Z methanesulfonic acid = 550Z450Z1

Flow rate: 0.7 mLZ min

Detector: UV detector

Measurement wavelength: 240nm

[0021] Force of M2 I ^^ 4 'I ^^ 4' from I ^^) 21 made by t! Tk decomposition 她

The aqueous layer obtained in Step 1 of Example 1 was extracted by adding 128.3 g of concentrated hydrochloric acid and 700 mL of toluene to recover trans-rich compound 21. 15.5 g of methyl pyruvate and 6.9 g of boron trifluoride ether complex were added to 50 mL of the toluene solution of the recovered compound 21 and reacted at 60 ° C for 8 hours. After the reaction, the mixture was washed with 77% 20% aqueous sodium hydroxide solution, 39ml 10% aqueous sodium hydroxide solution and 10ml 10% aqueous sodium chloride solution in this order. The organic layer was concentrated under reduced pressure to obtain 2.4 g of compound 4 ′.

[0022] Example 3 Production of NS-220 including production process for obtaining compound 7 by selective hydrolysis

(Step 1) Production of compound 7 by selective hydrolysis

Compound 5 having a cis-Z trans ratio of 3Z1 was produced by the method described in Patent Document 1. Powerful Compound 61.lg and Compound 6 34.4 g were dissolved in 192 ml of DMF, and 13.6 g of 85% aqueous potassium hydroxide solution was added with cooling and stirring. After stirring at 15 ° C or lower for 4 hours, 385 ml of toluene and 385 ml of water were added and extracted. The organic layer was washed successively with 1% aqueous hydrochloric acid solution (137 ml) and water (128 ml) and dried over anhydrous magnesium sulfate. After filtration, the filtrate was partially concentrated under reduced pressure to obtain a toluene solution of compound 7 (cis Z trans = 14.8). (Step 2) Production of Compound 8

Using the toluene solution of compound 8 obtained in step 1, a toluene solution of compound 8 was obtained in the same manner as in the method of step 4 of Example 1.

(Process 3) Manufacturing NS-220

Using a toluene solution of compound 8 obtained in step 2, purified NS-220 21.5 g (trans isomer 0.3%) was obtained in the same manner as in step 5 of Example 1.

Example 4 Production of Compound 6 Using TEMPO and Sodium Hypochlorite

(Step 1) Production of Compound 20

p 卜 NORE INOREC PU 100. Og was added dropwise to a solution of 1 amino-2 unomonore 79.2 g, 卜!; ethenolamin 78.5 g, toluene 500 ml. After stirring at 20 ° C. for 1 hour, 500 ml of water was added, and the precipitated crystals were filtered and dried under reduced pressure at 50 ° C. to obtain 20117.0 g of a white crystal compound.

(Step 2) Production of Compound 6

The compound obtained in Step 1 was mixed with 300.0 g of TEMPO 0.4851 g, sodium odorite 15. 97 g, magnesium sulfate 9.34 g, ethyl acetate 450 ml, water 30 ml, and sodium hypochlorite. Aqueous solution (effective chlorine 5% or more) A solution of 6.52 g of sodium bicarbonate in 222.2 g was dropped at 2 to -10 ° C. After stirring at 0 ° C for 40 minutes, the layers are separated, and the upper layer is a solution in which 2.558 g of rhodium iodide is dissolved in 56.6 g of 1% hydrochloric acid aqueous solution, 10% -Na 2 SO 4 aqueous solution 1

2 2 3

After washing with 20 ml, sodium bicarbonate aqueous solution 60 ml, sodium chloride aqueous solution 60 ml, it was dried over magnesium sulfate 6.00 g. After filtration, 240 mL of cyclohexane was added to the residue after concentration under reduced pressure, and the precipitated crystals were collected by filtration. Washing with 30 ml of methyl t-butyl ether and drying under reduced pressure at 50 ° C. gave 20.88 g of compound 6 as white crystals (total yield 6 6%).

Industrial applicability

As described above, the production method according to the present invention is a column chromatograph as compared to the conventional production method. It is useful as a medicine without using a metal compound.

NS-220 can be manufactured.

Claims

The scope of the claims

[1] Methyl 5- (4 chlorobutyl) -2-methyl-1,3-dioxane-2 Carboxylate cis-trans mixture, which is characterized by hydrolysis in the presence of a base. ) A process for producing 2-methyl 1,3 dioxane 1-carboxylate.

[2] 2-methyl-c-5- {4- [5-methyl-2- (4-methylphenol) -1,3-oxazol-4-yl] butyl}, comprising the production process according to claim 1 , 3 Dioxane r—

2—Method for producing strong rubonic acid.

[3] Methyl 5- (4-iodobutyl) -2-methyl-4- (3-iodobutyl) characterized by hydrolyzing a cis-trans mixture of methyl-1,3-dioxane-2 carboxylate in the presence of a base. -2-Method for producing methyl-1,3 dioxane 2 carboxylate.

[4] 2-Methyl-c-5- {4- [5-Methyl-2- (4-methylphenol) -1,3-oxazole-4-yl] butyl} 1 including the production process according to claim 1 , 3 Dioxane r— 2-Method for producing strong rubonic acid.

[5] Methyl 2-methyl-5-[(4 methylbenzoyl) amino] -6 oxoheptyl} — 1,3 Dioxane 2 Carboxylate is characterized by hydrolyzing a cis-trans mixture in the presence of a base. Cis 2-methyl-5-[(4 methylbenzoyl) amino] 6 -oxoheptyl} 1,3 Dioxane 2 carboxylate production method.

[6] 2-Methyl-c-5- {4- [5-Methyl-2- (4-methylphenol) -1,3-oxazole-4-yl] butyl} 1 including the production process according to claim 3 , 3 Dioxane r— 2-Method for producing strong rubonic acid.

[7] It is characterized by acidifying 4-methyl-N— (2 hydroxypropyl) benzamide with 2, 2, 6, 6-tetramethyl — 1-piberidi-loxy radical and sodium hypochlorite. A process for producing 4-methyl N- (2-oxopropyl) benzamide.

[8] 2-methyl-c-5- {4- [5-methyl-2- (4-methylphenol) -1,3-oxazol-4-yl] butyl} including the production process according to claim 5} 1 , 3 Dioxane r— 2—Method for producing strong rubonic acid.

2-methyl-c 5— {4 [5-methyl-2- (4 methylphenyl) 1,3-oxazole-4-yl] butyl} 1,3 dioxan r 2—force, including the production process according to claim 1 and 5 A method for producing norebonic acid.