JPS62158281A - Novel 3-methyl-phenylnaphthyridine and medicine containing the same - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a novel phenylnaphdyridine and to a method for producing its products, particularly for use as a therapeutic agent.

<Prior Art> The applicant has already applied for a compound coexisting with the present invention as French Patent Application No. 2.567.520.

<Problems to be solved by the invention> However, certain of the coexisting compounds have unexpectedly higher anti-inflammatory effects and/or therapeutic index than the coexisting compounds mentioned and exemplified in the application. was also found to be improved. ) Means for Solving the Problems> The present invention is a new compound selected from the following general formula (I>).

r Here, X, Y and 2 are selected from the following combinations.

(a) Y-Z-H and X is m-CH: +, m, p-
CEI, m-8CH3, m, o, p-F, m, p
-CN % m -CON H2, m
--CH20N yo Icoba n -ON, (b) Z-H and X and Y are fluorine, especially 2,5°2.
Fluorine at position 4 or 2,6, <C>Z=to1, X=DI-CN and Yf:
, J: p-C2 or p-F and ((l)
The present invention will be specifically described below.

In the present invention, for example, when an aromatic nucleus has only one substitution, this substitution is
If it is 1-12CN or CONH2, it must be in the meta position, if it is C-rich it can be in the meta or rose position, and if it is F it can be in the meta, ortho or rose position.

Thus, for example, it is advantageous for both nuclear substitutions to be F, in which case 3 in 2.6.2.5 and 2.4
Any combination is possible, but 2°5 and 2.4 positions are not preferred.

Further, a combination of 3-CN and 4-halogen (F or C1) is particularly preferred.

The compound of formula (I) according to the present invention can be synthesized by using the aldehyde of formula (II) shown below in the reactions (a) to (d) below.

(TI> In the formula, X, Y and Z are the same as above.

(a) Lifomatsky reaction by dehydration (b) Lighting reaction by D conversion (C) Perkin reaction or (d) Claisen reaction - In terms of In, aldehyde of formula (I[) is converted to alcohol of formula (DI) below to 1ylno2. It is a weak oxidizing agent that can be used in solvents such as medilene chloride and chloroform.
0 to 50°C temperature e'-FM (Koyotsu formula (I)
In [I), x, y, and z are the same as above.

An alcohol of formula (I) is a typical λ photoreaction of an acid of formula (IV) below or one of its esters with lithium aluminum hydride in a solvent such as detrahydrofuran. obtained by. Here, the phenyl nucleus is nitrile ii! Are you interested in certain reducing agents like L exchange? When the ester has a 9.1 delta substituent, the reducing agent for reducing the ester is selected such that it does not affect the 9.1 delta substituent, such as lithium borohydride, which is prepared from lithium borohydride and lithium chloride.

In formula (IV), x, y, z are as described above,
R3 is a water atom or alkyl.

On an industrial scale, a preferred method of synthesizing compound 1i71 of formula (1) is to convert the aldehyde of formula (It) to the following formula (V) where Vt = hydrate of the sodium salt of the corresponding acid using the known Perkin reaction. It consists of avoiding reactions in the presence of

This reaction is carried out neat or in a solvent such as N-methylpyrrolidone at a temperature of about 100-200°C.

Here, in the case of n-1, the sample number is 10 pionic acid and 1 (hydrate and thorium propionate).

Another industrially sound method uses the known Flybin reaction to convert aldehydes of formula (It) into compounds of the following formula (■ ) consists of reacting with ester.

R-C1-12-GOOR'' (VI) where R=C'hh, R- is argyl.

Y or 2 is obtained by converting the nitrile group of the corresponding compound into an amide by means of known methods, for example by reaction with 1r.

The compound in which X, Y or 2 is a hydroxyl group is X.

Y or Z can be prepared in a known manner, for example pyridine salt Ii!
14 by converting the corresponding compound to be alkoxy by reaction with 2Ju or hydrobromic acid.

According to the present invention, 1! for treatment of gastrointestinal ulcers! A convenient therapeutic drug composition is provided, the composition comprising at least one of the compounds of Formula 5 (I>) along with acceptable amounts of other ingredients.

Further characteristics and advantages of the present invention will become clear from the following description of the manufacturing process, but the present invention is not limited to these examples.

The surface treatment does not indicate the structural formulas of various compounds.

Example 1 2-(3-methylphenyl)amino-3-human Ooxymethylpyridine Formula ■: X atmosphere 3-CI13: Y-Z-+37.50
A solution of 2-(3-methylphenyl)aminonicotinic acid in anhydrous tetrahydrofuran was added dropwise to a suspension of 9.6 g of lithium aluminum hydride in 230 m+1 of anhydrous ether. After the dripping is finished,
The reaction mixture was stirred at air temperature for 3 hours. After cooling, excess hydride was destroyed by adding ethyl acetate followed by fXi Pi sodium. The precipitate formed was filtered and washed with ether. The resulting filtrate was evaporated under reduced pressure to obtain 34.50% of 2-(3-methylphenyl)amino-3-hydroxymethylpyridine in the form of an oil.

This will be used as a raw material in the next step.

By this method, the following derivatives were synthesized: 2-(3-
Chlorophenyl)amino-3-hydroxymethylpyridine Formula 1 [[:X-3-Cll: Y-Z-H oil;
Yield: 95% 2-(2,4-difluorophenyl)amino-3-hydroxymethylpyridine formula I [[:X-2-F: Y-4-F:Z-H oil;
Yield: 93% 2-(3-fluorophenyl)amino-3-hydroxymethylpyridine Formula m: X-3-F: Y=Z'-H crystal; Melting point = 77-78°C: Yield: 95% 2-(4-fluorophenyl)amino-3-hydroxymethylpyridine:X=4-F: Y-Z=I-4 crystal; Melting point=
89-90°C, Yield: 88% 2-(2-fluoro[1phenyl)amino-3-hydroxymethylpyridine Formula Ill: X-2-F: Y-Z-H crystal; Melting point = 96-98°C; Collection fS: 95%2- (2,
5-difluorophenyl)amino-3-hydroxymethylpyridine formula m:X-2-F: Y-5-F:
Z= To1 crystal; melting point -71 to 74°C, yield:
98% 2-(2,6-difluorophenyl)amino-
3-hydroxymethylpyridine formula m: X-2-F: Y-6-F: Z-H crystal;
Melting point -115°C; Yield*: 90% 2-(4-chloro[1
phenyl)amino-3-hydroxymethylpyridine Formula m: 3-hydroxymethylpyridine formula m: X-/1-QC)-13: Y-Z-H crystal; melting point -95~96°C, yield*: 95%
3,4,5-)-rimethoxyphenyl) 7minor 3-hydroxymethylpyridine formula m: X = 3- OCH3: Y -400
H3: Z=5-OCH3 Crystal: Melting point -127°C, Yield: 95% Example 2 2-(3-cyanophenyl)amino-3-hydroxymethylpyridine Formula I [[:X=3·-CN: Y =Z=H8g of lithium chloride is 39.3a of 2-(3-cyanphenyl)
A solution of methyl aminonicotine dissolved in 600 m of tetrahydrofuran containing 100 m of potassium Bo[I hydride was added little by little with stirring. After the addition was complete, the mixture was heated under rapid flow for 4 Il and then concentrated under reduced pressure. Water and ice were added to 1 q of the residue, extracted with ether, and the ether phase was washed with water and dried over sodium sulfate. After evaporating the ether, 31.6q of 2-(
3-cyanphenyl,)amino-3-hydroxymethylpyridine was obtained as crystals that dissolved at 126°C.

By this method, the following derivatives were synthesized: 2-(3-
cyanophenyl)amino-3-hydroxymethylpyridine Formula 1 [I:X”=4-CN: Y-Z-H crystal; Melting point -142°C: Yield: 93% 2-(2,4-cyanomethylphenyl) Amino-3-hydroxymethylpyridine:
Hydroxymethylpyridine EI: X=3-CN; Y-4-011: Z-H crystal; Melting point -147°C; Yield: 90% 2-(3-cyano-4-fluorophenyl)amino-3-hydroxymethyl Pyridine Formula I[:X-3-CN; Y-4-F:Z-H Crystal:
Melting point = 126°C: Yield: 90% performed 1 row 3 2-(3-methylphenyl)amine nicotinaldehyde Formula II: X-3-Cth: Y=Z-
8163 g of NnO2 was produced in run VA1 in 34.
5a, 2-(3-methylphenyl)amino-3-hydroxyethylpyridine, was added portionwise to a solution of 550+1 in 0O0 form.

After the addition was complete, the mixture was stirred at air temperature for 6 hours.

One bottle of reaction medium was then filtered through Celite and the filtrate was evaporated to dryness. The thus obtained crystals were recrystallized from isopropyl ether. Thus, 2-(3-methylphenyl)aminonicotinaldehyde 27a was recovered as crystals that dissolved at 95-7°C.

By this method, the following derivatives were synthesized: 2-(3-
Chlorophenyl) aminonicotinaldehyde Formula II: X = 3-CΩ: Y-Z- Recrystallization: Melting point -
99-100°C; yield near 8% 2-(3-methyldiophenyl)aminonicotinaldehyde formula Tr: X-3-8C 13: Y
=Z=I-1 crystal; Melting point = 63-64°C; Yield near 0% 2-<2.4-diflu'; Alophenyl) aminonicotinaldehyde Formula II: X-2-F: Y-4-F : Z=l-1
, crystal (isopropanol); melting point = 135-137°C; yield near 5% 2-(3-fluorophenyl)aminonicotinaldehyde formula II:X-3-F; Y=Z=H crystal; melting point = 70-72 °C; Yield near 8% 2-(4
-fluorophenyl)amine nicotinaldehyde formula IF: X-2-F: Y”Z-Recrystallization:! !
! Point -93~94℃; Yield near 0% 2- (2,5-
difluorophenyl) aminonicotinaldehyde Formula II:
-difluorophenyl) aminonicotinaldehyde Formula II: X-2-F: Y-6-F:Z- Recrystallization:
Melting point -106°C; Yield: 93% 2-(3-cyanophenyl)aminonicotinaldehyde Formula T:X-3-CN: Y-Z- Recrystallization; (acetonitrile); Melting point = 153-154°C; Yield :60% 2-(4-cyanophenyl)amine nicotinaldehyde formula 'ff: X = 4-CN'; Y =
Z-1” crystal; Melting point -166°C: Yield: 93%2
-(3-cyazumedelphenyl)aminonicotinaldehyde Formula T[:X-3-CI(2CN: Y=Z=l・1
Crystal; Melting point = 50°C; Yield: 92% 2-(3-cyano-4-chlorophenyl)aminonicotinaldehyde Formula TI:X-3-CN: Y=4-CD Z=H Crystal (acetonitrile): Melting point -20.3℃; Yield: 6
0% 2-(3-cyano-4-fluorophenyl)aminonicotinaldehyde Formula Ir: X=3-ON: Y-4-F Z=1-1
Crystal (acetonitrile) di Melting point = 193°C; Yield: 8
0% 2-(4-chlorophenyl)aminonicotinaldehyde formula iT:X=4-CΩ: Y=Z==
H crystal (isopropyl acetate): n points = 101 to 10
2°C; Yield: 609G 2-(3,4,5-4-rimethoxyphenyl)aminonicotinaldehyde Formula Ir:X-3-OCI-+3: Y=/1-OC
I-13: Z-5'-0CI-13 crystal; Melting point -104°C: Yield: 25% 2-(4-methoxyphenyl)aminonicotinaldehyde Formula I[:X-4-OCt-h; Y=Z =H result;
Crystal = 82-84°C; Yield: 50% Example 4 l-(3-methylphenyl)-1,2-dihydro-2-
4xo-3-methyl-1,8-naphthyridine Formula I: x=3-CH*: Y=Z=H 2-(3-methylphenyl)aminonicotinaldehyde synthesized in Example 3 100. 1 Ω of sodium propionate and 12 C of propionic aldehyde
Time: 15 minutes, )) Heat to a flying low! , :.

Cool the reaction mixture, add 100IIIQ of water,
Stir for 30 minutes at air temperature. Extraction was performed with methylene chloride, and the en phase was washed with water, 10% caustic soda solution, and water in that order, dried over sodium sulfate, and concentrated under reduced pressure.The ID residue was crystallized. After recrystallization from isopropanol, 4.89 1-(3-methylphenyl>1-.2-dihydro-2-oxo-3-methyl-1
, 8 naphthyridine was obtained as crystals with 1 fJ'ffl at 182-3°C.

The following derivatives were synthesized by this method.

Example 5 l-(3-chlorophenyl)-1,2-dihydro-2-
Oxo-3-methyl-1,8-naphthyridine Formula I: methyldiophenyl)-1,2-dihydro-
2-Oxo-3-methyl-1,8'-naphthyridine Formula I: 2,4-difluorophenyl)-1,2-dihydro-2-oxo-3-methyl-1,8-naphthyridine Formula I: X=2-F: Y-4-F: Z-H crystal (
Melting point = 188-189°C; Yield: 49% Example 8 l-(3-fluorophenyl)-1,2-dihydro-2
-'A xo-3-methyl-1,8-naphdyridine formula T: X = 3-F: Y = Z =!
-1 product (dimethylformamide): Melting point = 240 ~
241°C; Yield: 42% Example, 9 l-(4-fluorophenyl)-1,2-dihydro-2
-Oxo-3-methyl-1,8-naphthyridine Formula I: X=4-F: Y-Z=H Crystal (dimethylformamide); Melting point = 248-2
49°C; Yield: 50% Example 10 1-(2-fluorophenyl)-1,2-dihydro-2
-Oxo-3-methyl-1,8-naphthyridine Formula I: X=2-F: Y=Z-11 Crystal; (isopropatol): Melting point -161 to 163
°C; Yield: 40% Example 11 1-(2,5-difluorophenyl)-1,2-dihydro-2-ogiso-3-methyl-1,8-naphthyridine set T:X-2-F: Y-5-F: Z=H crystal (isopropanol); melting point -143 to 144°C;
Yield: 52% Example 12 1-(2,6-difluorophenyl)-1,2-dihydro-2-oxo-3-methyl-1,8-naphthyridine Formula T: X-2-F: Y-6 -F: Z-H crystal (
ethanol/-l) sFa point = 212-213°C: Yield: 5
2% Example 13 1-(3-cyanophenyl)-1,2-dihydro-2-
Oxo-3-methyl-1,8-naphthyridine formula fX-3-CN: Y-Z=1-1 crystal (dimethylformamide): Melting point = 266-267°C: Yield near 0% Example 14 1-(4 -cyanophenyl)-1,2-dihydro-2-
Oxo-3-methyl-1,8-naphthyridine Formula I: X-4-CN; Y-Z-H crystals (dimethylformamide); Melting point -265~26
7°C; Yield: 42% Example 15 1-(3-cyanomethylphenyl)-1,2-dihydro-2-Jquin-3-methyl-1,8-naphthyridine Formula x: x-a-CI- hcN: Y=Z=
H crystal (filtered with silica gel, dissolved V!c: Meshushinku O Ride/Ahiton 98/2); Melting point = 174-176
°C; Yield: 15% Example 16 1-(3-cyano-4-chlorophenyl)-1°2-dihydro-2-oxo-3-methyl-1,8-naphthyridine Formula I:X-3-CN: Y-4-(di Z=H crystal; (acetonitrile) Melting point -244~245°C:
Yield: 55% Example 17 1-(3-cyano-4-fluorophenyl)-1,2-
Dihydro-2-oxo-3-methyl-1°8-naphthyridine Formula I: X-3-CN: Y-4-F Z=H crystal (
Acetonitrile): Melting point -234; Yield: 57.5% Example 18 1-(4-chlorophenyl)-1,2-dihydro-2-
Aquin-3-methyl-1,8-naphthyridine Formula I:
55% Example 19 1-(3,4,5-trimethoxyphenyl)-1,2
-dihydro-2-;4xo-3-methyl-1°8-naphthyridine Formula I: X=3-OCl(s: Y=4-OCl
-13: Z=5-OCH3 crystal (acetonitrile); Melting point -244 to 245°C:
Yield: 20% Example 20 1-(4-methoxyphenyl)-1,2-dihyde 0-2
-'A giso 3-methyl-1,8-naphthyridine formula I:
Yield: 51% Example 21 1-(3-cyanoph[nyl)-1,2-dihydro-2-
2-(3-cyanophenyl)amine nicotinaldehyde synthesized in Example 3 109. Ethyl propionate 20m! 20 g of ethanol containing Q and 0.05/I mole of sodium ethylate (1.0 g of sodium in 20 ml of ethanol).
250) was stirred at room temperature for 4 hours.

The resulting precipitate was filtered, washed with water, and dried. After recrystallization from dimethylformamide, 5.3 g of 1-(3-cyanophenyl)-1,2-dihydro-2-oxo-3-methyl-1,8-naphthyridine are dissolved as crystals at 266-267 °C. Recovered.

Example 22 1-(3-carbamoylphenyl)-1,2-dihydro-2-oxo-methyl-1,8-naphthyridine 2:X=3-CONH2: Y=Z=H Synthesized in Example 13 and 21 1-(3-cyanophenyl)-1,2-dihydro-2-oxo-3-methyl-1,
8- Add 3.5 liters of naphthyridine little by little while stirring, 1v deep! Added into illomΩ.

After stirring for 24 hours at room temperature, 100 mΩ of water were added and the reaction mixture was made basic with aqueous ammonia solution.

The formed crystals were filtered, carefully washed with water, and then dried.

After recrystallization from dimethylformamide, 1.3 of 2.39
-(3-carbamoylphenyl)-1,2-dihydro-
2-oxo-3-methyl-1,8-naphthyridine is 29
It was obtained in the form of crystals melting at 3-295°C.

Example 23 1-(4-Human[coxyphenyl)-1,2-dihydro-2-oxo-3-methyl-1,8-naphthyridine Formula I: X = 4-01-1: Y = Z
= 1-1 1-(4-methoxyf) synthesized in Example 20 Next, the reaction solution was cooled, water and ice were added, and the mixture was neutralized by adding 0 sips of sodium bicarbonate solution. After recrystallization from an acetonitrile/dimethylformamide mixture, 6.3 g of 1-(4-hydroxyphenyl)-
1,2-dihydro-2-oxo-3-methyl-1,8-
Naphthyridine was obtained in the form of crystals melting at 308°C.

” ← JO OC 84 Pharmacological effect of ulcer suppression 11 activity 1, method OFA strain of 10 to 30 animals (IFFACREDO
(obtained from France), male rats weighing 160-180 g were kept on water alone for 24 hours after oral administration of test compound. ``After 30 minutes, Nikkei administered anti-inflammatory drug or anti-inflammatory agent (pure ethanol) to the maximum amount that causes gastric ulcers in mice.
Hiiragi! The patient was transferred 6 hours or 1 hour after receiving 2 doses. stomach (
1) Examination was made using a microscope (the large dents of the bulge were examined in the sub-chamber).

2. The result is 50% of the result.
As a result, there is a linear relationship between the prohibited percentage and the drug.

59% active drug M (Lipstick,...9 kg-1 display) (1) Anti-inflammatory (2) Administrative medicine to promote inflammation
Administration example 5 0.170 0.017 real muscle example 8
0.180 0.020 Example 9 0.340
0.035 Example 13 0.085 0.0
10 Example 17 0.164 0.024 (1)
Non-steroidal anti-inflammatory agents (2) Ethanol anti-secretory activity 1, method OFA strain (obtained from IFF' CREDO, France) of 5 rats, body ff 1180-200!
The pylorus of I was isolated under ether anesthesia.

A test compound was injected subcutaneously into one joint. rat 1-3
After a period of time, the gastric juice was collected and its TA level was 0.1.
For N caustic soda solution, P l-1,4 and 7'U
- titrated.

2. The result is expressed as 50% active mulberry (50% of 1 molluscum secretion amount), and the prohibited percentage of total secretion and usage circulation m
The linear VA ratio is shown between.

50% active drug content (mc+/kll-1 display, subcutaneous r/l) Example 5
0.038 Example 8 0.045 Example 9 0.040 Example 13 0.050 Example 17 0.064 Toxicity test a The first toxicity test was conducted on sprags, Douries, and rats that died after being exposed to a straw. Yuken, +91 showing 1 compound (7) using
It was shown that LDsahTT is 3001iIQ ・kQ-' Yoridaijs Ikama or equivalent.

<Effects of the Invention> The compounds of the present invention and their prefixed acids and salts mentioned in the specification of the present application are similar to those mentioned above, and their anti-inflammatory and anti-secretory activities. is French patent Kn2,
It is extremely strong and superior to the compound described in No. 567.520. These 5
It can be used as an injection or as a Nikkei medicine in the form of ampoules, tablets or gelatin capsules containing ~1001HJ.

Claims (1)

[Claims] (1) A novel compound corresponding to the following structural formula (I). ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) Here, X, Y and Z are selected from the following combinations. (a) Y=Z=H and X is m-CH_3, m, p-C
l, m-SCH_3, m, O, p-F, m, p-CN,
m-CONH_2, m-CH_2CN or p-OH, (b) Z=H and XYZ is fluorine, especially 2,5,2,
Fluorine at the 4 or 2,6 position, (c) Z=H, X=m-CN and Y is P-Cl or p-F, and (d) OCH_3 at the X=Y=Z=m-p-m position (2) A novel compound according to claim 1 selected from the following structural formula. ▲There are mathematical formulas, chemical formulas, tables, etc.▼▲There are mathematical formulas, chemical formulas, tables, etc.▼ ▲There are mathematical formulas, chemical formulas, tables, etc.▼▲There are mathematical formulas, chemical formulas, tables, etc.▼ ▲There are mathematical formulas, chemical formulas, tables, etc.▼ ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (3) An anti-inflammatory agent containing the novel compound described in any one of claims 1 and 2. (4) A method for producing a compound of the following structural formula (I) by any of the reaction methods (a) to (d) below. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) (a) Riphomatosky reaction to cyclize the following formula II aldehyde compound, (b) Witting reaction to cyclize the following formula II aldehyde compound, (c) Below Parkin reaction of formula II aldehyde compounds or (d) Claisen reaction of formula II aldehyde compounds below ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (II) However, in formulas (I) and (II), X, Y, and Z are as follows. selected from a combination of (a) Y=Z=H and X is m-CH_3, m, p-C
l, m-SCH3, m, o, p-F, m, p-CN, m
-CONH2, m-CH_2CN or P-OH, (b) Z=H and X and Y are fluorine, especially 2,5,2,
4 or 2,6-position fluorine, (c) Z=H, X=m-CN and Y is p-Cl or p-F, and (d) X=Y=Z=m-p-m OCH_3 (5) The above formula (II) aldehyde compound is formed by combining the following formula (III) alcohol compound with a weak oxidizing agent (such as MnO_2) in an organic solvent (such as methylene chloride or chloroform).
The manufacturing method according to claim 4, which is obtained by oxidizing at a temperature of 20 to 50°C. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) However, X, Y, and Z in formula (III) are the formulas (I), (
It is the same as II). (6) The alcohol compound of the above formula (III) has the following formula (IV)
) or its ester, (lithium,
The method according to claim 5, which is obtained by reduction with a reducing agent (such as aluminum hydride) in an organic solvent (such as tetrahydrofuran). ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) Here, X, Y, and Z in formula (IV) are the same as in formulas (I) to (III), and R_3 is a hydrogen atom or an alkyl group. be. (7) By Perkin reaction, the aldehyde compound of formula (II) according to claim 4 is combined with the aldehyde compound represented by the following formula (V) in the presence of a sodium salt of the corresponding acid and in the presence of a solvent. 4. A method for producing a compound of formula (I) according to any one of claims 1 to 3, characterized in that the reaction is carried out in the presence or absence of the compound. (8) The method of claim 7, wherein the reaction is carried out in a solvent (such as N-methylpyrrolidone) at a temperature of about 100-200°C. (9) Claim 7 in which n=1 in formula (V), that is, propionic anhydride and sodium propionate are used;
The manufacturing method described in Section 8. (10) The formula (I) according to claims 1 to 3 is obtained by reacting the aldehyde compound of formula (II) with the acid ester compound of formula (VI) below by Claisen reaction.
A method for producing a compound. R-CH_2-COOR'(VI) In formula (VI), R is a suitable organic group, preferably alkyl, especially CH_3, R' is alkyl. (11) The production method according to claim 10, wherein sodium or potassium alcoholate, sodium hydrite, or metallic sodium is present in the reaction system.