JPH01258668A - Production of dl-griseofulvin and intermediate thereof - Google Patents

Abstract

PURPOSE:To simply produce griseofulvin, by optically isomerizing a 7-chloro-2- alkylidene-4,6-dimethoxy-3(2H)-benzofuran to give a novel compound and treating the novel compound with an enolate of acetoacetic ester to effect ring formation. CONSTITUTION:A novel compound shown by formula I (Me is methyl; R is 1-3C alkyl, substituted or nonsubstituted aralkyl or heteroalkyl) is treated with 3-(trimethylsilyloxy)-1,1-dimethoxy-1,3-butadiene shown by formula II to give griseofulvin shown by formula III or 6'-position alkyl-substituted griseofulvin. The novel compound shown by formula I, for example, is obtained by processing relatively readily obtainable anhydrous fluoroglycine through 3,5-dimethoxyphenol, chlorinated material and compounds shown by formulas IV and V to give a compound shown by formula VI and irradiating this compound with light rays. The obtained compound is useful as a remedy for trychophytina, favus and tinea imbricata of mold fungi of skin.

Description

[Detailed Description of the Invention] [Industrial Application Field] Griseofulvin is an antifungal antibiotic used in Penicillium griseo.
A white to off-white crystal obtained from fulvin, etc., which can be used internally or externally to cause athlete's foot caused by dermatophytes.
It is widely used to treat jaundice and whirlpools.

The present invention provides a simple manufacturing method.

[Conventional technology]

In recent years, griseofulvin has been mostly produced by fermentation.

Of course, many synthetic methods, exemplified below, have already been proposed.

(1) A., Brossi, M., Baumann, M.
, Gereche and B., Kyburz et al., 1960
He1v, Chem, Acta; vol, 43.
2, which was synthesized by the following method, is reported on page 2071.

Loff (2) G, 5tork and M, Tomasz et al., J, Am, Chem Soc, 1962, vo.
l, dI! on page 84.310 in the following way! - Reported to have synthesized griseofulvin.

(3) D, Taub, C, H, Kuo, H9
L, 5lates, and N, L.

In 1963, Werdler et al.
on; vol.

On page 19.1, it is reported that dβ-griseofluton was synthesized by the following method.

(4) S, Danishefsky, and F, 1
Falker et al., J. Am., Che., 1979.
m, Soc; vol, page 101.7018, reports a simple method for obtaining dl-shrimp griseofulvin (1b), a stereoisomer of griseofulvin, by the following method. However, the antifungal effect of shrimp griseofulvin is extremely weak, making it unsuitable for use as a pharmaceutical.

Ros Δ (5) So S, Danishhesky and F, Wa
have also reported a method for synthesizing dl-griseofulvin (1a) through a very long process as follows.

However, these methods require specific reaction conditions and are therefore unsuitable for industrial production, and the resulting d
7! - It had various problems such as extremely low yield of griseofulvin.

From the above circumstances, it is industrially advantageous, that is, df
There was a desire for a production method with a high yield of f-griseofulvin, a short synthesis process, and an hour wheel.

The present invention satisfies these various demands.

[Problems with the invention and solutions]

First, the Danishefs shown in the above-mentioned synthesis method (4)
Intermediate 9 of the method of ky et al. has 7 tertiary structures.

Therefore, the inventor believes that if eight 9s can be used in this reaction, the product will be dI! - Shrimp griseofulvin (1b) but not dβ-griseofulvin (1a)
) was thought to be generated.

Furthermore, in the reaction of 4 with acetaldehyde, the Z-form 9 was selectively obtained in good yield, so an attempt was made to convert the 7-form 9 into the 8-form. That is, by dissolving seven 9s in a solvent (for example, anhydrous benzene, cyclohexane, toluene, tetrahydrofuran) and exposing them to sunlight, it was possible to convert them into eight 9s. Next, from a mixture of 8 and 7 9s in the reaction solution, only 8 9s were successfully isolated by silica gel column chromatography.

In addition, 4, which is a raw material for this synthesis method, is G, 5tork and M, Tomasz (J, Am, Chem, Soc;
Vol. 84, p. 310, 1962), 3,5-dimethoxyphenol alpha and sulfuryl chloride were reacted to synthesize the following formula.

However, in this method, the yield of 6 was 41%, which was not a satisfactory value. Furthermore, it was found that the separation operation in step 6 was essential because 0 gJ of 4-chloro-dimethoxyphenol was produced as a by-product.

Therefore, the present inventors combined 18 with N-chlorosuccinimide (
We have developed a method that allows 6 to be selectively obtained in high yield by reacting with 6 (hereinafter abbreviated as NC3).

[Structure of the invention]

The production method of the present invention using anhydrous phloroglucin, which is relatively easily available, is as follows.

However, the gist of the present invention lies in the following points.

(A) A novel production method for obtaining dl-griseofulvin (1a) by reaction of compound E-9 and a mixture of 10,
(See (G) in Example 1 below) (B) A new method for producing the compound of the novel intermediate E-9, which consists of irradiating the compound of Z-9 with sunlight, and by silica gel column chromatography. A novel method for isolating E-9 (see (F) in Example 1 below). A novel method for producing chloro-3,5-dimethoxyphenol (as described in Example 1 below)
See B). ) Therefore, regarding (8), (B), and (C) above, the following:
Add further explanation.

(8) griseofulvin of de (l 1 1 η 巳) 1 ≧ pull 1 j j ~: 2 no yo process In this reaction, a solvent can be used. For example, toluene, benzene, cyclo-xane, etc. can be used. Particularly preferred is toluene.

It is preferable that the cloud be surrounded by a flow of an inert gas such as nitrogen gas or argon.

The reaction time is 1 to 5 hours, preferably about 2 hours.

The reaction temperature is 80-140°C, preferably 110°C.

A large excess of compound 10 is used.

(B) New intermediate (E-9) and method for producing the same.

Compound (E-9) is a novel compound and is useful as a starting material in the production method of (A), that is, as an intermediate for the production of de-griseofulvin.

This compound can be obtained by irradiating Z-9 with sunlight in the presence of a solvent.

As the solvent, for example, benzene, cyclohexane, toluene, tetrahydrofuran, etc. are used.

(C) 2-chloro-3,5-dimethoxyphenol (6
) Novel manufacturing method.

A solvent can be used in this reaction.

For example, carbon tetrachloride, chloroform, etc. are used. Particularly preferred is the use of carbon tetrachloride.

The reaction time is 30 minutes to 5 hours, preferably about 1 hour.

The reaction temperature is -15 to 5°C, preferably -5°C.

Moreover, the molar ratio of compound 00 and NC3 is 1:1 to 1:1.
4, preferably 1:1.2.

Hereinafter, the present invention will be specifically illustrated by examples.

Example 1 (A) Method for producing 3.5-dimethoxyphenol α mark.

Dissolve anhydrous phloroglucin (11 (19.5 g) in absolute ethanol (400 mg) and add 95% sulfuric acid (10 m).
was added, and the mixture was heated under reflux for one day in a nitrogen stream. After the reaction was completed, the reaction solution was concentrated under reduced pressure and extracted with ether. After washing the ether layer with water and drying, the ether was distilled off. The residue was purified by silica gel chromatography (AcOBt: eluted with n-hexane-1 nia) to yield 17.8 g (75%) of 18. bp135-140℃ (3mHg)'H
-NMR (CDα3) δ: 3.72 (6H, s), 6
．． 11 (3H, s), 7.08 (IH, s).

(B) Method for producing 2-chloro-3,5-dimethoxyphenol (6).

3.5-dimethoxyphenol αEl (28.2 g) was dissolved in anhydrous carbon tetrachloride, and under water cooling, NC3 (27.5 g) was dissolved in anhydrous carbon tetrachloride.
) was gradually added, and after the addition was completed, the mixture was further stirred at the same temperature for 1 hour. After the reaction was completed, the precipitated succinimide was removed by filtration, and the filtrate was concentrated under reduced pressure.

The residue was purified by distillation under reduced pressure to obtain 24.5 g (71%) of 6. mp 58-60℃, 'H-NMR (CDCβ3
) δ: 3.77.3.86 (each 3H,s),
5.92 (LH, s), 6.15-6.40 (2H,
m) (C)3. Synthesis method of α-dichloro-4,6-simethoxy 2-hydroacetophenone 0υ.

Compound 6 (15g) of nitrobenzene (24mjl')
Chloracetyl chloride (18.8 g) was added dropwise to the solution under ice cooling. After the dropwise addition was completed, AlCl2 (20 g) was added, and the mixture was further stirred at room temperature for 12 hours. After the reaction was completed, the mixture was gradually added to ice water (500 mi'), and the precipitated crystals were filtered, washed with water and benzene, and dried.

Furthermore, 18.4g (88%) was recrystallized from ethyl acetate.
I got No.11. 'H-NMR (CF, C00D) δ
: 4.06(6H,s), 4.95(21(,s
), 6.37 (LH,s>.

(D) 7-chloro-4,6-dimethoxy3 (2H)-
(4) Production method of benzofuranone.

Compound 11 (8.1 g) was dissolved in 95% ethanol (100-
), and to this solution was added sodium acetate (A c [I
9.6 g of Na.3H2O) was added, and the mixture was heated under reflux for 1 hour.

After the reaction was completed, ethanol was distilled off under reduced pressure, the residue was washed with water, and then recrystallized from ethyl acetate, yielding 5.39 g.
(78%) of 4 was obtained.

'H-NMR (CDα3) δ: 3.92.4.02 (
each 3H,s), 4, 74 (2H,s>, 6.
44 (1)1. s).

(Snake) Method for producing 7-chloro-2-ethylidene-4,6-simethoxy3 (2H)-benzofuranone Z-9.

Compound 4 (1.0 g) was dissolved in anhydrous tetrahydrofuran (1.0 g).
A separately prepared tetrahydrofuran solution (12 ml, 4.8 mmol) of lithium isopropylamide (LDA) was dissolved in 50 mf) and heated at -78°C under an argon atmosphere.
was gradually dripped. After the dropwise addition, the mixture was stirred at the same temperature for 30 minutes, and freshly distilled acetaldehyde (440+
ng, l Q mmoβ) was added, and the mixture was further stirred for 15 minutes. After the reaction was completed, a 10% aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. Wash the ethyl acetate layer with water,
After drying, the solvent was distilled off and the residue was diluted with anhydrous dichloromethane (10
mg), anhydrous pyridine (20rd), and 4-dimethylaminopyridine (100 mg) were added, and the mixture was stirred under ice cooling under a nitrogen stream. Next, methanesulfonyl chloride (2rd) was added dropwise to the reaction solution under water cooling, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, ice water was poured into the reaction solution, acidified with 10% hydrochloric acid solution, and then extracted with dichloromethane. After washing the extract with water and drying, the solvent was distilled off at room temperature under reduced pressure. The residue was subjected to silica gel column chromatography (eluted with ethyl acetate:n-hexane=1:3), and 30 mg (2.7%) of E was obtained from the first eluate. 760 mg (68.3%) of 7 bodies were obtained from the second elution portion. 7 bodies were recrystallized from dichloromethane and ether and mp 174-
Crystals at 176°C were obtained.

'H-NMR (DC!,) δ: 2.04 (3H
, d, J=8Hz), 4, 05 (6H, s), 6.
21 (LH, m), 6.27 (LH, 5) (F) 7-chloro-2-ethylidene-4,6-simethoxy 3 (2
A method for producing E-9 by photoisomerization of 1()-benzofuran (abbreviated as Z-9).

Anhydrous benzene (11
) and stirred under an argon stream for 3 hours while being exposed to sunlight. After the reaction was completed, the solvent was distilled off at low temperature, and the residue was separated by silica gel column chromatography (eluted with ethyl acetate:n-hexane=1=3). mp
70 mg of E-9 as crystals at 165-167°C (28
%)Obtained.

'HNMR (CD C13) δ: 2.25 (
3)1. d, J=8Hz), 3.97(6H,
s), 6.25 (IH, m), 6.31 (IH, s)
.

(G) Method for producing dj7-griseofulvin (1a).

E-9 (82 mg) anhydrous) /L, Ene (l, 4
ml) and 3-(trimethylsilyloxy)-1
, 1-dimethoxy-1,3-butadiene QG (1,5rr
Le) was added thereto, and the mixture was refluxed for 2 hours under an argon atmosphere. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1:
3) and purified with dI! - griseofulvin (la
) 52 mg (46%) was obtained.

Claims (4)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼... (E-9) (Me is a methyl group, R is a C_1 to C_3 alkyl group, substituted or unsubstituted aralkyl group) Or, it represents a heteroalkyl group) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・(10) There are general formulas ▲Mathematical formulas, chemical formulas, tables, etc.▼ ...(1) A method for producing griseofulvin or 6'-alkyl-substituted griseofulvins represented by (Me and R have the meanings defined above). (2) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・(E-9)
' (R represents a C_1 to C_3 alkyl group, a substituted or unsubstituted aralkyl group, or a heteroalkyl group). (3) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・(Z-9)
' (R represents a C_1 to C_3 alkyl group, a substituted or unsubstituted aralkyl group, or a heteroalkyl group) isomerized by irradiating the compound with light, General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・(E-9)
' (wherein R is as defined above). (4) 3,5-dimethoxyphenol in the presence of a solvent,
A method for producing 2-chloro-3,5-dimethoxyphenol, which comprises reacting it with N-chlorosuccinimide.