JPS6219579A - Production of 6-acetyl-3,7-dihydroxy-5-methoxy-2,2-dimethylchroman - Google Patents

Abstract

PURPOSE:To obtain in high position selectively in high yield easily the titled compound effective as an intermediate for chemical synthesis of hamaudol useful as a drug having hypotensive action without isomers, by hydrogenating a specific compound, deprotecting it and treating the resultant compound with an acid. CONSTITUTION:A compound shown by the formula I (R is benzyl, 2,4- dinitrobenzyl, o-nitrobenzyl or p-bromobenzyl) is used as a raw material, hydrogenated, deprotected and treated with an acid (preferably formic acid) to give a compound shown by the formula II. The compound shown by the formula I is obtained by reacting 2',4',6'-trihydroxyacetophenone shown by the formula III with a 1-halogeno-3-methyl-2-butene shown by the formula IV in the presence of a base, reacting the reaction product with a halide and reacting the resultant compound with methyl iodide. Then, the reaction product, a compound shown by the formula V, is reacted with R1COOH to syntherize the compound.

Description

[Detailed Description of the Invention] [Prior Art] Optically active substance (3S)-hamaudol has already been used in the Umbelliferae plant Hamaud (Angelica japonica A,
Gray) by Nitta et al. [Pharmaceutical Journal, 80°742 (1960), 88.1168
(1968)]. In addition, Sasaki et al.
ouriella 5eseloides Wolff
(3S)-hamaudol was extracted and isolated from ) and confirmed that this compound has a blood pressure lowering effect (Japanese Patent Application Laid-Open No. 58-55420). Until now, the only way to obtain Hamaudol was to extract it from plants.

[Problems to be Solved by the Invention] In order to provide Hamaudol as a medicine, extracting it from plants would be undesirable in terms of both cost and labor.

Therefore, it has been desired to develop a method for producing Hamaudol by chemical synthesis.

[Means for Solving the Problems] The present inventors have conducted intensive studies to establish a method for producing Hamaudol by chemical synthesis, and as a result, have discovered a new and effective method for producing Hamaudol.

The present invention relates to a method for producing 6-acetyl-3,7-cyhydroxy-5-methoxy-2,2-dimethylchroman represented by the following formula (2), which is an important synthetic intermediate in this new method for producing Hamaudol. Hydrogenation of a compound represented by the following formula (+) (wherein, R represents a benzyl group, a valanitrobenzyl group, a 2,4-dinitrobenzyl group, an orthonitrobenzyl group, or a valabromobenzyl group) 6-acetyl-3,7-cyhydroxy-5-methoxy-2,2 represented by formula (2), which is deprotected by
-This invention relates to a method for producing dimethylchroman.

Examples of methods for obtaining the compound represented by formula (1) as a raw material used in the production method of the present invention include the method shown in the following formula.

To explain this in detail, a) In the presence of a base, 2°, 4', 6'-trihydroquinoacetophenone represented by the above formula (A), 7 formula (B)
When 1-halogeno-3-methyl-2-butene represented by formula (C) is reacted at room temperature, 2°, 4', 6
'l-lihydroxy-3'-(3-methyl-2=butenyl)acetophenone is obtained. In this case, as X in formula (B), bromine or chloro is used, but chloro is especially optimal, and the base in this case is lithium,
It is selected from metals such as sodium and potassium, alkoxides, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, etc., with sodium hydride or potassium carbonate being preferred. As the solvent, a solvent selected from ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethquinethane, and diethylene glycol dimethyl ether, or alcohols such as ethanol and methanol is used, with tetrahydrofuran being preferred.

) 2°,4',6°-trihydroquine represented by the prefix formula (C), 3°-(3-methyl-2-butenyl)acetophenone, in the presence of a base, with the general formula R, When the represented halide is reacted at room temperature, 4' of formula (C)
, the hydroxyl group at the 6°-position is protected by R3 (D
) is obtained. In the halides represented by the general formulas R and Examples include 4-dinitrobenzyl group, orthonitrobenzyl group, and valabromobenzyl group, with pennorpromide being particularly preferred. Since these protecting groups are easily eliminated by reduction, the reaction proceeds in the same way no matter which protecting group is used. As the base, sodium hydride or potassium carbonate is used, and as the solvent, acetone or dimethylformamide is used. In particular, a combination of potassium carbonate as the base and dimethylformamide as the solvent is preferably used.

c) Reacting the compound represented by formula (D) with methyl iodide in the presence of sodium hydride, or reacting it with dimethyl sulfate in acetone in the presence of potassium carbonate at room temperature. By methylating the 2°-position hydroxyl group, a compound represented by formula (E) is obtained.

2) When the compound represented by formula (E) is reacted with a filtered acid represented by formula (F), the double bond of the 3-methyl-2-butenyl group located at the 3"-position is epoxidized. The expression (
The compound represented by 1) can be obtained almost quantitatively. The filtering acid used is selected from any peracid in which R2 in formula (F) is a phenyl group, a varanitrophenyl group, a metachlorophenyl group, a hydrogen atom, an alkyl group, or a trifluoromethyl group, but especially , varanitroperbenzoic acid in which Rt is a varanitrophenyl group, or metachloroperbenzoic acid in which R7 is a metachlorophenyl group are preferred.

Methylene chloride or chloroform is used as the solvent, with methylene chloride being preferred. .

Specific examples of the production of the compound represented by formula (1), which is a raw material for the production method of the present invention, are shown below.

Specific Example 1 A suspension of 743 mg of sodium hydride (60% NaH) and anhydrous tetrahydrofuran was added at 2° and 4°.

A solution of 3.12 g of 6°-trihydroxyacetophenone in anhydrous tetrahydrofuran (+, OmJll) was added and the resulting mixture was stirred at room temperature for 1 hour, and then to this mixture,! -1.95 g of chloro-3-methyl-2-butene was slowly added with stirring. After stirring the reaction mixture at room temperature for 24 hours, it was extracted with ethyl acetate, and the ethyl acetate layer was sequentially washed with water, dried over anhydrous sodium sulfate, filtered, and
The solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography (column φ
'l, Ocm, 30 g of silica gel, 0.3 kg/
cm') and recrystallized from benzene to give 2°, 4°16°-trihydroxy-3'-(3-
2.8 g (yield: 63.9%) of methyl-2-butenyl)acetophenone was obtained as a pale yellow prism product.

Melting point: 173-174°C Proton nuclear magnetic resonance spectrum (δ7Pmf n CD
aOD): 1.64 (3H, s), 1.73 (
31-I, s).

2.6 0 (3H, S).

3. 2 5 (2H, d, J = 7.
．． 5 Hz).

5.2 0 (I H, L, J = 7.5 Hz)
.

5.9 0 (I H,s) Infrared absorption spectrum ν α゛1:3424.33
28,1638,1602°1566, +455.13
70.1280°1234.1+70.1150,10
70° mass spectrum: M/Z (%) 236 (M”, 89) 221 (31)
, 203(6).

193(25), l　81(100).

168 (33), 165 (22) Further, an example in which the above reaction was carried out by another method is shown below.

2°, 4°, 6°-trihydroxyacetophenone 50
．． 0 g was dissolved in 250 g of anhydrous tetrahydrofuran, 123.15 g of anhydrous potassium carbonate was added, and the mixture was stirred at room temperature for 30 minutes. Thereafter, 37.23 g of l-chloro-3-methyl-2-butene was added dropwise over 20 minutes, and the mixture was reacted at room temperature for 24 hours. After the reaction, the reaction mixture was extracted with ethyl acetate (2000 yd), and the ethyl acetate layer was sequentially washed with water (500, 1 l x 4) and shaken with saturated brine (300 yd).
Qx2), dried over anhydrous sodium sulfate, filtrated, and the solvent was distilled off to obtain a residue.

Recrystallization of this residue from benzene yields 2°, 4'.

6°-trihydroxy-3°-(3-methyl-2-butenyl)acetophenone as a pale yellow prism product 38.
6 g (yield 55, 0%) was obtained.

Specific Example 2 (Bn: N''/dal group) A mixture of 3.0 g of 2', 4', 6'-trihydroxy-3'-(3-methyl-2-butenyl)acetophenone and 5.27 g of potassium carbonate was After stirring vigorously in anhydrous dimethylformamide + 5 mfJ for 30 minutes at room temperature, a solution of benzylbromide 3,3- in dimethylformamide (10d) was added to the reaction mixture and stirred vigorously for an additional 3 hours at room temperature.After this, the reaction mixture was extracted with ethyl acetate, and the obtained ethyl acetate layer was sequentially washed with water, shaken with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off. The obtained residue was recrystallized with methanol. , 2.20 g (yield: 41.6%) of 4',6'-dibenzyloxy-2''-hydroxy-3°-(3-methyl-2-butenyl)acetophenone in the form of colorless needles were obtained.

Melting point: 116-117°C Proton nuclear magnetic resonance spectrum (δ9□in CDCl
5): 1.67((iI-1,s), 2.55(3
H,s).

3.32 (2H, d, J = 7.5 Hz).

5.03 (2H, s), 5.09 (2H, s).

5.22 (LH, t, J=7.5H2).

6.04 (IH, s), 7.36 (5H, s).

7.37 (5H, s).

13.91 (Disappeared by addition of I H, S, D 20) Infrared absorption spectrum "-"' 3416.1616,1592,1422°1276.
1234 Mass spectrum: M/Z (%) 4 1 6 (M”, 5),
36 1(2).

326(4), 325(13).

283(6), 181(3).

91 (+00) Specific example 3 4°,6°-dibenzyloxy-2°-hydroxy-3
°-(3-methyl-2-butenyl)acetophenone2.
0g and 2.8g of potassium carbonate in 20g of anhydrous acetone,
Stirred at room temperature for 30 minutes. Next, dimethyl sulfate 4.2
After adding 0 g and stirring for 4 days, 5- of water and 5- of ammonia were added and 1. The mixture was stirred at room temperature for 30 minutes and extracted with ether. The ether layer was sequentially washed with water, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off. The resulting residue was dissolved in a mixed solvent of n-hexane and ethyl acetate (n-hexane: ethyl acetate=
Silica gel column chromatography (column φ3, Ocm, 65 g of silica gel,
4°, 6°
1.88 g (yield 90.9%) of -dibenzyloxy-2°-methoxy-3'-(3-methyl-2-butenyl)acetophenone was obtained as a colorless oil.

Proton nuclear magnetic resonance spectrum (δ7pin CDC
l5) '1.67 (6H, s), 2.49 (3
H, s), -3,31 (2H, d, J = 7,
(OHz).

3.73. (3H, s), 5.00 (2H, s)
.

5.02 (2H, s).

5.15 (IH, t, J = 7.0 Hz).

6.3'3 (IH, s), 7.34 (5H, s).

7.36 (5H, s) Mass spectrum: M/Z (%) 4 3 0 (M”, 4 3).

340(6), 339(12).

297(1B), 249(12).

Further, an example in which the above reaction was carried out by another method is shown below.

4°,6°-Dibenzyloxy-2°-hydroxy-3°-(3-methyl-
A solution of 2.0 g of 2-butenyl)acetophenone in anhydrous tetrahydrofuran (7-) was added at 0° C. and stirred for 30 minutes. After this, after gradually returning to room temperature, methyl iodide 3
- was added and stirred overnight at room temperature. After the reaction is complete, a small amount of methanol is added, the reaction mixture is extracted with ethyl acetate, the ethyl acetate layer is sequentially washed with water, shaken with saturated brine, dried over anhydrous sodium sulfate, etc. The resulting oily residue was subjected to silica gel column chromatography (column φ2.Ocn+, silica gel 30 1.5 g of 4°,6°-dibenzyloxy-2°-methoxy-3'-(3-methyl-2-butenyl)acetophenone as a colorless oil. (yield 72.6%).

Specific pJ 4 4°,6°-dibenzyloxy-2°-methoxy-3゛(3-methyl-2-butenyl)acetophenone 1.29
methylene chloride (9-
) The solution was added in portions at 0° C. with stirring. The reaction mixture was stirred at 0° C. for 15 minutes and then at room temperature for 15 minutes. After that, 10% aqueous sodium thiosulfate solution was added and stirred, and the reaction mixture was extracted with ethyl acetate. Next, the ethyl acetate layer was sequentially shaken with saturated sodium bicarbonate solution, washed with water,
After shaking with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and distilling off the solvent, 4°,6′-dibenzyloxy-2°-methoxy-3′-(3- Methyl-2,3-evoquinbutyl)acetophenone 1.3g (
972% yield) was obtained as a single colorless oil.

Proton nuclear magnetic resonance spectrum (δppin CDC
+3) :1.16(3H,'s), 1
．． 23 (3H, s).

2.42 (3H, s).

2.70-2.85 (3H, m).

3.68 (3H, s), 4.93 (3H, s).

4.96 (2H, s), 6.27 (IH2s).

7.26 (5H, s), 7.28 (5H, s) Mass spectrum: M / Z (%) 44 6 (M”, l 3
).

376(11), 375(40).

333 (+5), 285 (8).

The manufacturing method of the present invention will be explained in detail below.

After deprotecting the compound represented by formula (1) by hydrogenating it, 6 represented by formula (2) is reacted with an acid.
-Acetyl-3,7-cyhydroxy-2,2-dimethyl-5-methoxychroman is obtained almost quantitatively.

Deprotection by hydrogenation is achieved by a commonly used reduction method. For example, platinum, palladium, nickel,
Examples include a hydrogenation reduction method using a catalyst such as rhodium.

As the solvent, ethyl acetate, ethanol, methanol, etc. can be used, but ethyl acetate is preferable.

In addition, protecting groups such as benzyl group, varanitrobennol group,
Since the 2.4-dinitrobenzyl group, orthonitrobenzyl group, and valabromobenzyl group are easily eliminated by reduction, the reaction proceeds in the same way no matter which protecting group is used.

Subsequently, the reaction mixture is treated with an acid, and examples of the acid used include acetic acid, formic acid, para-toluenesulfonic acid, and the like, with formic acid being particularly preferred.

An important condition for this reaction is to use an acid after hydrogenation and deprotection. If no acid is used, not only will the cyclization reaction be extremely slow, but the target 6-acetyl-3 ,7-cyhydroxy-5-methoxy-2,2-
In addition to dimethylchroman, the formation of nohydrobenzofuran derivatives that are difficult to separate 1) < Lieutenant L3 makes the reaction complex.

[Effects of the Invention] The effects of the manufacturing method of the present invention are as follows. ■High positional selectivity. ■High yield. ■There is no room for the formation of isomers through reaction.

[Example] The present invention will be explained in more detail with reference to Examples below.
The present invention is not limited in any way by this.

Examples 4″,6°-dibenzyloxy-2 obtained in specific example 4
°-Methoxy-3°-(3-methyl-2,3-eboxybutyl)acetophenone 43 g of ethyl acetate (40 mR
) solution with 5% palladium that has sufficiently absorbed hydrogen gas.
It was added to a suspension of carbon (3.0 g) and 40 mfl of ethyl acetate, and the resulting mixture was stirred under a hydrogen gas atmosphere at normal pressure and room temperature overnight. After this, formic acid IO- was added and 1
Stir for hours. After the reaction was completed, the reaction mixture was filtered, and the Shido liquid was extracted with ethyl acetate (300a (1)). Dry with anhydrous sodium sulfate,
The 6-
Acetyl-3゜7-cyhydroxy-5-methoxy-2,
2.56 g of 2-dimethylchroman was quantitatively obtained.

Melting point: 107-109°C Proton nuclear magnetic resonance spectrum (δ-in CDCl3
): 1.36 (6H, s).

2, 18 (disappeared with addition of IH, br, s, and D20).

2.67 (3H, s).

2.70 (IH, dd, J=17Hz, 5Hz).

2.94 (I H, dd, J = I 7 Hz, 5
Hz).

3.78 (3H, S).

3.82 (IH, t, J = 5 Hz).

6, l 9 (IH, s).

12.97 (11 (,s, disappeared by addition of DtO) infrared absorption spectrum ν2: CM-'・3464,297
6.2932. +630°1574.1478. +45
4.1422°+372.1330,1228.119
2゜1170.1136. I 096. I 076゜1
054.1024. Summer 008,972°9 5
2.9 2 8,9 1 0,8 04 Mass spectrum: M/Z (%) 266 (M'', 1.1).

251(40), 233(14).

196(12).

195(100), 177(21).

Claims (1)

[Claims] The following formula (1) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (1) (In the formula, R is a benzyl group, para-nitrobenzyl group, 2,4-dinitrobenzyl group, orthoni, trobenzyl group) The following formula (2) is characterized by hydrogenating and deprotecting a compound represented by a group or a parabromobenzyl group, and then allowing an acid to act on it. ▲Contains mathematical formulas, chemical formulas, tables, etc. ▼(2) 6-acetyl-3,7-dihydroxy-5- represented by
Method for producing methoxy-2,2-dimethylchroman.