JPS6020391B2 - Manufacturing method of dibenzopyrans - Google Patents

Description

Detailed Description of the Invention The present invention relates to the general formula (m) [wherein R and R2 each represent a lower alkyl group, an aryl (a-1) group, a carpoxyl group, or an alkoxycarbonyl group, and they are the same Even though
May be different.

Further, R and R2 may be bonded, for example, it is represented by a carbocyclic compound]. As a prior art related to the present invention, a method for obtaining cyclized penzopyrans (Inchromans) by reacting phenethyl alcohols with formaldehyde or paraformaldehyde is known (French Patent No. 2088 Patent No. 6). .

However, the reaction with ketones instead of such aldehydes is unknown. In view of the above technical situation,
The present inventors investigated the reaction between phenethyl alcohols and ketones in order to obtain novel penzopyrans, and as a result, they completed the present invention.

The gist is shown by the following formula.

(However, in the formula, R and R2 have the same meanings as above)
According to this synthesis method, the dibenzopyrans are 2-(3-
Hydroxyphenyl) cyclohexanol (1) and ketone (2) are reacted without a catalyst or in the presence of a catalyst such as hydrochloric acid, paratoluenesulfonic acid, trichloroacetic acid, etc., without a solvent or in an appropriate solvent. .

The solvent at this time may be any solvent as long as it does not participate in the reaction, such as lower alcohols such as methanol, ethanol, propyl alcohols, butyl alcohols, and amyl alcohols. It can also be used as a solvent. The reaction temperature varies depending on the substance, but is preferably between room temperature and about 200 oo.

The reaction time is about 1 hour to 30 hours. The next ketone to use is Siku.

Hexanone, acetophenone, methyl pyruvate, etc., but are not limited to the above compounds,
Most ketones represented by the general formula (b) can be applied to the present invention. In addition, carboxylic acid esters (
Carboxylic acids (V) can be produced by hydrolyzing W) in the presence of an alkali or acid catalyst. [However, in the formula, R3 represents a lower alkyl group or an aryl (a-1) group, and R4 represents a lower alkyl group] As a catalyst for hydrolysis of ester, sodium hydroxide as an alkali,
Potassium hydroxide, sodium carbonate, potassium carbonate, etc. are hydrolyzed in solvents such as water or hydrous alcohol.

Further, examples of acid catalysts include hydrochloric acid, hydrobromic acid, and sulfuric acid. The present inventors have previously developed various 1,1
-disubstituted inquinolines (Japanese Patent No. 611894 and Patent No. 657896) and phenanthuridines (Japanese Patent Laid-Open No. 47-27979) were synthesized.

This time, we replaced the nitrogen in phenethylamine with oxygen and applied it to the synthesis of dibenzopyran. 21 raw materials (3)
-hydroxyphenyl)cyclohexanol 1 is 2-(
It is obtained by reducing cyclohexanone (3-hydroxyphenyl), but the ratio of trans isomer la and cis isomer lb varies depending on the type of reducing agent. For example, trans-isomers la and lb were obtained at a ratio of 4:1 by Ladenburg ring addition. On the other hand, when reduced with sodium borohydride, trans isomer la and cis isomer lb were obtained at a ratio of 2:1.

Further, in the catalytic reduction in the presence of palladium on carbon, the ratio of trans isomer la and cis isomer was obtained at a ratio of 1:20.

The structures of the trans and cis forms were confirmed by nuclear magnetic resonance spectra of the respective acetyl forms. These trans isomer la and cis isomer lb are each ketone (0)
Dibenzopyrans can be produced by reacting with

In addition, trans or cis isomers and ketones (R, COR
2), diastereoisomers exist if R and R2 are different. Some of these compounds have anti-inflammatory effects, and therefore have medical value.

Next, the present invention will be explained with reference to examples, but the present invention is not limited by these examples.

Example 1 Process for producing 2-(3-hydroxyphenyl)cyclohexanol A 1.1 parts of 2-(3-hydroxyphenyl)cyclohexanone are dissolved in 50 parts of ethanol, and 2.2 parts of sodium metal is added little by little. .

The mixture was further heated under reflux for 1 hour to remove the solvent. Add 50 ml of water, wash with ether, acidify with hydrochloric acid, and extract with ethyl acetate. After drying the magnesium sulfate, the solvent was distilled off to obtain a pale yellow residue. This has a ratio of trans isomer and cis isomer of 4:
Contains at a ratio of 1. The crystals were recrystallized from ethanol to obtain colorless prism crystals (90%) (la:lb=6:1). This product was separated using Cagel thin layer chromatography using a developing solvent of ether and petroleum ether, and the melting point was 144-145.
o la750 of 9 (78%) was obtained. Elemental analysis value C
, 2 days, 602 Calculated value C, 74.97: Days, 8.39 Experimental values C, 75.08; Days, 8.648 After the reaction, the ethanol was removed and the residue was purified by silica gel column chromatography using benzene ether (5:1) as a developing solvent. 9 (20%) of lb405 was obtained as colorless prismatic crystals with a melting point of 114o.

Elemental analysis value C, 2 days, 602 Calculated value C, 74.
97: day, 8.39 experimental value C, 75.03: day,
8.64 and melting point 154-15? A la20 female (1%) was obtained as colorless prismatic crystals.

This sample was confirmed to be the same as sample la obtained by method A) by comparison of melting and instrument data.
Example 2 Preparation of 1-acetoxy-2-(3-acetoxyphenyl)cyclohexane A 1aloo compound 9 is dissolved in 2 diacetic acid anhydride and heated at 100 ml for 3 hours.

Acetic anhydride was removed under reduced pressure to obtain 137 (95%) as the acetyl compound of la as a colorless oil. Infrared absorption spectrum (Muid) 1730 arc-11.90 (Hata, singlet, CH-0-CO-CH) 2.16 (Muid, singlet,
ph-0-COCH3) 2.30 (IH, sextet, ph
-CH, J=1.08, 10.8 and 3. Group Z)4.
80 (IH, sextet, CH3COO-CH, J=10.
8, 10.8 and 4.2Hz) 6.72-7.24 (
4th, multiplet, aromatic nucleus proton) B 1bloo sail is dissolved in 2 parts of acetic anhydride and heated at 100°C for 3 hours.

Acetic anhydride was removed under reduced pressure to obtain 135O (94%) as the lb acetyl form as a colorless oil. Infrared absorption spectrum (Muid) 1730 skin-1 176 mountains-1 (C=○) Nuclear magnetic resonance spectrum 6 (carbon tetrachloride) 1.84 (muid, singlet,
CH-0-COCH land) 2.16 (group, single line, ph-
0-CO-CH3) 2.72 (IH, octet, ph-C
H, J = 10.8, 4.0 and 2.4Hz) 5.02
(IH, singlet, C ratio COO-CH) 6.7-7.2 (
4th, multiplet, aromatic nucleus proton) Example 31, 2, 3
, umbrella, 1 blood 1 hexahydro 6-spirocyclohexano-mother day 1 dibenzo[b,d]pyran-9-ol (ma
) Production method A A mixture of 1alg, 20M ethanol, and 5 parts of cyclohexanone was heated to 20,000 ml in an autoclave.
Heat the glue for an hour.

After removing the solvent, the product was separated by silica gel column chromatography using ether-benzene to obtain 39°C (28%) as colorless prism crystals with a melting point of 179-180°C. Nuclear magnetic resonance spectrum (Mudimethyl sulfoxide) 3.2 (I
H, -CHOH) 6.65 (IH, four perpendiculars, aromatic nucleus proton, J = 2.3
and 8. Thin Z) 6.75 (IH, doublet, aromatic nucleus proton, J = 2.3Hz) 6.95 (IH, doublet, aromatic nucleus proton, J = 8, thin Z) 8.61 (IH, single line,
phOH) Elemental analysis value C, 8 days 2402 Calculated value C, 79.37; day, 8.88 Experimental value C, 79.46: day, 8. Furthermore, 9 out of 420 raw materials were recovered.

B 1alg, 50% ethanol, 5% cyclohexanone
A mixture of 1 and 1 part of concentrated hydrochloric acid is heated under reflux for 1 hour.

After the solution was distilled off, the residue was recrystallized from benzene-hexane to give 1.2 (8.8 m) colorless prismatic crystals with a melting point of 179-1800.
6%). This was consistent with what was obtained in A) by instrumental analysis. A mixture of C1alg, 50% ethanol, 5% cyclohexanone, and 250% paratoluenesulfonic acid is heated under reflux for 1 hour.

After removing the solvent, the residue was recrystallized from benzene-hexane to give 1.1 g (78
%). This was consistent with that obtained in A). Example 4 1, 2, 3, 4, umbrella, 1 sail, hexahydro 6-methyl-6-phenylene, dibenzo[b,d]pyran-9
-Production method la of all (mb), ethanol 80 [,
A mixture of 10 parts of acetophenone, and 3 parts of concentrated hydrochloric acid.
Heat to reflux for an hour.

After distilling off the solvent, extract with benzene and wash with water. An additional 10%
Extract with aqueous sodium hydroxide solution, acidify the aqueous layer with hydrochloric acid, and extract with benzene. Benzene is removed and the residue is recrystallized from benzene. Two colorless needles (75%) were obtained with a melting point of 128-130°. Nuclear magnetic resonance spectrum (common dimethyl sulfoxide) 3.3-3.8 (IH, OC
H) 6.83 (IH, quartet, aromatic nucleus proton, J=2,3
and 8. Kasu Z) 6.93 (IH, doublet, aromatic nucleus proton, J = 2.9Hz) 7.15 (IH, doublet, aromatic nucleus proton, J = 8.9Hz) Elemental analysis value C2 Rainbow 22
02 Calculated value C, 81.60: day, 7.53. experiment
Value C, 81.86: day, 7.72. Example 51,2
, 3, 4, place, 1 rib-hexahydro-6-carboxy-
Process A for producing 6-methyl-8-dibenzo[b,d]pyran-9-ol (mc) 1a2. A mixture of about 20 parts of ethanol, 1 part of methyl pyruvate and 1 part of concentrated hydrochloric acid was heated under reflux on a water bath for 10 hours.

After the reaction, remove the solvent and add 10% aqueous sodium hydroxide solution 2.
Add 0' and heat on a water bath for 1 hour. The aqueous solution was acidified with a 10% aqueous hydrochloric acid solution and extracted.

The ether layer is extracted with saturated sodium chloride solution. 10% water layer
A colorless prism with a melting point of 200-202o is obtained by recrystallizing the crystals that are acidified with an aqueous hydrochloric acid solution and recrystallized from ethanol-water.
Obtained Hammer (85%). Infrared absorption spectrum (KBr)17
00en-1 (C〇〇H) nuclear magnetic resonance spectrum (key dimethyl sulfoxide) 1.60 (su, singlet, CH3) Elemental analysis value C, 5 days, 804 Calculated value C, 68.68; days, 6.92. experiment
Value C, 68. Spots; Sun, 6.75B A mixture of mdlg obtained in Example 6 and 10% aqueous sodium hydroxide solution on a desk was heated for 100,001 hours, and after cooling, 10% aqueous hydrochloric acid solution was added and the precipitated crystals were recrystallized from ethanol-water. colorless prismatic crystal with a melting point of 200-202 (83%)
) obtained.

Instrumental analysis of this product matched that obtained in A). Example 61, 2, 3, 4, umbrella, lob-hexahydro 6
-methoxycarbonyl-6-methyl-qH-dibenzo [
b, d] Method for producing pyran-9-ol (md) Dissolve mclg in 20 methanol saturated with hydrochloric acid gas and heat under reflux for 3 hours.

After removing the methanol, it was recrystallized from benzene-n-hexane to give colorless prism crystals with a melting point of 196-1 pseudo-O. Bandan (89
%). Infrared absorption spectrum (KBr) 335 Lus-
1 (OH) 1720 enemy-1 (C.

) Nuclear magnetic resonance spectrum (moodimethyl sulfoxide) 1.6 (3 days, singlet, CH3) 3.55 (patchy, singlet, COOCH3) Example 7 6-monosubstituted-1,2,3,4, umbrella, 1 blood-hexahydro-
Example 3 of the production method of fine-dibenzo[b,d]pyran derivative
Under the same reaction conditions as in B and C), la and various carbonyl compounds were heated under reflux in a solvent in the presence of an acid melting medium and post-reacted to produce the dibenzopyran derivatives (me,
prisoner f, mg, mh, mi, mj, dish k, ml, mm, m
n, mo and mp) were obtained.

Table 2 shows the elemental analysis values of the compound obtained in Example 7.

Table 1 Note) Note) In "catalyst", T represents para-toluene sulfonic acid, and "day" represents concentrated hydrochloric acid; in "solvent", E represents ethanol and B represents benzene.

Claims (1)

[Claims] 1 2-(3-hydroxyphenyl)cyclohexanol (I) ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ and general formula (II) R_1COR_2 (II) [However, in the formula, R_1 and R_2 are Each represents a lower alkyl group, an aryl group, a carboxyl group, or an alkoxycarbonyl group, and they may be the same or different. In addition, R_1 and R_2 may be bonded, for example, it is represented by a carbocyclic compound] General formula (III) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [However, in the formula, R_1 and R_2 are respectively the same as defined above.] A method for producing dibenzopyrans.