JPH0193554A - Organic compound - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (n is 11-12; R1 is lower alkyl; R2-R4 is H, lower alkyl or lower acyl). EXAMPLE:6-(12-Acetoxydodecyl)-2,3-dimethoxy-5-methylhydroquinone-1,4-d iacetate. USE:Immune promoting agent, smooth muscle relaxing agent, synthetic intermediate for medicine, etc. PREPARATION:A compound expressed by formula II is reacted with a compound expressed by formula III or the formula [YO(CH2)n-1CO]2O or the formula YO(CH2)n-1CN (Y is H, lower alkyl or lower acyl) in the presence of a catalyst such as a Lewis acid to afford a compound expressed by formula IV, which is reduced in the presence of a catalyst such as Pd-C and preferably a small amount of reaction promoter (e.g. hydrochloric acid) to give a compound expressed by formula V, which is oxidized using potassium persulfate, etc., to provide the compound expressed by formula I (R3 and R4 are H).

Description

Detailed Description of the Invention The present invention is based on the general formula (where n is an integer of 11-22, R1 is a lower alkyl group,
RIRl and R4 are the same or different and represent hydrogen, a lower alkyl group, or a lower acyl group.

As a result of many years of research into derivatives of 2,3-dialkoxy-5-methylphenol, the present inventor has completed the present invention.

In the above formula, the lower alkyl group represented by R1, R2, R5 or R4 is, for example, a methyl, ethyl, propyl or butyl group, and the number of carbon atoms thereof is generally preferably 4 or less. R2* The lower acyl group represented by R1 or R4 includes those having 1 to 8 carbon atoms, examples of which include aliphatic acyl groups such as formyl, acetyl, propionyl, and butyryl groups, and phenylacetyl groups. Examples include aromatic acyl groups such as araliphatic acyl groups or benzoyl groups.

The compound of formula (1) above can be produced, for example, as follows.

First, a compound represented by the general formula 0Rs (in the formula, each symbol has the same meaning as above) and the general formula (in the formula, n has the same meaning as above, and Y is hydrogen, a lower alkyl group, or a lower acyl group) , 2 represents a halogen atom) to obtain a compound represented by the general formula (in the formula, each symbol has the same meaning as above), and this is reduced to form the general formula ( In the general formula (1), Rs +
A compound in which 14 is hydrogen, that is, a compound represented by the general formula (in the formula, each symbol has the same meaning as above) can be produced.

A compound in which R4 and R4 are lower acyl groups in the general formula (1), that is, a compound having the general formula (wherein 几1.R2 has the same meaning as above;

R'4 represents a lower acyl group. The compound represented by ) can be produced by reacting compound (1-1) with a carboxylic acid anhydride.

Compounds in which R5 and R4 are lower alkyl groups in the general formula (I), that is, compounds of the general formula (wherein R1.R2 have the same meanings as above, and W3゜R4
represents a lower alkyl group. ) can be produced by reacting compound (I-1) with di-lower alkyl sulfuric acid.

In the above general formula (I[), the lower alkyl group represented by Y is, for example, a methyl, ethyl, propyl or butyl group, and the number of carbon atoms thereof is generally preferably 4 or less. Examples of lower acyl groups represented by Y include acetyl, propionyl, butyryl groups, aromatic aliphatic acyl groups such as phenylacetyl groups, and aromatic acyl groups such as benzoyl groups. 1-8 are mentioned. The halogen at 2 may be chloro, bromo or iodo.

The reaction between compound (If) and compound (III) is generally carried out under Friedel-Crafts reaction conditions. The reaction is preferably carried out in the presence of a catalyst, and any catalyst that can be used in Friedel-Crafts reactions may be used. Examples of preferred catalysts are mineral acids such as sulfuric acid, phosphoric acid, polyphosphoric acid; metal chlorides such as aluminum chloride, zinc chloride, stannic chloride, titanium tetrachloride, cuprous chloride, aluminum bromide, magnesium bromide, etc. and bromides; boron trifluoride and other Lewis acids.

The reaction is usually carried out in the presence of the above-mentioned catalyst using a solvent, but it can also be carried out without a solvent.

As the solvent, any solvent used in Friedel-Crafts reactions can be used. Preferred solvents include solvents having a nitro group such as nitrobenzene, nitromethane, and nitroethane; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,2-dichloroethylene, 1,1,2゜2-tetra Chlorethane, 1,1
, 2.2-Halogenated hydrocarbon type solvents such as tetrachloroethylene; ether, tetrahydrofuran, 1.2-
Ether type solvents such as dimethoxyethane, carbon disulfide.

When a solvent is not used, the reaction is usually carried out at a temperature range of -10° to 250°C, and when a solvent is used, the reaction is usually carried out at a temperature range of -10° to 250°C.
It is carried out at a temperature of 10° C. or around the boiling point of the solvent.

For the reduction reaction of compound (IV), any reaction that can convert a C=0 group into a >OH2 group can be used, but catalytic reduction is particularly advantageous. A preferred example of a catalyst in catalytic reduction is palladium-carbon (preferably 1-20
% palladium), Raney nickel, platinum oxide,
Wilkinson complexes obtained from rhodium-carbon (preferably containing 1-20% rhodium) or chlorides of platinum, palladium, rhodium, etc.

This reduction reaction is preferably carried out in the presence of a suitable solvent.

Any solvent may be used as long as it does not inhibit the desired reduction reaction. Examples of preferred solvents are acetate esters such as ethyl acetate, butyl acetate; methanol, ethanol,
These are lower alcohols such as butanol, and lower aliphatic carboxylic acids such as acetic acid, formic acid, and propionic acid.

The reaction is advantageously carried out in the presence of a small amount, for example 1-10%, of a reaction promoter (eg hydrochloric acid, perchloric acid, p-toluenesulfonic acid, etc.).

The reaction temperature is preferably selected from the range O'-150°C, but generally the reaction is carried out at room temperature.

The pressure of hydrogen used in the reaction may be selected within the range of 1 atm to 150 atm, but 1 atm is usually conveniently used.

Oxidation of compound (1) can be carried out by reacting compound (7) with, for example, potassium persulfate.

Examples of carboxylic anhydrides used in the reaction for leading compound (1-1') to compound (1-2) include acetic anhydride, propionic anhydride, and the like, as well as formic acid and acetic acid, propionic acid, etc. Examples include mixed acid anhydrides.

Examples of the di-lower alkyl sulfuric acid used in the reaction for leading compound (I-2) to compound (1-3) include dimethyl sulfate and diethyl sulfate.

Compound (I) of the present invention is new. It exhibits physiological bioresistance controlling effects, particularly immunostimulating effects, and smooth muscle relaxing effects, and is used, for example, in physiological bioresistance controlling effects in animals including humans, particularly as an immune adjuvant. Compound (1) is also useful as a synthetic intermediate for pharmaceuticals and the like.

For example, by subjecting compound (I) to an oxidation reaction using a conventional method, a compound represented by the general formula [in the formula, each symbol has the same meaning as above], which has an effect of improving myocardial tissue damage and brain tissue damage, is obtained. be able to. Compounds (I[) and (V)
is useful for improving myocardial tissue disorders and brain tissue disorders,
For example, it is effective in oxygen activation in ischemic and congestive heart failure and cerebral blood flow disorders in animals including humans.

Reference example 1 11-acetoxy-n-undecylic acid chloride (27,
Add aluminum chloride (28 g) to a 1,2-dichloroethane solution (150 ml) of 69) and stir at room temperature for 2 hours. This reaction solution was cooled to 5°C and added to 3.4.5-
Add a solution of trimethoxytoluene (19,19) in 1,2-dichloroethane (50 ml) and 1. Stir at room temperature for 72 hours.

The reaction mixture is then heated to 50°-60°C and stirred for an additional 30 minutes. After cooling, 300 ml of ice water was added to the reaction solution, and the product was extracted with dichloromethane.

Dichloromethane layer 14 was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give 6-(1
1-acetoxy-1-oxoundecyl)-2,5-dimethoxy-5-methylphenol (35f') is obtained.

IRνNeatcm': 1730 (OAc), IEi
80ax (CO), 1610.1580 (Ar) MSm/e: 3
94(M+), 352,334°6-(11-acetoxy-1-oxoundecyl)-2,3-dimethoxy-5
- Methylphenol (34f) methanol solution (30
Add sodium hydroxide (7y) to
Stir for an hour. After neutralizing the reaction solution by adding 5N hydrochloric acid,
When the solvent is distilled off, crude crystals are obtained. The ice crystals were washed with water and then recrystallized from ether-hexane (1:1) to yield colorless needle-like crystals of 6-(11-hydroxy-1-oxoundecyl)-2,3-dimethoxy-5-methylphenol (
30g) can be obtained.

Melting point 81℃ Elemental analysis Calculated value as C20HII205 C,68,15:H,9,15 Experimental value 0.6
8.47; H, 9,30KBr + .

L paper axCm, 3500 (OH), 3300 (
OH).

11370.1660(00), 1610.1580(
Ar) NMRδCD”: 1.2-1.9 [16H, m.

99m-(CHz)s-), 2.41(3H,s, C5-a
H,).

2.86 (2H,t, J=7Hz, 02-H2)
, 3.60 (2H, t, J=6Hz, -CH20H
), 3.83 (3H, s, OCHg), 18G (3H,
S, 00H3).

6.26 (IH, S, C4-H), 9.92 (1H,
s.

0, -OH) M8 m/e: 352 (M+), 334,195゜6
-(11-hydroxy-1-oxoundecyl)-2,
A solution of 3-dimethoxy-5-methylphenol (14 g) in acetic acid (200 ml) was mixed with 5% palladium-carbon (50
% hydrate) (3 g) and 70% perchloric acid (0.1 ml) were added, and catalytic reduction was carried out at room temperature and pressure. After hydrogen absorption is completed, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is extracted with dichloromethane, and the dichloromethane layer is washed with a 5% aqueous sodium bicarbonate solution and then dried over anhydrous magnesium sulfate. When the solvent was distilled off, a colorless oil was left.
(11-acetoxyundecyl)-2°3-dimethoxy-5-methylphenol (15 g) is obtained.

Neat IR'maxCm-': 3450 (OH), 173
0 (OAc).

1610.1580 (Ar).

NMRaCDCls: 1.1-1.9 [181i,
m, -(CH2)9pm-), 2. C2 (3u, s, oAc), 2.22 (3H
.

s, C5-CH5), 2.54 (2H,t, J=
7Hz.

a+', -42), 3.79 (3H, S, ocH,),
3.83 (3H, s, 0CHs), 4.01 (2H, t
, J=6Hz, -CH2・0AC), 5.78
(1H,S,0l-OH), 6.23 (IH,
s, 04-H).

MSm/e: 380 (M), 338,181 Example 1 Add persulfuric acid to a tetrahydrofuran solution (70 ml) of 6-(11-acetoxyundecyl)-2,3-dimethoxy-5-methylphenol (0,6y). lJum(2
, Of ) (7) Aqueous solution (20 ml) and stir for 42 hours at room temperature under a nitrogen stream. The product was quickly extracted with ether, the ether layer was washed with water under a nitrogen stream, dried over anhydrous magnesium sulfate, and the ether was distilled off to give 6-(11-acetoxyundecyl) as a colorless oil.
-2,3-dimethoxy-5-methylhydroquinone (0,
431) I am happy.

Neat -+.

L νmax cm, 3450 (OH), 17
30 (OAc), 1620 (Ar) -:], 2.02 (31 (,S, 0AC), 2.1
4 (3H.

s, C5-CH, 2.59 (2H, t, J=7
Hz.

(1-H2), 3.86 (6H, S, 0cH3X2
).

4.03 (2H, t, J=6Hz, CHtOAc
).

5.23 (IH, S, OH), 5.27 (IH, S, O
H) M8m/e: 396 (M+), 354.33
6.

Reference Example 2 When 6-(11-acetoxyundecyl)-2,3-dimethoxy-5-methylhydroquinone is treated with methanolic ferric chloride and then with methanolic concentrated hydrochloric acid following the steps in Reference Example 1, 6- (11-hydroxyundecyl)
-2,3-dimethoxy-5-methyl-1,4-dibenzoquinone is obtained.

Reference example 3 12-acetoxy-n-dodecylic acid chloride (8,5i
(7) 1,2-dichloroethane solution (30ml')
Add aluminum chloride (8,211) to the mixture and stir at room temperature for 2 hours. This reaction solution was cooled to 5°C, and 3.4
．． A solution of 5-trimethoxytoluene (5,6y) in 1,2-dichloroethane (20 ml) was added, and the mixture was stirred at room temperature for 72 hours. The reaction solution was then heated to 5o-so℃ for 30
Stir for a minute.

Add methanol (200 ml) to the reaction solution and leave for 3 hours 5
Stir at 0°C. The solvent is distilled off and the residue is extracted with dichloromethane. The dichloromethane layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain crude crystals. Recrystallization of the crystals from ether-hexane (1:1) yields colorless needle-like crystals of 6-(12-hydroxy-1-oxododecyl)-2,3-dimethoxy-5-methylphenol (8,59). . Melting point 82℃ Elemental analysis C'l I Calculated value as H5405 C,
68,82;H,9,35 Experimental value 0.69.00;H
, 9,46KBr -1゜IRν cm , 3500 (OH), 3200aX (OH), 1670 (C!O), 1610.1580 (
Ar) NMRδCD'': 1.1-1.9 (18H, m.

pm -(CH)9-], 2.41 (3H9S, C5-CH5
).

2.84 (2H, t, J=7Hz, C2-H2)
, 3.59 (2H,t, J=6Hz, -0H20H
), 3.83 (3H,s, 0CHs), 3.86 (5
H,s,0CHs).

6.26 (IEI, S, 04-H), 9.92 (IH,
S.

cl-oH).

MBm/l: 366 (M+), 348.1856-
(12-hydroxy-1-oxododecyl)-2,3-
5% palladium-carbon (50
% water content) (1,19) and 70% perchloric acid (0,1 m
l) and catalytic reduction at room temperature and pressure. When the absorption of hydrogen has ended, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is extracted with dichloromethane. The dichloromethane layer is washed with a 5% aqueous sodium bicarbonate solution and then dried over anhydrous magnesium sulfate. When the solvent was distilled off, 13-(12-acetoxydodecyl)-2,3 was obtained as a colorless oil.
-dimethoxy-5-methylphenol (6,89) is obtained.

Neat -1.

IRvmax cm, 3450 (OH), 1730
(OAC).

1610, 1580 (Ar) NMR bow trap'S: 1.1-1.8 (20H, m,
-(OH2),.

-), 2.02 (3H,8,0Ac), 2.
23 (3H.

S, 05-CH5), 2.55 (2H, t,
J=7Hz.

C1-Hz), 3.79-(3H,S,0OHa), 1
83 (3H, S, 0CHx), 4.02 (2H, t
, J=8Hz * OH20A c ), 5.78
(I H, s + C+ -OH).

8.23 (IH, s, 04-H) MSm/e: 394 (M ), 352,334° Example 2 6-(12-acetoxydodecyl)-2,3-dimethoxy-5-methylphenol (0, Potassium persulfate (2,
Add an aqueous solution (20 ml) of 5 F/ ) and stir at room temperature under a nitrogen stream for 48 hours. The product is quickly extracted with ether and the ether is distilled off. Acetic anhydride 5 to the residue
Add ml and leave for 2 hours. Excess acetic anhydride is distilled off and the residue is extracted with ether. The ether was washed with water, dried over anhydrous sodium sulfate, and then distilled off to give 6-(12-acetoxydodecyl)2,3-dimethoxy-5-methylhydroquinone-1,4-diaceter (0.61 g) as a colorless oil. is obtained.

Neat -1.

1 liter v Cm, 178 G, 1765
, 1735ax (OAc), 1620.1570 (Ar).

-: ] , 2.02 (3H, 8,0Ac), 2.06
(3H.

8.06-CH5), 2J2(6H,S, 0AcX2
).

2.46 (2H, t, J=7Hz, 0l-Ht),
3.81 (6H, S, 00H3X2), 4.05 (
2H,t, J=6Hz, CH20Ac).

MSm/e: 494 (M), 452,410°279.197° Reference Example 4 6-(12-acetoxydodecyl)-2,3-dimethoxy-5-methylhydroxy-1,4-diacetate in Reference Example 1 When treated with methanolic ferric chloride following the corresponding process, 6-(12-hydroxydodecyl)-
2,3-dimethoxy-5-methyl-1,4-benzoquinone is obtained.

MSm/e: 450 (M), 452 (M +2).

330.332,197,196,195° Reference Example 5 20-acetoxy-n-eicosanoic acid chloride (16F
) was added to a 1,2-dichloroethane solution (60 ml) of aluminum chloride (11y) and stirred at room temperature for 2 hours. Next, this reaction solution was cooled to 5°C, and 3.4.5
A solution of -trimethoxytoluene (7,49) in 1,2-dichloroethane (2 oml) is added and stirred at room temperature for 72 hours.

The reaction solution was then heated to 50°-60°C and stirred for 30 minutes. After cooling, add 200 ml of methanol and stir at room temperature for 4 hours. The solvent is distilled off and the residue is extracted with dichloromethane. The dichloromethane layer is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain crude crystals. Recrystallization from dichloromethane-ether (1:1) gives colorless needles of 6-(20-hydroxy-1-
Oxoeicosyl)-2,3-dimethoxy-5-methylphenol (11,4f/) is obtained. Melting point 105
°C Elemental analysis Calculated value as C29H5006 C,72,76:H,10,53 Experimental value
0,72.95:H,10,68IRshiKBrCm”
:3500(OH), 3450(OH).

aX 1670 (CO), 1610, 1580 (A
r).

NM⇠δCDCl5:1.1-1.9[:34H=m
--(CH2:bpm −], 2.42 (3H, S, C6-0R1), 2.85
(2H,t, J=7Hz, C2-H2), 3.62
(2H.

t, J=6Hz, CH20H)+3.83(3H,S.

0CRs), 3.88 (3H,s, 0CHx),
6.25 (IH, S, 04-H), 10.07 (IEl
,S.O.

-0H).

MSm/e: 478 (M), 460.195
6-(20-hydroxy-1-oxoeicosyl)-2
,3-dimethoxy-5-methylphenol (4,1f)
(7) In acetic acid solution (100 m6) 5% palladium-carbon (50% hydrated) (, 1 (/)) and 70% perchloric acid (
0.05 ml) was added and catalytic reduction was carried out at room temperature and pressure. After hydrogen absorption is completed, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. When water is added to the residue, coarse crystals are precipitated. When the main island is recrystallized from ether, 6-(20
-acetoxy-eicosyl)-2,3-dimethoxy-5
-Methylphenol (4,2y) is obtained. Melting point 59
℃ Elemental analysis cs+ H54o,.

Calculated value 0.73.47:H,10,74 experimental value
C, 73, 46; H, 10, 74 IR wire: To Cm-
': 3450 (OH), 1720 (OAc).

1 61 0, 1 680 (Ar).

NMICD”: 1.1-19 [34H,m,-
(OET2), 7pm i, 2.01 (3H,S,0AC), 2.22 (
3H.

S, 05-OHri 12.55 (2H, t l J=
7Hz.

02-H2), 3.83 (3H,S, 0cH3),
3.86 (3H, S, 0CHx), 4.02 (2
H,t,0H20Ac).

5.77 (IH, S, C1-0H), 6.23 (IH,
S.

C4-H).

MSm/e: 506 (M ), 464,446° 181° When the main island is deacetylated in the same manner as in Reference Example 1, 6-(20
-hydroxyeicosyl)-2,3-dimethoxy-5-
Methylphenol is obtained.

The above 6-(20-hydroxy-1-oxoeicosyl)-2,3-dimethoxy-5-methylphenol (2,
4y) in ethyl acetate (150 ml) with 5% palladium-carbon (50% hydrate) (1,.

y) and 70% permonic acid (o, o 5ml!).
t, catalytic reduction at room temperature and 50 atm. After hydrogen absorption is completed, the catalyst is filtered off and the filtrate is concentrated under reduced pressure to obtain crude crystals. When crystals are recrystallized from ether, colorless needle-like crystals of 6-(20-hydroxyeicosyl)-2,3-
Dimethoxy-5-methylphenol (2,21) is obtained. Melting point 72℃ Elemental analysis value Calculated value as 029H6204 C,74,95:H,11,28 Experimental value
0.75.19:H, 11,30IR, KBrcm
-+: 3450 (OH), 3150 (OH).

ax 1610.1580 (Ar).

NMRδCD”s: 1.1-1.9 Cs sa,
m, -(cut), 8pm -), 2.23 (3H, s, C5-OH5), 2.54
(2H, t, J = 7Hz, 02-H2), 3
．． 61 (2H.

t, J=6Hz, 0H20H), 3.80(3H,
S.

00Hx), 3.83 (3H,s, OOHg), 5.
80 (IH, S, 0l-OH), 6.25 (IH, S,
04-■).

MSm/e: 4G4 (M), 446.181° Example 3 A solution of 6-(20-hydroxyeicosyl)-2,3-simethoxy-5-methylphenol (0,6f) in tetrachodrofuran (80 ml) was added with a filter. Potassium sulfate (2,7(
Add the aqueous solution (20 ml) of 1) and stir at room temperature under a nitrogen stream for 72 hours. The product is quickly extracted with ether and the ether is distilled off. The residue 6-(20-
Add 1 ml of acetic anhydride to (hydroxyeicosyl)-2,3-dimethoxy-5-methylhydroquinone and let stand at room temperature for 3 hours. The product was extracted in a conventional manner and recrystallized from hexane to yield colorless needle-like crystals of 6-(20-acetoxyeicosyl)-2,3-dimethoxy-5-methylhydroquinone-1,4-diacetate (0,31y). is obtained.

Melting point 67℃ Elemental analysis C! Calculated value as H6a O8
0.69.50 :H,9,33 experimental value 0.69
．． 45;H,9,45■RvKBr-t.

maxCm, 1760 (OAC), 1730 (OA
c).

NMRδCDC1': 1.1-1.8 C36H-
m, (CH2)u+pm -), 2.01 (3H, S, 0AC), 2.03 (3H
,S.

0a-C! Ha), 2.03 (6H,s, 0Acx2)
.

2.2-2.6 (2H, m, O+-Ht), 3.79
(6H.

s , OOHg X2 ), 4.02 (2H,t ,
J=8Hz.

CH20AC).

M8m/e: 60G (M), 564,522° 462.197° Reference Example 6 6-(20-acetoxyeicosyl)-2,3-dimethoxy-5-methylhydroquinone-1,4-diacetate Reference Example 1 Following the corresponding step, treatment with methanolic concentrated hydrochloric acid and then with methanolic ferric chloride yields 6-(20-hydroxyeicosyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone. is obtained.

Patent applicant: Takeda Pharmaceutical Company Limited

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. or a lower acyl group).