JPH03193743A - Production of tropone derivative - Google Patents

Abstract

PURPOSE:To simply obtain the title compound in good yield by adding dichlorocarbene to 1-alkoxy-4-isopropyl-1,4-cyclohexadiene, oxidizing the reaction product and subjecting the oxidation product to the ring enlarging reaction. CONSTITUTION:Dichlorocarbene produced from chloroform-50% sodium hydroxide using a phase-transfer catalyst is added to a compound expressed by formula I (R is 1-3C alkyl) to give 1-alkoxy-4-isopropyl-7,7-dichlorobicyclo[4,1,0]hept-3-ene expressed by formula II, which is then oxidized using a oxidizing agent (preferably peracetic acid) and the resultant epoxidized compound expressed by formula III is subjected to ring-enlarging reaction using an acid catalyst to provide 2-chloro-5-isopropyltropone expressed by formula IV. The compound expressed by formula IV is useful as a synthetic intermediate of beta-thujapricin having cell activating action, antibacterial or antifungal action, gamma-thujapricin which is analog thereof and azulene derivative.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention is directed to β-β, which has excellent cell activation, antibacterial, and antifungal effects, and is used in hair growth agents, toothpaste, basic cosmetics, etc.
-Synthesis of thujapridine (4-isopropyl-2-hydroxycyclohebuta-2゜4.6-)dien-1-one or hinokitiol) and its homologue T-thujapridine (5-isopropyl-2-hydroxycyclohetyl) 2-, which is an important synthetic intermediate for the synthesis of hebuta-2,4,6-)dien-1-one) and for the synthesis of azulene derivatives.
The present invention relates to a method for producing chloro-5-isopropyltrobone.

[Conventional technology]

2-Hydroxycyclohebuta-2,4,6-drien-1-one (tropolone) derivative haheratrol is reacted with diazoacetate to form dimethoxycyclohebutatrienecarboxylic acid ester, which is oxidatively hydrolyzed with bromine. (Journal of Chemical Society I-J, Chem, Soc, 2351. (I951)
), and cyclopentadiene is reacted with dichloroketene obtained from dichloroacetic acid to form an adduct, which is then treated with sodium acetate in rice acetic acid to obtain tropolone (tetrahedron).
27, 4889. (I971), Special Publication 51-
33901). To synthesize cyclohebuta-2,4,6-drien-1-one (tropone), 4-isopropylanisole was subjected to Birch reduction with metallic sodium in liquid ammonia-ethanol, and 4-isopropyl-1-methoxycyclohexa-1, 4-diene is obtained, potassium t-butoxide is added to a pentane solution of this diene under a nitrogen stream, and a dichlorocarbene produced by adding a chloroform pentane solution is reacted to obtain an adduct.

Silver oxide was dissolved in fluoroboric acid, and an ethanol solution of the adduct was added thereto to obtain 4-isopropylcyclohepta-2.

4.6-) Dien-1-one (4-isopropyltrobone) has been obtained (J, Chem, Sac.

[', 1968.109)).

By the way, selective methods of synthesizing 2-chloro-5-isopropyltrobone include a method of synthesizing it by chlorination of T-thujapridine, and a method of synthesizing it by chlorination of T-thujapridine, and a method of synthesizing 2-chloro-5-isopropyltrobone by adding sodium trichloroacetate to a diene obtained by Birch reduction of triethylsilyl 4-isopropylphenyl ether. The resulting dichlorocarbene is added, followed by elimination of the triethylsilyl group, m-
A synthesis method is known that involves epoxidation with chlorperbenzoic acid and further ring expansion reaction with p-toluenesulfonic acid (Journal of Organic Chemistry J).

Org, CheIn, 43.3621 (I97
g) ).

[Problem to be solved by the invention]

As shown in the prior art above, 2-chloro-5-isopropyltrobone is synthesized from r-thujapridine,
Since it is difficult to synthesize T-thujapridine, it is of no commercial value, and tropone is synthesized from 4-isopropylanisole and cannot be converted into tropolone. Furthermore, the silyl group of trimethylsilyl ether of 4-isopropylphenol is eliminated during Birch reduction, and no Birch reduction product can be obtained. For this purpose, in the prior art, the trimethylsilyl group is replaced with a triethylsilyl group to obtain a Birch reduction product, dichlorocarbene is added thereto, and then epoxidation is performed to perform a ring expansion reaction to synthesize 4-isopropyl-2-chlorotropone. However, triethylsilyl chloride is very expensive and is not suitable for industrialization.

Also, when adding dichlorocarbene, sodium trichloroacetate/dimethoxyethane-tetrachloroethane is used, but sodium trichloroacetate and dimethoxyethane are expensive, and m-
Chloroperbenzoic acid is expensive and is not suitable for handling in large quantities.

Therefore, the object of the present invention is to solve the above-mentioned problems of the prior art,
The object of the present invention is to provide a manufacturing method for obtaining 2-chloro-5-isopropyltrobone in high yield using inexpensive raw materials.

[Means to solve the problem]

In order to solve the above problem, the present inventors have developed the following
As a result of intensive investigation of various reaction conditions that satisfy the conditions of
Using 4-isopropylanisole, which is an easy-to-handle and inexpensive raw material, as a starting material, 2-chloro-
A method for producing 5-isopropyltrobone was discovered and the present invention was completed.

■ Use cheap alkyl 4-isopropylphenyl ether instead of expensive triethylsilyl 4-isopropylphenyl ether ■ Use low-cost lowerform-50% sodium hydroxide-phase transfer catalyst system to generate dichlorocarbene ■ Epoxidizing agent The present invention converts cyclopropyl alkyl ether into a ketone using an oxidizing agent that is easy to handle and relatively inexpensive (peracetic acid, hydrogen peroxide water-oxidation catalyst system, etc.). , R represents a lower alkyl group having 1 to 3 carbon atoms.) 1-alkoxy-4-isopropyl-1,4 represented by
- 1-alkoxy represented by the formula (IV) "1 (wherein, R has the same meaning as above)" characterized by adding dichlorocarbene to cyclohexadiene to give the general formula (II) -4-isopropyl-7,7
-dichlorobicyclo[4,1,0]hept-3-ene, and then oxidize the compound of general formula (n) to obtain general formula (I
II) 1-alkoxy-4-isopropyl-3,4 represented by 1 (wherein R represents the same crane as above)
-Epoxy-7,7-dichlorobicyclo(4,1,0)
This is a method for producing 2-chloro-5-isopropyltrobone represented by the following formula: hebutane is obtained, and then a compound of general formula (III) is subjected to a ring expansion reaction using an acid catalyst.

The present invention will be explained in detail below.

1-Alkoxy-4-isopropyl-1 used in the present invention
, 4-cyclohexadiene (I), 1-alkoxy-4-isopropylbenzene, which is the raw material for 4-cyclohexadiene (I), can be easily produced from 4-isopropylphenol by a general etherification method. The alkyl group must not be eliminated by Birch reduction, and methyl, ethyl, n-propyl, and isopropyl groups, which are lower alkyl groups having 1 to 3 carbon atoms, are selected.

Birch reduction is a general method (Course published by Tokyo Kagaku Dojinsha)
Organic Reaction Mechanism 10, pages 271-280), the alkali metal is sodium or lithium, and the alcohol solvent is t-butanol, isopropanol,
Ethanol and methanol are used.

A phase transfer catalyst (benzyldimethyl-2hydroxyethylammonium chloride, triethylbenzylammonium chloride,
benzyltrimethylammonium hydroxide, heptyltrimethylammonium bromide, etc.) to add dichlorocarbene generated from chloroform-50% sodium hydroxide (tetrahedron letters T).
etrahedron letters Na 34,
3016. (Refer to I975) ■-Alkoxy 4
-isopropyl-7,7-dichlorobicyclo(4,1,
01hept-3-ene (II) is obtained. In this case, the reaction is carried out at room temperature to 60°C.

As a source of dichlorocarbene, chloroform-5
In addition to the 0% sodium hydroxide-phase transfer catalyst system, chloroform-potassium t-butoxide-pentane solvent system (reaction temperature -30°C to room temperature), sodium trichloroacetate-tetrachloroethylene/dimethoxyethane solvent system (reaction temperature 70°C) ~120℃) Ethyl trichloroacetate
Sodium ethoxide-pentane solvent system (reaction temperature -1
0° C. to room temperature), etc. can be used.

The oxidizing agent for epoxidizing 1-alkoxy-4-isopropyl-7,7-dichlorobicyclo[:4.1.0]hept-3-ene (II) is preferably peracetic acid, but oxidizing agents capable of epoxidizing, For example, m-chloroperbenzoic acid-dichloromethane solvent system, hydrogen peroxide solution-sodium tungstate-ethanol solvent system (JP-A-59-108793, Journal Organic Chemistry)
- J, Org, Chem,, 5
3. 1553. (I988)) etc. can be used.

Then, the obtained epoxide compound (I) in the presence of an acid catalyst,
It is subjected to a ring expansion reaction to give 2-chloro-5-isobrobyltropone (TV). In this case, the acid catalyst used is preferably trifluoromethanesulfonic acid, but I)
-) Luenesulfonic acid, methanesulfonic acid, β-naphthalenesulfonic acid, etc. are used, and the acid catalyst is used in an amount of 0.2 to 100 mol%, preferably 0.5 to 5 mol%, based on the epoxidized product. The solvent used is benzene, toluene, chloroform, etc., and the reaction can be carried out at room temperature to 90°C.

Various compounds are synthesized from 2-chloro-5-isopropyltrobone (IV) obtained by the method of the present invention by the following synthetic routes. For example, γ-thujapridine (V) is obtained by refluxing with 44% phosphoric acid in glacial acetic acid (Journal of Organic Chemistry J, Org.
Chem.

43, 3621. (I978)), ammonia is reacted at 0°C to give aminotrobone, which is refluxed in the presence of water-containing methanol neutral solution to obtain β-thujapridine (VI) (Block Japan Academy (Pro
c, Japan, ^cad,) 30.473.

(see I954)).

Azulene derivatives (■) are obtained by reacting chlortrobone (IV) with an active methylene group such as malononitrile, cyanoacetamide, ethyl cyanoacetate, diethyl malonate, etc. at low temperature in the presence of a base such as sodium alcoholade or t-butylamine. 2H-cyclohebuta[b]furan-
2-one (■) is derived as follows (Tetrahedron, 27.3359
.

(see I971)).

(IV) (V) (■) (■) [Example] The present invention will be described in detail below with reference to Examples showing specific synthesis examples.

(a) Synthesis of the compound of formula I Under a nitrogen atmosphere, 300 - of liquid ammonia and 11' of absolute ethanol 11'OWd! Add 20.00 g of 4-isopropylanisole to the mixed solution and stir at -65°C. In addition, sodium 19. 30 pieces of OOg cut into small pieces
Add in portions. After adding sodium, -6
Stir at 5°C for 5.5 hours. Add 50% water to the reaction solution at -65°C.
mj! After adding, the reaction solution is returned to room temperature and ammonia is removed. Add 50% of saturated brine to the residue, and extract with hexane (I001nl×3 times). The extract was washed with saturated brine (I00mt'X twice), dried over anhydrous sodium sulfate, filtered, concentrated, and distilled under reduced pressure to give a solution of 16.8
7 g (b, p, 92-94°C: yield 83%) of 1-
Methoxy-4-isopropyl-1,4-cyclohexadiene is obtained (References: J, Chem, Soc, (
C), 109 (I978).

NMR (CDCIs/Me4St) 1.02 (
d, J=6.6)+2.

6H); 2,20 (m, J=6.6Hz
, 01); 2.7G (m.

4H); 3.4B (s, 3H);
4.57 (m, 1i(); 5JO(m,
IH) ; m/e 152 (M”) 137
, 109 (base peak), 91
.

(b) Compound of formula (I)→Compound I of formula (n)-Methoxy4-isopropyl-1,4-cyclohexadiene 1
7.02 g and phase transfer catalyst (benzyldimethyl-2-
Add 1.00 g of hydroxyethylammonium chloride to 140 g of IJium aqueous solution and add 16.73 g of chloroform to this with vigorous stirring.
is added dropwise over 1.5 hours. The reaction solution was stirred at room temperature overnight, poured into 250-g water, and toluene (200 mf
Extract twice). After thoroughly washing the toluene extract with water, it was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 32.5 g of crude 1-methoxy-4-isopropyl-7,7-dichlorobicycloC4,1,01 hepto. -3
- Get En.

NMR (CD['ls/Me-Si) 0.98
(d, J=6.9Hz.

6H); 1.8B (d, J=7.8Hz, IH
); 2.22 (m.

2H); 2.46 (m, IH); 2.66
(m, 2N); 3.48 (s, 3H)
;5,26 (m, l1l); m/e234
(M”) 199 (base peak)
, 125, 7? .

(8) Dead metal of formula (II) - compound of formula (III) (0
) Crude 1-methoxy 4-isopropyl-7,7-
Dichlorobicyclo[4,1,03hept-3-ene was dissolved in 200% of dichloromethane, 49.1% of 30% peracetic acid containing 2.3 g of sodium acetate was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with dichloromethane. The extract was washed with an aqueous solution of hydrogen carbonate, an aqueous sodium sulfite solution, and water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude 1-methoxy-4-isopropyl-3,4-epoxy-7. , 7-cyclolpicic, [4,1,0]butane 34.3 g
get. This was carried out using silica gel column chromatography (
Wakogel C-300, 1000g, purified with developing solvent: hexane:ether = 4:1), 23.75
g of 1-methoxy-4-isopropyl-3,4-epoxy-7,7-dichlorobicycloC4,1,0)hebutane is obtained.

m, p, 68-69°C NMR (Cf, /Me, Si) 0.91
(d, J=6.9Hz.

3H); 0,99 (d, J=6,911z, 3
H); 1.52 (m.

J=6.9Hz, 1)1); 1.65 (dd
, J=9.6Hz, J=1.6Hz, IH
): 1.88 (dd, J=16.1Hz,
J=1.6Hz, IH); 2.28 (dd,
J=16.1Hz, J=9.6Hz.

IH); 2.44 (dd, J=16.5Hz
, J=2.6Hz, IH): 2.53 (dd
, J=16.5Hz, J=1.9Hz, LH
); 2.92 (m, IH); 3J? (s, 3
H); m/e 250 (M”) 215, 43
(base peak).

The yield from 1-methoxy-4-isopropyl-1,4-cyclohexadiene was 84.8% in two steps.

(d) Compound of formula (III) → 1-methoxy-4-isopropyl-3,4 obtained from compound (c) of formula (TV)
-Epoxy-7,7-dichlorobicyclo[4,1,03
Dissolve 25.10 g of hebutane in 800 ml of toluene, and slowly add 0.15 g of trifluoromethanesulfonic acid while stirring at 60°C. 6 of the reaction solution
After stirring at 0°C for 4 hours, the mixture was cooled to room temperature. The reaction solution was sequentially washed with water, an aqueous solution of hydrogen carbonate, and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude 2-chloro-5-isopropyltropone 21
．． Obtain 80 g. This was purified by silica gel column chromatography (Fuco-gel C-300, fucogel:ether = 1:1) to obtain an oily 2-
Chlor-5-isopropyltrobone (compound (5))
12.60 g is obtained.

NMR (CDCIs/Me,Si) 1.24
(d, J=6.9Hz.

6tl); 2,82 (m, J=6.9Hz, I
H); 6.79 (, d.

J=9.9Hz, IH); T,16 (d
, J=12.6Hz, IH); 7.23
(d, J=12.6Hz, IH); 7
．． 73 (d.

J=9.9Hz, IH); m/e 1B2
(M”) 139 (basepeak) 103
; I R (neat) 1635, 1595
, 950 cm-'.

The IR, NMR, and Mass spectra of this product matched those of the standard product.

1-Methoxy-4-isopropyl-3,4-epoxy-
7,7-Dichlorobicyclo [4.1.

0] Hebutane (compound (4)) yield was 69%. Also 1-methoxy-4-isopropyl-1.4-
The yield from cyclohexadiene was 58.5% in three steps.

The raw material 4-isopropylanisole is derived from 4-isopropylphenol from the literature (Bull).

Soc, Chim. , 37, 1379 (I
925) ) was synthesized by the method described.

After the compounds obtained in each experiment were isolated and purified, IRSNMR and Mass spectra were measured to confirm their structures.

〔Effect of the invention〕

According to the production method of the present invention, trobone derivatives can be obtained in higher yields than before, and β-1 or T-thujapridine, which could only be synthesized in the past, can be synthesized from this intermediate. This makes it extremely valuable industrially.

Claims (1)

[Claims] 1. General formula (I) ▲There are numerical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R represents a lower alkyl group having 1 to 3 carbon atoms.) 1 -alkoxy-4-isopropyl-1,4
- Dichlorocarbene is added to cyclohexadiene to produce 1-alkoxy represented by the general formula (II) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R has the same meaning as above.) -4-isopropyl-7,7
-dichlorobicyclo[4.1.0]hept-3-ene, and then oxidize the compound of general formula (II) to obtain general formula (III)
) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, R has the same meaning as above.) 1-Alkoxy-4-isopropyl-3,4 represented by
-Epoxy-7,7-dichlorobicyclo [4.1.0]
Formula (IV) is characterized by obtaining heptane, and then subjecting the compound of general formula (III) to a ring expansion reaction using an acid catalyst. A method for producing 2-chloro-5-isopropyltropone.