JPS5924972B2 - Process for producing chalcone ethers - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing novel chalcone ethers having anti-peptic ulcer activity.

More specifically, the general formula
represents the general formula 1t2 (wherein R1 and R2 are the same and represent a lower alkyl group or an allyl group, or together with the adjacent nitrogen atom, they form a piperidimeno group).

n is 2 or 3. ) represents a di-substituted amino (or piperidino) alkoxy group, and the remainder represents a 3-methyl-2-butenyloxy group or a hydrogen atom represented by the formula, at least one of which is 3-methyl The condition is that it represents a -2-butenyloxy group.

Y1 and Y2 represent a hydroxyl group or a hydrogen atom. ] In producing chalcone ethers or salts thereof, a compound generally represented by the general formula ((1) and (in the above formulas, X, , X2, X3, Yl and Y2 are It has the same meaning as ``thing''.

This invention relates to a process for producing chalcone ethers, which is characterized by combining the compounds represented by (1) and (2) or further acid-treating the resulting condensate to produce a salt thereof. In the condensation in the method of the present invention, a mixture of compound (IV) and the compound is dissolved or suspended in an organic solvent such as ethanol, methanol, isopropanol, or a water-containing substance thereof, and this is dissolved or suspended in an organic solvent such as ethanol, methanol, isopropanol, etc. The reaction is carried out at room temperature or under heating in the presence of an alkali such as sodium ethylate or a condensation aid such as hydrogen chloride or sulfuric acid.

These acid addition salts can be prepared by treating the resulting condensate with an acid, for example an organic acid such as maleic acid, fumaric acid, succinic acid, oxalic acid, malonic acid, or an inorganic acid such as sulfuric acid, nitric acid, or hydrogen bromide. can be obtained. In addition, the lower alkyl group in R1 and R2 of the di-substituted aminoalkoxy group represented by formula () means a methyl or ethyl group.

When introducing a group of formula () or () into compound (IV) or (), known methods such as Japanese Patent Publication No. 42
-19590 or the method described in the Examples described later, or the method described in Hemitsu Berichte, Vol. 3511 (1972). That is, the group of formula () is introduced by reacting a disubstituted amino (or piperidino) alkyl chloride with the corresponding hydroxyacetophenone or hydroxybenzaldehyde, and 3-methyl-2-butenyl bromide is reacted with the corresponding hydroxyacetophenone or hydroxybenzaldehyde. A group of formula () can be introduced by reaction with russacetophenone or hydroxybenzaldehyde. The compound obtained by the method of the present invention has antipeptic ulcer activity, and the compound formed into an acid addition salt has strong hydrophilicity. Table 1 shows the pylorus ligation method for rats (intraperitoneal administration, 15
It shows the ulcer suppressing effect using the time method). Furthermore, the compound of Practical Example 4 had an ulcer healing rate of 48.301) using the acetic acid ulcer method (10 rats, 50 rats/Kg, orally for 10 days).

Next, examples will be shown.

Example 1 18.69% of parahydroxybenzaldehyde was made into a sodium salt by a conventional method, and 300ml of anhydrous toluene was added to this.
and 26.19 g of N,N-dimethylaminoethyl chloride were added, and the mixture was refluxed for 3.5 hours, then distilled to give 4-(N,
N-dimethylaminoethoxy)benzaldehyde (VD
22.99 was obtained.

BplO4.5lO6.5 deC (0.2 degrees Hg). 4-
(3-Methyl-2-butenyloxy)acetophenone2.
59 and the above compound VI2.49 in 10 ml of ethanol.
Add 50% caustic potash 209 to 5.5% at room temperature.
Stir for hours.

Add dilute hydrochloric acid to pH 8, extract with methylene chloride,
After distilling off the solvent, recrystallization from isopropyl alcohol yields colorless needle-like crystals of 4-(N,N-dimethylaminoethoxy)4'
-(3-methyl-2-butenyloxy)chalcone 3.59
I got it. Mp8l, 5-82.0 C Example 2 3.59 liters of 4-(N,N-dimethylaminoethoxy)-4'-(3-methyl-2-butenyloxy)chalcone obtained in Practical Example 1 was dissolved in 20wL1 of acetone. To this was added 1.19 ml of maleic acid dissolved in 20 ml of acetone, and after leaving it at room temperature, the precipitate was recrystallized from a hexane-acetone mixture to give colorless needle-like crystals of 4-(N,N-dimethylaminoethoxy).
-4'-(3-methyl-2-butenyloxy)chalcone male inic acid 3.99% was obtained.

Mpl34. O-134ReC Example 3 Dissolve 2.79 of 2-hydroxy-4-(3-methyl-2-butenyloxy)acetophenone and 2.49 of the compound in 10 ml of ethanol, and add 20 ml of 50% caustic potassium solution to this.
9 was added and stirred at room temperature for 6 hours.

Add dilute hydrochloric acid to pH 8, extract with methylene chloride,
Recrystallize with isopropyl alcohol to obtain 2/2 yellow needle crystals.
-Hydroxy-4-(N,N-dimethylaminoethoxy)-4'-(3-methyl-2-butenyloxy)chalcone 3.39 was obtained. Mp82. O-82.5coC example
4 Dissolve 2.09 of 2'-hydroxy-4-(N,N-dimethylaminoethoxy)-4'-(3-methyl-2-butenyloxy)chalcone obtained in Example 3 in 10 ml of acetone, and add 10 ml of acetone to this. Maleic acid dissolved in
．． 69 was added, and the obtained crystals were recrystallized from a hexane-acetone mixture to give yellow needle-like crystals of 2'-hydroxy-4-(
1.99% of N,N-dimethylaminoethoxy)-4/1(3-methyl-2-butenyloxychalcone maleic acid) was obtained.

Mpl3l. O-132IC Example 5 4-(N,N-dimethylaminoethoxy)acetophenone [Bpl27. O-132.5AC (0.6m77t
-1g)] 2.69 and 4-(3-methyl-2-butenyloxy)benzaldehyde 2.4f! 10m of ethanol
1, add 50% caustic potassium solution 209,
Stirred at room temperature for 7.5 hours.

Add dilute hydrochloric acid to pH 8, extract with methylenetalolide,
Recrystallization from isopropanol gave pale yellow needle-like crystals of 4'-(
3.39% of N,N-dimethylaminoethoxy)-4-(3-methyl-2butenyloxy)chalcone was obtained. Mp85
．． 5-86.5 CoCNext, maleic acid was added to this chalcone in the same manner as in Practical Example 2, and recrystallized from an acetone/hexane mixture to give pale yellow needle crystals of 4'-(N,N -dimethylaminoethoxy)-4-(3-methyl-2-butenyloxy)chalcone maleate was obtained.

Mpl87.5-188.5ReC practical example 6 4-(3-methyl-2-butenyloxy)acetophenone 4.49 and 4-(N,N-dimethylaminopropyloxy)benzaldeced [Bpll5-12'C(0 .3m
Lol! Hg)] 4.559 was dissolved in ethanol 18111, 50 (Fb caustic soda solution 369 was added to it,
Stirred at 0°C for 3 hours.

Add dilute hydrochloric acid to pH 8, extract with methylene chloride,
Recrystallize with a mixture of acetone and hexane to obtain pale yellow plate-like crystals 4.
'-(3-methyl-2-butenyloxy)-4-(N,N
-dimethylaminopropyloxy)chalcone 7.69% was obtained. Mp69-71 KiC Next, maleic acid was added to this chalcone in the same manner as in Example 2, and recrystallized from a hexane-acetone mixture to give pale yellow plate-like crystals of 4'-(3-methyl-2
-buteronyloxy)4-4(N,N-dimethylaminoproxy)chalcone maleate was obtained.

Mpll8.5-119.5C Example 7 4-(N,N-dimethylaminopropyloxy)acetophenone [Bpl35-13645C (0.5mmHg
)] 159 and 4-(3-methyl-2-butenyloxy)benzaldehyde 13.19 were dissolved in 56 ml of ethanol, 50% caustic potassium solution 1129 was added thereto, and the mixture was stirred at room temperature for 5 hours.

Add dilute hydrochloric acid to adjust the pH to 8, extract with methylene chloride, and recrystallize with isopropanol to obtain pale yellow needle-like crystals of 4 (3
-Methyl-2-butenyloxy)4'-(N,N-dimethylaluminopropyloxy)chalcone 7.79% was obtained. M
p82.5-83.5coC Next, 7.5g of this chalcone
Maleic acid was added to the 4-(3
-methyl-2-butenyloxy)-4'-(N,N-dimethylaminopropyloxy)chalcone maleate 7.4
I got f1. Mpll4.5-115)C Example 84
-(N,N-dimethylaminopropyloxy)acetophenone 12.09 and 2-(3-methyl-2-butenyloxy)benzaldehyde 10.6g were dissolved in 46Tf11 of ethanol, 50% caustic potassium solution 929 was added thereto, Stir for hours.

Add dilute hydrochloric acid to adjust the pH to 8, extract with methylene chloride, evaporate the solvent, and apply silica gel column chromatography to obtain 2-(3-methyl-2-butenyloxy) as a yellow oil.
-4'-(N,N-dimethylaminopropyloxy)chalcone [Bpl33-136PC (0.1W!W!Hg)
] 8.19 was obtained. Next, maleic acid was added to 8.09 of this chalcone in the same manner as in Example 2, and distilled under reduced pressure to give 7.3 g of 2-(3-methyl-2-butenyloxy)-4.
'-(N,N-dimethylaminopropyloxy)chalcone maleate was obtained. Bpl4O~142C (0.0
9m7! LHg) Fruit Example 9 4-(N,N-dimethylaminoethoxy)acetophenone 4.19 and 4-geranyloxybenzaldehyde 4.
5f! was dissolved in 20 d of ethanol, 50% caustic potassium solution 409 was added thereto, and the mixture was stirred at 50° C. for 1.5 hours.

The pH was adjusted to 8 with dilute sulfuric acid, extracted with methylene chloride, and after distilling off the solvent, it was subjected to silica gel column chromatography to obtain 5.19 of an oily 4-geranyloxy-4'-(N,N-diethylaminoethoxy)chalcone. Ta. Bpl45
．． O ~ 147.0°C (0.09mmHg) Next, this chalcone 5.0f! Maleic acid was added to the mixture in the same manner as in Example 2, and distilled under reduced pressure to obtain 4.29 4-geranyloxy-4'-(N,N-diethylaminoethoxy)chalcone maleate.

Bpl47-150℃ (0.09mmHg) Example 1
04-(N,N-diallylaminoethoxy)acetophenone 4.99 and 2,4-bis(3-methyl-2-butenyloxy)benzaldehyde 5.29 were dissolved in 20 ml of ethanol, and 50% caustic potassium solution 409 was added thereto. ,
Stirred at room temperature for 5 hours.

The pH was adjusted to 8 with dilute hydrochloric acid, extracted with methylene chloride, and after distilling off the solvent, it was subjected to silica gel column chromatography to obtain an oily 2,4-bis(3-methyl-2-butenyloxy)-
4'-(N,N-diallylaminoethoxy)chalcone 6
．． 3f! I got it. Bpl33~135℃ (0.0871
(LmHg) Next, malonic acid was added to this chalcone 6,09 in the same manner as in Example 2 and distilled under reduced pressure to obtain 5.19-2.
,4-bis(3-methyl-2-butenyloxy)-4'(
N,N-diallylaminoethoxy)chalcone malonate was obtained.

Bpl34-136) C (0,06mlHg) Example
11 Dissolve 5.19 of 4-(3-methyl-2-butenyloxy)acetophenone and 5.69 of 4-(N,N-diethylaminoethoxy)benzaldehyde in 20 ml of ethanol, add 50% caustic potassium solution 409, and dissolve at room temperature. Stirred for 5 hours.

Adjust the pH to 8 with dilute hydrochloric acid, extract with methylene chloride,
Recrystallization from isopropanol gives white needle-like crystals of 4-(N,
N-diethylaminoethoxy)-4'-(3-methyl-
2-butenyloxy) chalcone (Mp69.O~7rC)
6.29 was obtained. Maleic acid was added to this chalcone 6.09 by the method of Example 2, and recrystallized with acetone to give a white needle-like crystal of 5.8f! 4-(N,N-diethylaminoethoxy)-4'-(3-methyl-2butenyloxy)chalcone maleate was obtained. MplO7-108C example
12 4-(2-piperidinoethoxy)acetophenone 5.5
9 and 4.59 of 4-(3-methyl-2-butenyloxy)benzaldehyde were dissolved in 20 ml of ethanol, 50% caustic potassium solution 409 was added thereto, and the mixture was stirred at room temperature for 3 hours.

Adjust the pH to 8 with dilute hydrochloric acid, extract with methylene chloride,
The oil was subjected to silica gel column chromatography.
-(3-Methyl-2-butenyloxy)-4'-1(2-piperidinoethoxy)chalcone 7.49 was obtained. Bpl4
O ~ 141C (0.0871t1LHg) Maleic acid dissolved in acetone was added to this chalcone 7.09 and distilled under reduced pressure to obtain 6.19 4-(3-methyl-2-butenyloxy)-4'-(2- Piperidinoethoxy) chalcone maleate was obtained.

Claims (1)

[Claims] 1. General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula,
_1, X_2 and
R_1 and R_2 are the same and represent a lower alkyl group or an allyl group, or represent a piperidino group together with adjacent nitrogen atoms. n is 2 or 3. ) for di-substituted amino (
or piperidino)alkoxy group, and the remainder represents a 3-methyl-2-butenyloxy group or a hydrogen atom represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼ (III), but at least one of these represents represents a 3-methyl-2-buteronoxy group. Y_1 and Y_2 represent a hydroxyl group or a hydrogen atom. ]
In producing chalcone ethers or their salts represented by (IV), there are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (IV) and general formulas ▲ mathematical formulas, chemical formulas, tables, etc. V) ((I
V) and (V), X_1, X_2, X_3, Y
_1 and Y_2 have the same meanings as above. ) or further acid-treating the resulting condensate to produce a salt thereof.