JPS58134057A - Production of p-cymene derivative - Google Patents

Abstract

PURPOSE:3-[2-(Dialkylamino)ethoxy]-p-cymene is converted into a salt of the side -chain amino group with a strong acid, then the salt is made to react with bromine in the presence of THF to give 2-bromo derivative used as an intermediate of a drug for cardiovascular system in high purity and yield. CONSTITUTION:A compound of formulaI(R is lower alkyl) is dissolved in a solvent that is unreactive with bromine, insoluble in water, but dissolving the salt formed in the course of the reaction such as chloroform or dichloromethane and hydrogen chloride or sulfuric acid is added to form a salt in the solvent, then THF is added thereto in an amount of 2-4 times moles of the compound of formulaI. Then, bromine is made to act on at -5-10 deg.C, the reaction mixture is neutralized with an alkali, solvent is distilled off to give high-purity 2-bromo- 5-[2-(dialkylamino)ethoxy]-p-cymene of formula II almost quantitatively. The product is used in the synthesis of tymoxamine hydrochloride of formula III.

Description

[Detailed description of the invention] The present invention is represented by the following general formula (II) CH /\ H, CCH.

(wherein R represents a lower alkyl group) 2-bromo-5-(2-(dialkylamino)ethoxycup)
- Concerning the production method of cymene.

The present invention provides a method for brominating 3-[2-(dialkylamino)ethoxy]-p-cymene represented by the following general formula (1) (where RH is the same as above), in which the amino group of the side chain is brominated with a strong acid, Convert to salt with
The present invention relates to a method for producing 2-bromo-5-(2-(dialkylamino)ethoxy)-p-cymene (1), which is characterized by reacting bromine in the presence of tetrahydrofuran.

The compound represented by the general formula (1) has a sympathoinhibitory effect K, Cr@dn@r, R, Gra@bne
r+ Arxn@im, -Forieh, , 17
, 305 (1967)), and the British Pharmacopoeia (British Pharmacopoeia) as a drug for the cardiovascular system.
It is a compound useful as an intermediate for synthesizing timoxa mine hydrochloride represented by the following formula (1), in which po@1m (1981) + P 455 ) K is also listed.

Generally, in order to bromine active aromatic nuclei, in addition to water, acetic acid, etc., chloroform, chlorinated hydrocarbons such as carbon tetrachloride, and inert aromatic hydrocarbons such as kunzene are used as solvents. are selected and used depending on the properties of the reactants, reaction conditions, etc. However, with these methods, when there are multiple active positions on the aromatic ring, it is difficult to selectively bromine only a specific 0 position. For example 3-
When [2-(dimethylamino)ethoxy]-P-cymene (formula (1), R = dimethyl is reacted with the same age bromine in an acetic acid solution, thin layer chromatography (conditions: Merck 6
0 F2,4 silica: developing medium, cyclohexane: toluene: diethylamine = 7.5: 1
: 1.5) with R, = 0.57 (Formula (II), R, = 0.4 in addition to R = dimethyl)
A product is obtained having several types of syfloms, including 2 syfuromes.

,,1.The present inventors aimed to simplify the reaction operation and improve the yield of the target product.As a result of various studies, after converting (1) into a salt with a strong acid, in the coexistence of tetrahydrofuran. By acting bromine on this layer, they succeeded in efficiently obtaining the desired 2-bromine compound (II) and completed the present invention. That is, a solvent that does not react with bromine, is insoluble in water, and dissolves the salt formed intermediately, such as chloroform; 1.
3-(2-
(dialkylamino)ethoxy)-P-cymene (1) is dissolved and then a strong acid such as hydrogen chloride or concentrated sulfuric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, etc. ~2 equivalents are added to form a wall in solution, or a strong acid salt of the compound of formula (1) is prepared in advance.
For example, hydrochloride and sulfate are prepared and dissolved in the above solvent. Next, 1 to 5 times the molar amount of tetrahydrofuran is added to this solution. The amount of tetrahydro7ran to be added is determined in order to form a complex with bromine, to capture hydrogen bromide generated as bromination progresses in the reaction system, and to improve the efficiency of cleaning operations after the reaction. Then, the above formula (1)
The molar amount is preferably 2 to 4 times that of the compound. In the solution thus prepared, at a temperature of -5 to 10°C, bromine, either alone or dissolved in the same solvent used to dissolve the compound of formula (1), is added. When added dropwise, bromination will be completed in a short time. If an oxidizing substance remains in the reaction solution, excess bromine is removed using a reducing agent such as sulfite. Then, after neutralizing the reaction solution with an alkali, the solvent is distilled off, and a highly pure motuprom compound of formula (TJ), which exhibits a slightly poetic color, is obtained almost quantitatively. The motuprome compound obtained here is pure enough to be used as is in the next reaction, but if necessary, it can be distilled under reduced pressure to obtain a pure $fb liquid.

The above 3-(2-(dialkylamino)ethoxy]-p-
Since cymene (1) has 7 tertiary amine groups in its side chain, when it is brominated in the form of a free amine, the amine group also participates in the reaction and a reddish-brown resinous substance is produced as a by-product. For example, 3-[2-
(Tmethylamino)ethoxy)-p-cymene (formula (1)
When R=dimethyl is brominated in the coexistence of tetrahydrofuran, the desired motuprome compound is obtained in a yield of about 65%, and other than i6, unreacted raw materials and a reddish brown resinous substance are produced. Therefore, the present bromination reaction ′? : When reacting, it is an essential condition to protect the amino group of the side chain of the reactant by using it as a platform with a strong acid.

Dioxane can also be used in place of tetrahydrofuran in this reaction. Bromine forms an insoluble adduct in dioxane, whereas in tetrahydrofuran the adduct formed is soluble in the solvent. Therefore, in this reaction, the same result can be obtained even if the required tetrahydrofuran is added to the bromine to be added dropwise without coexisting with the reactants in advance.

According to the method of the present invention, the selective bromination reaction of active aromatic compounds having an amino group as a substituent can be carried out safely and easily, and the desired 2-bromo-5-( 2-(Dialkylamino)ethoxy]-p-cymene (■) can be obtained in high yield.The present invention is a particularly excellent industrial production method.

1 Examples of the present invention are shown below.

Example 1 Reaction volume tsK unpurified commercially available tetrahydrofuran 43,2
9 (0.6 mol) and 3.0 g of sodium sulfite and stirred, 285 d of 1,2-dichloroethane
and 3-(2-(dialkylamino)ethoxy)-p
-cymene (formula (1), R=methyl) 48, 9111 (
0,221 mol) and then to the above mixture the ring group f
After adding s38.7d (0.45 mol), it was cooled to θ~5° in a cryogen bath. This solution ((-bromine 37.・1
0 g (0,232 mol) of 1,2-dichloroethane 70
The solution dissolved in m/m was added dropwise while maintaining the reaction temperature at 0 to 5°. Then sodium sulfite 5.69 (0
, 022 mol) dissolved in 20 ml of water was added dropwise,
Subsequently, 20% NaOH aqueous solution was added to neutralize. l,
The 2-dichloroethane was separated, dried over sodium sulfate, and the solvent was distilled off to obtain a pale brown oil. This was dissolved in hexane, thoroughly washed with water, dried, and then the hexane was distilled off to obtain a pale yellow oil (64.59).

Subtract this by F[:′j,・.

Distilled, boiling point 110℃: , / 0.3 mHg (D
2-7" C1mu-5-(2-(dimethylamine)ethoxy]-p-cymene (formula (II), R=methyl) was mixed with a colorless liquid at 1° sz, 9.9 (yield 94. This was dissolved in 1,2-dichloroethane and hydrogen chloride was passed through it.

The obtained crystals were recrystallized using 1,2-dichloroethane to obtain colorless needle-shaped hydrochloride salts with a melting point of 183-184°C.

Elemental analysis value, C,, C9A as H2sBrCtNO
Hg N% Calculated value 49.94 6.89 4.16 Actual value
49.74 6.88 4.06 Example 2 3-(2-(dimethylamino)ethoxy]-p-cymene hydrochloride (colorless needles, melting point 157-158°C) 25.
78 fi (0.1 mol) as po o * /l/
A130 scrap 1 and tetrahuman a7 y14.4p (
A solution of 16.7817 (0.105 mol) of bromine dissolved in 30 ynl of chloroform was added dropwise to this while maintaining the reaction temperature at 0 to 5°C. Thereafter, the procedure was exactly the same as in Example 1, and 28. 2.9 (yield 93.9%).

Example 3 After mixing and stirring 12 g (0,166 mol) of tetrahydrofuran and 0.5 fi (0,002 mol) of sodium sulfite, 70 n of 1,2-dichloroethane
l and 3-C2-(-)ethylamino)ethoxy)-
p-cymene (formula (I), R=ethyl) 13B29(0
,055 mol) and then 9.5 ml of concentrated hydrochloric acid (0
, 11 mol) and the reaction solution was cooled to 0-5°C.

While stirring 1 into this solution, add 9.9 (0,056
A solution prepared by dissolving mol) in 187+t of 1,2-dichloroethane was added dropwise. Thereafter, the procedure of Example 1 was followed to obtain a colorless oily 2-bromo-5-[2-(diethylamino) with a boiling point of 130-130.5°104
ethoxy]-p-somene (formula (n), R=ethyl)
6.92,! 7 (93.0 gk). ζt
When dissolved in benzene and treated with hydrogen chloride, colorless crystals were obtained. This was recrystallized using a method of crystallization, with a melting point of 13
A hydrochloride of colorless grism crystals of 5-136 υ was obtained.

Elemental analysis value, C91H as C, 6H2, BrCtNO
%NqA

Claims (1)

[Claims] Represented by general formula (1) (in the above formula, R represents a lower alkyl group) 3
A method for brominating −(2-(dialkylamino)ethoxycou p-cymene, characterized in that the amino group of the side chain is converted into a salt with a strong acid and bromine is reacted in the presence of tetrahydrone). 2-bromo-5-(2-(
Method for producing dialkylamino)ethoxy]-p-cymene.