JPH0499759A - (e)-2-alken-4-ynyl sulfonate derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:An (E)-alken-4-ynyl sulfonate derivative shown by formula I (R is lower alkyl, phenyl or p-tolyl; R<1> is H, lower alkyl, lower alkoxy or phenyl ; R<2> and R<3> may be the same or different H, lower alkyl or both R<2> and R<3> are bonded to form lower alkylene). EXAMPLE:(E)-6,6-Dimethyl-2-hepten-4-ynl methanesulfonate. USE:Useful as an intermediate for producing drugs such as an agent for alleviating hyperlipemia, antifungal agent, etc. PREPARATION:An alcohol shown by formula II is reacted with a compound shown by formula III in the presence of a base by using preferably equimolar amount, or a little excessive amount based on the compound shown by formula II of a compound shown by formula III in a solvent such as butyl acetate to give a compound shown by formula TV. Then this compound is subjected to intramolecular rearrangement to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel sulfonate derivative, more particularly to the field of medicine, particularly for the production of pharmaceuticals such as antihyperlipidemic agents or antifungal agents. (E)-2 useful as an intermediate in
-Alken-4-ynylsulfonate derivatives and methods for producing the same.

The present invention is directed to a novel (E)-2-alken-4-ynylsulfonate represented by Ichibui CI below, which is useful as an intermediate in the production of various pharmaceuticals. The present invention provides derivatives and methods for producing the same.

In the U formula, R is a lower alkyl group, a phenyl group, or p-1-
R1 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a phenyl group, and R2 and R
3 are the same or different and represent a hydrogen atom or a lower alkyl group, or both together represent a lower alkylene group] The compound of the above-Wuwei [I] provided by the present invention is:
In recent years, its value has been recognized as an intermediate raw material for the production of antihyperlipidemic agents or antifungal agents. [Science
ence), Vol. 224, p. 1239 (1984),
See Japanese Patent Application No. 63-296840]. In the prior art related to the compound of formula [11], 2-penten-4-ynyl methanesulfonate and 2-alken-4-ynyl bromide derivatives are known as its structural analogs [Journal of Chemical Society Perkin Transactions (J, Chem, Sac,
, Perkin Trans, ).

1981, 553 pages; Angewante Chemie International Edition in English (
Angew, Chem, Int, Ed, Eng
l, ) Vol. 26, p. 320 (1987) Japanese Patent Application Publication No. 1987
-Refer to Publication No. 142991]. This reference compound has an asymmetric double bond, so it is either E (trans) monolithic or Z(
Although these geometric isomers exist as a single entity or as a mixture, it has been extremely difficult to separate these geometric isomers and obtain a single isomer. That is, the (E)-
2-penten-4-ynyl methanesulfonate is (E
)-2-penten-4-ynyl alcohol, but the manual preparation of this raw alcohol requires complicated and uneconomical operations using liquid ammonia as a solvent [Journal of Chemical・Society (J
, Chem, Soc, 1947, p. 1583]. In addition, all other known 2-alken-4-ynyl bromide derivatives are treated as a mixture of E and Z, and their separation requires non-industrial special separation means such as preparative gas chromatography. be.

An object of the present invention is to provide an inexpensive and simple industrial method for producing (E)-2-alkene-4-ynylsulfonate x conductors by improving the conventional production methods for these related compounds.

-2' The present inventors have developed an alcohol derivative represented by the general formula % [1] [wherein R', R2 and R3 have the above-mentioned meaning], which is an easily available raw material. as the raw material, the objective (E)2
- As a result of examining various methods for producing the alkene-4-ynyl sulfonate derivative [I], it was found that - an alcohol derivative of - Wuyi [II] was added to the alcohol derivative of - Wuyi [II] in the presence of a base, - Wuyi % formula % [] [wherein R have the meanings given above] to obtain a compound represented by -Wuwei [wherein R, R', R' and R3 have the meanings given above], which is then reacted with By intramolecular transfer, (E)-2- represented by -Wuwei [I]
It has been found that alkene-4-ynylsulfonate derivatives can be obtained extremely easily and in high yields.

Furthermore, the inventors have found that the (E)-2-alken-4-ynylsulfonate derivative [I] obtained by the above production method has sufficient purity and reactivity as a synthetic intermediate for producing various pharmaceuticals. The inventors have completed the present invention by discovering that the present invention can be used as a raw material intermediate that is significantly superior to conventional intermediates and their production methods used for similar purposes.

Alcohol form of the starting compound used in this reaction [11
], for example, according to the following manufacturing method described in the literature [Journal of Medicinal Chemistry (J, MedCheIl.
l, ), Vol. 27, p. 1539 (1984);
JP-A No. 58-208252].

jul+ [In the formula, R1, R2 and R3 have the above-mentioned meanings] Next, definitions of various terms mentioned in the description of this specification and specific examples thereof will be explained.

The term "lower" is used to mean that the group or compound to which this term is attached has no more than 6 carbon atoms, preferably no more than 4 carbon atoms.

Therefore, as a lower alkyl group, for example, a linear or branched group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a 5ec-butyl group, a tert-butyl group, etc. Examples of lower alkoxy groups include those having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, 5ec-butoxy, or tert-butoxy. Straight-chain or branched alkoxy groups may be mentioned.

Bases include tertiary organic amines such as trimethylamine, triethylamine, pyridine, N,N-dimethylaniline, and 4-dimethylaminopyridine, or potassium hydroxide;
It refers to inorganic bases such as sodium hydroxide, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium carbonate, and sodium carbonate.

The step of reacting the above alcohol derivative [11] with the compound of -Muwei [I[1] in the presence of a base to obtain the compound represented by -Muwei [IV] is usually carried out in a solvent that does not participate in the reaction. This is carried out using the organic amines or inorganic bases exemplified above. The ratio of each raw material compound used in the reaction is usually 1% to 1% alcohol derivative [11] to 1% alcohol derivative [11].
I[] is an equimolar amount or a slight excess molar amount, and the base is an equimolar amount to an excess molar amount, preferably 1 to 3 times the molar amount. Solvents used at this time include, for example, halogenated hydrocarbons such as chloroform and methylene chloride, aromatic hydrocarbons such as benzene and toluene, ethers such as ethyl ether and tetrahydrofuran, and organic acids such as ethyl acetate and butyl acetate. Esters are preferred. The reaction temperature and reaction time are -8
The temperature is arbitrary within the range of 0°C to 1006C, 1 minute to 3 days, but preferably 1206C to 50°C, 10 minutes to 10 hours.

Next, the step of intramolecularly rearranging the compound of the general formula [IV] obtained above to obtain the (E)-2 alkene-4-ynyl sulfonate derivative represented by the general formula [1] is usually carried out. ,
This can be easily achieved by simply leaving the reaction at room temperature or under heating in a solvent that does not participate in the reaction. Moreover, from this, it is also possible to carry out the rearrangement reaction successively in the same reaction system as the above step of converting the alcohol derivative [11] to the compound [rV]. As for the solvent used in the reaction, when the reaction is carried out in the same reaction system as in the above step, the solvent used in the previous reaction system is usually used as is, but once compound [IV] is isolated, In the case of subsequent transfer, chloroform, halogenated hydrocarbons such as methylene chloride, dimethylformamide or dimethylsulfoxide, or mixtures thereof with other organic solvents are generally preferred.

The target compound [I] of the present invention obtained by the above reaction is:
It contains almost no unnecessary geometric isomer (Z), and therefore can be easily isolated and purified by conventional treatments such as extraction, separation, concentration, distillation, and column chromatography.

Furthermore, the thus obtained compound of the present invention [11] is very useful as a synthetic intermediate in the production of pharmaceuticals such as antihyperlipidemic agents and antifungal agents. That is, the compound [I] of the present invention can be used as it is, or by reacting with hydrobromic acid, sodium bromide, potassium bromide, sodium iodide, potassium iodide, triethylamine hydrobromide, etc. in an inert solvent. After substituting the sulfonate residue with another halogen residue, if a normal alkylation reaction is performed on various amines, trans en-yne (trans en-yne) is formed.
) can be easily produced. The amines obtained by such reactions include the antifungal agents and antihyperlipidemic agents disclosed in the above references.

EXAMPLES Hereinafter, the compound of the present invention and the method for producing the same will be explained in detail with reference to Examples.

Example 1 After stirring for a while, the precipitated triethylamine hydrochloride was filtered off. After concentrating the filtrate under reduced pressure, the obtained crude 4,4 dimethyl-
1-(2-propenyl)-2-pentynyl methanesulfonate is dissolved in 30 ml of methylene chloride and left at room temperature for 15 hours. The reaction solution was washed successively with a 5% aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 11.8 g (yield 94%) of the title compound as a colorless oil.

H-NMR (C[1CII) δ: 1.24 (9H, s)
, 3.02(3H,s), 4.72(2)1dd,
J'6.5Hz, 1.2Hz), 5.83(I
H, dt, J=15.7Hz, 1.287. ).

6,07 (I)l, dt, J-15,7Hz,
6.5Hz) Example 2 80g of 6-lonomethyl-l-hebuten-4-yn-3-ol and 4.8ml of methanesulfonyl chloride were dissolved in 50ml of diethyl ether, and a solution of 8.8ml of triethylamine in diethyl ether ( 24 ml) was added dropwise over 10 minutes. After completion of the dropwise addition, the reaction solution was diluted with 6.6-dimethyl-1-octen-4-yn-3 at room temperature for 2 hours.
0.25 g of -ol is dissolved in 20 ml of diethyl ether, 0.15 ml of methanesulfonyl chloride and 0.3 ml of triethylamine are added, and the mixture is stirred at room temperature for 1 hour. After filtering off the precipitated triethylamine hydrochloride, 15 ml of methylene chloride was added to the filtrate, and the mixture was left at room temperature for 24 hours. After washing the reaction solution with saturated brine, the solvent is distilled off to obtain 0.35!7 (yield: 92%) of the title compound as a colorless oil.

H-NMR (CDCL) δ: 0.95 (3H, t, J
=7.0llz), 1.18(6H,s).

1, 47 (2H, q, J-7,0Hz), 3. (
II (3)1. s), 4.72 (2H, d, J
+:6,5Hz), 5.84(IH,d, J=15
．． 5t(z) 6.11(1B, dt J=15.5
Hz, 6.5Hz) Example 3 6-methyl-6-phenyl-2-hepten-4-yn-
3-ol +, +, 7 was dissolved in 50 ml of diethyl ether, 1.0 ml of methanesulfonyl chloride and 2.0 ml of triethylamine were added, and the mixture was stirred for 2 hours under water cooling. The precipitated triethylamine hydrochloride is filtered off, and 30 ml of methylene chloride is added to solution f, and the mixture is left at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and the obtained (E)-6-methyl-6-phenyl-2-hebuten-4-ynyl methanesulfonate was dissolved in a mixture of 50 ml of hexane and 45 ml of 47% hydrobromic acid. , stir at room temperature for 3 hours. Separate the organic layer, wash with water,
Then, after drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound 1.1547 (yield 77%) as a colorless oil.

H-NMR (CDC1,) δ: 1.60 (6) 1.
s), 3.99 (21-1, d, J=6.5)
1z) 5, 82 (IH, d, J15.5Hz), 6
．． 25 (IH, dt, J=15.5Hz, 6.5
Hz), 7.16-7.61 (5H, m) and 1.Thus, according to the present invention, a novel compound represented by the general formula [T] is obtained from the alcohol derivative represented by the general formula [11]. (E)-2-alken-4-ynylsulfonate derivatives can be obtained easily and in high yields, and this target compound is very useful as an intermediate for the production of pharmaceuticals and the like.

Claims (4)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [I] [In the formula, R represents a lower alkyl group, phenyl group, or p-tolyl group, and R^1 represents a hydrogen atom, a lower alkyl group, a lower represents an alkoxy group or a phenyl group, and R^2 and R^3 are the same or different and represent a hydrogen atom or a lower alkyl group, or both together represent a lower alkylene group] (E )-2-alken-4-ynylsulfonate derivatives. (2) R is a methyl group, R^1, R^2 and R^3
(E)-2-alkene-4- which is the same as in the first claim
Inylsulfonate derivatives. (3) Alcohol represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [II] [In the formula, R^1, R^2 and R^3 have the meanings defined in the first claim] The derivative is reacted with a compound represented by the general formula R-SO_2Cl[III] [wherein R has the meaning defined in the first claim] in the presence of a base to form the general formula ▲mathematical formula, chemical formula, There are tables etc. ▼ [IV] A method characterized by obtaining a compound represented by [wherein R, R^1, R^2 and R^3 have the above-mentioned meanings] and then intramolecularly rearranging this compound. The general formula stated in the first claim ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] [In the formula, R, R^1, R^2 and R^3 have the above meanings] A method for producing (E)-2-alken-4-ynylsulfonate derivatives. (4) R is a methyl group, R^1, R^2 and R^3
(E)-2 of the third claim, where is the same as the third claim
- A method for producing an alkene-4-ynyl sulfonate derivative.