JPH06122641A - Production of 2-alkyloxy-3,3,3-trifluoro-1-propanol - Google Patents

Abstract

PURPOSE:To provide a method for simply and inexpensively producing the subject compound, especially its optically active isomer, useful as a raw material for physiologically active substances such as medicines and agrichemicals, or for functional organic compounds such as liquid crystals, surfactants and optically resolving agents. CONSTITUTION:The method for producing the 2-alkyloxy-3,3,3-trifluoro-1- propanol of the formula (R is methyl which may have a substituent) comprises monoanionizing 3,3,3-trifluoropropane-1,2-diol with an anionizing agent and subsequently reacting the reaction product with a compound equivalent to a primary carbocation.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The present invention relates to 2-alkyloxy-3,3, which is useful as a starting material compound for physiologically active substances such as pharmaceuticals and agricultural chemicals, liquid crystals, functional organic compounds such as surfactants and optical resolving agents. The present invention relates to a method for producing 3-trifluoro-1-propanol, particularly an optically active substance thereof.

[0002]

2. Description of the Related Art Generally, a compound obtained by replacing hydrogen of a known compound having physiological activity or functionality with fluorine has its physiological activity or function enhanced or a new physiological activity due to the specific electronic effect of the fluorine atom. And is known to gain functionality. Therefore, many fluorine-containing building blocks have been designed and synthesized, which have a structure in which specific hydrogen atoms etc. of raw material intermediates of known compounds are replaced with fluorine [for example, "90's fluorine-based physiologically active substance" supervised by Nobuo Ishikawa. Published by CMC (1991), `` Fluorine in Bioo
rganic Chemistry "JT Welch, S. Eswarakrishnan, Jo
Published by hn Wiley & Sons (1991)].

2-Alkyloxy-3,3,3-trifluoro-1-propanol is a highly reactive compound having a primary hydroxyl group, and can be expected to be widely used as a fluorine-containing building block. In particular, since the methine carbon to which the trifluoromethyl group is bonded is an asymmetric carbon in this compound, its optically active substance is highly valuable as a building block for simultaneously introducing a fluorine atom and an optically active center.

The present inventors have obtained an optically active 3,3,3-trifluoropropene oxide having an absolute conformation S-form obtained by microbial oxidation of trifluoropropene and having an optical purity of 75% ee (Japanese Patent Publication No. 61-14798). 1) by reacting with alcohols in the presence of a sulfuric acid catalyst.
A method for producing alkyloxy-3,3,3-trifluoro-2-propanol has been proposed (Japanese Patent Application No. 3-356626).
issue). However, the compound obtained by this method is a compound having a secondary hydroxyl group which is relatively poor in reactivity,
-Alkyloxy-3,3,3-trifluoro-1-propanol could not be prepared by reaction of this trifluoropropene oxide with alcohols.

[0005]

SUMMARY OF THE INVENTION The present invention has been made in view of the above circumstances, and an object of the present invention is to provide an optically active compound useful as a raw material for synthesis of physiologically active substances, functional organic compounds and the like. -Alkyloxy-3,3,3-trifluoro-1
-To provide a method for easily and inexpensively producing propanol.

[0006]

According to the present invention, 3,3,3-trifluoropropane-1,2-diol is monoanionized with an anionizing agent and then reacted with a primary carbocation equivalent. The following general formula 2

[Chemical 2] 2-alkyloxy-3,3,3-trifluoro-1-, represented by the formula (wherein R is a methyl group which may have a substituent)
A method for producing propanol, particularly an optically active substance having an asymmetric center on the methine carbon to which a trifluoromethyl group is bonded as the 3,3,3-trifluoropropane-1,2-diol. Optically active by using
-Alkyloxy-3,3,3-trifluoro-1-propanol, and particularly preferably sodium hydride as the anionizing agent and primary alkyl iodide as the primary carbocation equivalent. It consists of using.

The above 3,3,3-trifluoropropane-1,2-diol as a starting material can be easily obtained by hydrolyzing trifluoropropene oxide in the presence of a sulfuric acid catalyst. At this time, optical activity obtained by microbial oxidation of the above-mentioned trifluoropropene 3,
If 3,3-trifluoropropene oxide is used, 3,3,3-trifluoropropane-1, with an optical purity of 75% ee is obtained.
When 2-diol is obtained and recrystallized or the like, it can be made into an optically active substance having a ee of almost 100%.

This 3,3,3-trifluoropropane-1,
In 2-diols, the secondary hydroxyl group of the two hydroxyl groups is more easily anionized due to the strong electron-withdrawing property of the trifluoromethyl group than the primary hydroxyl group, and therefore, in terms of stericity, it is sterically compared with the primary hydroxyl group. The disadvantageous secondary hydroxyl group tends to be selectively anionized and alkylated. Therefore, 2-alkyloxy-3,3,3-trifluoro-1-propanol can be obtained by first anionizing with an anionizing agent and then alkylating with a carbocation equivalent.

The anionizing agent in this case is not particularly limited, but it is an ion close to the secondary hydroxyl group of the two hydroxyl groups of 3,3,3-trifluoropropane-1,2-diol. Those that form a pair and have little interaction with the primary hydroxyl group are desirable. Examples of such cation species include sodium cations, that is, examples of anionizing agents include sodium hydride and sodium hydroxide, but the latter is less preferable because water is generated with anionization.

Examples of the carbocation equivalent include alkyl iodide, alkyl bromide, alkyl chloride, alkyl methanesulfonate, alkyl p-toluenesulfonate and the like, and particularly alkyl iodide has high reactivity. Is preferred because it has This carbocation equivalent can be selectively obtained by using a primary carbocation equivalent having a small steric hindrance.

The alkyl group in this case, which finally corresponds to the alkyl group R in the above general formula 2, is not particularly limited, but it is a monosubstituted methyl group, that is, Examples include general primary alkyl groups such as methyl group, ethyl group, n-propyl group, n-butyl group and isobutyl group, and heteroatom-containing primary alkyl groups such as methoxyethyl group. However, in the case of a sterically large alkyl group, for example, a secondary alkyl group, due to steric hindrance, it reacts with the side of the primary hydroxyl group having less steric hindrance, resulting in a decrease in the yield and selectivity of the target product. The method of the present invention cannot be efficiently manufactured.

Further, this reaction is preferably carried out in the presence of a reaction solvent, and in this case, the reaction solvent is required so as not to react with the produced monoanion species and sufficiently dissolve the monoanion species. It is preferable to use one having polarity. However, when the polarity of the reaction solvent is extremely high, the ion pair between the cation species and the anion loses its closeness, or the salt formed in the reaction process interacts with the monoanion species, resulting in a reaction. It is not preferable because it may lower the selectivity of. In particular, ethers such as tetrahydrofuran (THF) or diethyl ether have suitable polarity and are preferred.

The reaction conditions can be usually from 0 ° C. to the boiling point of the solvent, but since the step of the anionization reaction of 3,3,3-trifluoropropane-1,2-diol is an exothermic reaction, it is at room temperature. Alternatively, it is preferable to keep the temperature at ice temperature. In the latter stage alkylation reaction, the progress of the reaction is slow. Post-treatment of the product, ammonium chloride aqueous solution was added to the reaction solution,
After that, the organic phase is extracted with ether or the like, the ether phase is washed with brine, dried over anhydrous sodium sulfate or the like, and the solvent can be removed.After this post-treatment, a column using silica gel can be used. Chromatographic method,
Alternatively, it can be isolated and purified using a conventional method such as distillation.

[0014]

【Example】

Example 1 25 ml of 6.5 g (50 mmol) of 3,3,3-trifluoropropane-1,2-diol having an optical purity of 75% ee
Dissolved in THF and added to a solution of 2.1 g (about 50 mmol) of sodium hydride in 115 ml of THF at 0 ° C.
Under the temperature condition of room temperature, the solution was slowly added dropwise. afterwards,
After reacting at room temperature for 1 hour, 10 g of methyl iodide (70 mm
ol) was dissolved in 5 ml of diethyl ether, and the solution was heated at an oil bath temperature of 60 ° C. for 6 hours. After cooling the reaction solution, aqueous ammonium chloride solution was added, followed by extraction with ether, and the ether phase was washed with saturated saline solution, and subsequently dried using anhydrous sodium sulfate.
From the resulting solution to the solvent, unreacted methyl iodide,
About 5.1 g of a fraction having a boiling point of 95-105 ° C. was obtained in a yield of about 70%. The product was analyzed by gas chromatography, and as a result, 3,3,3-tri produced by the reaction of the primary hydroxyl group of 3,3,3-trifluoropropane-1,2-diol with methyl iodide. Although the content of fluoro-1-methoxy-2-propanol was about 0.5%, the main product was 3,3,3-trifluoro-2-methoxypropanol, which was the target product according to the following spectroscopic properties. It was confirmed that there is. Boiling point: 95-100 ° C / 1 atm. ¹ H-NMR (CDCl ₃ ) δ: 3.2 (br, 1H), 3.4-3.9 (m, 6H)
ppm. ¹³ C-NMR (CDCl ₃ ) δ: 60.0 (s), 60.7 (s), 80.2
(q), 124.4 (q) ppm. IR (neat): 3300 cm ^{to 1} MS (rel.Int.): 51 (30), 63 (20), 94 (100), 95
(15), 113 (10)

As a result of measuring the optical purity of this compound by the optical resolution gas chromatography method, it was confirmed that the optical purity was about 75% ee.

(Example 2) Optical purity of the above Example 1 75
% 3,3,3-trifluoropropane-1,2-diol was replaced with 0.63 g (5 mmol) of 3,3,3-trifluoropropane-1,2-diol having an optical purity of 100% ee. And a similar reaction was performed.

After the reaction solution after the completion of the reaction was subjected to the same post-treatment as above, the optical purity thereof was examined by the optical resolution gas chromatography method.
It was confirmed to be 00% ee.

Example 3 In the same reaction as in Example 1, the reaction was carried out by using methyl paratoluenesulfonate in place of methyl iodide.

0.65 g (5 mmol) of 3,3,3-trifluoropropane-1,2-diol having an optical purity of 75% ee was dissolved in 5 ml of THF, and 0.2 g of sodium hydride (about 5 m) was dissolved.
(mol) was slowly added dropwise to a solution obtained by mixing 15 ml of THF under temperature conditions of 0 ° C to room temperature. Then, this viscous reaction solution was reacted at room temperature for 1 hour, and then a solution of methyl paratoluenesulfonate (0.95 g, 5 mmol) dissolved in 2 ml of diethyl ether was added dropwise, and then the oil bath temperature was 60 ° C.
Heated for 6 hours. After cooling the reaction solution, an aqueous solution of ammonium chloride was added, the mixture was extracted with ether, and the ether phase was washed with a saturated aqueous solution of sodium chloride, and subsequently dried using anhydrous sodium sulfate. Following the solvent from the resulting solution, about 0.3 g of a fraction having a boiling point of 95 to 105 ° C. was obtained with a yield of about 40%. This fraction is the target product, 3,3,3-trifluoro-2
Although it was -methoxypropanol, it was found as a result of analysis by gas chromatography that it contained 3,3,3-trifluoro-1-methoxy-2-propanol in an amount of about 3%.

Example 4 In the same reaction as in Example 1, the reaction was carried out using ethyl iodide instead of methyl iodide.

20 ml of 6.5 g (50 mmol) of 3,3,3-trifluoropropane-1,2-diol having an optical purity of 75% ee
In THF, which is added to a solution of sodium hydride (2.1 g, about 50 mmol) in THF (95 ml) at 0 ° C.
It was slowly added dropwise under the temperature condition of room temperature. Then, after reacting at room temperature for 1 hour, 7.8 g of ethyl iodide (50 mmo)
A solution of l) in 10 ml of diethyl ether was added dropwise and then heated at an oil bath temperature of 60 ° C. for 16 hours. After cooling the reaction solution, an aqueous solution of ammonium chloride was added, the mixture was extracted with ether, the ether phase was washed with a saturated saline solution, and subsequently dried using anhydrous sodium sulfate. From the obtained solution, about 3.0 g of a fraction having a boiling point of 70 to 80 ° C./100 mmHg was obtained, following the solvent and unreacted methyl iodide. As a result of analysis by gas chromatography, it was found that this fraction contained about 5% of 3,3,3-trifluoro-1-ethoxy-2-propanol. In addition, this fraction is 3,3,
It was confirmed to be 3-trifluoro-2-ethoxypropanol. Boiling point: 70-80 ° C./100 mmHg, ¹ H-NMR (CDCl ₃ ) δ: 1.26 (t, 3H), 2.95 (br, 1H),
3.5-3.9 (m, 5H) ppm ¹³ C-NMR (CDCl ₃ ) δ: 15.2 (s), 60.2 (s), 68.9
(s), 48.3 (q), 124.4 (q) ppm IR (neat): 3300cm ^{~ 1} , MS (rel.Int.): 65 (20), 80 (100), 108 (65), 1
27 (10), 141 (5)

Comparative Example In the same reaction as in Example 1, methyl iodide was replaced with isopropyl iodide, which is a secondary carbocation equivalent, to carry out the reaction.

40 ml of 6.5 g (50 mmol) of 3,3,3-trifluoropropane-1,2-diol having an optical purity of 75% ee
Dissolved in THF and added to a solution of 2.1 g (about 50 mmol) of sodium hydride in 40 ml of THF at 0 ° C.
It was slowly added dropwise under the temperature condition of room temperature. Then, after reacting at room temperature for 1 hour, 8.5 g of isopropyl iodide (5
A solution of 0 mmol) in 10 ml of diethyl ether was added dropwise and then heated at an oil bath temperature of 60 ° C. for 16 hours.
A small amount of this reaction solution was taken out, added with an aqueous solution of ammonium chloride, extracted with ether, and then analyzed by gas chromatography. However, the formation of the desired product was not confirmed, and the starting material, 3,3,3-trifluoropropane- Recovery of 1,2-diol was confirmed.

[0024]

INDUSTRIAL APPLICABILITY The present invention is 2-alkyloxy-3,3,3-useful as a raw material for physiologically active substances such as medicines and agricultural chemicals, or liquid crystal, functional organic compounds such as surfactants and optical resolution agents
Trifluoro-1-propanol, particularly its optically active substance, can be produced easily and inexpensively. Therefore, according to the present invention, it becomes possible to obtain 2-alkyloxy-3,3,3-trifluoro-1-propanol, which has been difficult to obtain conventionally, and particularly an optically active substance thereof. By doing so, it has become possible to produce various fluorine-containing organic compounds, which have been difficult to synthesize in the past.

Claims (4)

[Claims] 1. 3,3,3-Trifluoropropane-1,2-
The diol is monoanionized by using an anionizing agent, and then reacted with a primary carbocation equivalent. 2-alkyloxy-3,3,3-trifluoro-1-, represented by the formula (wherein R is a methyl group which may have a substituent)
Method for producing propanol. 2. The optically active substance having an asymmetric center on the methine carbon to which a trifluoromethyl group is bonded as 3,3,3-trifluoropropane-1,2-diol according to claim 1. Optically active 2 characterized by being used
-Method for producing alkyloxy-3,3,3-trifluoro-1-propanol. 3. The method according to claim 1, wherein sodium hydride is used as the anionizing agent.
Process for producing alkyloxy-3,3,3-trifluoro-1-propanol. 4. The 2-alkyloxy-3,3,3-trifluoro-, according to claim 1, characterized in that a primary alkyl iodide is used as a primary carbocation equivalent.
Method for producing 1-propanol.