WO2015129630A1 - Method for producing (s)-2-(5-chloro-2-nitrophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yne-2-ol - Google Patents

Abstract

[Problem] To provide a novel method for producing (S)-2-(5-chloro-2-nitrophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yne-2-ol. [Solution] An alkynyl ketone represented by belowmentioned formula (1) is reacted with (trifluoromethyl) trimethylsilane in a solvent in the presence of a basic group and a catalytic amount of a cinchona alkaloid phase transfer catalyst represented by belowmentioned general formula (3), (4), (5), or (6). (In the formulas, R¹, R², R³, R⁴ and X represent the meaning set forth in claim 1.)

Description

Process for producing (S) -2- (5-chloro-2-nitrophenyl) -4-cyclopropyl-1,1,1-trifluorobut-3-in-2-ol

The present invention relates to (S) -2- (5-chloro-2-nitrophenyl) -4-cyclopropyl-1,1,1-trifluorobutene, which is a key intermediate of efavirenz, an AIDS therapeutic agent This relates to a method for producing -3-in-2-ol.

Efavirenz, developed by Merck, is an AIDS onset inhibitor (non-nucleic acid reverse transcriptase inhibitor) and one of the world's top drugs. Efavirenz has an asymmetric carbon with a trifluoromethyl group and is known to have anti-HIV activity only in the (S) -form optical isomer and not in the (R) -form. Yes. However, in the current actual production process, optical resolution using (-)-Camphanyl chloride as a chiral auxiliary is currently used (Non-patent Document 1), and in optical resolution, the intermediate is racemic. Since the diastereomers are separated after synthesis and the action of an optical resolving agent, half of the compounds are discarded.

Also, production of (S) -2- (5-chloro-2-nitrophenyl) -4-cyclopropyl-1,1,1-trifluorobut-3-in-2-ol, which is a key intermediate of efavirenz There are two major methods. The first is an asymmetric alkynylation reaction for trifluoromethyl ketone, which is a conventional method (see Non-Patent Documents 2, 3, and 4), and the second is a direct method for alkynyl ketone, which is a new method. This is a simultaneous trifluoromethylation reaction (see Non-Patent Document 5).

However, although the present inventor has previously reported the second method, the enantioselectivity was not so high as moderate (50% ee).

Therefore, there has been a demand for the development of a new production method that is an improvement on the method previously reported by the present inventors so that the enantioselectivity can be further enhanced.

In view of the above points, the present invention is directed to (S) -2- (5-chloro-2-nitrophenyl) -4-cyclopropyl-1,1,1-trifluorobutene utilizing an enantioselective trifluoromethylation reaction. It is an object of the present invention to provide a novel method for producing to-3-in-2-ol.

In order to achieve the above-mentioned object, the present inventors have conducted intensive studies. As a result, a quinaalkaloid phase transfer catalyst having a partial functional group different from the catalyst described in Non-Patent Document 5 and (trifluoromethyl) trimethylsilane By using it, a highly enantioselective trifluoromethylation reaction to an alkynyl ketone represented by the following formula was successfully achieved.

That is, the invention described in claim 1 is a quinaalkaloid phase transfer catalyst represented by the following general formula (3), (4), (5) or (6) in a solvent in a base and a catalyst amount. (S) -2- (represented by the following formula (2) characterized by reacting an alkynyl ketone represented by the following formula (1) with (trifluoromethyl) trimethylsilane in the presence: This is a novel process for producing 5-chloro-2-nitrophenyl) -4-cyclopropyl-1,1,1-trifluorobut-3-in-2-ol.

(Wherein R ¹ represents an alkoxy group, R ² represents an ethyl group or a vinyl group, R ³ represents an alkyl group, an alkenyl group, an alkynyl group or an aryl group, and R ⁴ represents an alkyl group, an alkenyl group or an aralkyl group. Group, alkynyl group, aryl group, alkoxy group or amino group, and X represents a counter anion.)
The invention according to claim 1 uses a quinaalkaloid phase transfer catalyst represented by the general formula (3), (4), (5) or (6), wherein R ¹ is an alkoxy group. In addition, the quina alkaloid phase transfer catalyst described in Non-Patent Document 5 corresponds to that in which R ^{1 in} the general formulas (3), (4), (5), and (6) is a hydroxy group.

According to the invention described in claim 1, (S) -2- (5-chloro-2-nitrophenyl) -4-cyclopropyl-1,1,1-trifluorobut-3-in-2-ol Can be produced enantioselectively.

In the invention described in claim 1, like the invention described in claim 2, it is preferable to use a quinaalkaloid phase transfer catalyst in which R ¹ is a linear alkoxy group.

In the inventions described in claims 1 and 2, it is preferable to use a mixed solvent of toluene and methylene chloride as the solvent as in the invention described in claim 3.

In the inventions described in claims 1 to 3, it is preferable to use ammonium fluoride as the base as in the invention described in claim 4.

In the invention described in claim 1, like the invention described in claim 5, it is preferable to use a compound represented by the following general formula (7) as the quinaalkaloid phase transfer catalyst.

(Wherein R ⁵ represents a methyl group, an n-butyl group, an n-hexyl group, an n-octyl group, an n-decyl group or a cetyl group, and R ⁶ represents a phenyl group, 3,5-tBu ₂ C ₆ H ₃ group or 3,5- (CF ₃ ) ₂ C ₆ H ₃ group.)
According to the invention described in claim 5, compared to the production method described in Non-Patent Document 5, (S) -2- (5-chloro-2-nitrophenyl) -4-cyclopropyl-1,1 , 1-trifluorobut-3-in-2-ol can be produced with high enantioselectivity (7b, 7c, 7d, 7e, 7f, 7j, 7k in Table 1 in the examples described later). (Refer to reaction examples using 7 l and 7 m catalysts).

In the present invention, an alkynyl ketone represented by the above formula (1) and (trifluoromethyl) trimethylsilane are reacted in a solvent in the presence of a base and a quinaalkaloid phase transfer catalyst. Thus, the trifluoromethyl alcohol compound represented by the above formula (2), that is, (S) -2- (5-chloro-2-nitrophenyl) -4-cyclopropyl-1,1,1-trifluoro Lobut-3-in-2-ol is produced.

The alkynyl ketone represented by the formula (1) is 1- (5-chloro-2-nitrophenyl) -3-cyclopropyl-2-propyn-1-ol. As the alkynyl ketone represented by the formula (1), one produced by an existing production method can be used.

The quinaalkaloid phase transfer catalyst used in the reaction is a quinaalkaloid derivative represented by the above general formula (3), (4), (5) or (6). The compounds represented by the general formulas (3), (4), (5), and (6) are isomers and have the same performance. For this reason, any of the compounds represented by the general formulas (3), (4), (5), and (6) may be used as the quina alkaloid phase transfer catalyst. The use amount of the quina alkaloid phase transfer catalyst may be a catalyst amount that acts as a phase transfer catalyst.

In the general formulas (3), (4), (5) and (6), R ¹ represents an alkoxy group, R ² represents an ethyl group or a vinyl group, and R ³ represents an alkyl group, an alkenyl group or an alkynyl group. Or an aryl group, R ⁴ represents an alkyl group, an alkenyl group, an aralkyl group, an alkynyl group, an aryl group, an alkoxy group or an amino group, and X represents a counter anion.

In the present specification, as the alkyl group for R ³ and R ⁴ , for example, an alkyl group having about 1 to 20 carbon atoms can be used. Specifically, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, A hexadecyl group, a heptadecyl group, an octadecyl group, a nonadecyl group, an icosyl group, or a cyclic alkyl group or a branched alkyl group thereof can be used.

The number of unsaturated bonds contained in the alkenyl group or alkynyl group of R ³ and R ⁴ is not particularly limited, but is preferably about 1 to 2. The alkenyl group or alkynyl group may be linear or branched.

The aryl group represented by R ³ and R ⁴ also includes a heteroaryl group. Specific examples thereof include an aryl group having 2 to 30 carbon atoms, such as a phenyl group, a naphthyl group, an anthranyl group, a pyrenyl group, and biphenyl. A group, an indenyl group, a tetrahydronaphthyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridanidyl group, a piperazinyl group, a pyrazolyl group, an imidazolyl group, a quinylyl group, a pyrrolyl group, an indolyl group, and a furyl group.

The alkyl group may be substituted with a substituent such as a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, a nitro group, an aryl group, an acyl group, an alkoxy group, an aryloxy group, and an acyloxy group. When having the above substituents, they may be the same or different.

The alkenyl group may be substituted with a substituent such as a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, a nitro group, an aryl group, an acyl group, an alkoxy group, an aryloxy group, or an acyloxy group. When having the above substituents, they may be the same or different.

The alkynyl group may be substituted with a substituent such as a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, a nitro group, an aryl group, an acyl group, an alkoxy group, an aryloxy group, or an acyloxy group. When having the above substituents, they may be the same or different.

The aryl group may be substituted with a substituent such as an alkyl group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, a nitro group, an aryl group, an acyl group, an alkoxy group, an aryloxy group, and an acyloxy group. When it has two or more substituents, they may be the same or different.

Examples of the aralkyl group for R ⁴ include benzyl group, pentafluorobenzyl group, o-methylbenzyl group, m-methylbenzyl group, p-methylbenzyl group, p-nitrobenzyl group, naphthylmethyl group, furfuryl group, α -Phenethyl group and the like can be mentioned.

Examples of the amino group represented by R ⁴ include those in which one or two substituents of hydrogen, a substituted or unsubstituted alkyl group, an alkenyl group, an aralkyl group, an alkynyl group, and an aryl group are substituted on N. The substituents are independent of each other and need not be the same. The amino group can form a cyclic structure that can be formed by combining substituents. In particular, a monocyclic, bicyclic, or higher polycyclic structure composed of 3 to 20 members can be shown. Further, a part of the cyclic structure may be formed with or without hetero atoms.

The alkoxy group represented by R ¹ and R ⁴ is preferably an alkoxy group having 1 to 20 carbon atoms, and more preferably an alkoxy group having 1 to 10 carbon atoms. In the case of an alkoxy group, it may be substituted with the same substituent as in the case of the above alkyl group. From the viewpoint of further enhancing enantioselectivity, as shown in the examples described later, the alkoxy group of R ¹ is preferably a linear alkoxy group, and among them, a linear chain having 4 or 6 carbon atoms is preferable. Most preferred is an alkoxy group.

Examples of the counter anion represented by X include halogen and alkoxide, and more specifically, fluoride, chloride, bromide (Br), iodo, phenoxide, trifluoroborate (BF ₄ ), hexafluorophosphate (PF ₆ ). Etc.

The type of solvent used in the reaction is not particularly limited, and examples of the solvent include ether solvents such as diethyl ether, diisopropyl ether, n-butyl methyl ether, tert-butyl methyl ether, tetrahydrofuran, and dioxane; heptane, hexane, cyclopentane, Hydrocarbon solvents such as cyclohexane; Halogenated hydrocarbon solvents such as chloroform, carbon tetrachloride, methylene chloride, dichloroethane, trichloroethane; benzene, toluene, xylene, cumene, cymene, mesitylene, diisopropylbenzene, pyridine, pyrimidine, pyrazine, Aromatic solvents such as pyridazine; solvents such as dimethyl sulfoxide and dimethylformamide; methanol, ethanol, propanol, i-propyl alcohol, aminoethanol, N, N-di Alcohol solvents such as chill amino ethanol. These can be used alone or in combination of two or more. As a solvent used for the synthesis of enantioselective trifluoromethyl alcohol with respect to alkynyl ketone, a mixed solvent of toluene and methylene chloride is preferable, as shown in the examples described later, and the solvent ratio of toluene and methylene chloride is a 2: 1 mixture. A solvent is most preferred.

As the base used in the reaction, an inorganic base, an organic base, an organometallic reagent, or the like can be used. Examples of the base include carbonates such as potassium carbonate and cesium carbonate; acetates such as sodium acetate and potassium acetate; ammonium fluorides such as tetramethylammonium fluoride, tetraethylammonium fluoride and tetrabutylammonium fluoride; Alkali metal fluorides such as potassium and cesium fluoride; hydroxides such as sodium hydroxide and potassium hydroxide; alkoxide compounds such as sodium methoxide and potassium tert-butoxide; DABCO, DBU, triethylamine, N, N-dimethyl And organic bases such as aminopyridine; lithium salts such as n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, and hexamethyldisilazane lithium salt. As the base used for the synthesis of the enantioselective trifluoromethyl alcohol with respect to the alkynyl ketone, ammonium fluoride is preferable and tetramethylammonium fluoride is most preferable, as shown in the examples described later. The amount used is generally 0.1 to 10 equivalents, preferably 0.5 equivalents, relative to formula (1).

The reaction temperature is not particularly limited, but is usually −80 ° C. to 120 ° C., more preferably around room temperature. The reactor can be either an open-air reactor or a closed reactor such as an autoclave. The reaction pressure can be either atmospheric pressure or pressurized. The reaction time is not particularly limited, but the reaction is usually completed in 1 hour to 5 days.

After the reaction, the trifluoromethyl alcohol compound represented by the above formula (2) can be isolated and purified from the reaction solution by a general method. For example, after concentrating the reaction solution, purification by column chromatography using an adsorbent such as silica gel and alumina, salting out, recrystallization and the like can be mentioned.

In this reaction, the structure of the quina alkaloid phase transfer catalyst affects the asymmetric yield (enantioselectivity). In particular, in the present invention, R ¹ in the general formulas (3), (4), (5), and (6) is an alkoxy group, so that it is highly enantioselectively represented by the above formula (2). It is possible to produce trifluoromethyl alcohol compounds. In addition, this reaction is a safe reaction because a metal catalyst is not used as an impurity because no metal catalyst is used and a quinaalkaloid phase transfer catalyst is used.

Hereinafter, the present invention will be described more specifically with reference to examples. However, the scope of the present invention is not limited to the following examples.

As shown in the following reaction formula, an alkynyl ketone represented by the formula (1) and (trifluoromethyl) trimethylsilane (Me ₃ SiCF ₃ ) in a solvent in the presence of a base and a quinaalkaloid phase transfer catalyst. To produce a trifluoromethyl alcohol compound represented by the formula (2). In this reaction, a mixed solvent of toluene and methylene chloride (toluene / CH ₂ Cl ₂ ) is used as a solvent, tetramethylammonium fluoride (Me ₄ NF) is used as a base, and a quinaalkaloid phase transfer catalyst as described below. The compound represented by the general formula (7) (cat. (7)) was used. This reaction was carried out in a sealed container in a nitrogen atmosphere.

The quinaalkaloid phase transfer catalyst represented by the general formula (7) is represented by the above general formula (5), R ² is a vinyl group, R ³ is an aryl group, and R ⁴ is a methoxy group ( It corresponds to a quinaalkaloid phase transfer catalyst in which X is bromide. In this example, the catalysts 7a to 7m in which R ⁵ and R ⁶ in the general formula (7) are groups shown in Table 1 below were used. R ⁵ corresponds to a part of R ^{1 in} the general formula (5), and R ⁶ corresponds to a part of R ^{3 in} the general formula (5).

In the column of R ⁵ in Table 1 below, Me is a methyl group, n-butyl is an n (normal) -butyl group, n-hexyl is an n-hexyl group, Bn is a benzyl group, allyl is an aryl group, and n-pentyl Represents an n-pentyl group, n-octyl represents an n-octyl group, n-decyl represents an n-decyl group, and cetyl represents a cetyl group. In the R ⁶ column of Table 1, Ph represents an unsubstituted phenyl group, and the 3,5-tBu ₂ C ₆ H ₃ group and the 3,5- (CF ₃ ) ₂ C ₆ H ₃ group are substituted types. It is a phenyl group.

Specifically, alkynyl ketone (0.10 mmol), tetramethylammonium fluoride (0.05 mmol), and any one of quinaalkaloid phase transfer catalysts (0.01 mmol) shown in Table 1 in 7a to 7m were used as a solvent. Dissolved in 2 mL, (trifluoromethyl) trimethylsilane (0.20 mmol) was added at the temperature shown in Table 1. As shown in Table 1, the solvent ratio of toluene and methylene chloride (Tol./CH ₂ Cl ₂ ) used as the solvent was toluene: methylene chloride = 2: 1 or 1: 1.

And after stirring for the time shown in Table 1, saturated ammonium chloride aqueous solution was added and reaction was stopped. Extraction was performed using methylene chloride, and the collected organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, 1 mL of tetrahydrofuran (THF) and tetrabutylammonium fluoride (TBAF) were added, and the mixture was stirred at room temperature for 1 hour. Thereafter, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a trifluoromethyl alcohol compound represented by the following formula (2).

As an example of this example, the structural formula of the 7m quinaalkaloid phase transfer catalyst in Table 1 is shown below, and the formula (2) obtained when the 7m quinaalkaloid phase transfer catalyst in Table 1 is used. The analysis results of this compound by NMR and the like are shown below.

Compound (2): (S) -2- (5-chloro-2-nitrophenyl) -4-cyclopropyl-1,1,1-trifluorobut-3-in-2-ol
¹ H NMR (CDCl ₃ , 300 MHz) δ 0.79-0.92 (m 4H), 1.26-1.36 (m, 1H), 3.57 (s, 1H), 7.44-7.52 (m, 2H), 7.80 (s, 1H) ¹⁹ F NMR (CDCl ₃ , 188 MHz) δ-78.8 (s, 3F); MS (ESI, m / z) 318 [MH] ^- . The ee of the product was determined by HPLC using an OD-3 column ( n-hexane / i-PrOH = 95/5, flow rate 1.0 mL / min, λ = 254 nm, τ _maj = 8.4 min, τ _min = 9.5 min); [a] _D ²⁵ = -10.9 (c = 0.27, CHCl ₃ ), 74% yield, 80% ee.
Table 1 shows the enantioselectivity (Ee (%)) of the compound obtained in this example. From the results shown in Table 1, it can be seen that the compound of the formula (2) was obtained enantioselectively when any of the 7a to 7m quinaalkaloid phase transfer catalysts was used.

In addition, while the enantioselectivity in the production method described in Non-Patent Document 5 was 50% at the maximum, the quinaalkaloid phase of 7b, 7c, 7d, 7e, 7f, 7j, 7k, 7l, 7m When the transfer catalyst is used, the enantioselectivity is 60% or more, which indicates that the enantioselectivity is high as compared with the production method described in Non-Patent Document 5. Among these catalysts, 7c, 7d, 7e, 7f, 7j, 7k, and 7m correspond to quinaalkaloid phase transfer catalysts in which R ¹ is a linear alkoxy group in the general formula (5). Therefore, in the general formula (3), (4), (5) or (6), when a quinaalkaloid phase transfer catalyst in which R ¹ is a linear alkoxy group is used, the enantioselectivity tends to increase. I know that there is.

Further, when a 7f, 7m quinaalkaloid phase transfer catalyst is used, the enantioselectivity is as high as 80%. Therefore, it is represented by the general formula (7), and R ⁵ is an n-butyl group or an n-hexyl group. It can be seen that it is most preferable to use a quina alkaloid phase transfer catalyst.

Claims (5)

1. In the presence of a quinaalkaloid phase transfer catalyst represented by the following general formula (3), (4), (5) or (6) in a solvent and a base, the following formula (1): (S) -2- (5-chloro-2-nitrophenyl) -4 represented by the following formula (2), characterized by reacting the alkynyl ketone represented by (trifluoromethyl) trimethylsilane -Method for producing cyclopropyl-1,1,1-trifluorobut-3-in-2-ol.
   

   

   
   

   

   

   (Wherein R ¹ represents an alkoxy group, R ² represents an ethyl group or a vinyl group, R ³ represents an alkyl group, an alkenyl group, an alkynyl group or an aryl group, and R ⁴ represents an alkyl group, an alkenyl group or an aralkyl group. Group, alkynyl group, aryl group, alkoxy group or amino group, and X represents a counter anion.)
2. The (S) -2- (5-chloro-2-nitrophenyl)-according to claim ¹ , wherein the R ¹ is a linear alkoxy group as the quinaalkaloid phase transfer catalyst. A method for producing 4-cyclopropyl-1,1,1-trifluorobut-3-in-2-ol.
3. 3. The (S) -2- (5-chloro-2-nitrophenyl) -4-cyclopropyl-1,1,1-trifluoro group according to claim 1 or 2, wherein a mixed solvent of toluene and methylene chloride is used as the solvent. Production method of Lobut-3-in-2-ol.
4. 4. (S) -2- (5-Chloro-2-nitrophenyl) -4-cyclopropyl-1,1,1- according to claim 1, wherein ammonium fluoride is used as the base. A method for producing trifluorobut-3-in-2-ol.
5. The (S) -2- (5-chloro-2-nitrophenyl) -4-cyclopropyl- according to claim 1, wherein a compound represented by the following general formula (7) is used as the quinaalkaloid phase transfer catalyst. A method for producing 1,1,1-trifluorobut-3-yn-2-ol.
   

   

   (Wherein R ⁵ represents a methyl group, an n-butyl group, an n-hexyl group, an n-octyl group, an n-decyl group or a cetyl group, and R ⁶ represents a phenyl group, 3,5-tBu ₂ C ₆ H ₃ group or 3,5- (CF ₃ ) ₂ C ₆ H ₃ group.)