WO2011000532A2

WO2011000532A2 - Method for the enantioselective addition of organometallic carbon nucleophiles to trifluoromethyl ketones and use of the method in the synthesis of hiv reverse transcriptase inhibitors

Info

Publication number: WO2011000532A2
Application number: PCT/EP2010/003907
Authority: WO
Inventors: Michael Nonnenmacher; Jörg Jung; Andreas Meudt
Original assignee: Archimica Gmbh
Priority date: 2009-07-03
Filing date: 2010-06-25
Publication date: 2011-01-06
Also published as: WO2011000532A3; EP2448917A2

Abstract

The invention relates to a method for producing compounds of the formula A1, wherein the carbon atom to which both the CF3 group and the hydroxy group are bonded is a stereocenter having either the R or the S configuration and wherein R1 and R2 are a C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C4-C8 cycloalkenyl, C2-C8 alkynyl, C6-C14 aryl, or C5-C13 heteroaryl group independently of each other, wherein the alkyl, alkenyl, and alkynyl groups are straight-chained or branched and wherein all stated groups are unsubstituted or are mono- or polysubstituted with the same or different substituents selected from the group: halide, NO₂, SO₃H, SO₃Na, SO₃K, CN, OH, NH₂, NH-lower alkyl, N-di-lower alkyl, COOH, COO-lower alkyl, lower alkyl, and C3-C6 cycloalkyl, and wherein terminal OH-, NH₂-, and NH-lower alkyl groups and acidic H atoms are unprotected or are protected with a protective group, wherein a mixture of a zinc(II) salt, an enantiomerically pure or enantiomerically enriched auxiliary of the formula (I), wherein R3 and R4 are C6-C14 aryl, C5-C13 heteroaryl, C1-C8 alkyl, or C2-C8 alkenyl groups or hydrogen independently of each other and R5 and R6 are C6-C14 aryl, C5-C13 heteroaryl, C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl groups or hydrogen independently of each other or R5 and R6 together represent a C3-C7 alkylene or C3-C7 alkenylene group and at least one of the centers C1, C2, preferably both, is a stereocenter regardless of the configuration of the other center and has either the R or the S configuration and a second auxiliary, which is selected from the group comprising the alcohols, phenols, mercaptans, amines, carboxylic acids, urea derivatives, or the heterocycles containing nitrogen, oxygen, or sulfur, is reacted with an organic or inorganic base and then is reacted with an organometallic compound R1 -M in which R1 has the meaning specified above and in which M is selected from the group: lithium, sodium, potassium, magnesium halide, magnesium cyanide, magnesium-lower alkyl-alcoholates, and then is reacted with a trifluoromethyl ketone (II), wherein R2 has the meaning stated above.

Description

Process for the enantioselective addition of organometallic carbon nucleophiles to trifluoromethyl ketones and use of the process in the synthesis of HIV reverse transcriptase inhibitors

The present invention relates to a process for enantioselective addition reactions of organometallic nucleophiles with trifluoromethyl-substituted ketones. The target compounds are tertiary alcohols which also include a particular class of substances which are suitable intermediates for the synthesis of benzoxazinones, which in turn are useful as inhibitors of human immunodeficiency virus reverse transcriptase.

Background of the invention:

Efavirenz is used as a potent inhibitor of human immunodeficiency virus (HIV) reverse transcriptase. The manufacturing process involves a step of establishing a chiral center to which an amino-functional aryl group, an oxygen atom, a trifluoromethyl group and an alkynyl group are bonded. In the past, a racemate resolution was carried out as a key step to obtain the desired S-enantiomer with high ee values of over 99%. [SD Young et al., Antimicrobal Agents and Chemotherapy, 39, [1995] 2602-2605; EP 0 582 455 A1]. Since this half of the starting material is lost as a by-product from the outset and the reagents used are very expensive, this process results in significant overall costs. Therefore, methods were developed that allow an enantioselective alkynylation of the trifluoromethyl ketone. First, the alkyne nucleophile was used in the form of an organolithium compound. (1 R, 2S) -1-phenyl-2- (1-pyrrolidinyl) -1-propanol was added as a chiral auxiliary to achieve chiral induction. Because of the strongly basic reaction conditions, however, the NH ₂ function of the educt had to be protected, which required two additional reaction steps, namely introduction and removal of the protective group. In addition, more than two equivalents of Auxiliars and the nucleophile necessary, so that also incur high total costs. [AS Thompson, et al., Jetrahedron Lett., 36, [1995] 8937-8940; WO96 / 37457]. The introduction of zinc (II), to which the organometallic species can initially be transmetalated, allowed milder reaction conditions under which the amino group remains unaffected. Nevertheless, the success of this method has hitherto been limited to the use of expensive and difficult-to-handle dialkylzinc reagents [L. Tan, et al., Angew. Chem. Int. Ed., 38, [1999] 711-713; WO98 / 51676] or the use of a hard to access class of chiral auxiliaries [EP 1 614 672 A1]. In addition, the method from the last report provides only poorly reproducible results and suffers from considerable side reactions.

It has therefore been of particular interest to develop a new process that uses well-available and inexpensive inorganic zinc (II) salts rather than expensive dialkylzinc compounds, which are significantly harder to handle because of their extreme sensitivity to water, their liquid state and their fire hazard and a higher potential hazard. Dialkylzinc reagents must be introduced into the process in liquid form, while zinc salts which are solid at room temperature can be presented as a solid, which can also reduce the risk of carrying these environmentally hazardous substances into the environment. In addition, it was important to achieve very high ee values with a well-available standard reagent as a chiral auxiliary such as (1 R, 2S) -1-phenyl-2- (1-pyrrolidinyl) -1-propanol and to to refrain from costly auxiliary syntheses. Furthermore, the achieved results of the process should be reproducible. If the said carbon nucleophile is generated in equilibrium in-situ, as in 3c, then there is the danger of considerable side reactions and only poorly reproducible results can be achieved. Therefore, the use of organometallic carbon nucleophiles is of great importance. The inventive method meets all the requirements, since not only zinc salts such as inexpensive zinc (II) chloride can be used as a precursor for the formation of the chiral auxiliary complex, but also with standardized auxiliaries that are readily available in the market, excellent enantiomeric excesses are obtained. In addition, the process is very robust, provides virtually no secondary components and good yields. Summary of the invention:

The invention accordingly relates to a process for the preparation of compounds of the formula A1

A1

wherein the carbon atom to which both the CF3 group and the hydroxy group are attached represents a stereocenter having either the R or S configuration, and

wherein

R1 and R2 are independent of each other

C1-C8-alkyl, C3-C8-cycloalkyl, C2-C8-alkenyl, C4-C8-cycloalkenyl, C2-

C8-alkynyl, C6-C14-aryl or C5-C13-heteroaryl radicals, wherein the alkyl, alkenyl and alkynyl radicals are straight-chain or branched and wherein all the radicals mentioned are unsubstituted or monosubstituted or polysubstituted by identical or different substituents selected from the group: halide, NO ₂ , SO ₃ H, SO ₃ Na, SO ₃ K ₁ CN, OH, NH ₂ , NH-lower alkyl, N-di-lower alkyl, COOH ₁ COO-lower alkyl , lower-alkyl and C3-C6-cycloalkyl and wherein

terminal OH, NH ₂ and NH-lower alkyl groups and acidic H atoms are unprotected or protected with a protective group,

wherein a mixture of a zinc (l I) -SaiIz, an enantiomerically pure or enantiomerically enriched auxiliary of the formula - A -

^R5 \

HO ^N N-R6

C1 -C2

R3 R4 being

R3 and R4 independently of one another are C6-C14-aryl, C5-C13-heteroaryl, C1-C8-alkyl, C2-C8-alkenyl radicals or hydrogen and

R5 and R6 independently of one another are C6-C14-aryl, C5-C13-heteroaryl, C1-C8-

Alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl radicals or hydrogen are or

R5 and R6 together represent a C3-C7 alkylene or C3-C7 alkenylene radical and

at least one of the centers C1, C2, preferably both, independently of the

Configuration of the other center is a stereo center and has either the R or the S configuration

and a second auxiliary selected from the group of alcohols, phenols, mercaptans,

Amines, carboxylic acids, urea derivatives or the nitrogen-containing, oxygen-containing or sulfur-containing heterocycles is selected,

wherein the mixture is subsequently reacted with an organic or inorganic base and then with an organometallic compound

R1-M in which R1 has the abovementioned meaning and

in which M is selected from the group: lithium, sodium, potassium, magnesium halide, magnesium cyanide, magnesium lower alkyl alcoholate and then with a trifluoromethyl ketone

where R2 has the meaning given above, is implemented.

In WO2009 / 095931 a similar method is already proposed. However, this differs from the method according to the invention in that the first and the second auxiliary are first reacted with a base and only then are complexed with a zinc halide.

Heteroaryl is understood according to the invention to mean an aryl radical in which one or more carbon atoms are replaced by the heteroatoms N, S or O, where in the case of a plurality of heteroatoms they are identical or different.

According to the invention, halide is understood to mean fluoride, chloride, bromide, iodide, preferably chloride, bromide, iodide, very particularly preferably chloride or bromide.

By lower alkyl is meant according to the invention a straight-chain or branched C 1 -C 4 -alkyl radical; preferably a methyl, ethyl, propyl, isopropyl or butyl radical; especially a methyl, ethyl or propyl radical. According to the invention, a protective group is a carboxyl, preferably a 2,2-dimethylpropanoyl or an ethanoyl group, an alkoxycarbonyloxy, preferably a 2,2-dimethylpropanolylcarbonyloxy group, an alkoxymethyl,

Alkoxyalkylmethyl or benzyl group understood. The present invention thus relates to a process for the preparation of tertiary alcohols which carry a trifluoromethyl group; In particular, the method is suitable tertiary alcohols of the formula

manufacture.

An organometallic nucleophile is added to a trifluoromethyl ketone with the addition of a selectivity-controlling, enantiomerically pure or enantiomerically enriched auxiliary complex. In a preferred embodiment of the invention, one or more substituents of the tertiary alcohol is an aryl or heteroaryl radical, and in a particularly preferred embodiment of the invention, this aryl radical in the 2-position bears an amino function relative to the keto group. According to the invention, compounds of this type can be used for the synthesis of benzoxazinones which are used as inhibitors of the reverse transcriptase of the HI virus. In a very particularly preferred embodiment, the aryl radical mentioned above is 2-amino-5-chlorophenyl (= R 2) and the nucleophile is cyclopropylethynylmagnesium chloride, bromide, iodide or cyclopropylethynyl lithium (R 1 = cyclopropylethynyl) and the tertiary alcohol represented in this way with amino function can be cyclized to efavirenz.

The process is easy to handle, stably reproducible, requires only stable, storable and reasonably priced raw materials and delivers good yields and high enantioselectivities up to 100%.

Detailed description of the invention:

In a preferred embodiment, R1 is a substituted C2-alkynyl radical and in a particularly preferred embodiment, a cyclopropylethynyl radical. In a preferred embodiment, R 2 is a divalent substituted aryl radical and in a particularly preferred embodiment a (2-amino-5-chlorophenyl) radical.

In a preferred embodiment, M is selected from the group: MgCl, MgBr and MgI

In a preferred embodiment, the zinc (II) salt is zinc (II) chloride, bromide, iodide, cyanide, trifluoromethanesulfonate, benzenesulfonate, toluenesulfonate, methanesulfonate, oxide, acetate, acetylacetonate, citrate, nitrate, phosphate, - hydrogen phosphate, dihydrogen phosphate, stearate, sulfate, hydrogen sulfate, carbonate, bicarbonate, tetrafluoroborate, trifluoroacetate. In a particularly preferred embodiment, it is zinc (II) chloride, bromide, iodide, trifluoromethanesulfonate, benzenesulfonate, toluenesulfonate or methanesulfonate, and in a most preferred embodiment, zinc (II) chloride or zinc (II) trifluoromethanesulfonate.

In a preferred embodiment, R3 = phenyl, R4 = methyl and R5 and R6 bridging a pyrrolidine ring (= a C4 alkylene). In a particularly preferred embodiment, it is (1 R, 2S-1-phenyl-2- (1-pyrrolidinyl) -1-propanol of the formula

The reaction also takes place in the presence of an organic or inorganic base such as: amines, metal alkoxides, metal thiolates, metal amides, complex hydrides, metal hydrides, carbon bases such as methyllithium, butyllithium or tert-butyllithium, carbonates, phosphates, phosphazene bases and hydroxides. In a preferred embodiment with a inorganic base from the group of metal hydrides and complex hydrides and in a particularly preferred embodiment with a metal hydride selected from the group NaH, KH, LiH, LiAlH ₄ , NaBH ₄ , NaBH ₃ CN. In a most preferred embodiment with sodium hydride or potassium hydride.

Furthermore, the reaction is conveniently carried out in the presence of a second additive which is selected from the group of alcohols, phenols, mercaptans, amines, carboxylic acids, urea derivatives or the nitrogen-containing, oxygen-containing or sulfur-containing heterocycles. This is preferably an alcohol, particularly preferably tert-butanol, 2,2-dimethylpropan-1-ol or benzyl alcohol.

The process according to the invention is preferably carried out by initially adding 0.8 to 3 equivalents (all equivalent amounts based on organometallic nucleophile) of zinc salt, preferably 1 to 1.5 equivalents in an organic solvent, preferably a dialkyl ether, in an inertized stirred vessel and most preferably in tetrahydrofuran. To this solution are added at a temperature of -50 ° to +80 ⁰ C, preferably at a temperature of -30 ° C to +30 ⁰ C 0.8 to 3.6 equivalents, preferably 1 to 1 equivalent of the enantiomerically pure or 8 enantiomerically enriched auxiliaries and 0.8 to 3.6 equivalents, preferably 0.8 to 1, 5 equivalents of the second additive. Then 1 to 6 equivalents, preferably 1, 5 to 2.5 equivalents of base are added slowly. The reaction is stirred at a temperature of -50 ° to +110 ⁰ C, preferably at a temperature of 0 ⁰ C to 8O ⁰ C, more preferably between 50 ° and 70 ⁰ C for some time. Now, at a temperature of -70 ⁰ C to +50 ⁰ C, preferably at a temperature of -20 ⁰ C to +40 ⁰ C, one equivalent of the organometallic nucleophile added and stirred for some time. Thereafter, at a temperature of -70 to + 8O ⁰ C, preferably at a temperature of -30 ° to + 4O ⁰ C 0.1 to 1, 5 equivalents, preferably 0.5 to 1, 0 equivalents, particularly preferably 0 Add 8 equivalents of trifluoromethyl ketone and allow the mixture to stir for a while. Optionally, the temperature is raised by 10 to 100, preferably by 10 to 30 ° C during the stirring time. Sales control determines the end point of the reaction. The reaction mixture is then worked up using standard preparative organic chemistry techniques and the product isolated. With the method good to very good yields can be achieved to over 90%. The advantage lies in the fact that the obtained enantiomeric excess is in some cases over 99.9%.

The invention further relates to the reaction of the compound of the formula

which was prepared by the process according to the invention in a further reaction step with insertion of a CO unit to give 6-chloro-4- (cyclopropylethynyl) -i, 4-dihydro-4- (trifluoromethyl) -2H-3, 1-benzoxazine-2-one on

(Efavirenz)

In the following the invention will be explained in more detail by means of examples.

Examples: Example 1

1 - (2-Amino-5-chlorophenyl) -1-trifluoromethyl-3-cyclopropylprop-2-yn-1-ol:

In a round bottom flask with mechanical stirrer, reflux condenser, internal thermometer, nitrogen inlet, and filling opening 43,6g zinc trifluoromethanesulfonate in 160.0 g of dry tetra be presented hydrofu ran and - 20 ⁰ C cooled. There are 29.5 g (1 R, 2S) -1-phenyl-2- (1-pyrrolidinyl) -1-propanol and 7.10 g of tert-butanol and then in portions a total of 9.60 g of sodium hydride (60% suspension in mineral oil ) too. Slowly bring the suspension to room temperature. Then it is heated for 24 h at 50 to 60 ⁰ C, wherein the suspension clears.

In another round bottomed flask, 133 g of p-Tolylmagnesiumchlorid solution in toluene (0.9 mol / kg) are introduced and cooled to 0 ⁰ C. Is added dropwise 11, 33g of a 70% solution of cyclopropylacetylene in toluene and heated after complete addition for 3 h at 40 ⁰ C then the solution is cooled again. The resulting solution is then added slowly to the previously prepared solution. The mixture is stirred for a further 30 minutes and then cooled to ⁰ ° C. Then 15.0 g of 1,1-trifluoromethyl-2- (2-amino-5-chlorophenyl) -ethan-2-one are added in one portion and again Stirred for 12h, bringing the solution slowly to room temperature.

It is quenched by addition of 166 g of hexane and 254 g of 1 N citric acid, left to stir briefly and separates the phases. The organic phase is again with 127g of water and 170g sat. Saline solution and then distilled to 10-20% of the volume. To the residue is added 45 g of toluene and stirred for 1 h 0-5 ° C. The product is filtered off with suction and dried in vacuo (150 mbar) at 4O ⁰ C dried. This gives 12.1 g (62%, ee> 99.9%) of the desired aminoalcohol.

Example 2

1 - (2-Amino-5-chlorophenyl) -1-trifluoromethyl-3-cyclopropylprop-2-yn-1-ol:

In a round bottom flask with mechanical stirrer, reflux condenser, internal thermometer, nitrogen transfer and filling opening, 1.14 g of zinc chloride in 32.0 g of dry tetrahydrofuran are initially introduced at room temperature. 2.06 g (1R, 2S) -1-phenyl-2- (1-pyrrolidinyl) -1-propanol and 0.50 g tert-butanol are added followed by portionwise addition of 0.67 g of sodium hydride (60% suspension in mineral oil ). Now it is heated to 60 to 70 ⁰ C for 24 h.

In another round bottom flask 9.33 g of p-Tolylmagnesiumchlorid solution in toluene (0.9 mol / kg) are introduced and cooled to 0 ° C. Is added dropwise 0.79 g of a 70% solution of cyclopropylacetylene in toluene thereto, and heated after addition of ready for 3 h at 40 ⁰ C. Then the solution is cooled again. The resulting solution is then added slowly to the previously prepared solution. The mixture is stirred for 30 minutes and then cooled to 0 ⁰ C. Now, 1, 57g 1, 1, 1-trifluoromethyl-2- (2-amino-5-chlorophenyl) -ethan-2-one added in one portion and again Stirred for 12h, bringing the solution slowly to room temperature.

It is quenched by addition of 12 g of methyl tert-butyl ether and 18 g of 1 N citric acid, stirred briefly and separates the phases. The organic phase is washed once with 25g of water and 33g. Saline solution and then distilled to 10-20% of the volume. To the residue is added 30 g of toluene and stirred for 1 h at 0-5 ⁰ C. The product is filtered off with suction and dried at 40 ° C in vacuo (150mbar). This gives 1.49 g (74%, ee> 99.5%) of the desired aminoalcohol. Example 3

θ-Chloro- ^ cyclopropylethinyO-i ^ -dihydro ^ - rifluoromethyl ^ H-S.I-benzoxazin-Σ-one (efavirenz):

In a round bottom flask equipped with a mechanical stirrer, reflux condenser, internal thermometer, nitrogen blanketing and feed opening, 9.27 g of 1- (2-amino-5-chlorophenyl) -1-trifluoromethyl-3-cyclopropylprop-2-yn-1-ol and 20.8 g of carbonylbis (imidazole) initially dissolved in 134 g of tetrahydrofuran and heated to 60-70 ⁰ C. The mixture is stirred until the conversion is quantitative and cooled back to room temperature. 300 g of ethyl acetate are added and 200 g of the solvent mixture are distilled off. Then add 200g of water and separate the phases. The organic phase is washed twice with 100 g of 2% hydrochloric acid, once with 60 g of saturated potassium bicarbonate solution and once with 30 g of water and about 150-18Og of solvent are distilled off until a thick slurry remains. The product is precipitated by addition of 60 g of hexane, filtered off with suction and recrystallized from hexane.

9.50 g (94.4%, ee> 99.9%) of the desired benzoxazinone are obtained.

Example 4

6-Chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one (efavirenz) (solution in ethanol):

In a round bottom flask equipped with a mechanical stirrer, reflux condenser, internal thermometer, nitrogen transfer and feed opening, 5.79 g of 1- (2-amino-5-chlorophenyl) -1-trifluoromethyl-3-cyclopropylprop-2-yn-1-ol and 13.0 g of carbonyl bis (imidazole) initially dissolved in 120 g of tetrahydrofuran and at 60-70 ⁰ C. heated. The mixture is stirred until the conversion is quantitative and cooled back to room temperature. About 80 g of the solvent is distilled off. Then it is mixed with 10Og of water and 10Og of ethyl acetate and the phases are separated. The aqueous phase is extracted once more with 50 g of ethyl acetate and the combined organic phases are washed twice with 70 g of 2% hydrochloric acid, once with 30 g of saturated potassium bicarbonate solution and once with 30 g of water. The organic phase is dried over sodium sulfate (about 10 g) and the resulting suspension is filtered through Celite. Then about 80 g of solvent are distilled off and replaced by 80 g of ethanol. The process is repeated a total of three times. This gives 5.89 g (93.8%) of the desired benzoxazinone in ~ 7% solution in ethanol.

Claims

claims

1. Process for the preparation of compounds of the formula A1

A1 wherein the carbon atom to which both the CF3 group and the hydroxy group are attached represents a stereocenter having either the R or S configuration, and

wherein

R1 and R2 are independent of each other

C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 6 -C 14 aryl or C 5 -C 13 heteroaryl, wherein the alkyl, alkenyl and alkynyl radicals are straight-chain or branched and wherein all the radicals mentioned are unsubstituted or mono- or polysubstituted by identical or different substituents selected from the group: halide, NO ₂ , SO ₃ H, SO ₃ Na, SO ₃ K, CN, OH, NH ₂ , NH-lower alkyl, N-di-lower alkyl, COOH, COO-lower alkyl, lower-alkyl and C3-C6-cycloalkyl and wherein

terminal OH, NH ₂ and NH-lower alkyl groups and acidic H atoms are unprotected or protected with a protecting group being a mixture of a zinc (II) salt, an enantiomerically pure or enantiomerically enriched auxiliary of the formula R5 _χ

HO N-R6

C1 -C2

R3 R4 being

Alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl radicals or hydrogen are or

R5 and R6 together represent a C3-C7 alkylene or C3-C7 alkenylene radical and

at least one of the centers C1, C2, preferably both, independently of the

R1-M in which R1 has the abovementioned meaning and

where R2 has the meaning given above, is implemented.

2. A process according to claim 1 wherein the zinc (II) salt is selected from the group zinc chloride, zinc fluoride, zinc bromide, zinc iodide, zinc cyanide,

Zinc trifluoromethanesulfonate, zinc benzenesulfonate, zinc cresolsulfonate, zinc oxide, zinc acetate, zinc acetylacetonate, zinc nitrate, zinc phosphate, zinc hydrogen phosphate, zinc dihydrogen phosphate, zinc stearate, zinc sulfate, zinc hydrogen sulfate, zinc carbonate, zinc bicarbonate, zinc tetrafluoroborate, zinc trifluoroacetate, or mixtures thereof.

A method according to claim 2, wherein the zinc (II) salt is zinc chloride or zinc trifluoromethanesulfonate.

4. A process according to one or more of the preceding claims, wherein the base used is an organic base selected from the group of amines, phosphazene bases or alkyl lithium compounds.

5. A process according to one or more of claims 1 to 3, wherein the base used is an inorganic base selected from the group of metal alcoholates,

Metal amides, metal thiolates, metal hydrides or the complex metal hydrides.

6. A process according to one or more of claims 1, 2, 3, 5, wherein the base used is sodium hydride or potassium hydride.

7. A process according to one or more of the preceding claims, wherein the radical R1 of the organometallic compound is a cyclopropylethynyl radical.

8. A method according to one or more of the preceding claims, wherein the metal M of the organometallic compound is lithium.

A method according to one or more of the preceding claims, wherein the metal M of the organometallic compound is magnesium halide, magnesium cyanide or magnesium alcoholate.

10. A method according to one or more of the preceding claims, wherein the second auxiliary is an alcohol.

11. A process according to one or more of the preceding claims, wherein the second auxiliary is tert-butyl alcohol, neo-pentyl alcohol or benzyl alcohol.

12. A process according to one or more of the preceding claims, wherein the trifluoromethyl ketone is 1- (2-amino-5-chloro-phenyl) -2,2,2-trifluoroethanone.

13. A process according to one or more of the preceding claims, wherein the enantiomerically pure or enantiomerically enriched auxiliary is an N, N-disubstituted derivative of norephedrine.

14. A process according to one or more of the preceding claims, wherein the enantiomerically pure or enantiomerically enriched auxiliary is (1R, 2S) -1-phenyl-2- (1-pyrrolidinyl) -1-propanol.

15. The preparation of efavirenz starting from an aminoalcohol prepared according to one or more of the preceding claims.