MXPA99008913A - Asymmetric synthesis of benzoxazinones via new intermediates - Google Patents

Abstract

The present invention provides novel methods for the asymmetric synthesis of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one of formula (VI-i) which is useful as a human immunodeficiency virus (HIV) reverse transcriptase inhibitor. In an embodiment, the present invention provides a process for the preparation of an amino alcohol compound of formula (V-i) comprising adding a toluene solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to a toluene solution of a compound of formula (III-i), via a compound of formula (IV-i).

Description

ASYMMETRIC SYNTHESIS OF BENZOXAZINONAS THROUGH NEW INTERMEDIARIES Field of Invention The present invention provides novel methods for the asymmetric synthesis of (S) -6-chloro-4-cyclopropylethynyl-β-trifluoromethyl-1, -dihydro-2H-3, 1-benzoxazin-2 -one which is useful as an inhibitor of reverse transcriptase of the human immunodeficiency virus (HIV).

Background of the Invention Reverse transcription is a common form of retrovirus replication. Viral replication requires a virally encoded reverse transcriptase to generate DNA copies of viral sequences for reverse transcription of the viral RNA genome. Reverse transcriptase, therefore, is a clinically relevant target for the chemotherapy of retroviral infections because the inhibition of virally encoded reverse transcriptase can interrupt viral replication.

Ref: 031176 A number of compounds are effective in the treatment of the human immunodeficiency virus (HIV) which is the retrovirus that causes the progressive destruction of the human immune system with the resultant principle of AIDS. Effective treatment through the inhibition of HIV reverse transcriptase is known to be either nucleoside-based inhibitors, such as az idot imidine, and non-nucleoside-based inhibitors. Benz oxa zinones have been found to be useful inhibitors based on non-nucleosides of HIV reverse transcriptase. (S) -6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3, l-benzoxazin-2-one of formula (Vl-i): (Vl-i) Not only is it a highly potent reverse transcriptase inhibitor, it is also effective against resistance to HIV reverse transcriptase. Due to the importance of (S) -6-chloro-4-cyclopropylethynyl-trifluoromethyl-1,4-dihydro-2H-3, 1-benzoxazin-2-one as a reverse transcriptase inhibitor, it is necessary to develop its production a synthetic and efficient economic process.

Thompson et al, Te trahedron Le tt ers 1995, 36, 937-940, describes the asymmetric synthesis of an enantiomeric benzoxazinone by the addition of a highly enantioselective acetylide followed by cyclization with a condensing agent to form the benzoxazinone shown below.

The p-methoxybenzyl aniline starting material is synthesized by benzylation of the aniline nitrogen with p-me toxibenzyl chloride. Additionally, the general process generates a large volume of heavy metal waste in the waste stream due to the oxidation of ceric ammonium nitrate in the debenzylation step.

European Patent Application 582,455 Al describes the synthesis of benzoxazinones by means of a three-step process.

This general method teaches (1) the metallization of parachloroaniline pivalamide with n-butyllithium followed by a nucleophilic substitution with an ester to form a ketone, (2) the synthesis of a tertiary carbonyl by the addition of Grignard to the ketone, and (3) the cyclization of the unprotected amine with the carbonyl by the addition of a large excess of condensing agent to form a benzoxazinone. The process requires additional purification of the optical isomers using an optically active resolving agent such as an acid (-) camfánico.

Young et al, in PCT International Patent Application Number 9520389 Al discloses benzoxazinones useful in the inhibition of HIV reverse transcriptase, the prevention or treatment of HIV infection and the treatment of AIDS. Application WO 9520389 A1 describes synthesis methods that are provided with EP 582,455 A1. Additionally, Young et al, in An t imi crobi al Agen ts and Ch emo t erapy 1995, 39, 2602-2605, discussing the clinical benefit, the in vi tro activity, and the pharmacokinetic activity of benzoxazinone (VI) in the HIV treatment as an inhibitor of HIV reverse transcriptase, describes an abbreviated synthesis of benzoxazinone (VI) provided with EP 582.455 to the previous one wherein tertiary carbinol is synthesized by the addition of a cyclopropyl-ethynyl-lithium reagent before cyclizing the amine not protected with carbinol by the addition of a condensing agent.

Thompson et al, in PCT International Patent Application Number WO 9622955 Al discloses an improved synthesis of cyclopropylacetylene useful in the synthesis of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H -3, l-benzoxazin-2-one. The Application WO 9622955 Al discloses combinations of synthetic methods described in the above publications which continue to be inefficient in the general syntheses for which this invention makes significant improvements.

The above methods for the synthesis of benzoxazinones using combinations of relatively expensive materials, difficult to handle reagents, toxic, and inefficient chromatographic purification steps or general synthesis of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl- 1, 4-dihydro-2H-3, l-benzoxazin-2-one in low yields, thus, it is desired to discover new synthetic routes for long-range benzoxazinones with improvements on these limitations and to provide high yields of desirable benzoxazinones.

Accordingly, the present invention provides for a novel benzylation process, using acid catalyzed benzyl alcohols in place of the corresponding benzyl chloride analogues, which may be more expensive and unstable. The optimization of the procedure allows simplified processing since the product does not require isolation.

The present invention provides the preparation of (1R, 2S) -pyrrolidinyl norephedrine as a pure product that can be used as a solution stream reagent in the chiral addition of lithium cyclopropylacetylide. The present invention provides the preparation of cyclopropylacetylene as a pure product which can also be used as a solution current reagent in the chiral addition of the cyclopropylacetyl anion, for example, lithium cyclopropylacetyl.

The present invention provides an improved synthetic process for the asymmetric synthesis of benzoxazinones. The process of the present invention eliminates the use of highly toxic ceric ammonium nitrate, thereby eliminating cerium ions in the waste stream. The present invention provides an efficient non-chromatographic purification process to yield an enomerically pure product. Additionally, the present invention provides intermediates as stable solids that can be purified by recrystallization.

None of the references cited above describes the methods of the present invention for the synthesis of benzoxazinones useful as inhibitors of HIV reverse transcriptase.

Description of the invention.

The present invention concerns new processes for the preparation of benzoxazinone compounds that are useful as inhibitors of HIV reverse transcriptase. The processes are provided by a novel benzylation process of primary amines, using benzyl alcohols of catalytic acid. The processes of the present invention provide high yields, can be conducted on a kilogram scale, and provide stable intermediates. The invention is further provided for a non-chromatographic separation to improve the overall yields.

Therein is provided by this invention a process for the preparation of a compound of formula (VI): (VI) wherein: X is Cl or F, and A is -CF3, -C2F5 or -C3F7; said process comprises one of the following: (1) (addition) contact a compound of formula (I): (I) with a compound of formula (VII) or formula (VIII): wherein RJ is H or C? -6 alkyl, R is H, -CH3, -CH2CH3 or phenyl substituted with 0-3 R12, R3 is H, -CH3, -CH2CH3 or phenyl substituted with 0-3 R12, R4, R5, R4a, R5a, R6, R8 and R9 are independently selected from H, C? _6 alkyl, C1-6 alkoxy and C? _6 alkylthio, R, 1J2 is H, C? 5, alkoxy C? _6 alkylthio Ci e; Y is - (CH2) n or O, and n is O, 1, 2 or 3; in the presence of a methane sulphonic acid, p-toluene sulfonic acid or other appropriate acid catalyst to form a compound of formula (II): (II) where P is (2) (chiral addition) (a) contact IR norephedrine, 2S-pyrilidinyl with lithium .n-hexyl or other appropriate lithium alkyl and cyclopropylacetylide to form a mixture, (b) contacting the mixture of Step (2) (a) with a compound of the formula (II) to form a compound of the formula (III): (III) (3) (oxidative cyclization) contacting a compound of formula (III) with p-chloranil or other appropriate oxidizing agent to form a compound of formula (IV): (IV) where P "is (4) (de-benzylization) contact the compound of formula (IV) with the potassium hydroxide, sodium hydroxide or other appropriate partition agent, in the presence of sodium borohydride or other appropriate separation agent, to form a compound of formula ( V): (V) (5) (cyclization) contacting the compound of formula (V) with phosgene or other suitable cyclizing agent to form a compound of formula (VI).

Detailed description of the invention.

In a first embodiment, the present invention provides a novel process for the preparation of compound of formula (VI): (SAW) wherein X is Cl or F, and A is -CF3, -C2F5 or -C3F7; said process comprises: 1) contacting a compound of formula (I (I) with a compound of formula (VII) or formula (VIII): wherein: R1 is H, C? _6 alkyl, C? _6 alkylcarbonyl, R2 is H, R3 is H, -CH3, -CH2CH3 or phenyl substituted with 0-3 R12, R4, R5, R4a, R5a, R6, R8 and R9 are independently selected from H, C? _6 alkyl, C? -6 alkoxy and C? _6 alkylthio, R? 2 is H, C? _6 alkyl, C? _6 alkoxy or alkylthio C y Y is - (CH2) nu Or, and n is 0, 1, 2 or 3; in a suitable solvent, in the presence of an appropriate acid catalyst to form a compound of formula (II): (ID wherein P, a protective amino group, is (2) (a) contacting a compound of formula (IX): (IX) wherein R10 and R11 are independently C? -4 alkyl, or NR10R11 is pyrrolidinyl, piperidinyl or morpholinyl; with alkyl lithium and cyclopropylacet-ylene, in an appropriate solvent, to form a mixture, and (b) contacting the mixture of step (2) (a) with a compound of formula (II) to form a compound of formula (III): (III) (3) contacting a compound of formula (III), in a suitable non-aqueous solvent, with an appropriate oxidizing agent to form a compound of formula (IV): (IV) where P "is (4) contacting a compound of formula (IV) with a partition agent, in an appropriate solvent, in the presence of an appropriate separation agent, to form a compound of formula (V): Y (5) contacting a compound of formula (V) with an appropriate cyclizing agent, in an appropriate solvent, to form a compound of formula (VI).

In a preferred embodiment the process for the preparation of a compound of formula (VI) wherein X is Cl, and A is -CF3; includes: (1) contacting a compound of formula (I) with a compound of formula (VII), wherein: R 1 is H, C 1-6 alkyl or C 1 6 alkylcarbon, R 2 is H, R 3 is H, -CH 3, -CH 2 CH 3 or phenyl substituted with 0-3 R 12, R "R 5, R 4a, R 5a and R 6 are independently selected of H, C? _6 alkyl, C? _6 alkoxy and C? -6 alkylthio, and R 12 is H, C? _6 alkyl, C? _6 alkoxy or C? _6 alkylthio; in a suitable solvent, in the presence of an appropriate acid catalyst to form a compound of formula (II); (2) contacting norephedrine of 1R, 2S-pyrrolidinyl with lithium n-hexyl and cyclopropylacetylene, in an appropriate solvent, to form a mixture, and (b) contacting the mixture of step (2) (a) with a compound of formula (II) to form a compound of formula (III); (3) contacting a compound of formula (II) with an appropriate oxidizing agent, in an appropriate solvent, to form a compound of formula (IV); (4) contacting a compound of formula (IV) with an appropriate partitioning agent, in an appropriate solvent, in the presence of an appropriate separation agent, to form a compound of formula (V); Y (5) contacting a compound of formula (V) with an appropriate cyclizing agent, in an appropriate solvent, to form a compound of formula (VI).

In a more preferred embodiment, the process for the preparation of a compound of formula (Vl-i): (Vl-i) understands (1) contacting a compound of formula (I), wherein X is Cl and A is trifluoromethyl, with p-me toxibenzyl alcohol, in an appropriate solvent, in the presence of an appropriate acid catalyst, to form a compound of formula (H-i): (Il-i) (2) (a) contacting IR norephedrine, 2 S-pyrrolidinyl with the lithium n-hexyl and cyclopropylacetylene, in an appropriate solvent, to form a mixture, (b) contacting the mixture of step (2) (a) with a compound of formula (Il-i) to form a compound of formula (Ill-i): (IH-i) (3) contacting a compound of formula (Ill-i) with an appropriate oxidizing agent, in an appropriate solvent, to form a compound of formula (IV-i): e (IV-i) (4) contacting a compound of formula (IV-i) with a partition agent, in an appropriate solvent, in the presence of an appropriate separation agent, to form a compound of formula (V-i): (5) contacting a compound of formula (V-i) with an appropriate cyclizing agent, in an appropriate solvent, to form a compound of formula (Vl-i).

However in a more preferred embodiment in a process for the preparation of a compound of formula (VI): the appropriate acid catalyst is selected from the group: HCl, methanesulfonic acid, benzenesulfonic acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, trichloroacetic acid and p-toluenesulfonic acid, the appropriate oxidizing agent is selected from the group: n02, 2.3 -dichloro-5, 6-dicyano-l, 4-benzoquinone, p-tetrachlorobenzoquinone, o-tetrachlorobenzoquinone and iodobenzene diacetate, the partition agent is selected from the group: sodium alkoxide C?, lithium alkoxide C? _, potassium alkoxide C? _4, NaOH, LiOH, KOH and Ca (OH) 2, the separation agent is NaBH, NaHS03, hydroxyl amine, tosyl hydrazide or H202, and the appropriate cyclization agent is phosgene.

However in a further preferred embodiment, in a process for the preparation of a compound of formula (VI) the compounds of step (2) (a) and (b) are independently prepared and mixed as current solutions.

In a second embodiment, the present invention provides a process for the preparation of compounds of formula (II): (I) wherein: X is Cl or F, A is -CF3, -C2F5 or -C3F7, P is R 'is H, -CH3, -CH2CH3 phenyl substituted with R is H, -CH3, -CH2CH3 or phenyl substituted with 0-3 R 12 R 4, R 5, R 4a, R 5a, R 6, R 8 and R 9 are independently selected from H, C 1-6 alkyl C 1-6 alkoxy and C 1-6 alkylthio, R 12 is H, C 1-6 alkyl, C 1 alkylthio . Ci alkoxy 6 r Y is - (CH2) n u 0, and n is 0, 1, 2 or 3; said process comprises: contacting a compound of formula (I) (i) with a compound of formula (VII) or formula (VIII): wherein R1 is H or Ci-e alkyl or alkylcarbonyl, in a suitable solvent, in the presence of an appropriate acid catalyst to form a compound of formula (II).

In a preferred embodiment, a compound of formula (VII) is R] is H or methyl, R 2 is H or phenyl substituted with H or methoxy, R; is H or phenyl substituted with H or methoxy, R 4 is H or methoxy, and R ~ is H or methoxy.

In a further preferred embodiment, an appropriate acid catalyst is selected from the group: HCl, methosulonic acid, benzenesulonic acid, phosphoric acid, sulfuric acid, trichloroacetic acid, trifluoroacetic acid and p-toluene sulphonic acid.

In a third embodiment, the present invention provides a process for the preparation of compounds of formula (IV): (IV) where: X is Cl or F, A is -CF3, -C2F5 or • C3F7, P "is R- is H, -CH3, -CH2CH3 phenyl substituted with 0-3 R 12 R 4, R 5, R 4a, R 5a, R 6, R 8 and R 9 are independently selected from H, C 6 alkyl, C 6 alkoxy and C 1 6 alkylthio, R 12 is H, C 6 alkyl , alkylthio C-alkoxy C? _ 6 r Y is - (CH.) N or O, and n is O, 1, 2 or 3; said process comprises: contacting a compound of formula (III): (III) where it is Y R is H, in a non-aqueous solvent, with an appropriate oxidizing agent to form a compound of formula (IV).

In a preferred embodiment, a compound of formula (III) is In a more preferred embodiment, the appropriate oxidizing agent is selected from the group Mn02, 2,3-dichloro-5,6-di cyano-1,4-benzoquinone, p-tetrachlorobenzoquinone, oet-tehlorobenzoquinone and iodosobenzene diacetate.

In a fourth embodiment, the present invention provides a process for the preparation of compounds of formula (V): (V) wherein: X is Cl or F, and A is -CF3, C2F5 or -C3F7; said process comprises: contacting the compound of formula (IV) (IV) where P "is or: R is H, -CH3, -CH2CH3 or phenyl substituted with 0-3 R12, R4, R5, R4a, R5a, R6, R8 and R9 are independently selected from H, C? -6 alkyl, C? -6 alkoxy and C? _6 alkylthio, R12 is H, C? _6 alkylthio C? _6 or alkoxy C? _ Y is - (CH2) n or O, and n is O, 1, 2 or 3; with an appropriate partitioning agent, in an appropriate solvent, in the presence of an appropriate separation agent, to form a compound of formula (V).

In a preferred embodiment, a compound of formula (IV) is R3 is phenyl substituted with H or methoxy, R4 is H or methoxy, and R- is H or methoxy In a more preferred embodiment, the appropriate partition agent is selected from the group: C 1-4 alkoxide sodium, lithium C 1-4 alkoxide, potassium C 1-4 alkoxide, NaOH, LiOH, KOH and Ca (OH) 2, and the appropriate separation agent is selected from the group: NaBH, NaHS03, hydroxyl amine, tosyl hydrazide and H202.

In a fifth embodiment, the present invention additionally provides a process for the preparation of a compound of formula (VI): (SAW) wherein: X is Cl or F, and A is -CF3, -C2F5 or -C3F7; said process comprises (1) contacting a compound of formula (I): (i) with a compound of formula (VII) R wherein: R1 is H, alkyl Ci-e or alkylcarbonyl C? -6, R2 is -CH3, -CH2CH3 or phenyl substituted with 0-3 R12 R3 is -CH3, -CH2CH3 or phenyl substituted with 0-3 R12, R4, R5, R4a, R5a and R6 are independently selected from H, alkyl-β, alkoxy Ci-β and alkylthio ± -e, and R12 is H, alkyl -e, alkoxy- or alkylthio -6, in a suitable solvent, in the presence of an appropriate acid catalyst to form a compound of formula (II): (ID (2) (a) contacting a compound of formula (IX) wherein R 10 and R, 11 are independently C 1-4 alkyl, or -NR 10 R 11 is pi rrolidini, piperidinyl or morpholinyl, with alkyl of lithium and cyclopropylacetylene, in an appropriate solvent, to form a mixture, and (b) contacting the mixture of step (2) (a) with a compound of formula (II) to form a compound of formula (III) ): (III) (3) contacting a compound of formula (III) with an appropriate deprotecting agent, in an appropriate solvent, to form a compound of formula (V): (4) contacting a compound of formula (V) with an appropriate cyclizing agent, in an appropriate solvent, to form a compound of formula (VI).

In a seventh embodiment, the present invention provides a novel compound of formula (IV-i): (IV-i) or a pharmaceutically acceptable salt thereof In an eighth embodiment, the present invention provides a process for the preparation of a compound of formula (Il-i): (Il-i) comprising (1) heating an acetonitrile solution of a substituted aniline of formula (XII): and p-toluenesulfonic acid to a temperature of about 65 ° C to about 85 ° C while stirring; (2) adding an acetonitrile solution of a benzyl alcohol of formula (XIII): (XIII) for a period of from about 2 hours to about 10 hours to the solution of heated acetonitrile of the substituted aniline and p-toluenesulfonic acid; and (3) stirring the heated reaction mixture for about 30 minutes to about 2 hours to give the compound of the formula (Il-i).

In a preferred embodiment, the process for the preparation of a crystalline compound of formula (Il-i): (Il-i) understands (1) heating and stirring an acetonitrile solution of a substituted aniline of formula (XII): (XII) and p-toluenesulfonic acid up to a temperature of about 35 ° C to about 85 ° C; (2) adding an acetonitrile solution of a benzyl alcohol of formula (XIII) (XIII) for a period of from about 2 hours to about 10 hours to heat the acetonitrile solution of the substituted aniline and p-toluensulonic acid; (3) heating and stirring the reaction mixture for about 30 minutes to about 4 hours to give a crude solution of the compound of formula (I I-i); (4) cooling the crude solution of the compound of formula (I I-i); (5) add seed crystals at a temperature of around 20 ° C to around 30 ° C; (6) slowly adding water while stirring at a temperature of about 30 ° C to about 35 ° C to form a thick mixture of the crystalline compound of formula (Il-i); (7) stirring the thickened mixture for a reaction time of from about 2 hours to about 12 hours at about room temperature; (8) filtering the thick mixture of the crystalline compound of formula (Il-i) to isolate the crystalline compound of formula (Il-i); (9) washing the crystalline material with a mixture of acetonitrile and water in a volume up to a volume range of about 60:40 to about 40:60; Y (10) Dry the material under an inert atmosphere at a temperature of about 50 ° C.

In a ninth embodiment, the present invention provides a process for the preparation of an amino alcohol compound of formula (V-i): (Saw) which comprises (1) adding a toluene solution of 2,3-dichloro-5, β-dicyano-1,4-benzoquinone to a toluene solution of a compound of formula (in-i) while maintaining a reaction temperature of about 0 ° C to about 10 ° C; (2) maintaining the reaction temperature at about 0 ° C for about 1 hour to form a thick solution of 2,3-dichloro-5,6-dicyano-1,4-dihydroxybenzene and a compound of formula ( IV-i): (IV-i) (3) filter the solution. thick to remove 2, 3-dichloro-5,6-dicyano-1,4-dihydroxybenzene; (4) washing the waste cake of 2,3-dichloro-5,6-dicyano-1,4-dihydrobenzene with toluene; (5) combine the filtered and toluene washes; (6) concentrating in vacuo the solutions of the filtrate and toluene of the compound of formula (IV-i) with methanol to further remove the toluene; (7) add dropwise to the compound of formula (IV-i) in methanol at a temperature of about 40 ° C to about 45 ° C an aqueous solution of sodium hydroxide forming a clear solution of the amino and p-methoxy alcohol -benzaldehyde; (8) add dropwise to the clear solution of the amino alcohol a solution of NaBH4 in an aqueous solution of sodium hydroxide keeping the reaction temperature of about 40 ° C to about 45 ° C; (9) stirring the reaction mixture for about 30 minutes; (10) neutralizing the reaction with glacial acetic acid to a pH of about 8 to about 9; (11) add water to form a thick solution; (12) cooling the thick solution to about -15 ° C to about 0 ° C for about 1 hour; Y (13) filter the cooled thick solution of the amino alcohol and wash with water to give the crude crystalline amino alcohol as a pale yellow solid.

In a preferred embodiment, the present invention provides a process for the preparation of a pure crystalline amino alcohol compound of formula (V-i) comprising the additional steps of: (1) dissolving the crude amino alcohol in toluene at a temperature of about 60 ° C; (2) adding heptane to the toluene solution of the crude amino alcohol to form a thick solution of the pure amino alcohol; (3) cool the thick amino alcohol solution to about 0 ° C and keep at 0 ° C for about 1 hour; (4) filter the pure crystalline amino alcohol; (5) wash the pure crystalline amino alcohol with heptane; Y (6) Dry the pure crystalline amino alcohol in vacuo.

In a more preferred embodiment, the present invention provides a process for the preparation of a pure crystalline amino alcohol compound of formula (V-i) comprising the additional steps of: (1) dissolving the crude amino alcohol in a mixture of TBE-toluene at a temperature of about 20 ° C to about 30 ° C; (2) distill in vacuo the MTBE from the MTBE-toluene solution of the crude amino alcohol; (3) adding heptane to the toluene solution of the crude amino alcohol to form a thick solution of the pure amino alcohol; (4) cool the thick amino alcohol solution to about 0 ° C and keep at 0 ° C for about 1 hour; (5) filter the pure crystalline amino alcohol; (6) wash the pure crystalline amino alcohol with heptane; Y (7) Dry the pure crystalline amino alcohol in vacuo.

The processes of the present invention are useful for the preparation of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3, l-benzoxazin-2-one, which is useful as an inhibitor of human immunodeficiency virus (HIV) reverse transcriptase and compounds that are useful intermediates in the synthesis of (S) -6-chloro-4-cyclopropylethynyl-4-trifluorome ti 1-l, 4-dihydro-2H -3, l-benzoxazin-2-one. Such inhibitors of HIV reverse transcriptase are useful for the inhibition of HIV and the treatment of HIV infection. Such HIV reverse transcriptase inhibitors are useful for the inhibition of HIV in an ex vivo sample containing HIV or waiting to be exposed to HIV. In this manner, such HIV reverse transcriptase inhibitors can be used to inhibit HIV present in a body fluid sample (e.g., body fluid or semen sample) that contains or may contain or be exposed to HIV. Such reverse transcriptase inhibitors are also useful as standard or reference compounds for use in tests or assays to determine the ability of an agent to inhibit viral replication and / or reverse transcriptase, for example in a pharmaceutical resource program. In this way, such inhibitors of HIV reverse transcriptase can be used as a control or reference compound in such assays and as a quality control standard.

The following terms and abbreviations are used here and are defined as follows. The abbreviation: "THF" as used herein means tetrahydrofuran, "DMSO" as used herein means dimethyl sulfoxide, "DMAC" as used herein means dimethylacetamide, "MTBE" as used herein means methyl t-butyl ether, " BuLi "as used herein means butyllithium," NaH "as used herein means sodium hydride" LDA "as used herein means lithium diisopropylamide," TsOH "as used herein means p-toluensulonic acid," TMEDA "as used herein means N, N, N ', N'-te tramethyl-e-tynenediamine, and "DDQ" as used herein means 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, and "DDHQ "as used herein means 2,3-dichloro-5,6-dicyano-1,4-dihydroxybenzene otherwise known as 2,3-dichloro-5,6-dicyano-1,4-dihydrobenzoquinone.

The reactions of the synthetic methods claimed herein are carried out in appropriate solvents that can be readily selected by one skilled in the art of organic synthesis, said appropriate solvents generally being any solvent that is substantially unreactive with the starting materials ( reagents), intermediates, or products at the temperatures at which the reactions are carried out, that is, the temperatures that can be in the range from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in a solvent or a mixture of more than one solvent. Depending on the particular reaction step, the appropriate solvents for the particular reaction step can be selected.

Suitable halogenated solvents include chlorobenzene, fluorobenzene or dichloromethane.

Suitable ether solvents include: tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, or t-butyl methyl ether.

Suitable protic solvents may include, by way of example and without limitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2, 2, 2-t-rifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxy-tanol, 1-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene monomethyl ether glycol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol.

Aprotic solvents may include, by way of example and without limitation, rahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3, 4,5,6-tetrahydro-2 (H) -pyrimidinone (DMPÜ), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionylate, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane , N, N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexamethylphosphoramide.

Suitable basic solvents include: 2-, 3-, or 4-picoline, pyrrolo, pyrrolidine, morpholine, pyridine, or piperidine.

Suitable hydrocarbon solvents include: benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or naphthalene.

As used herein, the term "protecting amine group" (or "N-protecting") refers to any group known in the art of organic synthesis for the protection of amine group. Such 'amine protecting groups include those listed in Greene and Wust, "Protective Groups in Organics Synthesis" John Wiley & Sons, New York (1991), the description of which is incorporated herein for reference. Examples of protective amine groups include, but are not limited to, alkyl types such as benzyl, α-methylbenzyl, diphenylmethyl (benzhydryl), dimethoxybenzhydryl, triphenylmethyl (triflyl), 9-fluoroenyl, phenylfluoroenyl, dihydroanthracenyl, monomethoxytrityl, p-methoxybenzyl, 4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl.

As used herein, the term "chiral induced agent" or "chiral induction agent" refers to a non-reactive chiral agent that selectively induces the creation of a chiral center in excess of enantiomer during the addition of a non-chiral substrate to the center. -quiral. Examples of chiral induced agents include, but are not limited to, IR norephedrines, 2S-N-subsides such as IR, 2S-N-methylephedrine, norephedrine 1R, 2S-N-pyrrolidinyl, norephedrine IR, 2 SN-piperidinyl and norephedrine IR, 2 SN-morpholine.

As used herein, the term "acid catalyst" refers to any acidifying agent that catalyzes the addition of the alcohol derivative of an alkyl-type amine protecting group, such as benzyl alcohol, benzhydrol or trifyl alcohol, to a free base of a non-basic amine, such as the compound (I). Examples of catalyst acids include, but are not limited to, HCl, HBr, methanesulfonic acid, benzenesulonic acid, toluenesulfonic acid, sulfuric acid, trifluoroacetic acid, trichloroacetic acid, phosphoric acid and polyphosphoric acid.

As used herein, the term "oxidizing agent" refers to any agent that oxidizes a "benzylic" protected amine to the corresponding imine, thereby effecting the formation of the compound (IV) from a compound of the formula (III) by intramolecular cyclization. Examples of oxidizing agents include, but are not limited to, manganese dioxide, KMn0, K2SO5, KHSO5, DDQ, p-chloranil, s-chloranil and diacetate iodosobenzene.

As used herein, the term "deprotection agent" refers to any acidifying agent that can effect the removal of an alkyl-like amine protecting group, such as benzyl, benzhydryl or trifly, to a liberated base of an amine, such as the compound (IV). Examples of deprotection agents include, but are not limited to, HCl, HBr, methanesulfonic acid, benzenesulfonic acid, trichloroacetic acid, trifluoroacetic acid, phosphoric acid, and p-toluenesulfonic acid.

As used herein, the term "partition agent" refers to any agent that can effect the formation of a compound of formula (V) by the removal or debenzylation of P "from a hemiamine of formula (IV). Partitioning agents are strong bases, examples of these include, but are not limited to, metal hydroxides and metal alkoxides: NaOH, KOH, LiOH, Ca (OH) 2, NaOCH 3, NaOC 2 H 5, NaOC 3 H 8, NaOC 4 H 10, KOCH 3, KOC 2 H 5 and KOC4H? 0 As used herein, the term "separation agent" refers to any agent that can effect the conversion of a by-product to a material that can not react with the desired product compound (V), wherein, dding on the structure of P ", the by-product is an aromatic aldehyde or ketone during the removal or debenzylation of P" in a hemiamine of formula (IV). Separation agents, as used by one skilled in the art, are standard reducing agents, derivatizing agents or oxidizing agents; all of which are used for the selective reaction of a species in a solution on a second species in a solution. Examples of separation agent that reduce an aromatic aldehyde or ketone to an alcohol include, but are not limited to, sodium borohydride, lithium borohydride, potassium borohydride, sodium bisulfide and sodium trimethoxyborohydride; wherein sodium borohydride is preferred. Examples of separation agents that derivatize an aromatic aldehyde or ketone to an oxime or hydrazone include, but are not limited to, hydrozine, dimethyl hydrazine, hydroxyl amine and tosyl hydrazide. Examples of a separation agent that oxidizes an aromatic aldehyde to an aromatic carboxylic acid include, but are not limited to, hydrogen peroxide, t-butylhydroperoxide, K2SO5, and KHSO5.

As used herein, the term "cyclization agent" refers to any agent that can effect the formation of a benzoxazinone of the carbinol amino compound of formula (V). Examples of a cyclization agent include, but are not limited to, phosgene, 1, 1-carbonyldiimidazole, methyl chloroformate, and dimethyl carbonate.

As used herein, the term "lithiating agent" or "lithium alkyl" refers to an organolithium reagent that can titrically convert an alkyne to a lithium alkynyl. Examples of lithisation agents are, but are not limited to, n-hexyllithium, n-octyllithium, n-butyllithium, t-butyllithium, sec-butyllithium, isobutyllithium, lithium diisopropylamide, phenyllithium and triphenylmetillithium.

"Halo" or "halogen" as used herein refers to fluorine, chlorine and bromine.

"Alkyl" as used herein is projected to include both saturated straight or branched chain aliphatic hydrocarbon groups having from one to twelve carbon atoms. "Alkoxy" as used herein is projected to include an alkyl group of the number of carbon atoms indicated linked through an oxygen bridge; "alkylthio" as used herein is projected to include an alkyl group of the number of carbon atoms linked through a sulfur bridge.

The compounds described herein may have asymmetric centers. All chiral, diastereomeric, and racemic forms are included in the present invention. It will be appreciated that certain compounds of the present invention contain an asymmetrically substituted carbon atom, and can be isolated in racemic or optically active forms. The form for preparing optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials is well known in the art. All chiral, diastereomeric, racemic forms and all geometrically isomeric forms of a structure are tried, except the specific stereochemical or isomeric forms are specifically indicated.

Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. By stable compound or stable structure is shown here a compound that is sufficiently robust to survive isolated for a useful degree of purity from a reaction mixture.

The term "substituted", as used herein, means that one or more hydrogens on the designated atom is replaced with a selection of the indicated group, with the proviso that the designated atom does not exceed the normal valence, and that the substitution results in a stable compound.

The present invention is contemplated to be practiced on at least one multigram scale, kilogram scale, multikilogram scale, or industrial scale. The multigram scale, as used herein, is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, however more preferably at least 100 grams or more. The multikilogram scale, as used herein, is projected to mean the scale where more than one kilogram of at least one starting material is used. The industrial scale, as used here, is projected to mean a scale that is other than the laboratory scale and that is sufficient to distribute enough product for both clinical trials or distribution for consumers.

The methods of the present invention, as an example and without limitation, may be further understood by the reference in Scheme 1. Scheme 1 details the general synthetic method for asymmetric synthesis of the compounds of formulas (I) through (VI) wherein X is Cl and A is trifluoromethyl.

It will be understood that one skilled in the art of organic synthesis will be able to follow the methods described or exemplified herein to prepare homologs of the compounds of formula (I) up to (VI) wherein X is Cl or F and A is trifluoromethyl, pentafluoroethyl or heptafluoropropyl, by appropriately ligating a combination of p-chloroaniline or p-fluoroaniline with CF3C02Et, CF3CF2C02Et or CF2CF2C02Et in the preparation of compounds of formula (I).

It is burning 1 Dalqui lt ptio CFgCOgEl 2) HCI / solvent It is an object of the present invention to provide an improved process for the asymmetric synthesis of benzoxazinones which are useful as inhibitors of HIV reverse transcriptase.

Step 1: Addition: Preparation of Compounds of Formula (II).

This step is conducted by reacting a compound of formula (I), then converting the free base, in a suitable solvent at an appropriate temperature with benzyl alcohol, a benzyl ether, a benzhydryl alcohol or a benzhydryl ether in the presence of a catalyst suitable acid to form a compound of formula (II). For a general guide, the compound (I) in an aqueous / inorganic solvent at about room temperature can be neutralized based on around pH 7, contacting about 1 molar equivalent of a benzyl alcohol, a benzyl ether, an alcohol of benzhydryl or a benzhydryl ether, additionally connecting with from about 0.1 to about 5.0 mole% of an appropriate acid catalyst and heating at a temperature sufficient to form the compound (II). The compound (II) can be separated from the reaction as a stable solid by standard working methods. An example of standard work is shown in Example 3. Optionally, compound (II) can be leading in compounds of formula (III).

P is a benzyl or benzhydryl group derived from a compound of formula (VII) or (VIII), respectively, and is preferably p-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl or 4, '-dimethoxy benzhydryl. More preferably P is p-methoxybenzyl.

Preferred acid catalysts for step (1) include HCl, methane sulphonic acid, sulfuric acid, trifluoroacetic acid, trichloroacetic acid, and p-toluene sulphonic acid. The most preferred acid catalysts are metasulfonic acid and p-toluenesulfonic acid.

Preferred solvents and mixtures thereof for step (1) are toluene, dioxane, ethyl acetate, cyclohexane, dimethoxyethane, methylcyclohexane, 2-propanol and acetic acid. A more preferred solvent is toluene.

The preferred temperature range for step (1) is from about room temperature to about 120 ° C. More preferably when P is p-methoxybenzyl the temperature range is from about 60 to about 90 ° C.

It will be understood that one skilled in the art will be able to determine the preferred reaction time of Step 1 as a function of temperature, acid catalyst and group P. Generally, the reaction time is 0.5 to 12 hours.

Step 2: Chiral Induction: Preparation of the Compound of Formula (III).

This step, the chiral induction, comprises the alkylation of an achiral ketone carbonyl of a compound of formula (II) in the presence of a chiral induction agent of formula (IX) in an appropriate solvent, preferably at least about two equivalents. of a lithium cyclopropyl tinyl, said cyclopropylethynyl of lithium being generated in itself by the addition of a cyclopropylethynyl substituent to the compound (II) by contacting the cyclopropylacetylene with an appropriate lithium alkyl, for an appropriate length of time at a sufficient temperature to form a compound of formula (III). The generation of about two equivalents of lithium cyclopropylethynyl in situ can be carried out by contacting about two equivalents of cyclopropylacetylene with about four equivalents of an appropriate lithium alkyl in a solvent at a temperature below about -0 ° C. for about 1 to about 3 hours. It will be understood by one skilled in the art that about four equivalents of lithium alkyl are required to produce about two equivalents of cyclopropylethynyl lithium because about two equivalents of lithium alkyl react with two equivalents of the chiral induction agent. By means of a general guide, about two equivalents of a chiral induction agent of formula (IX), about four equivalents of an appropriate lithium alkyl and about two equivalents of cyclopropylacetylene are added, independently, by means of a few streams of solution and aged until a sufficient formation of cyclopropylethynyl lithium, in which about one equivalent of the compound of formula (II) in an appropriate solvent is added and maintained at a temperature below -30 ° C for 1- 3 hours to form the compound (III). The compound (III) can be separated from the reaction as a stable solid by standard working methods. An example of standard work is shown in Example 4.

It is preferred, but not required, that the reagents in this step be added as solution streams; that these be prepared separately as individual solutions before contacting each other. Reagents that can be quickly handled or handled can be added for the reaction mixture as such; for example, the compounds of formula (II) or chiral induction agents.

The preferred chiral induction agent for step (2) is IR norephedrine, 2 S-pyrrolidinyl.

Preferred lithium alkyl agents for step (2) include n-butyllithium, sec-butyllithium, t-butyllithium, isobutyllithium, n-hexylthio, and octyllithium. A more preferred lithium alkyl agent is n-hexylthio thio.

Preferred solvents and mixtures thereof for step (2) are tetrahydrofuran, hexane, cyclohexane, methylcyclohexane and toluene.

The preferred reaction times in step (2) are about two hours for the generation of cyclopropylethynyl lithium and about 1-2 hours for the addition of a compound (II) for norephedrine 1R, 2S-pyrrolidinyl / cyclopropylethynyl of lithium.

The preferred temperature ranges for step (2) are from about -50 to about -0 ° C for the generation of cyclopropylethynyl lithium and about -60 to about -40 ° C for the addition of the compound (II ) for cyclopropylethynyl lithium / IR norephedrine solution, 2S-pyrrolidinyl.

Step 3: Oxidative Cyclization: Preparation of the Compound of formula (IV).

This step comprises reacting a carbonyl compound of formula (III) in an appropriate solvent with preferably at least one equivalent of an appropriate oxidizing agent at a sufficient temperature for an appropriate length of time to form a compound of formula (IV). By means of a general guide, the compound (III) in a suitable non-aqueous solvent can be contacted with about one molar equivalent of an appropriate oxidizing agent and heated to a temperature for about one to about six hours sufficient to form a compound (IV). The compound (IV) can be separated from the reaction as a stable solid by quenching with an appropriate non-aqueous solvent, followed by standard working methods. A standard working example is shown in Example 5. Additionally, Compound (IV) can be lead without isolation in Step 4 for the preparation of Compound (V) as shown in Example 6b.

Preferred oxidation agents for step (3) include p-tetrachlorobenzoquinone and 2,3-dichloro-5,6-dicyano-1, -benzoquinone.

Preferred solvents and mixtures thereof for step (3) are toluene, heptane, ethyl acetate, methylt-butyl-ether, tetrahydrofuran, dichloromethane and cyclohexane.

For reactions when 2, 3-dichloro-5,6-dicyano- 1,4-benzoquinone use ethanol and methanol are suitable.

The reaction times for step (3) depend on the solvent and the temperature. A preferred reaction time for step (3) when the solvent is heptane / ethyl acetate followed by the addition of the oxidizing agent, is about four to about six hours.

A preferred temperature range for the addition of the oxidizing agent to the compound (III) depends on the solvent. A preferred temperature range for step (3) when the solvent is heptane / ethyl acetate is initially around room temperature and, then, reflux temperature.

Step Debutylation Preparation of Compound of Formula (V).

This step comprises. the reaction of a compound of formula (IV) in an appropriate solvent with an appropriate strong base at a temperature sufficient to form a compound of formula (V). Since a debinding product of the hemianima is an aromatic aldehyde or ketone, depending on the structure of P ", the aldehyde or ketone can be separated or converted by contact with an appropriate separation agent for a material that will not be able to react with the compound (V).

Three different methods of separation of an aromatic aldehyde or ketone by-product are possible. First, after reacting hemiamine (IV) with a strong base to form a compound of formula (V) and an aromatic aldehyde or ketone by-product, the by-product can be reduced for the corresponding alcohol with an appropriate reducing agent; allowing the amine (V) be isolated for neutralization of the reaction mixture followed by filtration.

Alternatively and secondly, the by-product can be separated by a reagent with higher affinity than the free amine (V) for the by-product, for example, the reaction of the by-product with hydroxyl amine for a corresponding oxime or, more preferably, the reaction of a sub-product with tosyl hydrazide to form the corresponding tosyl hydrazone, wherein the amine (V) can be isolated by a careful adjustment of the pH of the solution so as to crystallize or precipitate out the product of the desired amine (V) . Alternatively and third, the by-product, when an aromatic aldehyde, can be separated by a reagent which oxidizes the aldehyde to a corresponding acid but will not react with the amine or acetylene portions of (V); in such a way that a separation agent is a hydrogen peroxide under basic conditions.

By means of a general guide, the compound (IV) in an aqueous / organic solvent is contacted with an appropriate strong base, preferably sodium hydroxide or potassium hydroxide, at a temperature sufficient for an appropriate length of time to initiate the formation of a compound of formula (V) followed by the addition of an appropriate separating agent, preferably sodium borohydride, to a Sufficient temperature to quantitatively form the compound (V) while the aldehyde or ketone by-product is converted to its corresponding alcohol. Compound (V) can be separated from the reaction as a stable solid by quenching the separation agent, followed by pH adjustment of the solution and standard working methods. An example of standard work is shown in Example 6. Optionally, compound (V) may be leading in the synthesis of compounds of formula (VI).

Preferred strong bases for step (4) include sodium, potassium, lithium or calcium hydroxides, as well as metal alkoxides. The most preferable strong base is sodium hydroxide or potassium hydroxide.

Preferred separation agents are those which reduce the aromatic aldehyde / ketone by-product to an alcohol but do not react with the amine of the compound (V) or the acetylene of the compound (V). Of separation agents that are reducing agents, a preferred agent is sodium borohydride.

The preferred solvents for step (4) are alcohol mixed with water. The most preferred solvent is methanol and water.

The preferred reaction time for step (4) is from about one to about three hours.

A preferred temperature range for the addition of the base to the compound (IV) in step (4) is from about 0 to about 100CC; more preferably the temperature range is from about 30 to about 60 ° C, followed by the addition of a separating agent.

Step Cyclization Preparation of Compound of Formula (VI) This step comprises the cyclization of the chiral compound of formula (V) by contact with a cyclizing agent in an appropriate solvent at a temperature sufficient to form a compound of formula (VI). By means of guidance, about one equivalent of the compound (V) is contacted with about two equivalents of a cyclization agent and stirring at about 20 to about 25 ° C until the reaction is quantitative. The compound (VI) can be separated from the reaction as a stable solid by standard working methods. An example of standard work is shown in Example 7.

The preferred cyclization agent for step (5) is phosgene.

The preferred solvents in step (5) are heptanes, toluene and tetrahydrofuran. The most preferred solvent is a mixture of heptanes / tetrahydrofuran.

The preferred temperature range for the addition of the cyclizing agent in step (5) is less than or about 0 ° C.

With a judicious choice of reagents, it will be appreciated by one skilled in the art of organic synthesis, the claimed process can be performed in a clear manner to produce the compounds of formulas (II), (III), (IV), (V) ) and I saw) .

The present invention can be further exemplified by reference to Scheme 2 wherein R = H in an example of a compound of formula (VII).

E s qu ema 2 VI - The methods of the present invention, by way of example and without limitation, can be further understood by reference to Scheme 2a. This scheme further details the modalities of the general synthetic method for the preparation of a compound of formula (Il-i). The methods of Scheme 2a are provided for an excellent conversion of Compound (II-1) and facilitate crystallization of the product.

Scheme 2a.

By means of a general guide, a substituted aniline of formula (XII) and p-toluenesulfonic acid are heated and stirred in acetonitrile at a temperature of about 35 ° C to about 85 ° C so that a solution of acetonitrile from a benzyl alcohol of formula (XIII) is added over a period of time from about 2 hours to about 10 hours, preferably about 3 to about 8 hours; more preferably around 3 to about 6 hours. The molar ratio of the substituted aniline to p-toluenesulfonic acid is from about 1: 0.010 to about 1: 0.030; more preferably around 1: 0.015. the molar ratio of the substituted aniline to the substituted benzyl alcohol is from about 1: 1 to about 1: 1.2; more preferably around 1: 1.1. During the addition of the benzyl alcohol the reaction mixture is heated and further stirred for about 30 minutes to about 4 hours to give a crude solution of the compound of formula (II-1). The crude solution of the compound of formula (Il-i) is cooled to a temperature of about 20 ° C to about 30 ° C, preferably about 25 ° C.; after the seed crystals of (Il-i) are added. During the addition of the seed crystals, water is slowly added to form a thick mixture of the crystalline compound of formula (Il-i), while stirring the solution at a temperature of about 30 ° C to about 35 ° C. . The thick mixture is stirred for a reaction time of about 2 hours to about 12 hours at about room temperature after which the thick mixture is filtered to isolate the crystalline compound of formula (Il-i). The crystalline material is washed with a mixture of acetonitrile and water in a volume ratio of about 60:40 to about 40:60; preferably the volume to volume ratio of acetonitrile and water used is about 50:50. Finally, the crystalline material is dried under an inert atmosphere at a temperature of about 50 ° C.

The methods of the present invention, by way of example and without limitation, can be further understood by reference to Scheme 2b. This scheme further details the modalities of the general synthetic method for the preparation of a compound of formula (V-i). The methods of Scheme 2b allow 2, 3-dichloro-5,6-dicyano-1,4-dihydroxybenzene to be completely recovered, allowing to use less NaBH 4, and allowing recrystallization to proceed at a much lower temperature. In this way, this method allows crystallization a valuable intermediary.

Scheme 2b Ill-i IV- i V-i By means of a general guide, a toluene solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone is added to a toluene solution of a compound of formula (Ill-i) while maintaining a reaction temperature of about 0 ° C to about 10 ° C after which the reaction temperature is maintained at about 0 ° C for about 1 hour to form a thick solution of toluene of 2,3-dichloro- 5,6-dicyano-1,4-dihydroxybenzene and a compound of formula (IV-i). the thick solution is filtered to remove 2, 3-dichloro-5,6-dicyano-1,4-dihydroxybenzene; the waste cake resulting from 2,3-dichloro-5,6-dicyano-1,4-dihydrobenzene is washed with toluene. The washed filtrate and toluene are combined and concentrated in vacuo with the addition of methanol to remove more of toluene and yield the compound of formula (IV-i) in methanol at a temperature of about 40 ° C to about 45 °. C. To this solution is added an aqueous solution of sodium hydroxide drop by drop to form a clear solution of the amino alcohol (Vi) and p-methoxy-benzaldehyde during which a solution of NaBH 4 in an aqueous solution of sodium hydroxide is added. sodium drop by drop, all the time maintaining a reaction temperature of around 40 ° C to around 45 ° C. During the addition of the NaBH4 solution in an aqueous solution of sodium hydroxide, the reaction solution is stirred for about 30 minutes after which glacial acetic acid is added to neutralize the reaction at a pH of about 8 to about from 9. During the neutralization water is added to form a thick mixture and the thickened mixture is cooled to about -15 ° C to about 0 ° C for about 1 hour. The cooled thickened mixture of the amino alcohol (V-i) is filtered and washed with water to give the crude crystalline amino alcohol (V-i) as a pale yellow solid.

It is preferred to recycle (V-i) in toluene or in a mixture of MTBE-toluene. If the recrystallization proceeds in toluene, the crude crystalline amino alcohol is dissolved in toluene at a temperature of about 60 ° C after heptane is added to form a thick mixture of the pure amino alcohol. The thick mixture of amino alcohol is cooled to about 0 ° C and maintained at about 0 ° C for about 1 hour after which the pure crystalline amino alcohol is filtered. The pure crystalline amino alcohol is washed with heptane and dried in vacuo.

If the recrystallization proceeds in a mixture of MTBE-toluene, the crude crystalline amino alcohol is dissolved in a mixture of MTBE-toluene at a temperature of about 20CC to about 30 ° C after which the MTBE is distilled in vacuo. to form the MTBE-toluene solution. Heptane is added to form a thick mixture of the pure amino alcohol. The thick mixture of amino alcohol is cooled to about 0 ° C and maintained at about 0 ° C for about 1 hour after which the pure crystalline amino alcohol is filtered. The pure crystalline amino alcohol is washed with heptane and dried in vacuo.

The methods of the present invention, by way of example and without limitation, can be further understood by reference to Scheme 3 wherein none of R2 or R3 is H in an example of a compound of formula (VII). This scheme details additional embodiments of the general synthetic method for the preparation of compounds of formula (VI) using a very unstable amino acid protecting group. In addition to increasing the high yields of enantiomeric excess in the chiral induction step; the subsequent isolation of the compound (V) is carried out without chromatography in a one-step procedure, rapidly and under medium ambient temperature conditions.

It's burning 3 III VI Step 6: Addition: Preparation of the Compound of Formula (II) wherein R2 and R3 of compound (VII) or (VIII) are not H.

This step is conducted by the reaction of a compound of formula (I), then converting the free base to an appropriate solvent at an appropriate temperature with a compound (VII) or VIII), wherein neither R2 nor R3 are H, in the presence of an appropriate acid catalyst to form a compound of formula (II). By means of a general guide, the compound (I) in an aqueous / organic solvent at about room temperature can be neutralized with a base at around pH 7, contacting about 1 molar equivalent of a compound (VII) or (VIII) ), wherein neither R2 nor R3 are H, preferably trifly alcohol, additionally contacting with about 0.1 to about 5.0 mole% of an appropriate acid catalyst and heating at a temperature sufficient to form a compound (II). The compound (II) can be separated from the reaction as a stable solid by standard working methods. An example of standard work is shown in Example 11. Optionally, compound (II) can lead in the synthesis of compounds of formula (III).

The compound of (VII) or (VIII), wherein neither R nor R3 is H is preferably trifyl alcohol or trifyl alcohol substituted with methoxy.

Preferred acid catalysts for step (6) include HCl, sulfonic acid methane, sulfuric acid, trifluoroacetic acid and p-toluene sulfonic acid. The most preferred acid catalysts are sulphonic acid methane and p-toluene sulfonic acid.

Preferred solvents and mixtures thereof for step (6) are toluene, dioxane, cyclohexane, acetonitrile, ethyl acetate, dimethoxyethane, 2-propanol and acetic acid.

A preferred temperature range for the passage (1) is around room temperature to around 120 ° C. More preferably when the compound (VIII) is trifly alcohol the temperature range is from about 60 to about 90 ° C.

It will be understood that one skilled in the art will be able to determine the preferred reaction time of Step 1 depending on the temperature, acid catalyst and group P. Generally, the reaction time is 0.5 to 12 hours.

Step 7: The chiral induction step in the Scheme 3 is similar to the chiral induction step of Scheme 1; an example of the synthesis of a compound of formula (III) wherein P is a triflyl group is shown in Example 12.

Step 8: Destritylation: Preparation of the Compound of Formula (V).

This step comprises the reaction of a compound of formula (III), wherein the amino protecting group is very acidically unstable, for example triethyl, in a suitable solvent with from about 0.1 to about 2.0 equivalents of an appropriate acid at an average temperature sufficient to form a compound of formula (V). The destritylation by-product is an aromatic alcohol and subsequently needs not to be separated as in step (4) of Scheme 1, above. The compound (V) can be separated from the reaction as a stable solid by adjusting the pH of the solution and standard working methods. An example of standard work is shown in Example 13. Optionally, compound (V) can be leading in the synthesis of compounds of formula (VI).

The amino-protecting groups acceptable for step (8) are trifyl, p-methoxy triyl, 4,4'-dimethoxy triphenyl as well as non-trifly groups, such as 2,4-dimethoxy benzyl and 4,4'- dimethoxybenzhydryl. A preferred amino protecting group is trifly.

Preferred strong acids for step (8) include HCl, HBr sulfonic acid methane, trifluoroacetic acid and p-toluene sulphonic acid. A more preferred acid is HCl or trifluoroacetic acid.

The preferred solvents for step (8) are lower alkyl alcohols and do not need to be anhydrous, such as methanol, ethanol and propanols. The most preferred solvent is methanol.

A preferred temperature range for the addition of the acid to the compound (III) in step (8) is around 0 to about 50 ° C; more preferably the temperature range is from about 0 to about 30 ° C.

The preparation of cyclopropylacetylene, (X), which is a reagent in the formation of a compound of formula (III), is demonstrated in Scheme 4.

E s qu ema 4 1. NH4CI (aq) 2. P ase Sep. V 3. sieves 4. Fractional Dist. (XI) (X) The preparation of cyclopropylacetylene (X), by Scheme 4 is further illustrated in Example 15. This preparation of cyclopropylacetylene provides about 100% conversion of chloropentene (XI) and more than about 90% yield of cyclopropylacetylene, allowing thus the product (X) is used in a solution stream in the preparation of a compound of formula (III).

The following examples are mentioned to be illustrative of the present invention. These examples are presented to exemplify the invention and are not constructed as limiting the scope of the invention.

Example 1.

Preparation of N- (4-chlorophenyl) -2, 2-dimethyl propanamide 4-chloroaniline (52.7 kg, 413 moles) is dissolved in a mixture of t-butyl methyl ether (180 kg), 30% aqueous sodium hydroxide (61.6 kg, 463 moles) and water (24.2 kg), then cooled up to 15 ° C. The resulting thick mixture is charged with trimethylacetyl chloride (52.2 kg, 448 mol) for 1 hour, taking care of the temperature below 40 ° C. After stirring for 30 minutes at 30 ° C the thick mixture is cooled to -10 ° C and maintained for 2 hours. The product is collected by filtration, washed with a solution of 90/10 water / methanol (175 kg), then dried in vacuo to give 85 kg (97% yield of the title compound as a crystalline solid: mp. 152-153 ° C; XH NMR (300 MHz, CDC13) d 7.48 (d, J = Hz, 2H) 7.28 (d, J = 9 Hz, 2H); 13C NMR (75 MHz, CDC13) d 176.7, 136.6, 129.1 128.9, 121.4, 39.6, 27.6.

Preparation of N- (4-fluorophenyl) -2,2-dimethyl propanamide.

It will be understood that one skilled in the technique of organic synthesis that 4-fluoroaniline can be rapidly replaced by the above 4-chloroaniline to synthesize this compound.

Example 2 Preparation of the hydrochloride hydrate 4-chloro-2-trifluoroacetyl-aniline.

N- (4-chlorophenyl) -2,2-dimethyl propanamide (36.7 kg, 173 moles) is charged to a solution of TMEDA (20.2 kg, 174 moles) in anhydrous t-butyl methyl ether (271.5 kg) and cooled to - 20 ° C. To the cold thickened mixture is added n-butyllithium 2.4 N in hexane (101.9 kg, 393 moles) while keeping the temperature below 5 ° C. After aging 2 hours at 0 to 5 ° C, the solution is cooled down to -15 ° C and then reacting rapidly with ethyl trifluoroacetate (34.5 kg, 243 moles). After 30 minutes, the resulting solution is quenched in 3N HCl (196 L, 589 moles) taking care of the temperature below 25 ° C. After removing the aqueous phase, the organic solution is concentrated by distillation approximately 200 L of solvent. The acetic acid (352 kg) is added while distilling 325 kg of the solvent under 100 mm vacuum. After cooling the solution to 30 ° C, 12 N HCl (43.4 kg, 434 moles) is added and the mixture is heated to 65 to 70 ° C and maintained for 4 hours. The resulting thick mixture is cooled to 5 ° C and the product is collected by filtration, washed with ethyl acetate (50.5 kg) and dried in vacuo to give 42.1 kg (87%) of the title compound as a solid. crystalline white: pf 159-162 dec; 1R NMR (300 MHz, DMSO-d6) d 7.65-7.5 (complex, 2H), 7.1 (d, J = 8 Hz, 1H), 7.0 (brs, 3H); 19 F NMR (282 MHz, DMSO-d 6) d -69.5.

It will be understood by one skilled in the art of organic synthesis that CF3CF2C02Et or CF3CF2C02Et can be rapidly replaced by the above ethyl trifluoroacetate to synthesize additional homologues.

Example 3-a.

Preparation of 4-chloro-2-trifluoroacetyl-aniline.

The hydrochloride hydrate of 4-chloro-2-trifluoroacetylaniline (17.1 g, 62 mmol) is stirred in a mixture of toluene (100 mL) and water (50 mL). The mixture was neutralized to a pH of 7 with saturated NaHCO 3. The organic phase was concentrated in vacuo and the residue was recrystallized from heptane to give 12.5 g (91%) of the title compound as yellow strips: m.p. 98-99 ° C; 1H NMR (300 MHz, CDC13) d 7.70 (t, J = 2 Hz, 1H), 7.32 (dd, J = 2, 9 Hz, 1H), 6.7 (d, J = 9 Hz, 1H), 6.44 (brs, 2H), 13 C NMR (75 MHz CDC13) d 180.0, 151.6, 136.9, 130.1, 120.9, 119.0, 116.8, 111.4; 19F NMR (282 MHz, CDCI3) d-70.3.

E j us 3 Preparation of N- ((4'-methoxy) benzyl) -4-chloro-2-trifluoroacetylaniline. Compound (Il-i): To a thick mixture of 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate (40.0 kg, 144 moles) in toluene (140 kg) and water (50 L) was added 30% NaOH (18 kg) to a pH of 7.0 . After removing the aqueous phase, 4-methoxybenzyl alcohol (20 kg, 144 moles) and TsOH (1.0 kg, 5.3 moles) were added. The solution was heated to reflux and the azeotrope water / toluene distilled (30 L). The solution was cooled to room temperature and washed with saturated brine (80 kg). The organic solution was concentrated in vacuo to a volume of 35-40 L, then diluted with THF (52 kg). The weight percent of the title compound in toluene / THF was calculated by CLAP to be 43%. The yield based on CLAP% by weight analysis was 47.7 kg (96%). An analytical sample was obtained by stirring the solvent in va cuo and recris talizando from heptane: p.f. 82-84 ° C; 1 NMR (300 MHz, CDC13) d 9.04 (s, lH), 7.74 (d, J = Hz, 1H), 7.35 (dd, J = 2.9 Hz), 7.24 (d, J = Hz, 2H), (d, J = 8 Hz, 2H), 6.75 (d, J = 9 Hz, 1H), 4.43 (d, J = 6 Hz, 2H), 3.79 (s, 3H); 13 C NMR (75 MHz, CDC13) d 180.5, 159.2, 151.9, 137.4, 130.8, 128.9, 128.4, 119.9, 117.0, 114.4, 111.3, 55.3, 46.6.

E j us 4.

Preparation of (S) -5-chloro-a- (cyclopropylethynyl) -2- [(4-methoxyphenyl) methyl] -amino] a- (trifluoromethyl) benzenemethanol. Compound (iii-i): To a toluene solution of norephedrine (IR, 2S) -pyrrolidinyl (80 kg, containing 60.7 moles of norephedrine from (IR, 2 S) -pyrrolidinyl) was charged with triphenylmethane (100 g). The solution was concentrated in vacuo for about half of its original volume, anhydrous THF (35 kg) was added and the solution was cooled with the cooling jacket to -50 ° C. When the temperature reached -20 ° C, n-hexyl lithium (33% by weight in hexane, 33.4 kg, 119.5 moles) was charged while maintaining the temperature below 0 ° C. The resulting red solution was charged with a solution of cyclopropylacetylene (30% by weight in THF / hexanes / toluene, containing about 4 kg, 65 moles of cyclopropylacetylene) while maintaining an internal temperature below -20 ° C. The resulting solution was aged at -45 to -50 ° C for 1 hour. To the cold solution was charged a solution of N- (('-methoxy) benzyl) -4-chloro-2-trifluoroacetylaniline (43% by weight in THF / toluene, containing about 10 kg, 28.8 moles of N- ( (4'-methoxy) benzyl) -4-chloro-2-trifluoroacetylaniline) while maintaining a reaction temperature below -40 ° C. After aging the mixture at -43 +/- 3 ° C for 1 hour, the reaction was quenched in 140 kg of IN HCl, pre-cooled to 0 ° C. The organic layer was separated and extracted twice with portions of 25 kg of IN HCl, twice with 40 kg of water, and then concentrated in vacuo to a volume of about 29 L. Toluene (47 kg) was added. and the solution was concentrated to a volume of 28 to 30 L. Heptane was charged and the mixture was cooled and kept at -5 ° C for 4 hours. The product was filtered, washed twice with 10-kg portions of heptane and dried in vacuo to give 10 kg (85%) of the title compound as an off-white solid: m.p. 163-165 ° C; [a] 25D + 8.15 ° (c 1006, MeOH); 1 H NMR (300 MHz, CDC13) d 7.55 (brs, 1H), 7.23 (d, J = 8 2H), 7.13 (dd, J = 3, 9 4.95 (bs, 1H), 4.23 (s, 2H), 3.79 (s, 3H), 2.39 (, 1H), 1.34 (m, 1H), 0.84 (2H), 0.76 (m, 2H), 13C NMR (75 MHz, CDC13) d 158.9, 145.5, 130.6, 130.3, 130.2 , 128.6, 125.9, 122.0, 121.0, 121.6, 119.5, 114.8, 114.1, 94.0, 75.2, 74..7, 70.6, 55.3, 48.0, 8.6, -0.6, 19F NMR (282 MHz, CDC13) d-80.19.

E j a lo 5.

Preparation of (S) -6-chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluorornethyl) -2- (4'-ethoxyphenyl) -3,1-benzoxazine. Compound (V-i): To a solution of heptane (295.5 kg) and ethyl acetate (32.5 kg) was added p-chloranil (57 kg, 232 moles) and (S) -5-chloro-a- (cyclopropylethynyl) -2- [(4 - methoxyphenyl) methyl] -amino] -a- (tri fluoromethyl) benzenemethanol (89 kg, 217 moles). The mixture was refluxed with good stirring for 5.5 hours, and then with ethyl acetate (64.1 kg) and cooled to 30 ° C. The tetrahydroquinone te'trac was removed by filtration and washed with a mixture of heptane (104.7 kg) and ethyl acetate (31 kg). The filtrate was partially concentrated by distillation of 260 L of solvent, then diluted with heptane (177 kg) and cooled to -10 to 15 ° C. The resulting mixture was filtered and the product was washed with heptane (41 kg) and dried in the filtrate to less than 20% by weight of heptane (at least on drying). The yield of (IV), calculated by CLAP was 71 kg (80%). An analytical sample was obtained by triturating the sample with IN NaOH, followed by recrystallization from hexane / ethyl acetate: m.p. 130-131.7 ° C; 1 H NMR (300 MHz, DMSO-d 6) d 7.46 (d, J = 9 Hz, 2 H), 7.28-7.21 (, 3 H), 7.0 (d, J = 9 Hz, 2 H), 6.85 (d, J = 9 Hz, 1H), 5.52 (s, 1H), 3.78 (s, 3H), 1.52-1.47 (m, 1H), 0.980-0.84 (m, 2H), 0.72-0.68 (m.H); 13 C NMR (75 MHz, DMSO-dg) d 160.3, 143.8, 129.6, 129.3, 128.9, 125.8, 123.1, 121.7, 118.1, 117.8, 113.8, 93.6, 80.9, 74.1, 70.3, 55.2, 8.5, 8.4, -1.07; 19F NMR (282 MHz, CDC13) d -157.5 E j us 6 Preparation of Compound (V-i): (S) -5-Odor-a- (cyclopropylethynyl) -2-amino-a- (trxfluoromethyl) encenomethanol.

The (S) -5-chloro-4 - (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2-4'-methoxyphenyl) -3,1-benzoxazine (71 kg calculated dry weight) was charged to a mixture of methanol (301 kg), 30% NaOH (121 kg) and water (61 L). The mixture was heated to 60 ° C to give a clear solution which was then cooled to 30 ° C. A solution of sodium borohydride (3.2 kg, 84.2 moles) in 0.2 N NaOH (29 L) was added to the methanol solution for 20 minutes, taking care of the temperature below 35 ° C. After 30 minutes, the excess borohydride was quenched with acetone (5.8 kg) and the solution was diluted with water (175 L) and then neutralized to a pH of 8 to 9 with acetic acid. The resulting thick mixture was cooled to about 0 ° C, filtered and the product washed with water and then dried in vacuo at 40 ° C. The crude product was re-mixed with a mixture of toluene (133 kg) and heptanes (106 kg) initially at 35 ° C, and then with cooling below -10 ° C. The product was filtered, washed with heptanes (41 kg) and dried in vacuo at 40 ° C to give 44.5 kg (88%) of a pale yellow / off white crystalline solid. An analytical sample was recrystallized from t-butyl methyl ether / heptane: m.p. 141- 143 ° C; [α] 25D -28.3 ° (c 0.106, MeOH); 1 NMR (300 MHz, CDC13) d 7.54 (d.J = 2 Hz, 1H), 7.13 (dd, J = 9, 2 Hz, 1H), 6.61 (d, J = 9 Hz, 1H), 4.61 (brs , 1H), 4.40 (brs, 1H), 1.44-135 (m, 1H), 0.94-0.78 (m, 2H): 13C NMR (75 MHz, DMSDO-d6) d 146.7, 129.0, 124.3, 118.4, 118.97, 118.05, 92.3, 72.6, 71.0, 8.2, 8.1, -1.1; 19F NMR (282 MHz CDC13) d -80.5.

E xample 6b.

Preparation of Compound (V-i) from Compound (Ill-i) without isolating Compound (IV-i) in the previous step of synthesis: (S) -5-chloro-a- (cyclopropylethynyl) -2-ammo-a- (rxfluorornethyl) benzenemethanol.

To a thick mixture of DDQ (9.42 g, 41.5 mmol) in t-butyl methyl ether (33 ml) at 10 ° C was added a solution of (S) -5-chloro-a- (cyclopropylethynyl) -2- [ (4-methoxyphenyl) methyl] -amino-a- (t-rifluoro-yl) -benzenemethanol (16.38 g, 40 mmol). After 5 minutes, the resulting thick mixture was filtered at 30 ° C and the resulting solids were washed with 5 ml of t-butyl methyl ether. The filtrate was washed with 5% aqueous sodium bicarbonate and then partially concentrated by distillation of a solvent at 70 ml. Methanol (25 mL) was added followed by distillation of a solvent at 25 mL. Methanol (25 mL) and 6N NaOH (4 mL) were added followed by distillation of a solvent at 20 mL. 4N NaOH (26 mL) was added and the mixture was briefly heated to 58 ° C and then cooled to 30 ° C. A solution of sodium borohydride (0.60 g, 15.9 mmol) in 0.5 N NaOH was added. After 15 minutes, water (45 ml) was added followed by acetone (1 ml). After 0.5 hours, acetic acid (12 ml, 210 mmol) was added until a pH of 7.5, the resulting thick mixture was cooled to about 0 ° C, filtered and the product was washed with water and then dried in va at or 40 ° C. The crude product was re-mixed at room temperature with methylocyclohexane, cooled to about 0 ° C and filtered. This material was further purified by recrystallization from t-butyl methyl ether / hexanes to give 9.95 g (86%) as a white solid. The physical characteristics were identical to the product prepared by the process of step two (p-chloranil / NaBH4). (Example 6, previous.).

Example 7 Preparation of (S) -6-chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trxfluorornethyl) -2H-3, 1-benzoxazin-2-one. Compound (VI-x).

(S) -5-chloro-a- (cyclopropylethynyl) -2-amino-a- (t-rifluoromethyl) benzenemethanol (15.7 kg, 54.3 moles) was dissolved in a mixture of heptanes (32 kg) and THF (52 kg) under -10 ° C. Phosgene (~ 8.0 kg, 80 moles) was directly fed below the surface for about 1 hour, taking care of the temperature below 0 ° C. The resulting thick mixture was warmed to 20-25 ° C and held for 1 hour. Methanol (6.5 kg, 203 moles) was added and the solution was stirred for about 30 minutes. Heptanes (97 kg) were added and ~ 140 L of the solvent was distilled under reduced pressure. Heptans (97 kg) and THF (22 kg) were added and the solution was washed with 5% aqueous sodium bicarbonate (15 L), followed by water (15 L). the solution was warmed to 50 ° C and filtered in a cleaning reactor, followed by a rinse with heptanes. The solution was concentrated under reduced pressure, diluted with heptanes (22 kg) and cooled to -10 ° C. The product was filtered, washed with heptanes (37 kg) and dried in vacuo at 90-100 ° C to give 16.0 kg (95%) as an off-white to lightly pink solid. CLAP: 99.8 area%: p.f. 139-141 ° C; [α] 25D -94.1 ° (c 0.300, MeOH); 1 H NMR (400 MHz, DMSDO-d 6) d 11.05 (s, 1H), 6.99 (d, J = 7 Hz, 1H), 1.58 (m, 1H), (m, 2H), 0.77 (m, 2H); 13 C NMR (100 MHz, DMSO-d 6) d 146.23, 134.71, 132.04, 126.93, 126.57, 122.24, 116.83, 114.08, 95.63, 77.62, 65.85, 8.48, 8.44, -1.32; 19 F NMR (282 MHz, DMSO-d 6) d-81.1.

E j em lo 8.

Preparation of N- ((3 ', 4'-di ethoxy) benzyl) -4-chloro-2-trifluoroacetylanxoline. 4-Chloro-2-trifluoroacetylaniline (4.96 g, 40 mmol) and 3,4-dimethoxybenzyl alcohol (7.39 g, 44 mmol) were added to 2-propanol (40 mL). TsOH (76 mg, 0.4 mmol) was added and the mixture was heated to 60 ° C and maintained for 3.5 hours. The solution was concentrated in vacuo to half its original volume, diluted with water (10 mL) and stirred at room temperature. The resulting thick mixture was filtered and the product was dried in vacuo at 30 ° C to give 10.16 g (68%) of the title compound as a yellow powder. An analytical sample was obtained by recrystallization from acetonitrile: m.p. 82-84 ° C; XH NMR (CDC13) d 9.05 (brs, 1H), 7.75 (brt, J = 2 Hz, 1H), 7.35 (dd, J = 2, 8 Hz, 1H), 6.8 (d, J = 8 Hz, 3H) , 6.75 (d, J = 8 Hz, 1H), 4.43 (d, J = 5, Hz, 2H), 3.88 (s, 3H), 3.87 (s, 3H); 13C NMR (CDC13) d 179. 9, 151.9, 149.4, 148.7, 137.4, 130.8, 130.8, 130.7, 129.4, 110.4, 114.5, 111.5, 111.4, 110.3, 56.1, 56.0, 47.0; 19F NMR (CDC13) d -69.61.

Example 9 Preparation of (S) -5-chloro-a- (cyclopropyl-ethynyl) -2 - [(3,4-dimethoxyphenyl) methyl] -amino] -a- (trifluorornethyl) benzenemethanol.

A solution of 17.2% by weight of norephedrine of (IR, 2S) -pyrrolidinyl (254 g, 213 mmol) was concentrated by distillation to 160 mL of the solvent at atmospheric pressure. Triphenylmethane (0.2 g, 0.8 mmol) was added and the solution was cooled to room temperature. THF (130 mL) was added and the solution was cooled to -20 ° C. N-Hexyllium thio (2.0 M solution in hexane, 203 mL, 0.406 mol) was added while maintaining the temperature below 0 ° C. The mixture turned red after the addition of 108 mL. A solution of 16% by weight of cyclopropylacetylene (103 g, 0.25 mol) was added until the solution decolorized. The solution was stirred at -5 to 0 ° C for 20 minutes and then cooled to -45 ° C, at which point the compound N- ((3 ', 4'-dimethoxy) benzyl- -chloro was added. -2-trifluoroacetylaniline (29.7 g, 81.8 mmol) pre-dissolved in 50 mL of THF.After 1 hour at 45 ° C, the mixture was quenched in 2N HCl (400 mL) The organic layer was washed twice with HCl 2N (100 mL) and then concentrated in vacuo, toluene (150 mL) was added and the mixture was concentrated to a volume of 80 mL, heptane (100 mL) and the solvent ratio (determined by GC analysis) were added. ) heptane_toluene was adjusted to 60:40 by adding 43 mL of toluene After crystallization, the product was filtered and recrystallized from toluene: heptane (3: 1) to give 23.1 g (64%) of the title compound as a pale yellow solid: mp 128-129.5 ° C; [a] 25D + 11.00 ° (c 0.30, MeOH); 1 H NMR (300 MHz, CDC13) d 7.56 (m, 1H), 7.13 (dd, J = 9, 3 Hz, 1H), 6.84 (, 3H), 6.58 (d, J = 9 Hz, 1H), 4.24 ( m, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 1.34 (m, 1H), 0.90-0.74 (m, 4 H); 13C NMR (75 MHz, DMSO-d6) d 148.8, 147.8, 146.3, 131.4, 129.8, 129.4, 124.3, 119.1, 118.9, 118.2, 113.4, 111.8, 110.9, 92.7, 73.8, 70.9, 55.5, 55.3, 46.5, 8.2 , 8.1, -1-1; 19F NMR (282 MHz CDC13) d -80.0.

Example 10 Preparation of (S) -6-t-chloro-4- (cxclopropyl-ethynyl) -1,4-dihydro-4- (trifluoromethyl) -2- (3 ', 4'-dimethoxy) -3,1-benzoxazine.

To a solution of (S) -5-chloro-a- (cyclopropylethynyl) -2- [(3,4-dimethoxy phenyl) methyl] -amino] -a- (trifluoromethyl) benzenemethanol (2.68 g, 6.1 mmol) in methanol (10 mL) at 40 ° C was added DDQ (1.40 g, 6.1 mmol). The resulting thick mixture was cooled to 30 minutes in an ice bath and filtered. The product was washed with 5 mL of cold methanol and dried in vacuo to give 2.36 g (88%) of the title compound: m.p. 172-175 ° C; X H NMR (300 MHz, CDC13) d 7.48 (s, 1 H), 7.18 (dd, J = 2, 9 Hz, 1 H) 7.13 (d, J = 7 Hz, 1 H), 7.10 (s, 1 H), 6.87 ( d, J = 7 Hz, 1H), 6.70 (d, J = 9 Hz, 1H), 5.62 (d, J = 4 Hz, 1H), 4.33 (d, J = 4 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 1.33 (m, 1H), 0.90-0.72 (complex, 4H); 13 C NMR (75 MHz, CDC13) d 150.1, 149.3, 141.5, 129.9, 129.7, 127.3, 125.4, 125.0, 121.2, 120.8, 119.7, 119.0, 111.0, 109.7, 93.5, 81.4, 70.3, 56.0, 8.7, -0.4; 19 F NMR (282 MHz, CDCl 3) d -79.2.

Example 11 Preparation of N-rx enxlmetxl-4-chloro-2-fluoroacetylanilin. Method A. 4-Chloro-2-trifluoroacetylaniline (22.4 g, 100 mmol), triflyl chloride (30.0 g, 107 mmol), triethylamine (11.6 g, 115 mmol) and DMAP (0.5 g, 4 mmol) were dissolved in DMF ( 50 L) and maintained 14 hours at 60 ° C. The resulting thick mixture was cooled to room temperature, diluted with 20 mL of water and filtered to give 35.9 g (77%) of the title compound. An analytical sample was obtained by recrystallization from acetonitrile: m.p. 165-167 ° C; 1 H NMR (CDC13) d 10.4 (brs, 1H), 7.71 (brt, J = 2 Hz, 1H), '7.3 (brs, 15 H), 6.9 (dd, J = 2, 8 Hz, 1H), 6.27 ( s, J = 8 Hz, 1H) 13 C NMR (75 MHz, CDC13) d 180.5, 151.2, 144.1, 135.7, 130.7, 130.6, 129.2, 128.9, 128.7, 1286, 128.5, 128.2, 127.7, 127.5, 122.9, 120.3, 119.3, 119.1, 115.2, 112.3, 71.9; 19 F NMR (282 MHz, CDCl 3) d -69.5.

Preparation of N-triphenylmethyl-4-chloro-2-trifluoroacetylaniline. Method B.

Hydrochloride hydrate 4-chloro-2-trifluoroacetylaniline (84.4 g, 304 mmol), cyclohexane (350 mL), MTBE (95 mL), and water (100 mL) were stirred at room temperature. The resulting thick mixture was neutralized with 30 mL of 10 N NaOH. To the organic phase was added triethyl alcohol (91.0 g, 350 mmol) and TsOH (0.36 g, 1.9 mmol). The mixture was heated to reflux and 300 mL of the solvent was distilled. Acetonitrile (350 mL) and diisopropylethyl amine (0.5 mL) were added and distillation continued until an additional 220 mL of solvent was removed. The solution was cooled in an ice bath and the product was filtered to give 126.5 g (89%) of the product with the same spectrum and physical properties as those of the sample prepared in Method A.

Example 12 Preparation of 5-chloro-a- (cyclopropylethynyl) -2-triphenylmethyl] -amino] -a- (trifluoromethyl) benzenemethanol.

To a solution of cyclopropylacetylene (3.15 g, 48 mmol) and norephedrine of (IR, 2S) -pyrrolidinyl (10.9 g, 53 mmol) in THF (50 mL) was added n-hexilli t io 2N (46 mL, 92 mmol. ) taking care of the temperature below 0 ° C. It dissolved N-triphenyl-methyl-4-chloro-2-trifluoroacetylaniline (9.32 g, 20 mmol), in THF (20 mL) and added to the anionic solution and maintained at -45 to -50 ° C for 1 hour, then quenched with 1N citric acid (92 mL). The organic layer was separated, dried with sodium sulfate and concentrated to an oil. Crystallization from heptane / toluene gave 6.34 g (60%) of the title compound: p.f. 180-182 ° C; [a] 25D + 7.77 ° (c 1.004, CH3CN); 1 H NMR (300 MHz, CDC13) d 7.53 (d, J = 2 Hz, 1 H), 7.4-7.1 (complex, 16 H), 6.67 (dd, J = 2.7 Hz 1 H), 6.05 (d, J = 7 Hz, 1H), 3.17 (brs, 1H), 1.07, (, 1H) 0.72 (m, 2H), 0.62 (m, 2H); 13 C NMR (75 MHz, CDC13) d 143.7, 129.1, 129.0, 128.8, 128.1, 126.0, 122.2, 120.7, 118.7, 118.3, 94.7, 74.0, 71.6, 70.2, 8.4, 8.3, -0.8; 19 F NMR (282 MHz CDCl 3) d -79.9.

E j it lo 13.

Preparation of (S) -5-chloro-a- (cyclopropylethynyl) -2-amino-a- (trifluoromethyl) benzenemethanol. A Single Debying Step.

-Chloro-a- (cyclopropyl tinyl) -2- (tri phenylmethyl) -amino-a- (tri fluoromethyl) benzenemethanol (5.32 g, 10 mmol) was dissolved in methanol (25 L) and reacted with 12 N HCl (0.5 mL). ) at room temperature. After 15 minutes, 2N NaOH (2 mL) and water (20 mL) were added. The aqueous methanolic solution was extracted with cyclohexane (22 mL) followed by hexanes (20 mL) and then partially concentrated in vacuo and neutralized with acetic acid to pH 7. The product was filtered, washed with water and dried to give 2.65 g (92%): mp 140-143 ° C. The rostroscopic properties are identical with the material made by Example 6.

Example 14 Synthesis of (1R, 2S) -pyrrolidinyl norephedrine.

To a mixture of n-butanol (227 kg), water (144 kg) and potassium carbonate (144 kg, 1043 moles), was added (IR, 2 S) -norephedrine (68.6 kg, 454 moles). The mixture was heated to 90 ° C and 1,4-dibromobutane (113.4 kg, 525 moles) was added over 2 hours. The reaction was refluxed for 5 hours, and then cooled to 40 ° C. Water (181 kg) was added and the phases were separated at 30 ° C. To the organic phase was added 12N HCl (54.3 kg, 543 moles). The solution was heated to reflux and 150 L of the distillate was stirred at 200 to 300 mm. Toluene (39.5 kg) was added at 70 ° C and the resulting thick mixture was cooled to 0-5 ° C by crystallization. The product was collected, washed twice with toluene (39 kg each) and dried under a nitrogen purge to give 83.6 kg of the title compound as its hydrochloride salt. The hydrochloride salt was charged to toluene (392 kg) and water (42 kg) and treated with 30% NaOH (approximately 55 kg, 414 moles) to a pH higher than 12. After removing the lower aqueous phase, the The organic solution was partially concentrated by distillation of 140 L of the solvent to give a solution of 20% by weight of the title compound in toluene. The calculated yield was 50 kg (75%). An analytical sample was obtained by concentration of the toluene solution of the title compound in va cuo and then recrystallization from heptane: m.p. 46-48 ° C.

Example 15 Preparation of cyclopropylacetylene (X). 1. NH4CI (aq) 2. Phase Sep. 3. sieves 4. Fractional Diet. (XI) (X) A mixture of 5-chloro-1-pentyne, (XI), (23.0 kg, 224 moles) and anhydrous THF (150 kg) was cooled to -20 ° C. N-Hexyllithium (2.3 equivalents; 158 kg of 30% by weight) in hexane was added to the mixture at a ratio such as to not allow the temperature to rise from 5 ° C (about 2 hours). During the second half of the addition of n-hexyllithium, the temperature can remain above -5 ° C to prevent an organolithium build-up and a dangerous exothermic induction reaction. The reaction was aged at -5 to 0 ° C for 2 hours, until the GC analysis indicates at least 99% of the conversion. Toluene (35 to 40 kg) was then added and the reaction was concentrated under vacuum until the volume was reduced to ~ 1/3 of the original volume. The mixture was heated (to ~ 40 ° C) during the course of the concentration to maintain a good distillation ratio. The mixture was then cooled to 15 to -20 ° C and a solution of ammonium chloride (11 to 12 kg) in 50 to 60 L of water was added at a ratio such as to not allow the temperature to rise from 10 ° C. . After separation of the aqueous layer (approximately 70 kg), the reaction mixture was circulated through a tower containing 15 kg of 3Á molecular sieves until the water content was -300 ppm or less as determined by the Karl Fisher's analysis. The dried organic solution was then distilled through a column packed with steel wool at atmospheric pressure, collecting with cyclopropylacetylene, (X), as a solution in THF / toluene / hexane. The calculated yield was 14.0 kg.

E xemployment 16.

Synthesis of p-metoxxbenzyl-ketoanxlxna, I I -x XII-a XII Il-i Materials mw mol. e ui Ketoaniline-HCl 278.05 3,000 g 10.14 (94%) Xll-a t-butyl methyl 18 L ether (MTBE) Sodium acetate 82.03 1.419 g 17.3 1.7 Water D.I. 7.2 + 11 + 10 L Cetoaniline, XII 223.57 2,245 g 10.04 1.00 Alcohol of 4- 138.17 1,526 g 11.04 1.10 methoxybenzyl Acid p- 190.22 28.65 g 0.15 0.015 toluenesulfonic-H20 Acetonitrile 28 + 3 + 10 L Product Theory Il-i 343.73 3,451 g 10.04 1.00 Step A: Preparation of ketoaniline, XII.

In a 50 L extractor, D.I. water was charged. (3.6 L) and sodium acetate (1.419 g). The mixture was stirred at room temperature for 5-10 minutes, until the sodium acetate dissolved. Then t-butyl methyl ether (18 L) was added followed by the addition of the substrate Xll-a (3,000 g). The heterogeneous mixture was stirred at room temperature for 20-30 minutes or until the solids disappeared. The pH of the aqueous layer may be in the range of 4.0-6.0, otherwise HCl (6 N) or NaOH (5 N) are used to adjust the pH to the desired range. The batch is sealed and the two layers are separated. The organic layer is washed with D.I. (3.6 L) and transferred to a 50 L three-necked round bottom reaction flask equipped with a mechanical stirrer and a thermocoupler. The solution was concentrated to about 6-7 L, saturated with acetonitrile (2x12 L) and the volume of the final group adjusted with acetonitrile to 8-8.5 L. The ketoaniline XII in acetonitrile (the KF solution <300 mM) was analyzed by CLAP: a total of 2,245 g (10.04 moles) of XII was obtained after neutralization with a recovery of 99%.

Step B: Preparation of Il-i Under nitrogen, p-toluenesulfonic acid monohydrate (28.65 g, 0.15 mol) was added to a solution of ketoanilian XII in acetonitrile (8-8.5 L, 10.04 mol) in the 50 L flask, the reaction mixture was heated to 70 ° C with agitation. The alcohol of 4-methoxybenzyl (1.526 g, 11.04 moles) in acetonitrile was added for 5 hours, taking care of the group temperature at 68-72 ° C. The reaction was monitored by CLAP and this was usually completed within 2 hours after the alcohol addition.

The group was cooled to room temperature and fed. A bright yellow crystalline solid formed gradually. The thickened mixture is then aged at room temperature for 1-2 hours with stirring. Water (11 L) was added slowly over 2 hours at 35 ° C. After aging at room temperature for another 1-2 hours, the solid was filtered, washed with 50/50 acetonitrile / water (2x10 L). the wet cake was dried under vacuum (50 ° C, 28 in., 24 hours) to give the product Il-i (3.354 g, 99% by weight, 95% yield based on the LC test and 99.5 + LC area% ). The KF of the dry cake was less than 0.5 mol%.

Example 17 Synthesis of p-methoxybenzyl-ketoaniline, Il-i XII XIII Il-i Materials mw mol. equx, Cetoaniline, XII 223.57 250 g 1.12 1.00 Alcohol 4_ of 138.17 170 g 1.23 1.10 methoxybenzene XIII Acid p-190.22 3.19 g 0.018 0.15 toluenesulfonic- H20 Acetonitrile 1.7 L Water 1.5 L Product Theory Il-i 343.73 384.3 g 1.12 1.00 Under nitrogen, a 3-L three-necked round bottom flask, equipped with a mechanical stirrer, an addition funnel and a thermocoupler, was charged with acetonitrile (900 mL), ketoaniline XII (250 g, 1.12 mol) and p-toluenesulfonic acid monohydrate (3.19 g, 0.017 mol). The reaction mixture was then heated to reflux with stirring. 4-Methyl toxobenzyl alcohol (170 g, 1.23 mol) in acetonitrile (400 mL) was added by means of an addition funnel over a period of 4 hours. The group was nursed under reflux at 85 ° C. The reaction was monitored by CLAP and this was usually completed within 1 hour after the addition of the 4-metoxibenzyl alcohol.

The group was cooled to 45-50 ° C and fed. Water (1.1 L) was added in 30-40 minutes with agitation and the group became turbid. A bright yellow crystalline solid gradually formed during the process. The group is aged at room temperature for another 1-2 hours with shaking. The solid was isolated by filtration and the wet cake was washed with 50/50 acetonitrile / water (80 mL). This gave the product Il-i (361 g, 96.3% by weight, 90% yield and> 99.5% A) after drying. The water content in the cake was 0.6% per mole.

E xemployment 18.

Synthesis of Alcohol Amino, V-i Materials mw amount mol Protected amino alcohol- 409 1.14 kg 2.7 PMB Ill-i DDQ (98%) 227 0.64 kg 2.78 Toluene 12: L NaHC03 (5%) 84 2.50 L MeOH 14.0 L NaOH 5 N 40 2.50 L 12.51 NaBH4 (98%) 37.8 29.5 g 0.76 NaOH 0.5 N 295.0 mL Glacial acetic acid 778 imL Water 7.51 L Heptane 4.2 L Step A: Preparation of the amino alcohol, V-i. 2,3-Dichloro-5,6-dicyano-1-benzoquinone (DDQ) was dissolved in toluene (3.42 L at ~ 30 ° C and charged under N2 dropwise to a thick mixture of PMB-protected amino alcohol in toluene (5.7 L) at 0 ° C, maintaining the temperature between 0-10 ° C. The resulting mixture was aged at room temperature for 2 hours and filtered.The solid waste was washed with toluene (3 x 0.8 L). Filtration and washing were combined, washed with 5% aqueous NaHC03 and concentrated in vacuo to ~2 L at ~ 40 ° C. MeOH (9 L) was added in portions and the solution was concentrated to -2 L. The total volume of the solution was adjusted to 5 L with methanol.The solution was heated to 40 ° C and 5N NaOH (2.5 L) was added for -10 minutes The resulting clear solution was maintained at 40 ° C for 30 minutes A solution of NaBH in 0.5 N NaOH was added dropwise, maintaining the temperature at 40-45 ° C. The mixture was stirred at room temperature for 15 minutes, cooled to ~19 ° C, and neutralized with glacial acetic acid until pH -8.4 with an external cooling bath to maintain the temperature at 20-25 ° C. Water was added for 15 minutes. The mixture was maintained at 23 ° C for 1 hour and filtered. The solid was washed with one volume of the water cake and dried in vacuo to give a pale yellow solid: 823 g.

Step B: Recrystallization of the amino alcohol, V-i.

The crude product was charged in toluene (2.78 L) and heated rapidly to 60-64 ° C to give a clear solution. The solution was allowed to cool to room temperature while slowly adding heptane (4.17 L) (in 1 hour). The resulting thick mixture was cooled to 0 ° C and maintained for 1 hour. The solid was collected by filtration, washed with heptane (1 volume of solid), and dried in vacuo to give 734.2 g of the desired product as a white solid.

Alternative step B: Recrystallization of, V-i The crude product was charged in toluene (1.6 L) at 20-25 ° C. MTBE (0.66 L) was added to give a clear solution. The solution was concentrated in vacuo to -1.6 L. Toluene (0.5 L) was added. The solution was concentrated to -16 L again to give a thick mixture. Heptane (2.4 L) was charged into the thickened mixture for 1 hour. The resulting mixture was cooled to 0 ° C, aged for 1 hour, and filtered. The solid was washed with a solid volume of heptane and dried in vacuo to give the desired product as a white solid.

Although the present invention has been described with respect to the specific embodiments, the details of these modalities are not constructed as limitations. Various equivalents, changes and modifications can be made without departing from the spirit and scope of this invention, and it will be understood that such equivalent embodiments are parts of this invention. The present invention may be modified in other specific forms without departing from the spirit or essential attributions thereof and, consequently, reference may be made to the appended claims as further indications of the scope of the invention.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (13)

Claims

1. A process for the preparation of a compound of formula (Il-i): OR (Il-i) characterized in that it comprises (1) heating an acetonitrile solution of a substituted aniline of formula (XII): (XII) and p-toluenesulfonic acid to a temperature of about 65 ° C to about 85 ° C while stirring; (2) adding an acetonitrile solution of a benzyl alcohol of formula (XIII): (xiii) for a period of from about 2 hours to about 10 hours to the solution of heated acetonitrile of the substituted aniline and p-toluenesulfonic acid; Y (3) stir the heated reaction mixture for about 30 minutes to about 2 hours to give the compound of the formula (II-)).

2. The process for the preparation of a crystalline compound of formula (Il-i) characterized in that it comprises (1) heating and stirring an acetonitrile solution of a substituted aniline of formula (XII): (XII) and p-toluenesulfonic acid up to a temperature of about 35 ° C to about 85 ° C; (2) adding an acetonitrile solution of a benzyl alcohol of formula (XIII) (XIII) for a period of from about 2 hours to about 10 hours to heat the acetonitrile solution of the substituted aniline and p-toluenesulfonic acid; (3) heating and stirring the reaction mixture for about 30 minutes to about 4 hours to give a crude solution of the compound of formula (Il-i); (4) cooling the crude solution of the compound of formula (Il-i); (5) add seed crystals at a temperature of around 20 ° C to around 30 ° C; (6) slowly adding water while stirring at a temperature of about 30 ° C to about 35 ° C to form a thick mixture of the crystalline compound of formula (Il-i); (7) stirring the thickened mixture for a reaction time of about 2 hours to about 12 hours at about room temperature; (8) filtering the thick mixture of the crystalline compound of formula (Il-i) to isolate the crystalline compound of formula (Il-i); (9) washing the crystalline material with a mixture of acetonitrile and water in a volume up to a volume range of about 60:40 to about 40:60; Y (10) Dry the material under an inert atmosphere at a temperature of about 50 ° C.

3. The process as recited in claim 2, characterized in that the molar ratio of the substituted aniline to the toluenesulfonic acid is from about 1: 0.010 to about 1: 0.030.

4. The process as recited in claim 3, characterized in that the molar ratio of the substituted aniline to the substituted benzyl alcohol is from about 1: 1 to about 1: 1.2.

5. The process as recited in claim 4, characterized in that the reaction time in step 2 is about 3 up to about 8 hours.

6. The process as recited in claim 5, characterized in that the molar ratio of the substituted aniline to the toluenesulfonic acid is about 1: 0.015.

7. The process as recited in claim 6, characterized in that the molar ratio of the substituted aniline to the substituted benzyl alcohol is about 1: 1.1.

8. The process as recited in the rei indication 7, characterized in that the reaction time in step 2 is from about 3 to about 6 hours.

The process as recited in claim 8, characterized in that the temperature used in Step (5) is around 25 ° C.

10. The process as recited in claim 9, characterized in that the volume to volume ratio of the acetonitrile and water used in Step (9) is about 50:50.

11. A process for the preparation of an amino alcohol compound of formula (V-i): (Saw) characterized in that it comprises (1) adding a toluene solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to a solution of toluene of a compound of formula (I l-i) while maintaining a reaction temperature of about 0 ° C to about 10 ° C; (2) maintaining the reaction temperature at about 0 ° C for about 1 hour to form a thick solution of 2,3-dichloro-5,6-dicyano-1,4-dihydroxybenzene and a compound of the formula (I Vi) ): (IV-i) (3) filter the thick solution to remove 2, 3-dichloro-5,6-dicyano-1,4-dihydroxybenzene; (4) washing the waste cake of 2,3-dichloro-5,6-dicyano-1,4-dihydrobenzene with toluene; (5) combine the filtered and toluene washes; (6) concentrating in vacuo the solutions of the filtrate and toluene of the compound of formula (IV-i) with methanol to further remove the toluene; (7) add dropwise to the compound of formula (IV-i) in methanol at a temperature of about 40 ° C to about 45 ° C an aqueous solution of sodium hydroxide forming a clear solution of the amino and p-methoxy alcohol -benzaldehyde; (8) add dropwise to the clear solution of the amino alcohol a solution of NaBH4 in an aqueous solution of sodium hydroxide keeping the reaction temperature of about 40 ° C to about 45 ° C; (9) stirring the reaction mixture for about 30 minutes; (10) neutralizing the reaction with glacial acetic acid to a pH of about 8 to about 9; (11) add water to form a thick solution; (12) cooling the thick solution to about -15 ° C to about 0 ° C for about 1 hour; Y (13) filter the cooled thick solution of the amino alcohol and wash with water to give the crude crystalline amino alcohol as a pale yellow solid.

12. The process for the preparation of the pure crystalline amino alcohol compound of formula (V-i) as recited in claim 11, characterized in that it comprises the additional steps of: (1) dissolving the crude amino alcohol in toluene at a temperature of about 60 ° C; (2) adding heptane to the toluene solution of the crude amino alcohol to form a thick solution of the pure amino alcohol; (3) cool the thick amino alcohol solution to about 0 ° C and keep at 0 ° C for about 1 hour; (4) filter the pure crystalline amino alcohol; (5) wash the pure crystalline amino alcohol with heptane; Y (6) Dry the pure crystalline amino alcohol in vacuo.

13. The process for the preparation of the pure crystalline amino alcohol compound of formula (V-i) as recited in the claim 11, characterized in that it comprises the additional steps of: (1) dissolving the crude amino alcohol in a mixture of MTBE-toluene at a temperature of about 20 ° C to about 30 ° C; (2) distill in vacuo the MTBE from the MTBE-toluene solution of the crude amino alcohol; (3) adding heptane to the toluene solution of the crude amino alcohol to form a thick solution of the pure amino alcohol; (4) cool the thick amino alcohol solution to about 0 ° C and keep at 0 ° C for about 1 hour; (5) filter the pure crystalline amino alcohol; (6) wash the pure crystalline amino alcohol with heptane; Y (7) Dry the pure crystalline amino alcohol in vacuo Summary of the Invention The present invention provides new methods for the asymmetric synthesis of (S) -6-chloro-4-cyclopropylethynyltrifluoromethyl-1,4-dihydro-2H-3, 1-benzoxazin-2 -one of formula (VII-1) ) which is useful as an inhibitor of human immunodeficiency virus (HIV) reverse transcriptase. In one embodiment, the present invention provides a process for the preparation of an amino alcohol compound of formula (V-i) which comprises adding a solution of toluene of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to a solution of toluene of a compound of formula (Ill-i) or medium of a compound of formula (IV- i