MXPA99005410A

MXPA99005410A - Asymmetric synthesis of benzoxazinones

Info

Publication number: MXPA99005410A
Application number: MXPA/A/1999/005410A
Authority: MX
Inventors: Ernest Pierce Michael; Choudhury Anusuya; Lawrence Parsons Rodney Jr; Alicia Radesca Lilian
Original assignee: Dupont Pharmaceuticals Company
Priority date: 1996-12-16
Filing date: 1999-06-10
Publication date: 2000-04-24

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.

Description

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

Background of the Invention Reverse transcription is a common feature of retrovirus replication. Viral replication requires a virally encoded reverse transcriptase to generate DNA copies of viral sequences by 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 would interrupt viral replication.

A number of compounds are effective in Ref.: 30502 treatment of the human immunodeficiency virus (HIV) which is the retrovirus that causes progressive destruction of the human immune system with the resultant onset of AIDS. Effective treatment through the inhibition of HIV reverse transcriptase is known for both nucleoside-based inhibitors, such as azidothymidine, and non-nucleoside-based inhibitors. Benzoxazinones have been found to be useful non-nucleoside-based inhibitors 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-il Not only is it a highly potent reverse transcriptase inhibitor, it is also effective against the resistance of reverse transcriptase to HIV. Due to the importance of (S) -6-chloro-4-cyclopropylethynyl-trifluoromethyl-1, -dihydro-2H-3, l-benzoxazin-2-one as an inhibitor of reverse transcriptase, the synthetic process needs to be developed economic and efficient for its production.

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

The initial material of p-methoxybenzyl aniline is synthesized by means of the benzylation of nitrogen with p-methoxybenzyl chloride. Additionally, the overall process generates a large volume of heavy metal residue in the waste stream due to the oxidation of ceric ammonium nitrate in the descending step.

European Patent Application 582, 455 A1 describes the synthesis of benzoxazinones via a three-step process. its general method indicates (1) metalation of parachloroaniline pavalamide with n-butyl lithium followed by nucleophilic substitution with an ester to form a ketone, (2) synthesis of a tertiary carbinol by addition of Grignard to the ketone, and (3) ) cyclization of the non-protected amine with carbinol by the addition of a large excess of condensing agent to form a benzoxazinone. The process requires additional purification of the optical isomers through the use of an optically active resolving agent such as (-) canfánico acid.

Young et al, PCT International Patent Application Number WO 9520389 A1 describes benzoxazinones useful in the inhibition of HIV reverse transcriptase, the prevention or treatment of HIV infection and the treatment of AIDS. Application WO 9520389 Al discloses synthesis methods that are commensurate with EP 582,455 To the previous. In addition, Young et al., Anxi-crobial Agents and Chemo Therapy 1995, 39, 2602-2605, in which the clinical benefit, the in vi tro activity, and the pharmacokinetic activity of benzoxazinone (VI) in the treatment of HIV as an inhibitor of HIV reverse transcriptase exhibits an abbreviated synthesis of benzoxazinone (VI) commensurate with EP 582, 455 A1 where tertiary carbinol is synthesized by the addition of a cyclopropyl-ethynyl-lithium reagent before cyclization of the amine not protected with carbinol by the addition of a condensing agent.

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

The above methods for the synthesis of benzoxazinones use combinations of toxic reactants, difficult to handle, relatively expensive materials and inefficient chromatographic purification steps or in general the total synthesis of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl- 1,4-dihydro-2H-3, 1-benzoxazin-2-one in low yields. Thus, it is desirable to discover novel synthetic routes for large-scale benzoxazinones that improve these limitations and provide high yields of the desired benzoxazinones.

Therefore, the present invention provides a new benzylation process, which uses benzyl alcohols catalysed with acid instead of the corresponding benzyl chloride analogs, which can be very expensive and unstable. The optimization of the procedure allows the processing in line of current since the product does not require isolation.

The present invention provides the preparation of (IR, 2S) -pyrrolidinyl norephedrine since such a pure product could be used as a solution of stream reagent in the chiral addition of lithium cyclopropylacetylide. The present invention provides the preparation of cyclopropylacetylene since such a pure product could also be used as a solution of stream 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 the cerium ions in the waste stream. The present invention provides an efficient non-chromatographic purification process for producing the enantiomerically pure product. In addition, the present invention provides intermediates as stable solids purifiable by crystallization.

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.

Brief Description of the Invention The present invention relates to novel processes for the preparation of benzoxazinone compounds which are useful as inhibitors of HIV reverse transcriptase. The processes provide a new process for benzylation of primary amines, which uses benzyl alcohols catalyzed by acid. The process of the present invention provides high yields, which can be conducted on a kilogram scale, and produce stable intermediates. The invention also provides a non-chromatographic separation to improve the total production.

A process for the preparation of a compound of formula (VI) is provided by this invention: (VI) where: X is Cl or F, and A is -CF3, -C2-F5 or -C3F7; the process comprises one or more of the following: (1) (addition) contacting a compound of formula (I): (I) with a compound of formula (VII) or formula (VIII) where: R1 is H or C1.6 alkyl, R2 is H, -CH3, -CH2CH3 or phenyl substituted with 0-3 R12, R3 is H, -CH3, -CH2CH3 or phenyl substituted with 0-3 R12, R ", R5, R 4a, R 5a, R 6, R 8 and R 9 are independently selected from H, alkyl Ca 6, alkoxy C 4 and alkylthio Cr 6, R12 is C1.6alkyl, alkoxy6 or alkylthio Cj6, Y is - (CH2) n or 0, and n is 0, 1, 2 or 3; in the presence of methanesulfonic acid, p-toluenesulfonic acid or other suitable acid catalyst to form a compound of formula (II): where P is (II) (2) (chiral addition) (a) contacting IR, 2S-pyrrolidinyl norephedrine with n-hexyl lithium or other suitable alkyl lithium and cycpropylacetylene to form a mixture of IR, 2S-pyrrolidinyl norephedrine and lithium cyclopropylacetylide, (b) contacting a mixture of Step (2) (a) with a compound of formula (II) to form a compound of formula (III) (3) (oxidative cyclization) contacting a compound of formula (III) with p-chloranil or other suitable oxidizing agent to form a compound of formula (IV): (IV) where P "is (4) (debenzylation) contacting the compound of formula (IV) with potassium hydroxide, sodium hydroxide or other suitable cutting agent, in the presence of sodium borohydride or other suitable entrapment agent, to form a compound of formula (SAW) : (5) (cyclization) contacting a compound of formula (V) with phosgene or another suitable cyclization agent a compound of formula (VI).

Detailed description of the invention In a first embodiment, the present invention describes a new process for the preparation of compounds of formula (VI): (SAW! where: X is Cl or F, and A is -CF3, -C2F5 or -C3F7; the process comprises: (1) contacting a compound of formula (I) : D with a compound of formula (VII) or formula (VIII) where R1 is H, CX_6 alkyl or C1.6 alkylcarbonyl, R2 is H, R5 is H, -CH, -CH2Ch3 or phenyl substituted with 0-3 R12 R4, R5, R4a, R5a, R6, R8 and R9 are independently selected from H, C1.6alkyl, Ca_6alkoxy and alkylthio Cj.g, R12 is H, alkyl Cj_6, alkoxy Cj_6 or alkylthio Ca_6, Y is - (CH2) n or O, and n is O, 1, 2 or 3; in the presence of a suitable acid catalyst to form a compound of formula (II): P di; wherein P, an amine protecting group, is (2) (a) contacting a compound of formula (ix: (IX) wherein R10 and R11 are independently Cl.i alkyl, or -NR10R: 1 is pyrrolidinyl, piperidinyl or morpholinyl; with alkyl lithium and cyclopropylacetylene to form a mixture of a compound of formula (IX) and lithium cyclopropylacetylide, and (b) contacting the mixture of step (2) (a) with a compound of formula (II) to form a compound of formula (III): : IID (3) contacting a compound of formula (III) with a suitable oxidation agent to form a compound of formula (IV): (IV) where P "is (4) contacting a compound of formula (IV) with a suitable cutting agent, in the presence of a suitable entrapment agent, to form a compound of formula (V): (V) (5) contacting a compound of formula (V) with a suitable cyclization agent 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; comprises: (1) contacting a compound of formula (I) with a compound of formula (VII), wherein: R1 is H, C1.6 alkyl or C1.6 alkylcarbonyl, R2 is H, R3 is H, -CH3, -CH2CH3 or phenyl substituted with 0-3 R12 R4, R5, Ra, R5a, and R6, are independently selected from H, Cl 6 alkyl, C 1 alkoxy and C 1-6 alkylthio, and R12 is H, alkyl Cj_6, alkoxy C ^ and alkylthio C ^, in the presence of an appropriate acid catalyst to form a compound of formula (II); (2) (a) contact IR, 2S-pyrrolidinyl norephedrine with n-hexyl lithium and cyclopropylacetylene to form a mixture of IR, 2S-pyrrolidinyl norephedrine and lithium cyclopropylacetyl, 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 (III) with a suitable oxidizing agent to form a compound of formula (IV); (4) contacting a compound of formula (IV) with a suitable cutting agent, in the presence of a suitable entrapment agent, to form a compound of formula (V); Y (5) contacting a compound of formula (V) with a suitable cyclization agent to form a compound of formula (VI).

In a more preferred embodiment the process for the preparation of a compound of formula (Vl-i): (V -Í: includes: (1) contacting a compound of formula (I), wherein X is Cl and A is trifluoromethyl, with p-methoxybenzyl alcohol, in the presence of a suitable acid catalyst, to form a compound of formula (Il-i): (2) (a) contact IR, 2S-pyrrolidinyl norephedrine with n-hexyl lithium and cyclopropylacetylene to form a mixture of IR, 2S-pyrrolidinyl norephedrine and lithium cyclopropylacetylide, (b) contacting the mixture of step (2) (a) with a compound of formula (Il-i) to form a compound of formula (Ill-i): (III-i! (3) contacting a compound of formula (III-i) with a suitable oxidizing agent to form a compound of formula (IV-i): (IV-iJ 4) contacting a compound of formula (IV-i) with a suitable cutting agent, in the presence of a suitable entrapment agent, to form a compound of formula (V-i): (Saw) (5) contacting a compound of formula (V-i) with a suitable cyclization agent to form a compound of formula (Vl-i).

In a still more preferred embodiment in a process for the preparation of a compound of formula (VI): the suitable acid catalyst is selected from the group: HCl, methanesulfonic acid, benzenesulfonic acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, trichloroacetic acid and p-toluene sulphonic acid, the suitable oxidizing agent is selected from the group Mn02, 2,3-dichloro-5,6-dicyan-1,4-benzoquinone, p-tetrachlorobenzoquinone, o-tetrachlorobenzoquinone and iodosobenzene diacetate, the suitable cutting agent is selected from the group: C1_i alkoxide of sodium, lithium alkoxide Cl.i, alkoxide Ca.4 of potassium, NaOH, LiOH, KOH and Ca (HO) 2, the suitable entrapment agent is NaBH4, NaHS03, hydroxyl amine, tosyl hydrazide or H202, and the suitable cyclization agent is phosgene.

In a still further preferred embodiment in a process for the preparation of a compound of formula (VI) the compounds of step (2) (a) and (b) are prepared independently and mixed as solution streams.

In a second embodiment, the present invention provides a process for the preparation of compounds of formula (II): where X is Cl or F, A is -CF3, -C2F5 or C3F7, P is R: is H, -CH3, -CH2CH3 or phenyl substituted with 0-3 R1-, R- is H, -CH ,, -CH2CH3 or phenyl substituted with 0-3 R12, R1 R; R < R = Re and are independently selected from H, C: _6 alkyl, C: _ "alkoxy and C: _6f alkylthio.

R12 is H, C1.6alkyl alkylthio Cj_6 or alkoxy Cj.g, Y is - (CH2) n or 0, and n is O, 1, 2 or 3; the process comprises: contacting a compound of formula (I): (I) with a compound of formula (VII) or formula (VIII) (V I) where R1 is H, alkyl Cj_6 or alkylcarbonyl Cl.6 f in the presence of a suitable acid catalyst to form a compound of formula (II).

In a preferred embodiment a compound of formula 'VII) is R1 is H or methyl, R2 is H or phenyl substituted with H or methoxy, R3 is H or phenyl substituted with H or methoxy, R4 is H or methoxy, and R5 is H or methoxy.

In a further preferred embodiment a suitable acid catalyst is selected from the group: HCl, methanesulfonic acid, benzenesulfonic 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 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, C1.6alkyl, C2.alkyloxy and alkylthio Ca_6 , R12 is H, C1.6alkyl, C1.6alkylthio or Cx.6alkoxy, Y is - (CH2) n or O, and n is 0.1.2 or 3; The process includes: contacting a compound of formula (III): where P is R2 is H, in a non-aqueous solvent, with a suitable 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 suitable oxidizing agent is selected from the group MnO :, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, p-tetrachlorobenzoquinone, o-tetrachlorobenzoquinone and iodobenzene diacetate.

In a fourth embodiment, the present invention provides a process for the preparation of compounds of formula (V): (V) where: X is Cl or F, and A is -CF3, -C2F5 or -C3F7; The process includes: contacting the compound of formula (IV) (IV) where P "is R3 is H, -CH3, -CH2CH3 or phenyl substituted with 0-3 R12, R4, R5, Ra, R5a, R6, R8, and R9 are independently selected from H, C1.6 alkyl, C6 alkoxy, and C1.6 alkylthio, R: 2 is H, C1.6 alkyl, C12 alkylthio, or alkoxy C? _6, Y is - (CH;) nu O, and n is 0,1,2 or 3; with a suitable cutting agent, in the presence of a suitable entrapment 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 R5 is H or methoxy.

In a more preferred embodiment, the suitable cutting agent is selected from the group: sodium C 1 alkoxide, lithium C 4. Alkoxide, potassium C 1 alkoxide, NaOH, LiOH, KOH and Ca (OH) 2, and the entrapment agent is selected from the group: NaBH ,, NaHSO-, hydroxyl amine, tosyl hydrazide and H; 02 In a fifth embodiment, the present invention further 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; The process includes: (1) contacting a compound of formula (I) with a compound of formula (VII) (VINE where: R1 is H, C1_6 alkyl or CX.6 alkylcarbonyl, R2 is -CH3, -CH2CH3 or phenyl substituted with 0-3 R12, R3 is -CH3, -CH2CH3 or phenyl substituted with 0-3 R12, R 4, R 5, R 4a, R 5a, and R 6 are independently selected from H, C: 6 alkyl, C 1 alkoxy and C 1 6 alkylthio and R12 is H, alkyl or CX_6 alkylthio; in the presence of a suitable acid catalyst to form a compound of formula (II): (ID (2) (a) contacting a compound of formula (IX IX) wherein R10 and R11 are independently alkylCa_4, or -NR10R :: is pyrrolidinyl, piperidinyl or morpholinyl; with alkyl lithium and cyclopropylacetylene to form a mixture of a compound of formula (IX) and lithium cyclopropylacetyl, 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 (III) with a suitable deprotection agent to form a compound of formula (V): (V) (4) contacting a compound of formula (V) with a suitable cyclization agent to form a compound of formula (VI).

In a seventh embodiment, the present invention provides a novel compound of formula (IV-i): e (IV-i) or a pharmaceutically acceptable salt thereof 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 a human immunodeficiency virus (HIV) reverse transcriptase inhibitor and compounds that are useful intermediates in the synthesis of (S) -6-chloro-4-cyclopro? iletinyl-4-trifluoromethyl-1,4-dihydro-2H- 3, l-benzoxazin-2-one. Such HIV reverse transcriptase inhibitors are useful for the inhibition of HIV and the treatment of HIV infection. Such inhibitors of HIV reverse transcriptase are useful for the inhibition of HIV in an ex vivo sample that contains HIV or is expected to be exposed to HIV.

Thus, such inhibitors of HIV reverse transcriptase could be used to inhibit the HIV present in a body fluid sample (e.g., a sample of body fluid or semen) that contains or is suspected to contain or be exposed to HIV. Such reverse transcriptase inhibitors are also useful as standard compounds or reference compounds for use in tests or assays to determine the ability of an agent to inhibit viral replication and / or HIV reverse transcriptase, for example in a research program. pharmaceutical Thus, such reverse transcriptase inhibitors could be used as a control or reference compound in such tests and as a standard quality control.

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 dimethylsulfoxide, "DMAC" as used herein means dimethylacetamide, "MTBE" as used herein means methyl t-butyl ether, "BuLi" as used herein means butyl lithium, "NaH" as used herein. use here means sodium hydride, "LDA" as used herein means lithium diisopropylamide, "TsOH" as used herein means p-toluenesulfonic acid, "TMEDA" as used herein means N, N, N ', N', - tetramethyl-ethylenediamine, and " DDQ "as used herein means 2,3-dichloro-4,5-dicyanobenzoquinone.

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

Suitable halogenated solvents include chlorobenzene, fluorobenzene or dichloromethane.

Suitable ether solvents include: tetrahydrofuran, diethyl ether, ethylene glycol di ethyl 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 could include, by way of example and without limitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2- methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glyph .col monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol.

Suitable aprotic solvents could include, by way of example and without limitation, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3, 4, 5, 6-tetrahydro-2 (OH) ) -pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, 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, pyrrole, 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 "amine protecting group" (or "N-protected") refers to any group known in the art of organic synthesis for the protection of amine groups. Such amine protecting groups include those listed in Greene and Wuts, "Protective Groups in Organic Synthesis" John Wiley & Sons, New York (1991), the exhibition of this is incorporated here by reference. Examples of amine protecting groups include, but are not limited to, alkyl types such as benzyl, -methylbenzyl, diphenylmethyl (benzhydryl), dimethoxybenzhydryl, triphenylmethyl (triflyl), 9-fluorenyl, phenylfluorenyl, dihydroanthracenyl, mon orne t oxitriitre 1 , p-me t ox i be nci 1, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl.

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

As used herein, the term "acid catalyst" refers to any acidic agent that catalyzes the addition of the alcohol derived from an alkyl-type amine protecting group, such as benzyl alcohol, benzhirdrol or trityl alcohol, to a free base form of a non-basic amine, such as compound (I). Examples of acid catalysts include, but are not limited to, HCl, HBr, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, sulfuric acid, trifluoroacetic acid, trichloroacetic acid, phosphoric acid and polyphosphoric acid.

As used, 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) of a compound of the formula (III) by intramolecular cyclization. Examples of oxidizing agents include, but are not limited to, manganese dioxide, KMn04, K2S05, KHS05, DDQ, p-chloroanil, o-chloroanil and iodosobenzene diacetate.

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

As used herein, the term "cutting agent" refers to any agent that can effect the formation of a compound of formula (V) by the removal of P "from a hemiaminal of formula (IV). cut-outs are strong bases, examples of these include, but are not limited to, metal hydroxides and metal alkoxides: NaOH, KOH, LiOH, Ca (0H) 2, NaOCH 3, NaOC 2 H 5, NaOC 3 H 8, NaOC 4 H 10, KOCH 3, KOC 2 H 5 and KOC 4 H 10.

As used herein, the term "entrapment agent" refers to any agent that can effect the conversion of a by-product to a material that will not react with the desired product compound (V), wherein, depending on the structure of P " the by-product is an aromatic aldehyde or ketone in the removal or debenzylation of P "in a hemiaminal of formula (IV). Entrapment agents, as used by one skilled in the art, are standard reducing agents, derivatizing agents or oxidation 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 a trapping agent that reduces an aromatic aldehyde or ketone to an alcohol include, but are not limited to, sodium borohydride, lithium borohydride, potassium borohydride, sodium bisulfite and sodium trimethoxyborohydride; where sodium borohydride is preferred. Examples of entrapment agents that derive an aromatic aldehyde or ketone to an oxime or a hydrazone include, but are not limited to, hydrazine, dimethyl hydrazine, hydroxyl amine and tosyl hydrazide. Examples of a trapping agent that oxidizes an aromatic aldehyde to an aromatic carboxylic acid includes, but is not limited to, hydrogen peroxide, t-butylhydroperoxide, K2S05, and KHS05.

As used herein, the term "cyclization agent" refers to any agent that can effect the formation of a benzoxazinone from the amino carbinol compound (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 "alkyl lithium" refers to an organolithium reagent that can quantitatively convert an alkyne to an alkynyl lithium. Examples of lithiating agents are, but are not limited to, n-hexyl lithium, n-octyl lithium, n-butyl lithium, t-butyl lithium, sec-butyl lithium, isobutyl lithium, lithium diisopropylamide, phenyl lithium and triphenylmethyl lithium.

"Halo" or "halogen" as used herein refers to fluoro, chloro and bromo.

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

The compounds described herein could 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 could be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, of optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is 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 meant a compound that is sufficiently robust to survive isolation for a useful degree of purity of a reaction mixture.

The term "substituted", as used herein, means that one or more hydrogens at the designated atom is replaced with a selection of the indicated group, provided that the normal valence of the designated atom is not exceeded, and that 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, even more preferably at least 100 grams or more. The multikilogram scale, as used herein, is understood to mean the scale where more than one kilogram of at least one starting material is used. The industrial scale as used herein is understood to mean a scale that is different from a laboratory scale and that is sufficient to supply sufficient product for clinical testing or distribution to consumers.

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

It is understood that one skilled in the art of organic synthesis could follow the methods described or exemplified herein for preparing homologs of compounds of formula (I) to (VI) wherein X is Cl or F and A is trifluoromethyl, pentafluoroethyl or heptafluoropropyl, by choosing suitably a combination of p-chloroaniline or p-fluoroaniline with CF3C02Et, CF3CF2C02Et or CF3CF2CF2C02Et in the preparation of compounds of formula (I).

It is the 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 the Compound of Formula (II) This step is conducted by reacting a compound of formula (I), after conversion to the free base, in a suitable solvent at a suitable temperature with a benzyl alcohol, a benzyl ether, a benzhydryl alcohol or a benzhydryl ether in the presence of a suitable acid catalyst to form a compound of formula (II). As a general guide, the compound (I) in an aqueous / organic solvent at about room temperature could be neutralized based on about pH 7, contacted with about 1 molar equivalent of a benzyl alcohol, a benzyl ether, a benzhydryl alcohol or a benzhydryl ether, additionally contacting about 0.1 to about 5.0 mol% of a suitable acid catalyst and heating at a temperature sufficient to form the compound (II). The compound (II) could 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) could be developed in the synthesis of compounds of formula (III).

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

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

A 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 is understood that one skilled in the art can determine the preferred reaction time of Step 1 as temperature dependent, acid catalyst and group P. In general, the reaction time is 0.5 to 12 hours. • * Step 2: Chiral Induction: Preparation of the Compound of Formula (III) This step, a chiral induction, comprises the alkylation of an achiral carbonyl ketone of a compound of formula (II) in the presence of a chiral induction agent of formula (IX) in a suitable solvent with preferably at least about two equivalents of a cyclopropyynyl lithium, the cyclopropyynyl lithium which is generated in itself by the addition of a cyclopropyynyl substituent to the compound (II) by contacting cyclopropylacetylene with a suitable alkyl lithium, for a suitable duration of time at a temperature sufficient to form a compound of the formula III). The generation of approximately two equivalents of cyclopropyyllithium in situ could be carried out by contacting about two equivalents of cyclopropylacetylene with about four equivalents of a suitable alkyl lithium in a suitable solvent at a temperature of about below -0 ° C for about 1 to about 3 hours. As a general guide approximately two equivalents of an induction agent of formula (IX), about four equivalents of a suitable alkyl lithium and about two equivalents of cyclopropylacetylene are added, independently, by solution streams and matured to sufficient formation of ciclopx inyl lithium, wherein about one equivalent of the compound of formula (II) in a suitable solvent is added and maintained at a temperature of -30 ° C for 1-3 hours to form compound (III) . The compound could 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; which are prepared separately as individual solutions before contacting each other. Reagents that can be handled or handled easily as solids can be added to the reaction mixture as such; for example compounds of formula (II) or chiral induction agents.

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

The preferred alkyl lithium agents for the passage (2) includes n-butyl lithium, sec-butyl lithium, t-butyl lithium, iso-butyl lithium, n-hexyl lithium and octyl lithium. A most preferred agent of alkyl lithium is n-hexyl lithium.

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 the compound (II) to IR, 2S-pyrrolydinyl norephedrine / cyclopropylethynyl lithium.

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

Step 3: Oxidative Cyclization: Preparation of Compound of Formula (IV) This step comprises reacting a carbinol compound of formula (III) in a suitable solvent with preferably at least about one equivalent of a suitable oxidizing agent at a temperature sufficient for a suitable duration of time to form a compound of formula (IV). As a general guide, the compound (III) in a suitable non-aqueous solvent could be contacted with about one molar equivalent of a suitable oxidizing agent and heated at a temperature for about one to about six hours sufficient to form the compound (IV ). The compound (IV) could be separated from the reaction as a stable solid by quenching with a suitable non-aqueous solvent, followed by standard working methods. An example of standard work is shown in Example 5. Additionally, compound (IV) could be developed without isolation in step 4 for the preparation of compound (V) as shown in example 6b.

Preferred oxidizing agents for step (3) include p-tetrachlorobenzoquinone and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

Preferred solvents and mixtures thereof for step (3) are toluene, heptane, ethyl acetate, 1-methyl-1-butyl, tetrahydrofuran, dichloromethane and cyclohexane. For reactions when 2, 3-dichloro-5,6-dicyano-1,4-benzoquinone is used, methanol and ethanol 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 from 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 about room temperature, hereinafter, reflux temperature.

Step 4: Debhenylation: Preparation of the Formula Compound (V) This step comprises the reaction of a compound of formula (IV) in a suitable solvent with a suitable strong base at a temperature sufficient to form a compound of formula (V). Since a hemiaminal debinding product is an aromatic aldehyde or ketone, which depends on the structure of P ", the aldehyde or ketone must be trapped or converted by contacting a suitable entrapment agent with a material that will not react with the compound (V).

Three different methods are feasible for trapping a byproduct of aromatic aldehyde or ketone. First, after the hemiaminal (IV) reacts with a strong base to form a compound of formula (V) and a byproduct of aromatic aldehyde or ketone, the by-product can be reduced to the corresponding alcohol with a suitable reducing agent; which allows the amine (V) to be isolated by neutralization of the reaction mixture followed by filtration. Alternatively and secondly, the by-product can be trapped by a reagent with higher affinity for the by-product than the free amine (V), for example, the reaction of the by-product with hydroxyl amine to form a corresponding oxime or, more preferably, the reaction of the by-product with tosyl hydrazide to form the corresponding tosyl hydrazone, wherein the amine (V) can be isolated by taking care of the pH adjustment of the solution so as to crystallize or precipitate the desired amine product (V).

Alternatively and third, the byproduct, when it is an aromatic aldehyde, can be trapped by a reagent which oxidizes the aldehyde to a corresponding acid but will not react with the amine or acetylene radicals of (V); such entrapment agent is hydrogen peroxide under basic conditions.

As a general guide, the compound (IV) in an aqueous / organic solvent was contacted with a suitable strong base, preferably sodium hydroxide or potassium hydroxide, at sufficient temperature for an adequate duration of time to initiate the formation of a compound of formula (V) followed by the addition of a suitable entrapment agent, preferably sodium borohydride, at a temperature sufficient to quantitatively form the compound (V) while converting the aldehyde or ketone by-product to its corresponding alcohol. Compound (V) could be separated from the reaction as a stable solid by quenching the entrapment agent, followed by pH adjustment of the solution and standard working methods. An example of standard work is shown in Example 6. Optionally, the compound (V) could be developed in the synthesis of compounds of formula (VI).

Preferred strong bases for step (4) including hydroxides of soa.o, potassium, lithium or calcium, as well as, metal alkoxides. More preferably, the strong base is sodium hydroxide or potassium hydroxide.

Preferred entrapment agents are those that 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 the entrapment agents which are reducing agents, a preferred agent is sodium borohydride.

The preferred solvents for step (4) are alcohol mixed with water. More preferably the 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 100 ° C; more preferably the temperature range is from about 30 to about 60 ° C, followed by the addition of the entrapment agent.

Step 5: Cyclization: Preparation of the compound of Formula (IV) This step comprises the cyclization of the chiral compound of formula (V) by contacting a cyclization agent in a suitable solvent at a temperature sufficient to form a compound of formula (VI) ). As a general guide, about one equivalent of the compound (V) is contacted with about two equivalents of the cyclization agent and is stirred at about 20 to about 25 ° C until the reaction is quantified. The compound (VI) could 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. More preferably the solvent is a mixture of heptanes / tetrahydrofuran.

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

With a judicious selection of reagents, as is well appreciated by one skilled in the art of organic synthesis, the claimed processes can be developed in an integral manner to produce the compounds of formulas (II), (III), (IV), (V) ) and I saw).

The present invention could be further exemplified by reference to Scheme 2 wherein R2 = H in an example of a compound of formula (VII).

Essuema? V-l Vl-i The methods of the present invention, by way of example and without limitation, could be further understood by reference to Scheme 3 wherein neither R2 nor R3 is H in an example of a compound of formula (VII). This scheme details additional modalities of the general synthetic method for the preparation of compounds of formula (VI) that use an amino acid protecting group very labile. Obtaining also high yields of excess enantiomer in the chiral induction step; the subsequent isolation of the compound (V) is achieved without chromatography in a one-step procedure, rapidly and under very moderate room temperature conditions.

Scheme step pyrrolidinyl neVephedrine II uj III V SAW Step 6: Addition: Preparation of the Compound of Formula (II) wherein R2 and R3 of compound (VII) U (VIII) are not H.

This step is carried out by reacting a compound of formula (I), after conversion to the free base, in a suitable solvent at a suitable temperature with a compound (VII) or (VIII), wherein neither R2 nor R3 is H, in the presence of an acid catalyst to form a compound of formula (II). As a general guide, the compound (I) in an aqueous / organic solvent at about room temperature could be neutralized based on about pH 7, contacted with about 1 molar equivalent of a compound (VII) or (VIII), in where neither R2 nor R3 is H, preferably trityl alcohol, additionally contacting about 0.1 to about 5.0 mole% of a suitable catalyst and heating at a temperature sufficient to form the compound (II). The compound (II) could be separated from the reaction as a suitable solid by standard working methods. An example of standard work is shown in Example 11. Optionally, compound (II) could be developed in synthesis of compounds of formula (III).

The compound (VII) or (VIII), wherein neither R2 nor R3 is H is preferably trityl alcohol or trityl alcohol substituted with methoxy.

Preferred acid catalysts for step (6) include HCl, methanesulfonic acid, sulfuric acid, trifluoroacetic acid and p-toluenesulfonic acid. The most preferred acid catalysts are methanesulfonic acid and p-toluenesulfonic 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 step (1) is from about room temperature to about 120 ° C. More preferably when the compound (VIII) is trityl alcohol the temperature range is 60 to about 90 ° C.

It is understood that one skilled in the art can determine the preferred reaction time of step 1 as temperature dependent, acid catalyst and group P. In general, 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: Detritylation: 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 acid labile, for example, trifly, in a suitable solvent with about 0.1 to 2.0 equivalents of a suitable acid at a sufficiently moderate temperature to form a compound of formula (V). The detritylation by-product is an aromatic alcohol and subsequently does not need to be trapped 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, the compound (V) can be made in synthesis of compounds of the formula (VI).

The acceptable protective amino groups of step (8) are trifyl, p-methoxytrityl, 4,4'-dimethoxytrityl as well as non-triphenyl groups, such as 2,4-dimethoxybenzyl and 4,4'-dimethoxybenzhydryl. A preferred amino protecting group is trifly.

Preferred strong acids for step (8) include HCl, HBr, methanesulfonic acid, trifluoroacetic acid, and p-toluenesulfonic acid. A more preferred acid is HCl or trifluoroacetic acid.

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

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

Scheme 4 1 . NH4CI (ac) 2. Sep. of phases V 3. screening 4. Dest. Fractionated (X) The preparation of cyclopropylacetylene, (X), by Scheme 4 is further illustrated in Example 15. This preparation of cyclopropylacetylene provides about 100% chloropéritino conversion and more than about 90% yield of cyclopropylacetylene, thereby allowing the Product (X) is used in a solution stream in the preparation of a compound of the formula (III).

The following examples are illustrative means 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 mol) was dissolved in a mixture of t-butyl methyl ether (180 kg), 30% aqueous sodium hydroxide (61.6 kg, 463 mol) and water (24.2 kg), then cooled at 15 ° C. The resulting suspension was charged to trimethylacetyl chloride (52.2 kg), 448 mol) for 1 h, keeping the temperature below 40 ° C. After stirring for 30 min at 30 ° C the suspension was cooled to -10 ° C and maintained for 2 hours. The product was collected by filtration, washed with a water / methanol 90/10 solution (175 kg), then dried to give 85 kg (97% yield) of the title compound as a crystalline solid: m.p. 152-153 ° C; XH NMR (300 MHz, CDC13) d 7.48 (d, J = 9 Hz, 2H) 7.28 (d, J = 9 Hz, 2H); 13 C NMR (75 MHz, CDC13) d 176.7, 13.6, 129.1, 128.9, 121.4, 39.6, 27.6.

Preparation of N- (4-fluorophenyl) -2,2-dimethyl propanamide. It is understood by an expert in the art of organic synthesis that the -fluoroaniline can be easily replaced by the 4-chloroaniline before synthesizing this compound.

Example 2 Preparation of hydrated 4-chloro-2-trifluoroacetylaniline hydrochloride. N- (4-chlorophenyl) -2,2-dimethylpropanamide (36.7 kg, 173 mol) was added to a solution of TMEDA (20.2 kg, 174 mol) in anhydrous t-butyl methyl ether (271.5kg) and cooled to - 20 ° C. 2.7N N-butyl lithium in hexane (101.9 kg, 393 mol) was added to the cooled suspension while maintaining it at a temperature below 5 ° C. After 2 h of maturation from 0 to 5 ° C, the solution was cooled down to -15 ° C then reacted rapidly with ethyl trifluoroacetate (34.5 kg, 243 mol). After 30 min, the resulting solution was quenched in 3N HCl (196 L, 589 mol) keeping the temperature below 25 ° C. After the aqueous phase was removed, the organic solution was concentrated by distillation approximately 200 L of solvent. Acetic acid (352 kg) was added while distilling 325 kg of solvent at 100 mm vacuum. After cooling the solution to 30 ° C, 12 N HCl (43.4 kg, 434 mol) was added and the mixture was heated to approximately 65 to 70 ° C and maintained for 4 hours. The resulting suspension was cooled to 5 ° C and the product was collected by filtration, washed with ethyl acetate (50.5 kg) and dried in va cuo to give 42.1 kg. (87%) of the title compound as a white crystalline solid: p. F. 159-162 dec; XH NMR (300 MHz, DMSO-d6) d 7.65-7.5 (complex, 2H), 7.1 (d, J = 8 Hz, ÍH), 7.0 (brs, 3H); 19 F NMR (282 MHz, DMSO-d 6) d -69.5.

It is understood by an expert in the art of organic synthesis that CF3CF2C02Et or CF3CF2CF2C02Et can easily be replaced by ethyl trifluoroacetate before further homologs are synthesized.

Example 3-a Preparation of 4-chloro-2-trifluoroacetylaniline. Hydrated 4-chloro-2-trichloroacetylaniline hydrochloride (17.1 g, 62 mmol) was stirred in a mixture of toluene (100 mL) and water (50 mL). The mixture was neutralized to pH 7 with NaHCO 3. The organic phase was concentrated and the residue was recrystallized from heptane to give 12.5 g (91%) of the title compound as yellow needles: p. F. 98-99 ° C; XH NMR (300 MHz, CDC13) d 7.70 (t, J = 9 Hz, ÍH), 7.32 (dd, J = 2, 9 Hz, ÍH), 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, CDC13) d -70.3.

Example 3 Preparation of N- ((4'-methoxy) benzyl) -4-chloro-2-tri luoroacetylaniline. Compound (II): % NaOH (18 kg) was added to a suspension of hydrated 4-chloro-2-trifluoroacetylaniline hydrochloride (40.0 kg, 144 mol) in toluene (140 kg) and water (50 L) until pH 7.0. After removing the aqueous phase, 4-methoxybenzyl alcohol (20 kg, 144 mol) and TsOH (1.0 kg, 5.3 mol) were added. The solution was heated to reflux and distilled (30 L) from the water / toluene azeotrope. The solution was cooled to room temperature and washed with saturated brine (80kg). The organic solution was concentrated to a volume of 35-40 L, then diluted with THF (52 K). The weight percent of the title compound in toluene / THF was calculated by HPLC to be 43%. The yield based on the HPLC% weight analysis was 47.7 Kg (96%) An analytical sample was obtained by removing the solvent in va cuo and recrystallizing from heptane: p. F. 82-84 ° C; JH NMR (300 MHz, CDC13) d 9.04 (s, ÍH), 7.74 (d, J = 2 Hz, ÍH), 7.35 (dd, J = 2, 9 Hz), 7.24 (d, J = 8 Hz, 2H ), 6.91 (d, J - 8 Hz, 2H), 6.75 (d, J = 9 Hz, ÍH), 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, 114.5, 114.4, 111.3, 55.3, 46.6.

Example 4 Preparation of (S) -5-chloro- (cyclopropyl-ethynyl) -2 - [(4-methoxyphenyl) methyl] -amino] a- (trifluoromethyl) benzenemethanol. Compound (Ill-i): Triphenylmethane (100 g) was charged to a toluene solution of (IR, 2S) -pyrrolidinyl norephedrine (80 kg, containing 60.7 mol (IR, 2S) -pyrrolidinyl norephedrine). The solution was concentrated in vacuo to approximately half the original volume. Anhydrous THF (35 kg) was added and the solution was cooled with jacketed cooling equipment at -50 ° C.

When the temperature reached -20 ° C, n-hexyl lithium (33% weight in hexanes, 33.4 kg, 119.5 mol) was charged while maintaining the temperature below 0 ° C. A solution of cyclopropylacetylene (30% by weight) was charged to the resulting red solution.

THF / hexanes / toluene; containing approximately 4 kg, 65 mol of cyclopropylacetylene) while maintaining an internal temperature below -20 ° C. The resulting solution was aged at -45 to -50 ° C for one hour. A solution of N- ((4'-methoxy) benzyl) -4-chloro-2-trifluoroacetylaniline (43% by weight in THF / toluene, containing approximately 10 kg, 28.8 mol N- was charged to the cold solution). (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 it was quenched in 140 kg of IN HCl, precooled at 0 ° C. The organic layer was separated and extracted twice with portions of 25 kg of IN HCl, twice with 40 kg of water, then concentrated in vacuo. 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 (23 kg) was charged and the mixture was cooled and kept at -5 ° C for 4 hours. The product was filtered, washed two times with 10-kg portions of heptane and dried in vacuo to yield 10 kg (85%) of the title compound as a non-white solid: mp [a] 25D + 8.15 ° (c 1.006 , MeOH); XH NMR (300 MHz *, CDC13) d 7.55 (brs, 1H), 7.23 (d, J = 8 Hz, 2H), 7.13 (dd, J = 3, 9 Hz), 6.86 (d, J = 8 Hz, 2H), 6.59 (d, J = 8 Hz, ÍH), 4.95 (bs, ÍH), 4.23 (s, 2H), 3.79 (s, 3H), 2.39 (m, 1H), 1.34 (, ÍH), 0.84 (m, 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, 121.6, 119.5, 114.8, 114.1, 94.0, 75.2, 74.7, 70.6, 55.3, 48.0, 8.6, 8.5, -0.6; 19F NMR (282 MHz, CDC13) d -80.19.

Example 5 Preparation of (S) -6-chloro-4- (cyclopropyl-ethynyl) -1,4-dihydro-4- (trifluoromethyl) -2- (4'-methoxyphenyl) -3,1-benzoxazine. Compound (IV-i): They were added to a solution of heptane (295.5 kg) and ethyl acetate (32.5 kg), p-chloranil (57 kg, 232 mol) and (S) -5-chloro-a (cyclopropylethynyl) -2- [(4- methoxyphenyl) methyl] -amino] - a - (trifluoromethyl) benzenemethanol (89 kg, 217 mol). The mixture was refluxed with good stirring for 5.5 h then it was diluted with ethyl acetate (64.1 kg) and cooled to 30 ° C. The tetrachlorohydroquinone was removed by filtration and washed with a methane of heptane (104.7 kg) and ethyl acetate (31 kg). The filtrate was partially concentrated by distillation of 260 L of solvent, then diluted in heptane (177 kg) and cooled to -10 to -15 ° C. The resulting suspension was filtered and the product was washed with heptane (41 kg) and dried to less than 20% by weight of heptane on the filter (for loss in drying). The yield of (IV), calculated by HPLC, was 71 kg (80%). An analytical sample was obtained by grinding the sample with 1N NaOH, followed by recrystallization with hexane / ethyl acetate: p. F. 130-131 ° C; ÍH RMN (300 MHz, DMSO-d6) d 7.46 (d, J = 9 Hz, 2H), 7.28-7.21 (m, 3H), 7.0 (d, J = 9 Hz, 2H), 6.85 (d, J = 9, ÍH), 5.52 (s, ÍH), 3.78 (s, 3H), 1.52-1.47 (m, ÍH), 0.90 -0.84 (m, 2H), 0.72-0.68 (m, ÍH); 13C NMR (75 MHz DMSO-d6) 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.

Example 6 Preparation of the compound (V-i): (S) -5-chloro- - (c i c l o p r o p i l e t i n i l) - 2 - a m i n o - - (trifluoromethyl) benzenemethanol.

(S) -5-Chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2- (4'-methoxyphenyl) -3,1-benzoxazine crude (71 kg calculated on dry weight) 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 then cooled to 30 ° C. A solution of sodium borohydride (3.2 kg, 84.2 mol) in 0.2 N NaOH (29 L) was added to the methanolic solution during min, keeping the temperature below 35 ° C.

After 30 min, excess borohydride was quenched with acetone (5.8 kg) and the solution was diluted with water (175 L) was then neutralized to pH 8 to 9 with acetic acid. The resulting suspension was cooled to about 0 ° C, filtered and the product was washed with water then dried at 40 ° C. The crude product was again suspended with a mixture of toluene (133 kg) and heptanes (106 kg) initially at 25 ° C then with cooling below -10 ° C. The product was filtered, washed with heptanes (41 kg) and dried at 40 ° C to give 44.5 kg (88%) as a non-white / pale yellow crystalline solid. An analytical sample t-butyl methyl ether / heptane was recrystallized: p. F. 141-143 ° C; [a] 25D -28.3 ° (c 0.106, MeOH); XH NMR (300 MHz, CDC13) d 7.54 (d, J = 2 Hz, ÍH), 7. 13 (dd, J = 9, 2 Hz, ÍH), 6.61 (d, J = 9 Hz, ÍH), 4.61 (brs, ÍH), 4.40 (brs, ÍH), 1.44-1.35 (m, ÍH), 0.94-0.78 (m, 2H): 13 C NMR (75 MHz DMSO-A6) d 146.7, 129.4, 129.0, 124.3, 118.4, 118.07, 118.05, 92.3, 72.6, 71.0, 8.2, 8.1, -1.1; 19 F NMR (282 MHz, CDC13) d -80.5.

Example $ b Preparation of the compound (V-i) from Compound (Ill-i) without isolation of Compound (IV-i) in the preceding step of synthesis.

(S) -5-chloro-a- (cyclopropylethynyl) -2-amino-a- (trifluoromethyl) benzenemethanol.

A solution of (S) -5-chloro-a (cyclopropylethynyl) -2- [(() was added to a suspension of DDQ (9.42 g, 41.5 mmol) in t-butyl methyl ether (33 ml.) At 10 ° C. 4-ethoxyphenyl) methyl] -amino] -a- (trifluoromethyl) benzenemethanol (16.38 g, 40 mmol). After 5 minutes the resulting suspension 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 then partially concentrated by distilling 70 ml of solvent. Methanol (25 ml) was added followed by distillation of 25 ml of solvent. Methanol (25 ml) and 6 N NaOH (4 ml) were added followed by distillation of 20 ml of solvent. 4N NaOH (26 ml) was added and the mixture briefly heated to 58 ° C then cooled to 30 ° C. A solution of sodium borohydride (0.60 g) was added, 15.9 mmol) in 0.5 N NaOH (6ml). 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 at a pH of 7.5. The resulting suspension was cooled to about 0 ° C, filtered and the product was washed with water then dried in vacuo at 40 ° C. The crude product was again suspended 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 in the two-step process (p-chloranil / NaBH4). (Example 6, above).

Example 7 Preparation of (S) -6-chloro-4- (cyclopropyl-ethynyl) -1,4-dihydro-4- (trifluoromethyl) -2 H -3,1-benzoxaasin-2-one. Compound (Vl-i).

(S) -5-chloro-a (cyclopropylethynyl) -2-amino-a- (trifluoromethyl) benzenemethanol (15.7 kg, 54.3 mol) was dissolved in a mixture of heptanes (32 kg) and THF (52 kg) below - 10 ° C. Phosgene (-8.0 kg, 80 mol) was directly fed under the surface for about 1 hr, keeping the temperature below 0 ° C. The resulting suspension was heated to 20-25 ° C and held for 1 hour. Methanol (6.5 kg, 203 mol) was added and the solution was stirred approximately 30 min. Heptans (97 kg) were added and ~ 140 L of solvent were distilled off 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 heated to 50, oC and filtered into a clean reactor, followed by a 40 kg heptane rinse. The solution was concentrated under reduced pressure, diluted with heptanes (22 kg) and cooled down to -10 ° C. The product was filtered, washed with heptanes (37 kg) and dried at 90-100 ° C to give 16.0 kg (95%) as a solid with a crude to pinkish color. HPLC: 99.8% area: p. F. 139-141 ° C; [α] 25D -94.1 ° (c 0.300, MeOH); H NMR (400 MHz, DMSO-d6) d 11.05 (s, ÍH), 7.54 (dd, J = 2.5, 7 Hz, ÍH), 7.43 (d, J = 2.5 Hz, ÍH), 6.99 (d, J = 2.5 Hz, HH), 6.99 (d, J = 7 Hz, 1H), 1.58 (m, HH), 0.92 (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, 8.42, -1.32; 19 F NMR (282 MHz, DMSO-d 6) d-81.1.

Example 8 Preparation of N- ((3 ', 4'-dimethoxy) benzyl) -4-chloro-2-trifluoroacetylaniline.

They were added to 2-propanol (40 ml), 4-chloro-2-trifluoroacetylaniline (4.96 g, 40 mmol) and 3,4-dimethoxybenzyl alcohol (7.39 g, 44 mmol). TsOH (76 mg, 0.4 mmol) was added and the mixture was heated to 60 ° C and maintained 3.5 hours. The solution was concentrated in vacuo to 1/2 of the original volume, diluted with water (10 ml) and stirred at room temperature. The resulting suspension was filtered and the product was dried at 30 ° C to give 10.16 g. (68%) of the title compound as a yellow powder. An analytical sample was obtained by r -crystallization with acetonitrile: p. F. 82-84 ° C; H NMR (CDC13) d 9.05 (brs, ÍH), 7.75 (brt, J = 2 Hz, ÍH), 7.35 (dd, J = 2, 8 Hz, ÍH), 6.8 (d, J = 8 Hz, 3H) , 6.75 d, J = 8 Hz, ÍH), 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, 119.4, 114.5, 11.5, 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] -α- (trifluoromethyl) benzenemethanol.

A solution of 17.2% by weight of (IR, 2S) -pyrrolidinyl norephedrine (254 g, 213 mmol) was concentrated by distillation of 160 ml of 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-hexyl lithium (2.0 M solution in hexane, 203 ml, 0.406 mol) was added while maintaining the temperature below 0 ° C. The mixture changed to red after the addition of 108 ml. A solution of cyclopropylacetylene (103 g, 0.25 mol) was added until the solution was discolored. The solution was stirred at -5 to 0 ° C for 20 min and then cooled to -45 ° C, at this point N- ((3 ', 4'-dimethoxy) benzyl) -4-chloro-2- was predisolded. trifluoroacetylaniline (29.7 g, 81.8 mmol) in THF 50 ml. After 1 hr at 45 ° C, the mixture was quenched in (400 mL) 2N HCl. The organic layer was washed twice with (100 ml) of 2N HCl then concentrated in vacuo. Toluene (150 ml) was added and the mixture was concentrated to a volume of 80 ml. Heptane (100 ml) was added and the heptane: toluene solvent ratio (determined by GC analysis) 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: p. F. 128-129.5 ° C; [a] 25D + 11.00 ° (c 0.300, MeOH); lH NMR (300 MHz, CDC13) d 7.56 (m, ÍH), 7.13 (dd, J = 9, 3 Hz, ÍH), 6.84 (m, 3H), 6.58 (d, J = 9 Hz, 1H), 4.24 (m, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 1.34 (m, ÍH), 0.90-0.74 (m, 4H); 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-chloro-4- (cyclopropyl-ethynyl) -1,4-dihydro-4- (trifluoromethyl) -2 - (3 ', 4 • -dimethoxy-enyl) -3,1-benzoxazine.

DDQ (1.40 g, 6.1 mmol) was added to a solution (S) -5-chloro-a (cyclopropylethynyl) -2- [(3,4-dimethoxyphenyl) methyl] -amino] -α- (trifluoromethyl) benzenemethanol (2.68 g, 6.1 mmol) in methanol (10 ml) at 40 ° C. The resulting suspension was cooled 30 min 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: p. F. 172-175 ° C; aH NMR (300 MHz, CDC13) d 7.48 (s, ÍH), 7.18 (dd, J = 2.9 Hz, ÍH), 7.13 (d, J = 7 Hz, ÍH), 7.10 (s, ÍH), 6.87 (d, J = 7 Hz, ÍH), 6.70 (d, J = 9 Hz, ÍH), 5.62 (d, J = 4 Hz, ÍH), 4.33 (d, J = 4 Hz, ÍH), 3.90 (s) , 3H), 3.87 (s, 3H), 1.33 (m, ÍH), 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; 19F NMR (282 MHz, CDC13) d -79.2.

Example 11 Preparation of N-trif-enylmethyl-4-chloro-2-difluoroacetylaniline. method? 4-Chloro-2-trifluoroacetylaniline was dissolved (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) in DMF (50 ml) and maintained 14 h at 60 ° C. The resulting suspension 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: p. F. 165-167 ° C; ÍH NMR (CDC13) d 10.4 (brs, ÍH), 7.71 (brt, J = 2 Hz, ÍH), 7.3 (brs, 15H), 6.9 (dd, J = 2, 8 Hz, ÍH), 6.27 (d, J = 8 Hz, ÍH), 13C NMR (75 MHz, CDC13) d 180.5, 151.2, 144.1, 135.7, 130.7, 130.6, 129.2, 128.9, 128.7, 128.6, 128.5, 128.2, 128.0, 127.7, 127.5, 122.9, 120.3 , 119.3, 119.1, 115.2, 112.3, 111.3, 71.9; 19F NMR (282 MHz, CDC13) d -69.5.

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

Hydrated 4-chloro-2-trifluoroacetylaniline hydrochloride (84.4 g, 304 mmol), cyclohexane (350 ml), MTBE (95 ml), and water (100 ml) were stirred at room temperature, the resulting solution was neutralized with 30 ml of N NaOH. Trityl alcohol (91.0 g, 350 mmol), and TsOH (0.36 g, 1.9 mmol) were added to the organic phase. The mixture was heated to reflux and 30 ml of solvent was distilled. Acetonitrile (350.0 ml) and diisopropylethylamine (0.5 ml) were added and the distillation was continued to remove 220 ml of additional solvent. 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 the sample prepared in the method.

Example 12 Preparation of (S) -5-chloro- - (scylopropyl-e'tinyl) -2-t r i f e n i l m e t i l] - a m i n o] - a - (trifluoromethyl) benzenemethanol. 2N-hexyl lithium (46 ml, 92 mmol) was added to a solution of cyclopropylacetylene (3.15 g, 48 mmol) and (IR, 2S) -pyrrolidinyl norephedrine (10.9 g, 55 mmol) in THF (50 ml) maintaining the Temperature below 0 ° C. Anionic solution N-triphenylmethyl-4-chloro-2-trifluoroacetylaniline (9.32 g, 20 mmol), dissolved in THF (20 mmol) was added and maintained at -45 to -50 ° C for 1 hr, then it was quenched with citric acid (92 ml). The organic layer was separated, dried with sodium sulfate and concentrated to an oil. Crystallization of heptane-toluene gave 6.34 g (60%) of the title compound: p. F. 180-182 ° C; [a] 25D + 7.77 ° (c 1.004, CH3CN); aH NMR (300 MHz, CDC13) d 7.53 (d, J = 2 Hz, ÍH), 7.4-7.1 (complex, 16H), 6.67 (dd, J = 2.7 Hz, ÍH), 6.05 (d, J = 7 Hz, HH), 3.17 (brs, ÍH), 1.07 (m, HH), 0.72 (, 2H), 0.62 (m, 2H); 13 C NMR (75 MHz CDC13) d 14307, 129.1, 129.0, 128.8, 128.1, 126.9, 126.0, 122.2, 120.7, 118.7, 118.3, 94.7, 74.0, 71.6, 70.2, 8.4, 8.3, -0.8; 19F NMR (282 MHz, CDC13) d -79.9.

Example 13 Preparation of (S) -5-chloro-a- (cyclopropylethynyl) -2-amino- (trifluoromethyl) benzenemethanol. A one-step debenzylation.

(S) -5-Chloro-a-cyclopropylethynyl) -2- (triphenylmethyl) -amino-a- (trifluoromethyl) benzene-methanol was dissolved (5.32 g, 10 mmol) in methanol (25 ml) and reacted with (0.5 ml) of 12 N HCl at ambient temperature.

After 15 min, 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) 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%): p. F. 140-143 ° C. The spectroscopic properties are identical with the material made in Example 6.

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

(IR, 2S) -norefedrine (68.6 kg, 454 mol) was added to a mixture of n-butanol (227 kg), water (144 kg) and potassium carbonate (144 kg, 1043 mol). The mixture was heated to 90 ° C and 1,4-dibromobutane (113.4 kg, 525 mol) was added over 2 hours. The reaction was refluxed 5 hr then cooled to 40 ° C. Water (181 kg) was added and the phases were separated at 30 ° C. 12 N HCl (54.3 kg, 543 mol) was added to the organic phase. The solution was heated to reflux and 150 L of distillate were removed at 200 to 300 mm. Toluene (39.5 kg) was added at 70 ° C and the resulting suspension was cooled to 0-5 ° C for 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 mol) at a pH higher than 12. After removing the lower aqueous phase, the Organic solution was partially concentrated by distilling 140 L of solvent to give a 20% weight solution of the title compound in toluene. The calculated yield was 50 kg (75%). An analytical sample was obtained by concentrating the toluene solution of the title compound in va cu, then recrystallized from heptane: p. F. 46-48 ° C.

Example 15 Preparation of cyclopropylacetylene (X) 1. NH4C! (ac) 2. Sep. of phases V 3. screening 4. Dest. Fraction (x; A mixture of 5-chloro-1-pentyne (23.0 kg, 224 mol) and anhydrous THF (150 kg) was cooled to -20 ° C. N-hexyl lithium (2.3 eq, 158 kg, 30% weight) in hexane was added to the mixture in a proportion such that it does not allow the temperature to exceed 5 ° C (about 2 hours). During the second half, the addition of n-hexyl lithium should keep the temperature above -5 ° C to prevent an accumulation of organolithium and a dangerously exothermic induction reaction. The reaction was aged at -5 to 0 ° C for 2 hours, until GC analysis indicated at least 99% conversion. Then toluene (35 to 40 kg) was added and the reaction was concentrated in vacuo until the volume was reduced to -1/3 of the original volume. The mixture was heated (to ~ 40 ° C) in the course of concentration to maintain a good distillation speed. The mixture was then cooled to 15 to -20 ° C and an ammonium chloride solution (11 to 12 kg) was added in 50 to 60 L of water at a rate such that the temperature did not exceed 10 ° C. After separation of the aqueous layer (approximately 70 kg), the reaction mixture was circulated through a tower containing 15 kg of 3A molecular sieve until the water content is -300 p.p. . or smaller as determined by the Karl Fisher analysis. The dried organic solution was then distilled through a column packed with steel fiber at atmospheric pressure collecting cyclopropylacetylene as a solution in THF / toluene / hexane. The calculated yield is 14.0 kg.

Although the present invention has been described with respect to specific embodiments, the details of these embodiments are not construed as limitations. Various equivalents, changes and modifications can be made without departing from the scope and perspective of this invention and it is understood that such equivalent embodiments are part of this invention. The present invention could be embodied in other specific forms without departing from the scope or essential attributes of these and, therefore, the reference can be made to the appended claims as further indicating 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

1. A process for the asymmetric synthesis of a compound of formula (VI): (saw; wherein:: is Cl or F, and A is -CF3, -C2F5 or -C3F7; The process is characterized in that it comprises: (1) contacting a compound of formula (I) with a compound of formula (VII) or formula (VIII) R wherein: R 1 is H, alkyl 0 ^ 6.0 alkylC 6 alkylcarbonyl, R 2 is H, R 3 is H, -CH 3, -CH 2 C h 3 or phenyl substituted with 0-3 R 12 R <R5>, Ra <R>, R <5a>, R <6>, R <8> and R <9> are independently selected from H, alkyl .6, Cx.sub.6 alkoxy and C.sub.12 alkylthio, R1- is H, alkyl Cj.g, alkoxy-, .6 or alkylthio C: _6, Y is - (CH:) n or 0, and n is 0, 1, 2 or 3; in the presence of a suitable acid catalyst to form a compound of formula (II): (II) wherein P, an amine protecting group, is (2) (a) contacting a compound of formula ix, ' IX) wherein R1 ^ and R11 are independently alkyl: -4 / O-NR10Rn is pyrrolidinyl, piperidinyl or morpholinyl; with alkyl lithium and cyclopropylacetylene to form a mixture of a compound of formula (IX) and lithium cyclopropylacetylide, 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 (III) with a suitable oxidation agent to form a compound of formula (IV): where P "is (4) contacting a compound of formula (IV) with a suitable cutting agent, in the presence of a suitable entrapment agent, to form a compound of formula (V): (V) (5) contacting a compound of formula (V) with a suitable cyclization agent to form a compound of formula (VI).

2. A process according to Claim 1 for the preparation of a compound of formula (VI), wherein: X is Cl, and A is -CF3; characterized in that it comprises: (1) contacting a compound of formula (I) with a compound of formula (VII), wherein: R1 is H, C6_6 alkyl or Cx_6 alkylcarbonyl, R2 is H, R3 is H, -CH3, -CH, CH3 or phenyl substituted with 0-3 R12 R4, R5, Ra, R5a, and R6, are independently selected from H, alkyl C? .6 t alkoxy Ca_6 and alkylthio 1.6, and R1 'is H, C? _6 alkyl, Cj_6 alkoxy and C1.6 alkylthio, in the presence of a suitable acid catalyst to form a compound of formula (II); (2) (a) contact IR, 2S-pyrrolidinyl norephedrine with n-hexyl lithium and cyclopropylacetylene to form a mixture of IR, 2S-pyrrolidinyl norephedrine and lithium cyclopropylacetyl, 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 (III) with a suitable oxidizing agent to form a compound of formula (IV); (4) contacting a compound of formula (IV) with a suitable cutting agent, in the presence of a suitable entrapment agent, to form a compound of formula (V); Y (5) contacting a compound of formula (V) with a suitable cyclization agent to form a compound of formula (VI).

3. A process according to Claim 2 for the preparation of a compound of formula (Vl-i): (Vi-i; characterized because it comprises: (1) contacting a compound of formula (I), wherein X is Cl and A is trifluoromethyl, with p-methoxybenzyl alcohol, in the presence of a suitable acid catalyst, to form a compound of formula (Il-i): e (ii-i: (2) (a) contact IR, 2S-pyrrolidinyl norephedrine with n-hexyl lithium and cyclopropylacetylene to form a mixture of IR, 2S-pyrrolidinyl norephedrine and lithium cyclopropylacetylide, (b) contacting the mixture of step (2) (a) with a compound of formula (Il-i) to form a compound of formula (Ill-i): (Ill-i) (3) contacting a compound of formula (III-i) with a suitable oxidizing agent to form a compound of formula (IV-i): (IV-i) (4) contacting a compound of formula (IV-i) with a suitable cutting agent, in the presence of a suitable entrapment agent, to form a compound of formula (V-i): (V-i) (5) contacting a compound of formula (V-i) with a suitable cyclization agent to form a compound of formula (Vl-i).

4. A process according to claim 1 for the preparation of a compound of formula (VI), characterized in that: the suitable acid catalyst is selected from the group: HCl, methanesulfonic acid, benzenesulfonic acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, trichloroacetic acid and p-toluenesulphonic acid, the suitable oxidizing agent is selected from the group: Mn02, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, p-tetrachlorobenzoquinone, o-tetrachlorobenzoquinone and iodosobenzene diacetate, the suitable cutting agent is selected from the group : alkoxide Cj_4 of sodium, alkoxide C ^ of lithium, alkoxide d-, of potassium, NaOH, LiOH, KOH and Ca (HO) 2, the suitable entrapment agent is NaBH4, NaHS03, hydroxyl amine, tosyl hydrazide or H202, and the suitable cyclization agent is phosgene.

5. A process according to Claim 2 for the preparation of a compound of formula (Vl-i), characterized in that: the suitable acid catalyst is selected from the group: HCl, methanesulfonic acid, benzenesulfonic acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, trichloroacetic acid and p-toluenesulphonic acid, the suitable oxidizing agent is selected from the group: Mn02, 2,3-dichloro-5,6-dicyan-1,4-benzoquinone, p-tetrachlorobenzoquinone, o-tetrachlorobenzoquinone and diacetate of iodosobenzene, The suitable cutting agent is selected from the group: sodium alkoxide Cx_4, lithium alkoxide C1.i, alkoxide C? _ < of potassium, NaOH, LiOH, KOH and Ca (H0) 2, the suitable entrapment agent is NaBH4, NaHS03, hydroxyl amine, tosyl hydrazide or H202, and the suitable cyclization agent is phosgene.

6. A process according to Claim 3 for the preparation of a compound of formula (VI-i), characterized in that: the suitable acid catalyst is selected from the group: HCl, methanesulfonic acid, benzenesulfonic acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, trichloroacetic acid and p-toluenesulphonic acid, the suitable oxidizing agent is selected from the group: Mn02, 2,3-dichloro-5,6-dicyan-1,4-benzoquinone, p-tetrachlorobenzoquinone, o-tetrachlorobenzoquinone and iodosobenzene diacetate, the suitable cutting agent is selected from the group: sodium alkoxide C: _4, lithium alkoxide C: _4, potassium alkoxide C? _4, NaOH, LiOH, KOH and Ca (HO) 2, the suitable entrapment agent is NaBH4, NaHS03, hydroxyl amine, tosyl hydrazide or H202, and the suitable cyclization agent is phosgene.

7. A process according to claim 1 for the preparation of a compound of formula (VI), characterized in that the compounds of step (2) (a) and (b) are prepared independently and mixed as solution streams.

8. A process according to Claim 2 for the preparation of a compound of formula (VI-i), characterized in that the compounds of step (2) (a) and (b) are prepared independently and mixed as solution streams.

9. A process according to Claim 3 for the preparation of a compound of formula (VI-i), characterized in that the compounds of step (2) (a) and (b) are prepared independently and mixed as solution streams.

10. A process for the preparation of a compound of formula (II): (ID where X is Cl or F, A is -CF3, -C2F5 or C3F7, P is R- is H, -CH3, -CHCH3 or phenyl substituted with 0-3 R32, R "'is H, -CH ,, -CH; CH: or phenyl substituted with 0-3 R ::, R4, R5, Ra, R5a, R6, R8 and R9 are independently selected from H, C ^ alkyl, C1.6 alkoxy and C, 6 alkylthio, R12 is H, C1.6 alkyl, Ccy6 alkylthio or alkoxy Ca_6, Y is - (CH2) n or 0, and n is 0, 1, 2 or 3; the process is characterized in that it comprises: contacting a compound of formula (I): (I) with a compound of formula (VII) or formula (VIII) RJ wherein R is H, C1.6 alkyl or C1.6 alkylcarbonyl in the presence of a suitable acid catalyst to form a compound of formula (II).

11. A process according to Claim 10, wherein a compound of formula (II) is: Il-a) the process is characterized in that it comprises: contacting a compound of formula (I), wherein X is Cl and A is trifluoromethyl, with a compound of formula (VII) in the presence of a suitable acid catalyst, to form a compound of formula (Il-a).

12. A process according to Claim 11, characterized in that: R: is H, methyl, ethyl, methylocarbonyl or etylcarbonyl, R2 is H, -CH3 or phenyl substituted with 0-3 R12, R3 is H, -CH3 or phenyl substituted with 0-3 R: 2, R4, R5 , R4a, R5a and R6 are independently selected from H, methyl, ethyl, methoxy and ethoxy, and R12 is H, methoxy or ethoxy.

13. A process according to Claim 11, characterized in that: a compound of formula (VII) is R is H or methyl, R 2 is H or phenyl substituted with h or methoxy, R 3 is H or phenyl substituted with H or methoxy, R 4 is H or methoxy, and R- is H or methoxy.

14. A process according to Claim 11, characterized in that: A suitable acid catalyst is selected from the group: HCl, methanesulfonic acid, benzenesulfonic acid, phosphoric acid, sulfuric acid, trichloroacetic acid, trifluoroacetic acid and p-toluenesulfonic acid.

15. A process according to Claim 11, characterized in that: a suitable acid catalyst is methanesulfonic acid or p-toluenesulfonic acid,

16. A process according to Claim 11, characterized in that: a compound of formula (VII) is p-methoxy benzyl alcohol, and the suitable acid catalyst is methanesulfonic acid or p-toluenesulfonic acid.

17. A process according to Claim 11, characterized in that: a compound of formula (VII) is trityl alcohol, and the suitable acid catalyst is methanesulfonic acid or p-toluenesulfonic acid.

18. A process for the preparation of a compound of formula (IV): (IV) where: X is Cl or F, A is -CF3, -C2F5 or -C3F7, P "is R- is H, -CH ,, -CH CH :, or phenyl substituted with 0-3 R11, R4, Ra, R4 R t > to R \ R8, R- are independently selected from H, C ^ alkyl, C6-6 alkoxy and C ^ alkylthio, R 12 is H, C 1-6 alkyl, C, 6 alkylthio or C: 6 alkoxy, Y is - (CH 2) n 0, and n is 0,1,2 or 3; the process is characterized in that it comprises: contacting a compound of formula (III): where P is R2 is H, in a non-aqueous solvent, with a suitable oxidizing agent to form a compound of formula (IV).

19. A process according to claim 18, characterized in that a compound of formula (IV) is: (IV-a) wherein: R3 is H, -CH3, -CH2CH3 or phenyl substituted with 0-3 R12 ', R- ", R5, R4a, R5a and R6' are independently selected from H, C: _6 alkyl, alkoxy? 6 and C1.6 alkylthio, and R12 is H, C: .6 alkyl, alkylthio or Cx_6 alkoxy; the process is characterized in that it comprises: contacting a compound of formula (Ill-a) wherein R2 is H, in a non-aqueous solvent, with a suitable oxidizing agent to form a compound of formula (IV-a).

20. A process according to Claim 19, characterized in that: R3 is H, -CH3 or phenyl substituted with 0-3 R12, R4, R5, R4a, R5a and Rfe are independently selected from H, methyl, ethyl, methoxy and ethoxy, and R 12 is H, methoxy or ethoxy.

21. A process according to Claim 19, characterized in that: a compound of formula (Ill-a) is: R3 is phenyl substituted with H or methoxy, R4 is H or methoxy, and RE is H or methoxy.

22. A process according to claim 19, characterized in that the suitable oxidizing agent is selected from the group: MnO, 2, 3-dichloro-5,6-dicyan-1,4-benzoquinone, p-tetrachlorobenzoquinone, o-tetrachlorobenzoquinone and diacetate of allodosin.

23. A process according to claim 19, characterized in that the suitable oxidizing agent is p-tetrachlorobenzoquinone.

24. A process according to claim 19, characterized in that the compound of formula (Ill-a) is: the suitable oxidizing agent is p-tetrachlorobenzoquinone.

25. A process for the preparation of a compound of formula (V): (V) wherein: X is Cl or F, and A is -CF ,, -C.F, or -CF-; The process is characterized because it comprises: contacting the compound of formula (IV; (IV) where P "is R3 is H, -CH ,, -CH-CH, or phenyl substituted with 0-3 R12, R \: R a, R5a, R °, Rs, and R9 are independently selected from H, C, ^ alkyl, Alkoxy C: .and alkylthio C: .í f R-- is H, C: .f alkyl, Cthylthio: "or C 1 - alkoxy, Y is - (CH 2) nu O, and n is 0,1,2 or 3; with a suitable cutting agent, in the presence of a suitable entrapment agent, to form a compound of formula (V).

26. A process according to Claim 25, characterized in that: a compound of formula (IV) is R3 is H, -CH3, -CH2CH3 or phenyl substituted with 0-3 R12, R4, R5, R4a, R5a and R6 are independently selected from H, C: _6 alkyl, C1_6 alkylthio and C ^ alkoxy, and R12 is H, Alkylthio C: _6 alkyl or C: _6 alkoxy.

27. A process according to Claim 26, characterized in that: R3 is H, -CH3 or phenyl substituted with 0-3 R12, R4, R5, R4, R5a and R € are independently selected from H, methyl, ethyl, methoxy and ethoxy, and R12 is H, methoxy or ethoxy.

28. A process according to claim 26, characterized in that a compound of formula (IV-a) is R3 is phenyl substituted with H or methoxy, R4 is H or methoxy, and R5 is H or methoxy.

29. A process according to Claim 26, characterized in that: the suitable cutting agent is selected from the group: sodium alkoxide C: _4, lithium alkoxide C: _, potassium alkoxide C: _, NaOH, LiOH, KOH and Ca (OH) 2, the suitable entrapment agent is NaBH4 or NaHS03.

30. A process according to Claim 26, characterized in that: the suitable cutting agent is selected from the group: sodium alkoxide d_4, lithium alkoxide d-, potassium alkoxide d_4, NaOH, LiOH, KOH and Ca (OH) 2, and the suitable entrapment agent is hitiroxyl amine or tosyl hydrazide.

31. A process according to Claim 26, characterized in that: The suitable cutting agent is selected from the group: sodium alkoxide _4, lithium alkoxide d_4, potassium alkoxide d_4, NaOH, LiOH, KOH and Ca (0H) 2, the suitable entrapment agent is H202.

32. A process for the asymmetric synthesis of a compound of formula (VI): (SAW) wherein: X is Cl or F, and A is -CF3, -C2F5 or -C3F7; The process is characterized because it comprises: (1) contacting a compound of formula (I) with a compound of formula (VII) wherein: R1 is H, alkyl d6 or alkylcarbonyl d6 / 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 d-e / alkoxy d-e and alkylthio d-e and R12 is H, alkyl d-e / alkoxy d6 or alkylthio d6; in the presence of a suitable acid catalyst to form a compound of formula (II): 2) (a) contacting a compound of formula (i?; (IX) wherein R10 and R11 are independently alkyl d-i / o -NRi0R :? is pyrrolidinyl, piperidinyl or morpholinyl; with alkyl lithium and cyclopropylacetylene to form a mixture of a compound of formula (IX) and lithium cyclopropylacetylide, 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 (III) with a suitable deprotection agent to form a compound of formula (V): (V) (4) contacting a compound of formula (V) with a suitable cyclization agent to form a compound of formula (VI).

33. A process according to Claim 32 for the preparation of a compound of formula (VI): characterized in that: X is Cl, A is -CF3, R1 is H, alkyl d6 or alkylcarbonyl d6, R2 is phenyl substituted with 0-3 R12, R3 is phenyl substituted with 0-3 R: 2, R4, RR R and R (are independently selected from H and alkoxy of / and R12 is H or d6 alkoxy.

34. A compound according to Claim 33 for the preparation of a compound of formula (Vl-i): (VI-i characterized because it comprises: (1) contacting a compound of formula (I), wherein X is Cl and A is trifluoromethyl, with trityl alcohol, in the presence of a suitable acid catalyst, to form a compound of formula (Il-ii): (2) (a) contact IR, 2S-pyrrolidinyl norephedrine with n-hexyl lithium and cyclopropylacetylene to form a mixture of IR, 2S-pyrrolidinyl norephedrine and lithium cyclopropylacetylide, (b) contacting the mixture of step (2) (a) with a compound of formula (Il-ii) to form a compound of formula (III-ü): (3) contacting a compound of formula (III-ii) with a suitable deprotecting agent to form a compound of formula (V-i): (V-i) (5) contacting a compound of formula (V-i) with a suitable cyclization agent to form a compound of formula (Vl-i).

35. A process according to claim 32 for the preparation of a compound of formula (VI), characterized in that: the suitable acid catalyst is selected from the group: HCl, methanesulfonic acid, sulfuric acid, trifluoroacetic acid and p-toluenesulfonic acid, The suitable deprotecting agent is selected from the group: HCl, HBr, methanesulfonic acid, trifluoroacetic acid and p-toluenesulfonic acid, and The proper cyclising agent is phosgene.

36. A process of agreement.-.- Claim 33 for the preparation of a compound of formula (VI-i), characterized in that: the suitable acid catalyst is selected from the group: HCl, methanesulfonic acid, sulfuric acid, trifluoroacetic acid and p-toluenesulfonic acid, The suitable deprotecting agent is selected from the group: HCl, HBr, methanesulfonic acid, trifluoroacetic acid and p-toluenesulfonic acid, and The proper cyclising agent is phosgene.

37. A process according to claim 34 for the preparation of a compound of formula (Vl-i), characterized in that: the suitable acid catalyst is selected from the group: HCl, methanesulfonic acid, sulfuric acid, trifluoroacetic acid and p-toluenesulfonic acid, The suitable deprotecting agent is selected from the group: HCl, HBr, methanesulfonic acid, trifluoroacetic acid and p-toluenesulfonic acid, and The proper cyclising agent is phosgene.

38. A process according to Claim 32 for the preparation of a compound of formula (VI), characterized in that the compounds of step (2) (a) and (b) are prepared independently and mixed as solution streams.

39. A process according to claim 33 for the preparation of a compound of formula (VI-i), characterized in that the compounds of step (2) (a) and (b) are prepared independently and mixed as solution streams.

40. A process according to Claim 34 for the preparation of a compound of formula (VI-i), characterized in that the compounds of step (2) (a) and (b) are prepared independently and mixed as solution streams.

41. A compound of formula : iv-i: or a pharmaceutically acceptable salt thereof