LT4646B - Asymmetric synthesis of benzoxazones - Google Patents

Abstract

The invention presents a new method of asymmetric synthesis of (S)-6-chlor-cyclopropylethynyl-trifluormethyl-1, 4-dihydro-2H-3, 1-benzoxazine-2-one, the formula of which is (VI-i),<IMAGE>which is the reverse transcriptase inhibitor of human immunodeficiency virus (HIV).

Description

Field of the Invention

This invention provides novel asymmetric syntheses of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, an inhibitor of human immunodeficiency virus (HIV) reverse transcriptase. ways.

State of the art

Reverse transcription is a common feature of retroviral replication. Viral replication requires virus-encoded reverse transcriptase to generate copies of DNA sequences by reverse transcription of viral genome RNA. Therefore, reverse transcriptase is a clinically relevant target in chemotherapy for retroviral infections, since inhibition of the virus-encoded reverse transcriptase would stop viral replication.

A number of compounds are effective against human immunodeficiency virus (HIV), a retrovirus that causes the progressive destruction of the human immune system, leading to AIDS. Both nucleoside-based inhibitors such as azidothymidine and non-nucleoside-based inhibitors are known to be effective in the treatment of HIV reverse transcriptase inhibition. Benzoxazinones have been shown to act as non-nucleoside inhibitors of HIV reverse transcriptase. (S) -O-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one of formula (VI-i):

Cl (VI-i) is not only a potent inhibitor of reverse transcriptase, but is also effective against HIV reverse transcriptase stability. Due to the importance of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as an inhibitor of HIV reverse transcriptase, there is a need to develop a cost-effective and efficient route for its synthesis.

Thompson et al., Tetrahedron Letters 1995, 36, 937-940, describe an asymmetric synthesis of enantiomeric benzoxazinones by addition of a highly enantioselective acetylide followed by cyclization with a condensing agent to form benzoxazinone, as shown below.

The starting p-methoxybenzylaniline is synthesized by benzylation of the aniline nitrogen with pmethoxybenzyl chloride. In addition, heavy metal waste is generated throughout the process due to the use of cerium ammonium nitrate for oxidation in the debenzylation stage.

European Patent Application 582 455 A1 describes the synthesis of benzoxazinones in a three-step process.

Cl

Φα

1.2 eq. n-BuLi / THF / O'C 2. Cr-jCOOEt / O'C ukj n 3. 3N HCL'vir. with return refrigerator ..

C F3 R-MgBf

NH ₂ THF / 0 ° C - R 7

The basic methodology involves: (1) metalization of para-chloroaniline pivalamide with n-butyllithium followed by nucleophilic substitution of the ester to form the ketone, (2) synthesis of tertiary carbinol in the Grignard binding reaction, and (3) cyclization of the unblocked amine with carbinol; adding large excess of the condensing agent to form benzoxazinone. The process requires further purification of the optical isomers using an optically active solubilizing agent such as (-) - campanic acid.

Young et al., International PCT Application WO 9520389 A1 describe benzoxazinones useful for inhibiting HIV reverse transcriptase. HIV prevention or treatment and AIDS treatment. WO 9520389 A1 describes synthesis methods identical to those described in EP 582 455 mentioned above. In addition, Young et al., Antimicrobial Agents and Chemotherapy 1995, 39, 2602-2605 discussing the clinical benefits, in vitro activity, and pharmacokinetic activity of benzoxazinone (VI) as an HIV reverse transcriptase inhibitor. in the treatment of HIV, provides a truncated synthesis of benzoxazinone (VI) analogous to the aforementioned EP 582 455 A1, in which tertiary carbinol is synthesized by the addition of a cyclopropylethyl lithium reagent before cyclization of an unblocked amine with carbinol with the addition of a condensing agent.

Thompson et al., PCT International Application WO 9622955 A1, describe an improved synthesis of the cyclopropylacetylene required for the preparation of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one. . WO 9622955 A1 discloses a combination of the synthesis routes described in the above publications, which remains ineffective throughout the synthesis, in which the invention provides significant improvements.

The above benzoxazinone synthesis methods employ toxic, difficult-to-digest reagents, relatively expensive materials, and an ineffective chromatographic purification step, or all of (S) -6-chloro-4-cyclopropylethynyl-410 trifluoromethyl-1,4-dihydro-2H-3, l. The synthesis of benzoxazin-2-one yields low yields. In this way, it would be useful to find novel bulk syntheses of benzoxazinones, which would overcome previous drawbacks and yield high yields of the desired benzoxazinones.

Therefore, the present invention provides a novel benzylation procedure using acid-catalyzed benzyl alcohols in place of the corresponding benzyl chloride analogs which would be more expensive and unstable. The optimization of the procedure allows for a continuous process as the product does not need to be isolated.

The present invention describes the preparation of (IR, 2S) -pyrrolidinylnorephedrine in a form such that it can be used as a continuous process reagent in the chiral coupling of lithium cyclopropylacetylide. The present invention describes the preparation of cyclopropylacetylene in a form such that it can also be used as a continuous process reagent in the chiral coupling of a cyclopropylacetylide anion such as lithium cyclopropylacetylide.

The present invention provides an improved method of asymmetric synthesis of benzoxazinones.

The process of the present invention does not use highly toxic cerium ammonium nitrate, thereby eliminating cerium ions from wastewater. The present invention provides an efficient non-chromatographic purification process which yields an enantiomerically pure product. The present invention further describes intermediates in the form of stable solids which can be purified by crystallization. None of the above-mentioned sources discloses methods for the synthesis of benzoxazinones acting as HIV reverse transcriptase inhibitors analogous to the methods of the present invention.

Summary of the Invention

This invention relates to novel syntheses of benzoxazinones which inhibit HIV reverse transcriptase. The present invention provides a novel process for benzylation of primary amines using acid-catalyzed benzyl alcohols. The process of the present invention allows high yields, can be implemented in kilograms, and provides stable intermediates. The invention further provides a non-chromatographic separation method to improve overall yield.

Herein is provided a process for the preparation of the present invention with a compound of formula (VI)

where:

X is. Cl or F and

A is -CF 3, -C 2 F 5, or -C 3 F 7;

wherein said method comprises one or more of the following steps:

(1) (attachment) of a compound of formula (I):

(I) Reactions with a compound of formula (VII) or (VIII):

(VIII) in which:

R ¹ is H or C 1-6 alkyl,

R ² is H, -CH ₃ , -CH 2 CH ₃ or phenyl substituted with 0-3 R ¹² ,

R ^J is H, -CH ₃ , -CH 2 CH ₃ or phenyl substituted with 0-3 R ¹² ,

R ⁴ , R ³ , R ^4a , R ^5a , R ⁶ , R ⁸ and R ^{9 are} independently selected from

H, C 1-6 alkyl, C 1-6 alkyl. ₆ alkoxyl and C 1-6 alkylthio,

R ¹² is H, C 1-6 alkyl, C 1-6 alkoxyl, or C _x 1.6 alkylthio;

Y is - (CHijn or O and n is 0, 1, 2 or 3;

in the presence of methanesulfonic acid, p-toluenesulfonic acid or other suitable acidic catalyst to form a compound of formula (II):

where P is

or (2) (chiral attachment) (a) reaction of IR, 2S-pyrrolidinylnorephedrine with n-hexyl lithium or other suitable alkyl lithium and cyclopropylacetylene to form a mixture of IR, 2S-pyrrolidinylnorephedrine and lithium cyclopropylacetylide;

(b) reacting a reaction mixture from step (2) (a) with a compound of formula (II) to form a compound of formula (III):

i

P (III) (3) (oxidative cyclization) reaction of a compound of formula (III) with pchloranil or another suitable oxidizing agent to give a compound of formula (IV):

H (IV) wherein P 'is present

(4) (debenzylation) reaction of a compound of formula (IV) with potassium hydroxide, sodium hydroxide or other ring-breaking agent in the presence of sodium borohydride or other suitable binding agent to form a compound of formula (V):

(5) (cyclization) of a compound of formula (V) by reaction with phosgene or another suitable cyclization agent to give a compound of formula (VI).

Detailed Description of the Invention

According to a first embodiment of the present invention, the present invention provides a novel process for the preparation of compounds of formula (VI):

where:

ίο X is Cl or F, and

A is -CF 3, -C 2 F 5 or C 3 F 7; where said method consists of:

(1) Compound of Formula (I):

Reactions with a compound of formula (VII) or (VIII):

R ¹ is H, Ci. ₆ alkyl or C _b6 alkylcarbonyl,

R ² is H,

R ³ is H, -CH 3, -CH 2 CH 3 or phenyl substituted with 0-3 R ¹² ,

R ⁴ , R ⁵ , R ^4a , R ^aa , R ⁶ , R ⁸ and R ^{9 are} independently selected from

H, C 1-6 alkyl, C 1-6 alkoxyl and C 1-6 alkylthio;

R ¹² is H, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylthio;

Y is - (CHŲn or O, and n is 0, 1, 2 or 3;

in the presence of a suitable acidic catalyst to form a compound of formula (II):

(2) Compound (a) of formula (IX)

(IX).

wherein R ¹⁰ and R ^{11 are} independently alkyl, or NR ¹⁰ R ⁿ is pyrrolidinyl, piperidinyl or morpholinyl;

reactions with alkyl lithium and cyclopropylacetylene to form a mixture of a compound of formula (IX) and lithium cyclopropylacetylide, and reaction of a reaction mixture of step (b) (2) (a) with a compound of formula (II) to form a compound of formula (III):

(HI);

(3) reacting a compound of formula (III) with a suitable oxidizing agent to form a compound of formula (IV):

(IV) in which P ^! 'is

or (4) reacting a compound of formula (IV) with a suitable ring-opening agent in the presence of a suitable binding agent to form a compound of formula (V):

and (5) reacting a compound of formula (V) with a suitable cyclizing agent to form a compound of formula (VI).

In a preferred embodiment of the invention, the compound of formula (VI) wherein

X is Cl and A is -CF 3;

(1) reacting a compound of formula (I) with a compound of formula (VII) wherein: R ¹ is H, C 1-6 alkyl or C 1-6 alkylcarbonyl,

R ² is H)

R ³ is H, -CH 3, -CH 2 CH 3 or phenyl substituted with 0-3 R ¹² ,

R ⁴ , R 1 R ^4a , R ³³ and R ^{6 are} independently selected from H, C 1-6 alkyl, C 1-6 alkoxyl and C 1-6 alkylthio;

R ¹² is H, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylthio;

in the presence of a suitable acidic catalyst to form a compound of formula (II);

(2) reacting (a) 1R, 2S-pyrrolidinylnorephedrine with n-hexyl lithium and cyclopropylacetylene to form a mixture of 1R, 2S-pyrrolidinylninephrephrine and lithium cyclopropylacetylide, and (b) reacting the reaction mixture of step (2) (a) with a compound of formula (II) , 10 to form a compound of formula (III);

(3) reacting a compound of formula (III) with a suitable oxidizing agent to form a compound of formula (IV);

(4) reacting a compound of formula (IV) with a suitable ring-opening agent in the presence of a suitable binding agent to form a compound of formula (V); and (5) reacting a compound of formula (V) with a suitable cyclizing agent to form a compound of formula (VI).

In a more preferred embodiment of the invention, the compounds of formula (VI-i):

The preparation of (VI-i) consists of:

(1) Reaction of 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 (II-i):

(H-1);

OMe (2) Reactions of (a) 1R, 2S-pyrrolidinylnorephedrine with n-hexyl lithium and cyclopropylacetylene to form a mixture of 1R, 2S-pyrrolidinylnorephedrine and lithium cyclopropylacetylide, and (b) Reaction of step (2) (a) with (ΙΙ-i). ) to form a compound of formula (ΙΙΙ-i):

(IIII);

(3) Reactions of a compound of formula (ΙΙΙ-i) with a suitable oxidizing agent to give a compound of formula (IV-i):

(IV-i);

(4) Reactions of a compound of formula (IV-i) with a suitable ring-opening agent in the presence of a suitable binding agent to form a compound of formula (V-i)

(V-i); and (5) reacting a compound of formula (V-i) with a suitable cyclizing agent to form a compound of formula (VI-i).

In a more preferred embodiment of the invention, the process for the preparation of compounds of formula (VI) is characterized in that:

a suitable acidic catalyst is selected from the group of agents: HCl, methanesulfonic acid, benzenesulfonic acid, phosphoric acid, sulfonic acid, trifluoroacetic acid, trichloroacetic acid and p-toluenesulfonic acid, a suitable oxidizing agent is selected from the group of agents: MnO ₂ , 2,3dichloro -dicyano-1,4-benzoquinone, p-tetrachlorobenzoquinone, otetrachlorobenzoquinone and iodosylbenzene diacetate, a suitable ring-opening agent selected from the group consisting of sodium C1.4 alkoxide, lithium C1.4 alkoxide, potassium C1.4 alkoxide, NaOH, LiOH , KOH and Ca (OH) ₂ , a suitable binding agent is NaBFLt, NaHSC 5, hydroxylamine, tosylhydrazide or H ₂ O ₂ , and a suitable cyclizing agent is phosgene.

In a more preferred embodiment of the invention, the compounds of formula (VI) in the process of preparation (VI) are prepared separately and mixed by mixing the solutions.

According to a second embodiment of the present invention, the present invention provides compounds of formula (II):

(Π) where X is Cl or F,

A is -CF 3, -C 2 F 5 or C 3 F 7; P is

or

R ² is H, -CH 3, -CH ² CH 3 or phenyl substituted with 0-3 R ¹² ,

R ³ is H, -CH 3, -CH 2 CH 3 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 alkyl. Alkoxy ₆ and C 1-6 alkylthio;

R ¹² is H, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylthio;

Y is - (CF 1 ·),) or O, and n is 0, 1, 2 or 3;

a method of receiving, comprising:

of a compound of formula (I):

(I) Reactions with a compound of formula (VII) or (VIII):

(VIII) wherein R ¹ is H, C 1-6 alkyl or C 1-6 alkylcarbonyl in the presence of a suitable acidic catalyst to form a compound of formula (II).

In a preferred embodiment, the compound of formula (VII) is

R ⁴ R ⁵ R ³

R ¹ O-) R ²

R ¹ 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 ³ is H or methoxy.

In a more preferred embodiment, the suitable acid catalyst is selected from the group consisting of HCl, methanesulfonic acid, benzenesulfonic acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, trichloroacetic acid and p-toluenesulfonic acid.

According to a third embodiment of the invention, the present invention provides compounds of formula (IV):

(IV) in which:

X is Cl or F,

A is -CF 3. -C2F5 or -C3H7 P 'is present

R ⁴

or

R ³ is H, -CH 3, -CH 2 CH 3 or phenyl substituted with 0-3 R ¹² ,

R ⁴ . R ³ , R ⁴³ , R ³³ , R ⁶ , R ^s and R ^{9 are} independently selected from

H, C 1-6 alkyl, C 1-6 alkoxyl and C 1-6 alkylthio;

R ¹² is H, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylthio;

Y is - (CEl ·) ,, or O, and n vra 0. 1. 2 or 3;

method of obtaining. which consists of:

of a compound of formula (III):

NH

X (III) wherein: P is

R ² is H, in a reaction in a non-aqueous solvent with a suitable oxidizing agent to form a compound of formula (IV).

In a preferred embodiment, the compound of formula (III) is

OMe

In a more preferred embodiment, a suitable oxidizing agent is selected from the group consisting of MnO2, 2,3-dichloro-5,6-dicyano-l, 4-benzoquinone, p-tetrachlorobenzoquinone, o-tetrachloro-benzoquinone, and iodosylbenzene diacetate.

According to a fourth embodiment, the present invention provides compounds of formula (V):

(V) in which:

X is Cl or F, and

A is a process for the preparation of -CF3, -C2F5 or -C3F7 consisting of: a compound of formula (IV):

R ³ is H, -CH 3, -CH 2 CH 3 or phenyl substituted with 0-3 R ¹² ,

R ⁴ , R ³ , R ^4a , R ^5a , R ⁶ , R ⁸ and R ^{9 are} independently selected from H, C 1-6 alkyl, Cu alkoxyl and C 1-6 alkylthio;

R ¹² is H, C _x .6 alkyl, C _x .6 alkoxy or Ci_6 alkylthio;

Y is - (CH ₂ ) _n or O, and n is 0,1, 2 or 3;

with a suitable ring-opening agent in the presence of a suitable binding agent to form a compound of formula (V).

In a preferred embodiment, the compound of formula (IV) is

R ³ is phenyl substituted with H or methoxy,

R ⁴ is H or methoxy,

R ³ is H or methoxy.

In a more preferred embodiment, a suitable ring-opening agent is selected from the group consisting of C 1 -C 4 alkoxide, C 1 -C 4 lithium, C 1 -C 4 potassium, NaOH, LiOH, KOH, and Ca (OH) ₂ , a suitable binding agent. is selected from the group: NaBK », NaHSO3, hydroxylamine, tosylhydrazide or H2O2.

According to a fifth embodiment, the present invention provides a compound of formula (VI):

where:

X is Cl or F, and A is a process for the preparation of -CF 3, -C 2 F 5 or - C 3 F 7, comprising:

(1) Compound of Formula (I):

reactions with a compound of formula (VII):

(VII) in which:

R ¹ is H, C 1-6 alkyl or C 1-6 alkylcarbonyl,

R ² is -CH 3, -CH ² CH 3, or phenyl substituted with 0-3 R ¹² ,

R ³ is -CH 3, -CH 2 CH 3 or phenyl substituted with 0-3 R ¹² ,

R ⁴ , R ⁵ , R ^4a , R ^3a , R ^{6 are} independently selected from H, C 1-6 alkyl, C 1-6 alkoxyl and Cpe alkylthio; and

R ¹² is H, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylthio;

in the presence of a suitable acidic catalyst to form a compound of formula (II):

(Π) (2) Compound (a) of formula (IX):

(IX) wherein R ¹⁰ and R ^{11 are} independently C 1-4 alkyl, or NR ¹⁰ R ^H is pyrrolidinyl, piperidinyl or morpholinyl;

reactions with alkyl lithium and cyclopropylacetylene to form a mixture of a compound of formula (IX) and lithium cyclopropylacetylide, and reaction of a reaction mixture of step (b) (2) (a) with a compound of formula (II) to form a compound of formula (III):

(3) reacting a compound of formula (III) with a suitable deprotecting agent to form a compound of formula (V):

Reactions of a compound of formula (V) and (4) (V) with a suitable cyclizing agent to give a compound of formula (VI):

According to a seventh embodiment, the present invention provides a novel compound of formula (IV-i):

(IV-i) or a pharmaceutically acceptable salt thereof.

The methods of preparation of this invention are used to obtain (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one which acts as a reverse transcriptase for human immunodeficiency virus (HIV). inhibitors, and compounds that are intermediates in the synthesis of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H3,1-benzoxazin-2-one. Such HIV reverse transcriptase inhibitors are used for the inhibition of HIV and the treatment of HIV infections. HIV reverse transcriptase inhibitors are used to inhibit HIV in ex vivo samples in which HIV is present or is expected to come into contact with HIV. Thus, such HIV reverse transcriptase inhibitors can be used to inhibit HIV in a sample of body fluids (e.g., body fluid or semen) in which HIV is or is suspected to be HIV-positive or in contact with HIV. Such HIV reverse transcriptase inhibitors are also used as standard or comparative compounds in assays or methodologies for determining an agent's ability to inhibit viral replication and / or HIV reverse transcriptase, for example, in pharmaceutical assay programs. Thus, these HIV reverse transcriptase inhibitors can be used as control or comparison compounds in such assays and as quality standards.

Abbreviations used herein mean:

THF - tetrahydrofuran,

DMSO - dimethylsulfoxide,

DMAC - dimethylacetamide,

MTBE for methyl t-butyl ether,

BuLi - butyl,

NaH - sodium hydride,

LDA- Lithium diisopropylamide,

TsOH - p-toluenesulfonic acid,

TMEDA-N, N, N ', N'-tetramethylethylenediamine and

DDQ - 2,3-dichloro-4,5-dicyano-benzoquinone.

The reactions of the synthesis methods disclosed herein are carried out in suitable solvents readily selected by one skilled in the art of organic synthesis; such a suitable solvent is usually any solvent which does not react with the starting materials (reagents), intermediates or reaction products at the reaction temperature, i.e., at a temperature ranging from the freezing point of the solvent to the boiling point of the solvent. The reaction may be carried out in a single solvent or mixture of solvents. Depending on the particular reaction stage, a particular suitable solvent may be selected.

Suitable halogenated solvents include chlorobenzene, fluorobenzene or dichloromethane.

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

Suitable protic solvents include, but are not limited to, 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 3pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, glycerol.

Suitable aprotic solvents include, but are not limited to, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU). ), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide. N-methylformamide, acetonitrile, dimethylsulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethylmethylketone, ethyl acetate, sulfolane, Ν, Ν-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene or hexamethylene.

Suitable base 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-protecting group" refers to any group known in the art of organic synthesis used to block an amino group. Such amine protecting groups include those listed by Greene and Wuts, Protective Groups in Organic Synthesis, by John Wiley & Sons, New York (1991). Amine protecting groups include, but are not limited to, alkyls such as benzyl, α-methylbenzyl, diphenylmethyl (benzhydryl), dimethoxybenzhydryl, triphenylmethyl (trityl), 9-fluorenyl, phenylfluorenyl, dihydroanthracenyl, monomethoxytrityl, p-methoxybenzyl, , 4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl.

As used herein, the term "chiral inducing agent" or "chiral induction agent" refers to a nonreactive chiral agent that selectively induces the creation of a chiral center in an enantiomer by attaching a non-chiral substrate to a prochiral center. Chiral inducing agents include, but are not limited to, 1R, 2S-N * substituted ephedrines such as 1R, 2S-N-methylnephedrine, lR, 2S-N-pyrrolidinylnephephrine. "Chiral induction agent" means a non-reactive chiral agent that selectively induces the formation of a chiral center in the enantiomer upon attachment of the non-chiral substrate to the prochiral center. Chiral inducing agents include, but are not limited to, 1R, 2S-N-substituted ephedrines such as 1R, 2S-N-methylephedrine, 1R.2S-N-pyrrolidinylnorephedrine, 1R, 2S-N-piperidinylnorephedrine, and 1R, 2S-Nmorpholinyl.

As used herein, the term "acidic catalyst" refers to any acidifying agent that catalyzes the attachment of an alkyl derivative of an amine protecting group, such as benzyl alcohol, benzhydrol, or trityl alcohol, to the free base form of an amine such as compound (I). Examples of acidic catalysts include, but are not limited to, HCl, HBr, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, sulfuric acid, trifluoroacetic acid, trichloroacetic acid, phosphate acid, and polyphosphoric acid.

As used herein, the term "oxidizing agent" refers to any agent that oxidizes a bezyl-protected amine to an imine, thereby enabling intramolecular cyclization of the compound of formula (III) to form compound (IV). Examples of oxidizing agents include, but are not limited to, manganese dioxide, KMnO ₄ , K2SO5, KHSO5, DDQ, p-choranyl, o-chloranyl and iodosylbenzene diacetate.

As used herein, the term "deprotecting agent" refers to any acidifying agent that can effectively remove an alkyl-type amine protecting group, such as benzyl, benzhydryl, or trityl, to form an amine free base such as compound (IV). Examples of blocking agents include, but are not limited to, HCl, HBr, methanesulfonic acid, trichloroacetic acid, trifluoroacetic acid, phosphate acid, and p-toluenesulfonic acid.

As used herein, the term "ring-opening agent" refers to any agent that can act to form a compound of formula (V) by removing or debenzylating P "from the hemiaminal of formula (IV). Such ring-opening agents are strong bases, examples of which 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 _s , NaOC ₄ H _I0 , KOCH ₃ , KOC ₂ H ₅ and KOC ₄ Hi ₀ .

As used herein, the term "binding agent" refers to any agent that can effect the conversion of a byproduct by removal or debenzylation of P "from the hemiaminal of formula (IV) to a substance that will not react with the desired compound (V), where Structure, the by-product is an aromatic aldehyde or ketone. Binding agents used by those skilled in the art include standard reducing agents, derivatizing agents, or oxidizing agents; all of which are used to selectively react with one compound in the solution and not react with the other. Examples of binding agents that reduce the aromatic aldehyde or ketone to alcohol include, but are not limited to, sodium borohydride, lithium borohydride, potassium borohydride, sodium bisulfite, and sodium trimethoxyborohydride; sodium borohydride is preferred. Examples of binding agents that form oxime or hydrazone derivatives with aromatic aldehydes or ketones include, but are not limited to, hydrazine, dimethylhydrazine, hydroxylamine, and tosylhydrazide. Examples of binding agents that oxidize an aromatic aldehyde to an aromatic carboxylic acid include, but are not limited to, hydrogen peroxide, t-butyl hydroperoxide, K ₂ SO _3, and KHSOs.

As used herein, the term "cyclizing agent" refers to any agent that contributes to the formation of benzoxazinone from an aminocarbinol compound of formula (V). Examples of cyclizing agents include, but are not limited to, phosgene, i, l-carbonyldiimidazole, methyl chloroformate, and dimethyl carbonate.

As used herein, the term "soldering agent" or "alkyllithium" refers to an organic lithium reagent that can quantitatively convert alkyne to alkynylite. Examples of fluxing agents include, but are not limited to, n-hexyl lithium, n-octyl lithium, n-butyllithium, t-butyllithium, sec-butyl lithium, isobutyl lithium, lithium diisopropylamide, phenyl lithium, and triphenylmethyl lithium.

As used herein, "halogen" means fluorine, chlorine and bromine.

As used herein, "alkyl" includes both branched and straight chain saturated aliphatic hydrocarbon groups having from one to twelve carbon atoms.

As used herein, "alkoxyl" includes an alkyl group of a specified number of carbon atoms attached through an oxygen bridge; as used herein, "alkylthio" includes an alkyl group of the specified number of carbon atoms attached through a sulfur bridge.

The compounds described herein may have asymmetric centers. The present invention includes all chiral, diastereomeric and racemic forms. It is understood that some of the compounds of the present invention have an asymmetrically substituted carbon atom and may be isolated in optically active or racemic forms. Ways of obtaining optically active forms, such as by resolution of the racemic form or by synthesis from optically active starting materials, are well known in the art. Unless a particular stereomeric or isomeric form is used, all chiral, diastereomeric, racemic and geometric isomers are meant.

Combinations of substituents and / or variables are permissible only if they yield stable compounds. By stable compound or stable structure is meant a compound which is sufficiently stable by isolation from the reaction mixture and purification to a useful purity.

As used herein, the term "substituted" means that one or more hydrogens at the designated atom is replaced by a selected specified moiety, provided that the normal valence of the indicated atom is unchanged and the substitution results in a stable compound.

The present invention is designed to be implemented on a gram scale, a kilogram scale, a kilogram scale or an industrial scale. As regards the gram scale, it is meant that the amount of at least one starting material is 10 grams or more, preferably at least 50 grams or more, and more preferably at least 100 grams or more. In terms of kilogram weight, it is understood that the volume of at least one starting material is greater than one kilogram. By industrial scale, we mean a volume that is different from a laboratory and can provide sufficient product for both clinical trials and consumers.

The methods of the present invention may be better understood by reference to Scheme 1, which is provided by way of example, without limiting the scope of the invention. Scheme 1 details the general synthesis routes for asymmetric synthesis of compounds of formula (I) via (VI) wherein X is Cl and A is trifluoromethyl.

It will be appreciated that one skilled in the art of organic synthesis may, using the techniques described herein, prepare homologues of compounds of formula (I) via (VI) wherein X is Cl or F and A is trifluoromethyl, pentafluoroethyl, or heptafluoropropyl by appropriately selecting pchloraniline for or a combination of p-fluoroaniline with CFsCCFEt, CFaCFiCCĘEt or CFsCFsCFzCCHEt.

scheme

pivaloyl-Cl

NaOH solvent stage

1) Alkylitis CFįCOjEt

2) HCL insoluble

stage

It is an object of the present invention to provide an improved method of asymmetric synthesis of benzoxazinones which are inhibitors of HIV reverse transcriptase.

stage: login. Preparation of a compound of formula (II).

This step is carried out by reacting a compound of formula (I) with a free base, in a suitable solvent and at a suitable temperature, with benzyl alcohol, benzyl ether, benzhydryl alcohol or benzhydryl ether in the presence of a suitable acidic catalyst to form a compound of formula (II). According to general instructions, compound (I) in aqueous / organic solvent may be neutralized with a base to a pH of about 7 at about room temperature, further reacted with about 1 molar equivalent of benzyl alcohol, benzyl ether, benzhydryl alcohol, or benzhydryl ether. 0.1-5.0 mol% of a suitable acidic catalyst, and heated to a temperature sufficient to form compound (II). Compound (II) can be isolated from the reaction mixture in the form of a solid stable solid according to standard processing procedures. An example of standard processing is shown in Example 3.

Compound (II) may optionally be used for the synthesis of compounds of formula (III).

P is a benzyl or benzhydryl group of compounds of formula (VII) or (VIII), respectively, preferably p-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl or 4,4'-dimethoxybenzhydryl. Even better, P is pmethoxybenzyl.

Preferred acidic catalysts of step (1) include HCl, methanesulfonic acid, sulfuric acid, trifluoroacetic acid, trichloroacetic acid and ptoluenesulfonic acid. Methanesulfonic acid and ptoluenesulfonic acid are more preferred.

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

The preferred temperature range of step (1) is from about room temperature to about 120 ° C, with P being pmethoxybenzyl, more preferably from about 60 to about 90 ° C.

It will be appreciated that one skilled in the art can determine the best field for the reaction time of Step 1, depending on temperature, acidic catalyst, and group P. typically, the reaction time is 0.5 to 12 hours.

stage: induction of chirality. Preparation of a compound of formula (III).

This step of inducing chirality comprises the alkylation of achiral ketone carbonyl of a compound of formula (II) in the presence of a chiral inducing agent of formula (IX) in a suitable solvent, preferably at least about two equivalents of cyclopropylethyl lithium, ) by reacting cyclopropylacetylene with a suitable alkylene, for a suitable period of time, at a temperature sufficient to form a compound of formula (III). Generation of about two equivalents of cyclopropylethynyl lithium in situ can be accomplished by reacting about two equivalents of cyclopropylacetylene with about four equivalents of the appropriate alkyl lithium in a suitable solvent at a temperature below 0 ° C for about 1-3 hours. According to the general instructions, about two equivalents of the chiral inducing agent of formula (IX), about two equivalents of the appropriate alkylate and about two equivalents of cyclopropylacetylene are added in independent solutions, followed by the addition of one equivalent of formula (II). of the compound in a suitable solvent and kept below -30 ° C for 1-3 hours to form compound (III). Compound (III) may be isolated from the reaction mixture in solid form according to standard processing procedures. An example of standard processing is given in Example 4.

It is desirable, but not necessary, for the reagents to be added at this stage in the form of solutions, that is to say, separate solutions thereof prior to mixing.

Reagents which are easy to manipulate in solid form, in such form, can be added to the reaction mixture, for example, compounds of formula (II) or chiral inducing agents.

In step (2), the chiral inducing agent lR, 2S-pyrrolidinylnorephedrine is preferred.

Preferred alkylating agents in step (^) include n-butyllithium, sec-butyllithium, t-butyllithium, isobutyllithium, n-hexyllithium, and octyl lithium. Preferably, n-hexyllithium is preferred.

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

The duration of step (2) is preferably about two hours for the formation of cyclopropylethynyl lithium and about 1-2 hours for the incorporation of compound (II) to 1R, 2S-pyrrolidinylnorephedrine / cyclopropylethynyl lithium.

The preferred temperature range of Step (2) is from about -50 to about 0 ° C for the formation of cyclopropylethyl lithium, and from about 60 to about -40 ° C for the addition of (II) to 1R, 2Spyrrolidinyl norephedrine / cyclopropylethyl lithium.

Stage I: Oxidative cyclization. Preparation of a compound of formula (IV).

This step consists in reacting the carbinol - compound of formula (III) in a suitable solvent, preferably with at least one equivalent of a suitable oxidizing agent, at a temperature sufficient to form a compound of formula (IV). In general, compound (III) in a suitable non-aqueous solvent may be reacted with about one molar equivalent of a suitable oxidizing agent when heated for about 1-6 hours at a temperature sufficient to form compound (IV). Compound (IV) may be isolated from the reaction mixture in the form of a solid by addition of a suitable non-aqueous solvent and subsequent treatment by standard procedures. An example of a standard methodology is given in Example 5. In addition, Compound (IV) without isolation can be used in Step 4 as shown in Example 6b.

Preferred oxidizing agents of Step (3) include petrachlorobenzoquinone and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

Preferred solvents and mixtures thereof in step (3) include toluene, heptane, ethyl acetate, methyl-t-butyl ether, tetrahydrofuran, dichloromethane, and cyclohexane. Ethanol and methanol are suitable for the reactions employing 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

The reaction time of step (3) depends on the solvent and temperature. When the solvent of step (3) is heptane / ethyl acetate, it is preferable that the addition of the oxidizing agent takes about 4-6 hours.

The best temperature range for binding the oxidizing agent to compound (III) depends on the solvent. When the solvent of step (3) is heptane / ethyl acetate, the temperature range from about room temperature to the boiling point of the solvent is preferred.

stage: debenzylation. Preparation of a compound of formula (V).

This step consists in reacting a compound of formula (IV) in a suitable solvent with a suitable strong base to form a compound of formula (V). Because the hemiaminal debenzylation product is an aromatic aldehyde or ketone, depending on the P ′ structure, it must be bound or converted to a suitable binding agent to form a substance which does not react with compound (V).

There are three ways in which the aromatic aldehydes or ketones can be bound. First, when the hemiaminal (IV) is reacted with a strong base to form a compound of formula (V) and a by-product of the aromatic aldehyde or ketone, the by-product may be reduced with a suitable reducing agent to the corresponding alcohol; enabling the isolation of the amine (V) by neutralization of the reaction mixture and subsequent filtration. Second, the by-product may be coupled with a reagent that reacts significantly better with the by-product than with the free amine (V), for example, by reaction of the by-product with hydroxylamine to form the corresponding oxime, or preferably by reaction with the tosylhydrazide, in which the amine (V) can be isolated by carefully adjusting the pH to crystallize or precipitate the amine (V) product. Third, the by-product, if it is an aromatic aldehyde, may be coupled with a reagent that oxidizes the aldehyde to the corresponding acid but does not react with the (V) amino group or acetylene moiety; such a binding agent is hydrogen peroxide in an alkaline environment.

In general, compound (IV) is reacted in an aqueous / organic solvent with a suitable strong base, preferably sodium hydroxide or potassium hydroxide, at a suitable temperature for a sufficient period of time to form a compound of formula (V) followed by addition of a suitable binding agent, preferably sodium borohydride. at a temperature sufficient to yield the compound (V) in quantitative yield while converting the foreign aldehyde or ketone to the corresponding alcohol. Compound (V) may be isolated from the reaction mixture in the form of a solid stable solid by addition of a binding agent followed by determination of the pH of the solution and treatment by standard techniques. An example of standard processing is given in Example 6. Compound (V) may optionally be used in the synthesis of compounds of formula (VI).

The strong bases preferred in step (4) include sodium, potassium, lithium or calcium hydroxides as well as metal alkoxides. Sodium or potassium hydroxide is most preferred.

Binding agents that reduce the foreign aldehyde / ketone to the alcohol but do not react with either the amino group of the compound (V) or the acetylene moiety are preferred. Of the binding agents which are co-reducing agents, sodium borohydride is preferred.

Preferred solvents of step (4) are mixtures of alcohol and water. Most preferred is methanol and water.

(4) The duration of the stage is preferably about 1-3 hours.

The temperature range for base attachment to compound (IV) in step (4), preferred, is about 0-100 ° C; a temperature range of about 30-60 ° C followed by binding of a binding agent is more preferred.

stage: cyclization. Preparation of the compound of formula (VI).

This step comprises the cyclization of a chiral compound of formula (V) by reaction with a cyclizing agent in a suitable solvent at a temperature sufficient to form a compound of formula (VI). According to general instructions, about one equivalent of compound (V) is added to about two equivalents of the cyclizing agent and stirred at about 20-25 ° C until the reaction is quantified. Compound (IV) may be isolated from the reaction mixture in the form of a stable solid according to standard work-up procedures. An example of standard processing is given in Example 7.

The cyclizing step (5) agent phosgene is preferred.

Preferred solvents in step (5) are heptanes, toluene and tetrahydrofuran. The heptane / tetrahydrofuran mixture is most preferred.

The best temperature for the coupling of the cyclizing agent in step (5) is below or about 0 ° C.

As will be understood by those skilled in the art of organic synthesis, the compounds of formulas (II), (III), (IV), (V) and (VI) are readily obtained by the wise selection of reagents.

The present invention is further illustrated by reference to Scheme 2 wherein R ² = H in the example with a compound of formula (VII).

scheme

1C

pivaloyl-Cl

NaOH toiuen

Cl

1) BuLi / EtTFA

2) HCl / HOAc p-MeOBzlOH

Cl

pyrrolidinylnorephedrine n-hexillitis

OMe

VI of VI

The methods of the present invention are provided by way of example, but are not limited to the following

O Λ is better understood by referring to Scheme 3 wherein neither R nor R is H in the example with the compound of formula (VIII). The scheme further elaborates further the general methods for the synthesis of a compound of formula (VI) using an acid-unstable amine protecting group. In addition to obtaining high enantiomeric yields in the step of inducing chirality, it is possible to isolate Compound (V) without one step chromatography under fast and gentle conditions at room temperature.

scheme

stage

pyrrolidinylnorephedrine

I i - = _ XI

stage: login. Preparation of a compound of formula (II) wherein R ² and R ³ do not contain H.

This step comprises reacting a compound of formula (I) converted into the free base in a suitable solvent at a suitable temperature with a compound of formula (VII) or (VIII) wherein neither R ² nor R ³ is H in the presence of a suitable acidic catalyst. compound. According to general instructions, compound (I) in aqueous / organic solvent may be neutralized at about room temperature with a base to pH about 7, about 1 molar equivalent of compound (VII) or (VIII) in which neither R nor R is H, preferably trityl, is added. of alcohol, additionally about 0.1-5.0 mol% of a suitable acidic catalyst, and heating at a temperature sufficient to form compound (II). Compound (II) can be isolated from the reaction mixture in the form of a solid stable solid according to standard processing procedures. An example of standard processing is given in Example 11. Compound (II) may optionally be used to synthesize a compound of formula (III).

Preferably, the compound (VII) or (VIII) wherein neither R ² nor R ³ is H is trityl alcohol or methoxy substituted trityl alcohol.

Preferred acidic catalysts in step (6) include HCl, methanesulfonic acid, sulfuric acid, trifluoroacetic acid and p-toluenesulfonic acid. Methanesulfonic acid and p-toluenesulfonic acid are more preferred.

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

The reaction temperature from about room temperature to 120 ° C is preferred. When compound (VIII) is a trityl alcohol, a temperature range of about 60 to 90 ° C is more preferred.

It will be appreciated that one skilled in the art can determine the best reaction time depending on temperature, acid catalyst and P group. The reaction time is usually 0.5 to 12 hours.

Step 3: The chirality induction step in Scheme 3 is analogous to the chirality induction step in Scheme 1; An example of the synthesis of a compound of formula (III) wherein P is a trityl group is given in Example 12.

Stage: Detritilization. Preparation of a compound of formula (V).

This step comprises reacting a compound of formula (III) wherein the amine protecting group is highly labile with an acid in a suitable solvent with about 0.1-2.0 equivalents of the appropriate acid to form a compound of formula (V) at sufficiently mild temperatures. The by-product of detritylation is an aromatic alcohol and does not need to be bound thereafter as in Scheme 1 (4). Compound (V) can be isolated from the reaction mixture in the form of a stable solid by adjusting the pH of the solution and treatment according to standard procedures. An example of standard processing is given in Example 13. Compound (V) may further optionally be used to synthesize a compound of formula (VI).

Acceptable amine protecting groups in step (8) are trityl, pmethoxytrityl, 4,4'-dimethoxytrityl, as well as non-trityl groups such as 2,4-dimethoxybenzyl, and 4,4'-dimethoxybenzhydryl. More preferred is the trityl group.

The strong acids preferred in step (8) include HCl, HBr, methanesulfonic acid, trifluoroacetic acid, and p-toluenesulfonic acid. HCI or trifluoroacetic acid is more preferred.

Preferred solvents in step (8) are lower alkyl alcohols and must be anhydrous, such as methanol, ethanol and propanol. Most preferred is methanol.

Preferably, the temperature of the acid addition to compound (III) in step (8) is about 0-50 ° C, more preferably about 0-30 ° C.

The synthesis of cyclopropylacetylene (X) which is involved in the formation of a compound of formula (III) is shown in Scheme 4.

v scheme

Cl

alkyl-Li

THF 0 ° C

1. NH ₄ CI (aq) Phase Separation

2. Distill. in a vacuum

3. Sieves

4. Frake. dist.

II (X)

The preparation of cyclopropylacetylene (X) according to Scheme 4 is shown in Example 15. This synthesis of cyclopropylacetylene provides about 100% conversion of chlorpentine and greater than about 90% yield of cyclopropylacetylene, so that the product (X) can be used in solution to synthesize a compound of formula (III).

The following examples are provided by way of illustration of the present invention. The following examples illustrate the invention but do not limit its scope.

example

Synthesis of N- (4-chlorophenyl) -2,2-dimethylpropanamide. 4-Chloraniline (52.7 kg, 413 mol) was dissolved in a mixture of t-butyl methyl ether (180 kg) in 30% aqueous sodium hydroxide (61.6 kg, 463 mol) and water (24.2 kg), then cooled to 15 °. C. To the formed porridge within 1 hour. trimethylacetyl chloride (52.2 kg. 448 mol) was added while maintaining the temperature at 40 ° C. After stirring for 30 min. At 30 ° C, the mixture is cooled to -10 ° C and held for 2 hours. The product is isolated by filtration, washed with 90/10 water / methanol (175 kg), dried in vacuo to give 85 kg (97% yield) of the title compound as a solid crystalline solid. Lyd. temp. 152-153 ° C; 1 H NMR (300 MHz, CDCl 3) δ 7.48 (d, J = 9 Hz, 2H) 7.28 (d, J = 9 Hz, 2H); ¹³ C NMR (75 MHz, CDCl 3) δ 176.7, 136.6, 129.1, 128.9, 121.4, 39.6, 27.6.

Synthesis of N- (4-fluorophenyl) -2,2-dimethylpropanamide. It will be apparent to one skilled in the art of organic synthesis that replacing 4-chloroaniline with 4-fluoroaniline will readily afford the title compound.

example

Synthesis of 4-Chloro-2-trifluoroacetylaniline hydrochloride. To a solution of TMEDA (20.2 kg, 174 mol) in dry t-butyl methyl ether (271.5 kg) was added N- (4-chlorophenyl) -2,2-dimethylpropanamide (36.7 kg, 173 mol) and cooled to -20 °. C. To the cooled semi-liquid mixture was added 2.7 N n-butyllithium in hexane (101.9 kg, 393 mol) while maintaining the temperature below 5 ° C. 2 or more. At 0-5 ° C, the solution was cooled to -15 ° C and then allowed to react rapidly with ethyl trifluoroacetate (34.5 kg, 243 mol). After 30 min, the resulting solution was poured into 3N HCl (196 L, 589 mol), maintained below 25 ° C. After separation of the aqueous phase, the organic solvent is concentrated by distillation of about 200 L of solvent. Acetic acid is added and 325 kg of solvent are distilled off under 100 mm vacuum. After cooling the solution to 30 ° C, 12 N HCl (43.4 kg, 434 mol) was added and the mixture heated at 65-70 ° C for 4 hours. The resulting semi-solid mixture is cooled to 5 ° C, the product is isolated by filtration, washed with ethyl acetate (50.5 kg) and dried under vacuum to give 42.1 kg (87%) of the title compound as a white crystalline solid. Lyd. temp. 159-162 ° C (dec.); Ή NMR (300 MHz, DMSO-d ₆₎ d 7.65 to 7.5 (complex, 2H), 7.1 (d, J = 8 Hz, 1H), 7.0 (br.s., 3H) ; ¹⁹ F NMR (282 MHz, DMSO-d 6) δ -69.5.

It will be clear to one skilled in the art of organic synthesis that CF3CF2CO2Et or CF3CF2CF2CO2Et can be readily substituted with ethyl trifluoroacetate to synthesize the respective homologs.

Example 3

Synthesis of 4-Chloro-2-trifluoroacetylaniline. 4-Chloro-2-trifluoroacetylaniline hydrochloride (17.1 g, 62 mmol) was stirred in a mixture of toluene (100 mL) and water (50 mL). The mixture is neutralized with saturated NaHCO ₃ solution to pH 7. The organic phase is concentrated in vacuo and the residue is recrystallized from heptane; yields 12.5 g (91%) of the title compound as yellow needles. Lyd. temp. 98-99 ° C; 1 H NMR (300 MHz, CDCl ₃ ) δ 7.70 (t, J = 2 Hz, 1H), 7.32 (dd, J = 2, 9 Hz, 1H), 6.7 (d, J = 9 Hz, 1H), 6.44 (e.g., 2H); ¹³ C NMR (75 MHz CDCl ₃ ) δ 180.0, 151.6, 136.9.

130.1, 120.9, 119.0, 1166.8, 111.4; ¹⁹ F NMR (282 MHz, CDCl 3) δ -70.3.

example

Synthesis of N - ((4'-methoxy) benzyl) -4-chloro-2-trifluoroacetylaniline. Compound (IIi). To a semi-liquid mixture of 4-chloro-2-trifluoroacetylaniline hydrochloride in toluene (140 kg) and water (50 L) was added 30% NaOH (18 kg) to pH 7.0. After separation of the aqueous phase, 4-methoxybenzyl alcohol (20 kg, 144 mol) and TsOH (1.0 kg, 5.3 mol) were added. The solution was refluxed and 30 L of an aceotropic water / toluene mixture was distilled off. The solution is cooled to room temperature and washed with a saturated solution of table salt (80 kg). The organic solution is concentrated in vacuo to 35-40 L and then diluted with THF (52 kg). HPLC indicates that the toluene / THF solution contains 43% of the title compound. According to these data, the yield is 47.7 kg (96%). Evaporation of the solvent in vacuo and recrystallization from heptane gave an analytical sample. Lyd. temp. 82-84 ° C; ¹ H NMR (300 MHz, CDCl 3) δ 9.04 (s, 1H), 7.74 (d, J = 2 Hz, 1H), 7.35 (dd, J = 2, 9 Hz), 7.24 (d, J = 8Hz, 2H), 6.91 (d, J = 8Hz, 2H), 6.75 (d, J = 9Hz, 1H), 4.43 (d, J = 6Hz, 2H), 3.79 (s, 3H); ¹³ C NMR (75 MHz, CDCl 3) δ

180.5, 159.2, 151.9, 137.4, 130.8, 128.9, 128.4, 117.0, 114.5, 114.4, 111.3, 55.3,

46.6.

Example S Synthesis of (S) -5-chloro-α- (cyclopropylethynyl) -2 - [(4-methoxyphenyl) methyl] -amino] -α (trifluoromethyl) benzenemethanol. The compound (ΙΙΙ-i). Triphenylmethane (100 g) was added to a solution of (IR, 2S) pyrrolidinylnephrephrine (80 kg, 60.7 mol) in toluene. The solution is concentrated in vacuo to about half the initial volume. Dry THF is added and the solution is cooled in a -50 ° C thermostat. When the temperature drops to -20 ° C, n-hexyl lithium (33% w / w in hexane, 33.4 kg, 119.5 mol) is added while maintaining the temperature below 0 ° C. To the resulting red solution was added a cyclopropylacetylene solution (30% w / w THF / hexane / toluene; containing about 4 kg, 65 mol cyclopropylacetylene) while maintaining the reaction temperature below -20 ° C. The resulting solution is stored at -45 to -50 ° C for 1 hour. to the cold solution was added N - ((4'-methoxy) benzyl) -4-chloro-2-trifluoroacetylaniline (43% by weight in THF / toluene containing about 10 kg, 28.8 mol N ((4'-methoxy) benzyl) -4 -chloro-2-trifluoroacetylaniline) while maintaining the reaction temperature below -0 ° C. After 1 hour at -43 to +/- 3 ° C, the reaction mixture is poured into 140 kg of 1N HCl, cooled to 0 ° C. The organic layer was separated and twice with 25 kg of 1N HCl, twice with 40 kg of water, then concentrated in vacuo to about 29 L. Toluene (47 kg) was added and the solution concentrated to 28-30 L. Add 23 kg of heptane, cool and keep at -5 ° C for 4 hours. The product is filtered off, washed twice with 10 kg of heptane and dried in vacuo; yields 10 kg (85%) of the title compound as a whitish solid. Lyd. temp. 163-165 ° C; [α] ²⁵ D + 8.15 ° (c 1.006, MeOH); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.55 (m.s., 1H), 7.23 (d, J = 8 Hz, 2H), 7.13 (dd, J = 3, 9 Hz) 1 H), 6.86 (d, J = 8 Hz,

2H), 6.59 (d, J = 8Hz, 1H), 4.95 (cf., 1H), 4.23 (s, 2H), 3.79 (s, 3H), 2.39 (m, 1H), 1.34 (m, 1H), 0.84 (m, 2H), 0.76 (m, 2H); ¹³ C NMR (75 MHz, CDCl 3) δ 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; ¹⁹ F NMR (282 MHz, CDCl 3) δ -80.19.

Example S Synthesis of (S) -6-chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2- (4'methoxyphenyl) -3,1-benzoxazine. Compound (IV-I). To a mixture of heptane (295.5 kg) and ethyl acetate (32.5 kg) was added p-chloranyl (57 kg, 232 mol) and (S) -5-chloro-cyclopropylethynyl-2 - [(4-methoxyphenyl) methyl] - amino] -? - (trifluoromethyl) benzenemethanol (89 kg, 217 mol). The mixture was refluxed for 5.5 hours with vigorous stirring, then diluted with ethyl acetate (64.1 kg) and cooled to 30 ° C. The tetrachlorohydroquinone is filtered off, 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 / -15 ° C. The resulting semi-liquid mixture is filtered and the product is washed with heptane (41 kg), dried on a filter until less than 20% heptane is left. The yield of (IV) calculated from HPLC data is 71 kg (80%). The analytical sample was obtained by deleting the sample with IN NaOH followed by recrystallization from hexane / ethyl acetate. Lyd. temp. 130-131.7 ° C; ^! 1 H NMR (300 MHz, DMSO-d 6) δ 7.46 (d, J = 9 Hz, 2H), 7.287.21 (m, 3H), 7.0 (d, J = 9 Hz, 2H), 6, 85 (d, J = 9Hz, 1H), 5.52 (s, 1H), 3.78 (s, 3H), 1.52-1.47 (m, 1H), 0.90-0.84 (m, 2H), 0.72-0.68 (m, 1H); ¹³ C NMR (75 MHz, DMSO-d 6) δ 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; ¹⁹ F NMR (282 MHz, CDCl 3) δ 157.5.

example

Synthesis of compound (Vi): (S) -5-Chloro-α- (cyclopropylethyl) -2-amino-α- (trifluoromethyl) benzenemethanol. Crude (S) -5-chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2- (4'-methoxyphenyl) -3,1-benzoxazine (71 kg dry weight) was added to methanol (301 kg), 30% NaOH (121 kg) and water (61 L). The reaction mixture is heated to 60 ° C until the solution becomes clear, then cooled to 30 ° C. To the methanolic solution over 20 min. add a solution of sodium borohydride (3.2 kg, 84.2 mol) in 0.2 N NaOH (29 L) at a temperature not exceeding 35 ° C. After 30 minutes The excess borohydride is decomposed with acetone (5.8 kg), diluted with water (175 L), then neutralized with acetic acid to pH 8-9. The resulting semi-liquid mixture is cooled to about 0 ° C, filtered, the product washed with water and dried in vacuo at 40 ° C. The crude product is mixed with a mixture of toluene (133 kg) and heptane (106 kg), initially at 25 ° C, then freezing below -10 ° C. The product is filtered off, rinsed with heptane (41 kg), dried in vacuo at 40 ° C; yields 44.5 kg (88%) of whitish-pale yellow crystals. The analytical sample is recrystallized from t-butyl methyl ether / heptane. Lyd. temp. 141143 ° C; [α] ²⁵ D -28.3 ° (c 0.106, MeOH); 1 H NMR (300 MHz, CDGR) δ 7.54 (d, J = 2 Hz, 1H), 7.13 (dd, J = 9.2 Hz, 1H), 6.61 (d, J = 9 Hz) , 1H), 4.61 (e.g., 1H), 4.40 (e.g., 1H), 1.44-135 (m, 1H), 0.94-0.78 (m, 2H) ) ^I3 C NMR (75 Hz, DMSO-d6) δ 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 CDCl 3) δ -80.5.

Example 6b

Preparation of compound (V-i) from compound ((-i) without isolation of compound (IV-i) in the previous synthesis step: (S) -5-chloro-α- (cyclopropylethynyl) -2-amino-α (trifluoromethyl) benzenemethanol. To a mixture of DDQ (9.42 g), 41.5 mmol) and t-butyl methyl ether (33 mL) was added (S) -5-chloro-α (cyclopropylethynyl) -2 - [(4-methoxyphenyl) methyl] - at 10 ° C. amino] -? - (trifluoromethyl) benzenemethanol (16.38 g, 40 mmol). After 5 minutes the resulting semi-liquid mixture was filtered at 30 ° C and the resulting solid was washed with 5 mL of t-butyl methyl ether. The filtrate is washed with 5% aqueous sodium bicarbonate solution and then partially concentrated by distilling off 70 ml of solvent. Methanol (25 mL) and 6N NaOH (4 mL) were added followed by distillation with 20 mL solvent. 4N NaOH (26 mL) was added and the mixture was briefly heated to 58 ° C, then cooled to 30 ° C. A solution of sodium borohydride (0.60 g, 15.9 mmol) in 0.5 N NaOH (6 mL) was added. In minutes 45 ml of water are added followed by 1 ml of acetone. After 0.5 or. acetic acid (12 mL, 210 mmol) was added to pH 7.5. The resulting semi-liquid mixture is cooled to about 0 ° C and filtered. The material was further purified by recrystallization from t-butyl methyl ether / hexane; yields 9.95 g (86%) of a white solid. The physical characteristics are the same as those of the product obtained from the two-step process (from p-chloranyl / NaBH 3, see Example 6).

Example S Synthesis of (S) -6-chloro-4- (cyclopropylethyl) -1,4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one. Compound (VI-i). (S) -5-Chloro-α- (cyclopropylethynyl) -2-amino-α- (trifluoromethyl) benzenemethanol (15.7 kg, 54.3 mol) was dissolved in a mixture of heptane (32 kg) and THF (52 kg) at a temperature below -10 ° C. Add to solution for 1 hour. phosgene (-8.0 kg, 80 mol) was allowed while maintaining the temperature below 0 ° C. The resulting semi-liquid mixture is heated and stored at 20-25 ° C for 1 hour. Methanol (6.5 kg, 203 mol) was added and the solution was stirred for about 30 min. Heptane (97 kg) was added followed by distillation under reduced pressure of -140 L of solvent. Add 97 kg of heptane and 22 kg of THF and wash with 5% aqueous sodium bicarbonate solution (15 L) followed by water (15 L). The solution is heated to 50 ° C, filtered into a clean reactor, where 40 kg of heptane are added. The solution was concentrated under reduced pressure, diluted with heptane (22 kg) and cooled below -10 ° C. The product was filtered off, rinsed with heptane (37 kg), dried in vacuo at 90-100 ° C; yields 16.0 kg (95%) of a whitish-reddish solid. HPLC: 99.8 area%: m.p. temp. 139-141 ° C; [α] ²¹ D 94.1 ° (c 0.300 MeOH); NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.54 (dd, J = 2.5, 7 Hz, 1H), 7.43 (d, J = 2.5 Hz, 1H), 6.99 (d, J = 7Hz, 1H), 1.58 (m, 1H), 0.92 (m, 2H), 0.77 (m, 2H); ¹³ C NMR (100 MHz, DMSO-d 6) δ 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 ) δ -81.1.

example

N - ((3 ', 4'-dimethoxy) benzyl) -4-chloro-2-trifluoroacetylaniline. To 2-propanol (40 mL) was added 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 heated at 60 ° C for 3.5 h. The solution is concentrated in vacuo to an initial volume of Vi, diluted with water (10 mL) and stirred at room temperature. The resulting semi-liquid mixture is filtered and the product dried under vacuum at 30 ° C; yields 10.16 g (68%) of the title compound as a yellow powder. An analytical sample was obtained by recrystallization from acetonitrile. Lyd. temp. 82-84 ° C; Ή NMR (CDCB) δ 9.05 (m.p. 1H), 7.75 (m.p., 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); ¹³ C NMR (CDCB) δ 179.9, 151.9, 149.4, 148.7, 137.4, 130.8, 130.8, 130.7, 129.4, 119.4, 114.5 ,

111,5,111,4,110,3, 56,1, 56,0, 47,0; ¹⁹ F NMR (CDCB) δ -69.61.

Example (S) -5-Chloro-α- (cyclo] opropylethynyl) -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 atmospheric distillation in 160 mL of solvent. 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. While maintaining the temperature below 0 ° C, add n-hexillite (2.0 M solution in hexane, 203 mL, 0.406 mol). After adding 108 ml, the mixture becomes red. A solution of 16% by weight cyclopropylacetylene (103 g, 0.25 mol) is added until the reaction mixture is quenched. The solution was stirred at -5 / 0 ° C for 20 min, then cooled to -45 ° C, and then n- (3 ', 4'-dimethoxy) benzyl-4-chloro-2-trifluoroacetylaniline (29.7 g, 81%) was added. 8 mmol) dissolved in 50 mL of THF. 1 hour or more. At 45 ° C, the mixture was poured into 2N HCl (400 mL). The organic layer was washed twice with 2 N HCl (100 mL) then concentrated in vacuo. 150 ml of toluene are added and the mixture is concentrated to 80 ml. Add 100 ml of heptane plus 43 ml of toluene, solvent ratio heptane: toluene 60:40 by gas chromatography. After crystallization, the product is filtered off and recrystallized from toluene: heptane (3: 1); yields 23.1 g (64%) of the title compound as a pale yellow solid. Lyd. temp. 128-129.5 ° C; [α] ²³ D + 11.00 ° (c 0.300, MeOH); 1 H NMR (300 MHz, CDCl 3) δ 7.56 (m, 1H), 7.13 (dd, J = 9, 3 Hz, 1H), 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, 1H), 0.90-0, 74 (m, 4H); ¹³ C NMR (75 MHz, DMSO-d 6) δ 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; ¹⁹ F NMR (282 MHz CDCl 3) δ -80.0.

Example 5 (S) -6-Chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2- (3 ', 4'-dimethoxyphenyl) -3,1-benzoxazine. To a solution of (S) -5-chloro-α- (cyclopropylethynyl) -2 - [(3,4-dimethoxyphenyl) methyl] -amino] -α- (trifluoromethyl) benzenemethanol (2.68 g, 6.1 mmol) of methanol at 40 ° C was added DQQ (1.40 g, 6.1 mmol). The resulting semi-liquid mixture was stirred for 30 min. chilled in an ice bath, then filtered. The product is washed with 5 ml of cold methanol, dried in vacuo; yields 2.36 g (88%) of the title compound. Lyd. temp. 172-175 ° C Ή NMR (300 MHz, CDC1 ₃₎ δ 7.48 (s, 1H), 7.18 (dd, J = 2, 9 Hz, 1H), 7.13 (d, J = 7 Hz, 1H), 7.10 (s, 1H), 6.87 (d, J = 7Hz, 1H), 6.70 (d, J = 9Hz, 1H), 5.62 (d, J4) Hz, 1H), 4.33 (d, J = 4Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 1.33 (m, 1H), 0.90- 0.72 (complex, 4H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 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_BMR (282 MHz, CDCl ₃ ) δ -79.2.

example

N-triphenylmethyl-4-chloro-trifluoroacetylaniline. Method A. 4-Chloro-2-trifluoroacetylaniline (22.4 g, 100 mmol), trityl chloride (30.0 g, 107 mmol), triethylamine (11.6 g, 115 mmol) and DMAP (0.5 g, 4 mmol) ) were dissolved in DMF (50 mL) and stored at 60 ° C for 14 h. The resulting semi-liquid mixture is cooled to room temperature, diluted with 20 ml of water and filtered; yields 35.9 g (77%) of the title compound. An analytical sample was obtained by recrystallization from acetonitrile. Lyd. temp. 165-167 ° C, 1 H NMR (CDCl 3) δ 10.4 (m.p., 1H), 7.71 (m.p., J = 2 Hz, 1H), 7.3 (m.p. , 15H), 6.9 (dd, J = 2.8 Hz, 1H), 6.27 (d, J = 8 Hz, 1H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 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; ¹⁹ F NMR (282 MHz, CDCl 3) δ -69.5.

N-triphenylmethyl-4-chloro-trifluoroacetylaniline. Method B. 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 semi-liquid mixture is neutralized with 30 mL of 10 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 is heated under reflux and 300 ml of solvent are distilled off. 350 ml of acetonitrile and 0.5 ml of diisopropylethylamine are added and 220 ml of solvent are further distilled off. The solution is cooled in an ice bath, filtered, and obtained 126.5 g (89%) of the product having the same spectral and physical characteristics as the product prepared by Method A.

Example S Synthesis of (S) -5-chloro-α- (cyclopropylethyl) -2-triphenylmethyl] -amino] -α- (trifluoromethyl) benzenemethanol. To a solution of cyclopropylacetylene (3.15 g, 48 mmol) and (IR, 2S) pyrrolidinyl norephephrine (10.9 g, 53 mmol) in 50 mL of THF was added 2N n-hexyl lithium (46 mL, 92 mmol) while maintaining the temperature below 0 ° C. To the anionic solution was added N-triphenylmethyl-4-chloro-2-trifluoroacetylaniline (9.32 g, 20 mmol) dissolved in 20 mL of THF and held for 1 h. At -45 / -50 ° C, then quenched with 1 N citric acid (92 mL). The organic layer was separated, dried over sodium sulfate and concentrated to an oil. Crystallization from heptane / toluene yields 6.34 g (60%) of the title compound. Lyd. temp. 180-182 ° C; [α] ²⁵ D + 7.77 ° (c 1.004, CH 2 CN); ^! 1 H NMR (300 MHz, CDCl ₃ ) δ 7.53 (d, J = 2 Hz, 1H), 7.4-7.1 (complex, 16 H), 6.67 (dd, J = 2.7 Hz) , 1H), 6.05 (d, J = 7Hz, 1H), 3.17 (e.g., 1H), 1.07 (m, 1H), 0.72 (m, 2H), 0, 62 (m, 2H); ¹³ C NMR (75 MHz, CDCl 3) δ 143.7, 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; ¹⁹ F NMR (282 MHz, CDCl 3) δ -79.9.

Example S Synthesis of (S) -5-chloro-α- (cyclopropylethyl) -2-amino] -c- (trifluoromethyl) -benzene methanol. Single-stage debenzylation. A solution of 5-chloro-α- (cyclopropylethynyl) -2 (triphenylmethyl) -amino-α- (trifluoromethyl) benzenemethanol (5.32 g, 10 mmol) in methanol (25 mL) was reacted with 12 N HCl (0.5 mL) at room temperature. ml). After 15 minutes 2 mL of 2 N NaOH and 20 mL of water were added. The aqueous methanolic solution was extracted with cyclohexane (22 mL) followed by hexane (20 mL), then partially concentrated in vacuo and neutralized with acetic acid to pH 7. The product was filtered off, washed with water and dried; yields 2.65 g (92%); melt temp. 140-143 ° C. The spectral characteristics are the same as those of Example 6.

Example 1 Synthesis of (IR, 2S) -pyrididinylnorephedrine. To a mixture of n-butanol (227 kg), water (144 kg) and potassium carbonate (144 kg, 1043 mol) is added (IR, 2S) norephedrine (68.6 kg, 454 mol). The mixture is heated to 90 ° C for 2 hours. 1,4-dibromobutane (113.4 kg, 525 mol) was added. The reaction mixture was refluxed for 5 hours, then cooled to 40 ° C. 181 kg of water are added and the phases are separated at 30 ° C. 12N HCl (54.3 kg, 543 mol) was added to the organic phase. The solution is heated under reflux and 150 ml of distillate are distilled off at 200 to 300 mm pressure. 39.5 kg of toluene are added at 70 ° C, the resulting semi-liquid mixture is cooled to 0-5 ° C to crystallize. The product is separated off, washed twice with 39 kg of toluene, dried under a nitrogen atmosphere to give 83.6 kg of the title compound as the hydrochloride salt. The hydrochloride salt is added to a mixture of toluene (392 kg) and water (42 kg) and treated with 30% NaOH (approximately 55 kg, 414 mol) to a pH greater than

After removing the aqueous phase, the organic solution is partially concentrated by distillation of 140 L of solvent; yields a solution of 20% by weight of the title compound in toluene. The estimated yield is 50 kg (75%). The analytical sample was obtained by concentrating the toluene solution in vacuo, followed by recrystallization of the title compound from heptane. Lyd. temp. 46-48 ° C.

example

Synthesis of cyclopropylacetylene (X).

1. n-hexillitis hexane

THF at 0 ° C

2. toluene

3 · Distillation. in a vacuum

1. NH ₄ CI (aq)

2. Phase Separation

3. Sieves

4. Frake. dist.

(X)

A mixture of 5-chloro-l-pentine (23.0 kg, 224 mol) and dry THF (150 kg) was cooled to -20 ° C. at a rate such that the temperature does not rise above 5 ° C (about 2 hours) The second half portion of the n-hexyl lithium should be maintained above -5 ° C to avoid organic lithium accumulation and violent exothermic reaction. At -5 / 0 ° C until gas chromatography determines that the reaction is at least 99%, then toluene (35-40 kg) is added, the reaction mixture is concentrated in vacuo to 1/3 initial volume and heated to about 40 ° C. The mixture is then cooled to 15 / -20 ° C and a solution of ammonium chloride (11-12 kg) in 50-60 liters of water is added at such a rate that the temperature does not rise above 10 ° C. After separation of the aqueous layer (ca. kg), the reaction mixture is passed through a column of approx 15 kg o

molecular sieves of 3A until the water content as determined by the Karl Fisher method is about 300 parts per million or less. The dried organic solution is distilled through a rectifying column loaded with a steel wire under atmospheric pressure, separating the cyclopropylacetylene in the form of a solution in THF / toluene / hexane. The estimated yield is 14.0 kg.

While the present invention has been described with reference to specific embodiments, the details of these embodiments are not intended to limit the invention. Without departing from the spirit and scope of the invention, various equivalents, modifications, and modifications may be made and it is to be understood that they are all part of the present invention. The present invention may be embodied in other specific forms without departing from its spirit and essential features and, accordingly, should be within the scope of the appended appendix in determining the scope of the invention.

Claims (4)

DEFINITION OF INVENTION 1. Compounds of formula (VI): where: X is Cl or F, and A is a method of asymmetric synthesis of -CF ₃ , -C 2 F 5 or -C ₃ H ₇ , characterized in that it consists of: (1) Compound of Formula (I): Reactions of (I) with a compound of formula (VII) or (VIII): (VII) in which: R ¹ is H, C 1-6 alkyl or C 1-6 alkylcarbonyl, R ² is H, R ³ is H, -CH 3, -CH 2 CH 3 or phenyl substituted with 0-3 R ¹² , R ⁴ , R ³ , R ^4a , R ^5a , R ⁶ , R ⁸ and R ^{9 are} independently selected from H, C 1-6 alkyl, C 1-6 alkyl. ₆ alkoxyl and Ci. ₆ alkylthio; R ¹² is H, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylthio; Y is - (CH ₂ ) _n or O, and n is 0,1, 2 or 3; in the presence of a suitable acidic catalyst to form a compound of formula (II): (2) reacting (a) a compound of formula (IX) wherein R ¹⁰ and R ^{11 are} independently C 1-4 alkyl or NR ¹⁰ R ⁿ is pyrrolidinyl, piperidinyl or morpholinyl; reactions with alkyl lithium and cyclopropylacetylene to form a mixture of a compound of formula (IX) and lithium cyclopropylacetylide, and reaction of a reaction mixture of step (b) (2) (a) with a compound of formula (II) to form a compound of formula (III): (III) Reactions of a compound of formula (III) with a suitable oxidizing agent, (IV) wherein P 'is a reaction of a compound of formula (4) with a suitable ring-opening agent in the presence of a suitable binding agent. (V) for a compound of the formula: Reactions of a compound of formula (V) and (5) with a suitable cyclizing agent to give a compound of formula (VI). A process according to claim 1 for the preparation of a compound of formula (VI) wherein X is Cl and A is -CF 3, which comprises: (1) reacting a compound of formula (I) with a compound of formula (VII) wherein: R ¹ is H, C 1-6 alkyl or C 1-6 alkylcarbonyl, R ² is H, R ³ is H, -CH ₃ , -CFFCFL ·} or phenyl substituted with 0-3 R ¹² , R ⁴ , R ⁵ , R ^4a , R ^5a and R ^{6 are} independently selected from H, C 1-6 alkyl, C 1-6 alkoxyl and C 1-6 alkylthio; R ¹² is H, C _b6 alkyl, Ci-6 alkoxy, or Ci. ₆ alkylthio; in the presence of a suitable acidic catalyst to form a compound of formula (II); (2) reacting (a) 1R, 2S-pyrrolidinylnorephedrine with n-hexyl lithium and cyclopropylacetylene to form a mixture of 1R, 2S-pyrrolidinylninephrephrine and lithium cyclopropylacetylide, and (b) reacting the reaction mixture of step (2) (a) with a compound of formula (II) to form a compound of formula (III); (3) reacting a compound of formula (III) with a suitable oxidizing agent to form a compound of formula (IV); (4) reacting a compound of formula (IV) with a suitable ring-opening agent in the presence of a suitable binding agent to form a compound of formula (V); and (5) reacting a compound of formula (V) with a suitable cyclizing agent to form a compound of formula (VI). obtain, characterized in that it consists of: (1) Reaction of 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 (II-i): Reactions of OMe (II-i) (2) (a) 1R, 2S-Pyrrolidinylnorephedrine with n-hexyl lithium and cyclopropylacetylene to form a mixture of 1R, 2S-Pyrrolidinylnorephedrine and lithium cyclopropylacetylide, and (b) Step (2) (a) with a compound of formula (Π-i) to form a compound of formula (ΙΙΙ-i): Reactions of the OMe (3) compound of formula (ΙΙΙ-i) with a suitable oxidizing agent to give a compound of formula (IV-i): Reaction of OMe (4) with a suitable ring-opening agent in the presence of a suitable coupling agent to form a compound of formula (Vi) Reaction of a compound of formula (Vi) with a suitable cyclizing agent to form (VI-i) compound. 4. A process for the preparation of a compound of formula (VI) according to claim 1, characterized in that: a suitable acid catalyst is selected from the group of agents: HCl, methanesulfonic acid, benzenesulfonic acid, phosphoric acid, sulfonic acid, trifluoroacetic acid, trichloroacetic acid and p-toluenesulfonic acid, A suitable oxidizing agent is selected from the group consisting of: ΜηΟ ₂ , 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, p-tetrachlorobenzoquinone, otetrachlorobenzoquinone and iodosylbenzene diacetate, a suitable ring-opening agent is selected from the group consisting of: sodium Cp 4 alkoxide, lithium C _H alkoxide, potassium Cu alkoxide, NaOH, LiOH, KOH and 20 Ca (OH) ₂ , a suitable binding agent is NaBHt, NaHSCb, hydroxylamine, tosylhydrazide or H2O2, and a suitable cyclizing agent is phosgene. 5. A process for the preparation of a compound of formula (VII-i) according to claim 2, characterized in that: a suitable acidic catalyst is selected from the group of agents: HCl, methanesulfonic acid, benzenesulfonic acid, phosphoric acid, sulfonic acid, trifluoroacetic acid, trichloroacetic acid and p-toluenesulfonic acid, a suitable oxidizing agent is selected from the group of agents: MnO ₂ , 2,3dichloro -dicyano-1,4-benzoquinone, p-tetrachlorobenzoquinone, otetrachlorobenzoquinone and iodosylbenzene diacetate, the appropriate ring-opening agent is selected from the group consisting of sodium Cj. Alkoxy, lithium Cm alkoxide, potassium Cm alkoxide, NaOH, LiOH, KOH and Ca (OH) ₂ , a suitable binding agent is NaBH ₄ , NaHSO 2, hydroxylamine, tosylhydrazide or H ₂ O ₂ , and a suitable cyclizing agent is phosgene. A process according to claim 3 for the preparation of a compound of formula (VI-i), characterized in that: a suitable acid catalyst is selected from the group consisting of: HCl, methanesulfonic acid, benzenesulfonic acid, phosphate acid, sulfuric acid, Suitable oxidizing agent for trifluoroacetic acid, trichloroacetic acid and p-toluenesulfonic acid, is selected from the group consisting of MnO ₂ , 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, p-tetrachlorobenzoquinone, otetrachlorobenzoquinone, and iodosylbenzene, a suitable ring-opening agent is selected from the group consisting of sodium Ci. 20 ₄ alkoxide, lithium Cm alkoxide, potassium Cm alkoxide, NaOH, LiOH, KOH and Ca (OH) ₂ , a suitable binding agent is NaBH ₄ , NaHSO ₃ , hydroxylamine, tosylhydrazide or H ₂ O ₂ , and a suitable cyclizing agent is phosgene. 7. A process for the preparation of a compound of formula (VI) according to claim 1, wherein the compounds of steps (2) (a) and (b) are prepared separately and mixed in the form of solutions. 8. A process according to claim 2 for the preparation of a compound of formula (VI-i), characterized in that the compounds of steps (2) (a) and (b) are prepared separately and mixed in the form of solutions. 9. A process according to claim 3 for the preparation of a compound of formula (VI-i), characterized in that the compounds of steps (2) (a) and (b) are prepared separately and mixed in the form of solutions. 10. Compound of formula (II): where: where X is Cl or F, A is -CF 3, -C 2 F 5 or -C 3 H 7; P is either R ² is H, -CH 3, -CH ² CH 3 or phenyl substituted with 0-3 R ¹² , R ³ is H, -CH ₃ , -CH 2 CH ₃ 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 1-6 alkoxyl, or C 1-6 alkyl. ₆ alkylthio; Y is - (CH ₂ ) _n or O, and n is 0, 1, 2 or 3; A process for preparing a compound of formula (I): (I), Reactions with Compound of Formula (VII) or (VIII): (VIII) wherein R ¹ is H, C 1-6 alkyl or C 1-8 alkylcarbonyl in the presence of a suitable acidic catalyst to form a compound of formula (II). 11. The process of claim 10, wherein the compound of formula II is Cl (Il-a) and the method of preparation consist of: reacting 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 acidic catalyst to form a compound of formula (ΙΙ-a). 12. A process according to claim 11, wherein R ¹ is H, methyl, ethyl, methylcarbonyl or ethylcarbonyl, R ² is H, -CH 3 or phenyl substituted with 0-3 R ¹² , R ^J is H, -CH 3 or phenyl substituted with 0-3 R ¹² , R ⁴ , R ³ , R ^4a , R ^3a and R ⁶ are independently selected from H, methyl, ethyl, methoxy and ethoxy, and R ¹² is H, methoxy or ethoxy. 13. A process according to claim 11 wherein the compound of formula (VII) is R ⁴ R ⁵ R ³ R ¹ OR ² // OMe where R ¹ 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 ⁵ is H or methoxy. 14. The process of claim 11, wherein the suitable acid catalyst is selected from the group consisting of HCl, methanesulfonic acid, benzenesulfonic acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, trichloroacetic acid and p-toluenesulfonic acid. 15. The process according to claim 11, wherein the suitable acid catalyst is methanesulfonic acid or p-toluenesulfonic acid. 16. A process according to claim 11 wherein the compound of formula (VII) is p-methoxybenzyl alcohol and the appropriate acid catalyst is methanesulfonic acid or p-toluenesulfonic acid. 17. A process according to claim 11, wherein the compound of formula (VII) is trityl alcohol and the appropriate acid catalyst is methanesulfonic acid or p-toluenesulfonic acid. 18. Compound of formula (IV): (IV), 10 where: X is Cl or F, A is -CF 3, -C 2 F 5 or -C 3 H 7, P 'is R ³ is H, -CH 3, -CH 2 CH 3 or phenyl substituted with 0-3 R ¹² , R ⁴ , R ³ , R ^4a , R ^3a , R ⁶ , R ⁸ and R ^{9 are} independently selected from H, C 1-6 alkyl, C 1-6 alkoxy and C 1-8 alkylthio; R ¹² is H, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylthio; Y is - (CFF 3 or O and n is 0, 1, 2 or 3; A process for preparing a compound of formula (III): R ² is H, in a reaction in a non-aqueous solvent with a suitable oxidizing agent to form a compound of formula (IV). 19. The process of claim 18 wherein the compound of formula (IV) is (IV-a) wherein: R ³ is H, -CH ₃ , -CH 2 CH ₃ or phenyl substituted with 0-3 R ¹² , R ^4, R ^5, R ^4a, R ^5a and R ⁶ are independently from each other are selected from H, Ci- ₆ alkyl, C 1-6 alkoxy and C _b6 alkylthio; R ¹² is H, C ^ alkyl, C _b 6 alkoxy or C _b 6 alkylthio; and said process comprises: of a compound of formula (IIII-a): wherein R ² is H, in a non-aqueous solvent with a suitable oxidizing agent to form a compound of formula (IV-a). 20. The process of claim 19, wherein: R is H, -CH ₃ , or phenyl substituted with 0-3 R, R ⁴ , R ³ , R ^4a , R ^3a and R ⁶ are independently selected from H, methyl, ethyl, methoxy and ethoxy; and R ¹² is H, methoxy or ethoxy. 21. The process of claim 19, wherein the compound of formula (II-a) is Cl OMe R ³ is phenyl substituted with H or methoxy, R ⁴ is H or methoxy, and R ³ is H or methoxy. 22. The process of claim 19, wherein the suitable oxidizing agent is selected from the group consisting of: MnO :, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, p-tetrachlorobenzoquinone, o-tetrachloro-benzoquinone, and iodosylbenzene diacetate. 23. The process of claim 19, wherein the suitable oxidizing agent is p-tetrachlorobenzoquinone. 24. A process according to claim 19 wherein the compound of formula (II-a) is Cl H OMe and a suitable oxidizing agent are p-tetrachlorobenzoquinone. 25. Compound of Formula (V): (V) in which X is Cl or F, and A is a process for the preparation of -CF3, -C7F5 or -C3H7 ', characterized in that it comprises: a compound of formula (IV): (IV) wherein P 'is present Ti R ³ is H, -CH ₃ , -CH 2 CH _3, or phenyl substituted with 0-3 R ¹² , R ⁴ , R ³ , R ^4a , R ^5a , R ⁶ , R ⁸ and R ^{9 are} independently selected from H, C 1-6 alkyl, alkoxyl and C 1-6 alkylthio; R ¹² is H, C _b 6 alkyl, Ci-6 alkoxy or alkylthio CUG; Y is - (CH 2) _n or O, and n is 0, 1, 2 or 3; with a suitable ring-opening agent in the presence of a suitable binding agent and forming a compound of formula (V). 26. The process of claim 25, wherein the compound of formula (IV) is R ⁵ (IV-a) R ³ is H, -CH ₃ , -CH 2 CH ₃ or phenyl substituted with 0-3 R ¹² , R ⁴ , R ⁵ , R ^4a , R ^3a and R ^{6 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 1-6 alkoxy or C 1-6 alkylthio. 27. The process of Claim 26 wherein R ³ is H, -CH 3 or phenyl substituted with 0-3 R ¹² , R ⁴ , R ³ , R ^4a , R ^3a and R ^{6 are} independently selected from H, methyl, ethyl, methoxy and ethoxy; and R ¹² is H, methoxy or ethoxy. 28. A process according to claim 26 wherein the compound of formula (IV-a) is R ³ is phenyl substituted with H or methoxy, R ⁴ is H or methoxy, R ³ is H or methoxy. 29. The process of claim 26, wherein the suitable ring-opening agent is selected from the group consisting of sodium C 1-4 alkoxide, lithium C 1-4 alkoxide, potassium C 1-4 alkoxide, NaOH, LiOH, KOH and CaOH), and the appropriate binding agent is NaBH. ₄ or NaHSO3. 30. The process of claim 26, wherein the suitable ring-opening agent is selected from the group consisting of C 1-4 alkoxide, C 1-4 alkoxide, C 1-6 alkoxide, NaOH, LiOH, KOH and Ca (OH) i, and a suitable binding agent. is hydroxylamine or tosylhydrazide. 31. The process of claim 26, wherein the suitable ring-opening agent is selected from the group consisting of C 1-4 alkoxide, C 1-4 alkoxide, C 1-6 alkoxide, NaOH, LiOH, KOH and Ca (OH) ₂ , and a suitable binding agent. is HjO ?. 32. Compound of formula (VI): where: 25 X is Cl or F, and A is a process for the preparation of -CF 3, -C 2 F 5 or - C 3 F 7, characterized in that it comprises: (1) a compound of formula (I): reactions with a compound of formula (VII): (VII) in which: R ¹ is H, C 1-6 alkyl or C 1-6 alkylcarbonyl, R ² is -CH 3, -CH ² CH 3, or phenyl substituted with 0-3 R ¹² , R ³ is -CH 3, -CH 2 CH 3 or phenyl substituted with 0-3 R ¹² , R ⁴ , R ⁵ , R ^4a , R ^3a , R ^{6 are} independently selected from H, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylthio; and R ¹² is H, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylthio; in the presence of a suitable acidic catalyst to form a compound of formula (II): (IX). wherein R ¹⁰ and R ¹¹ independently of one another are C _1-6 alkyl, or NR ¹⁰ R ⁿ is pyrrolidinyl, piperidinyl or morpholinyl; reactions with alkyl lithium and cyclopropylacetylene to form a mixture of a compound of formula (IX) and lithium cyclopropylacetylide, and reaction of a reaction mixture of step (b) (2) (a) with a compound of formula (II) to form a compound of formula (III): Reactions of R ⁵ R ⁶ (UI) (3) with a suitable deprotecting agent of formula (III) to give a compound of formula (V): Reactions of a compound of formula X (V) and (4) (V) with a suitable cyclizing agent to form a compound of formula (VI). 33. A process according to claim 26 wherein the compound of formula (VI) is obtained wherein: X is Cl, A is -CF ₃ , R ¹ is H, C 1-6 alkyl or C 1-6 alkylcarbonyl, R ² is phenyl substituted with 0-3 R ¹² , R ³ is phenyl substituted with 0-3 R ¹² , R ⁴ , R ⁵ , R ^4a , R ^5a and R ^{6 are} independently selected from H, C 1-6 alkoxyl and R ¹² is H or Cpe alkoxyl. 34. Compound of Formula (VII-i): Process for the preparation of a compound according to claim 33 comprising: (1) reacting 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 (II) -ii): (Π-ϋ) (2) Reactions of (1) 1R, 2S-pyrrolidinylninephrephrine with n-hexyl lithium and cyclopropylacetylene to form a mixture of 1R, 2S-pyrrolidinylninephrephrine and lithium cyclopropylacetylide, and (b) Reaction mixture of (2) (a) with Reaction of a compound of formula (Π-ii), a compound of formula (I-ii) (III-ii) with a suitable deprotecting agent to give a compound of formula (Vi): (4) Reactions of a compound of formula (V-i) with a suitable cyclizing agent in the presence of a suitable binding agent to form a compound of formula (Vl-i). A process for the preparation of a compound of formula (VI) according to claim 32, characterized in that: a suitable acidic catalyst is selected from the group consisting of HCl, methanesulfonic acid, sulfuric acid, trifluoroacetic acid, and p-toluenesulfonic acid, a suitable deprotecting agent selected from the group consisting of HCl, HBr, methanesulfonic acid, trifluoroacetic acid, and p-toluenesulfonic acid, and cyclic. Process for the preparation of a compound of formula (VIII-i) according to claim 33, characterized in that: a suitable acidic catalyst is selected from the group consisting of HCl, methanesulfonic acid, sulfuric acid, trifluoroacetic acid, and p-toluenesulfonic acid, a suitable deprotecting agent selected from the group consisting of HCl, HBr, methanesulfonic acid, trifluoroacetic acid, and p-toluenesulfonic acid, and cyclic. Process for the preparation of a compound of formula (VIII-i) according to claim 34, characterized in that: a suitable acidic catalyst is selected from the group consisting of HCl, methanesulfonic acid, sulfuric acid, trifluoroacetic acid, and p-toluenesulfonic acid, a suitable deprotecting agent selected from the group consisting of HCl, HBr, methanesulfonic acid, trifluoroacetic acid, and p-toluenesulfonic acid, and cyclic. Process for the preparation of a compound of formula (VI) according to claim 32, characterized in that the compounds of steps (2) (a) and (b) are prepared separately and mixed in the form of solutions. Process for the preparation of a compound of formula (VI-i) according to claim 33, characterized in that the compounds of steps (2) (a) and (b) are prepared separately and mixed in the form of solutions. Process for the preparation of a compound of formula (VI-i) according to claim 34, characterized in that the compounds of steps (2) (a) and (b) are prepared separately and mixed in the form of solutions. 41. A compound of formula (IV-i): (IV-i), or a pharmaceutically acceptable salt thereof.