CZ349099A3 - Asymmetric syntheses of benzoxazinones via novel intermediates - Google Patents

Abstract

The present invention relates to novel processes for preparing intermediates for asymmetric synthesis of (S) -6-chloro-4-cyclopropylenethinyl-4- trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one VI-I, which is useful as an HIV-reverse inhibitor transcriptase. In one embodiment, it provides a method preparing an amino alcohol compound V-i, comprising adding toluene solution of 2,3-dichloro-5,6-dicyano-1,4- benzoquinone to a toluene solution of the compound of formula II-i via the compound of formula IV-i. In the second embodiment, the solution provides a process for the preparation of a compound of formula (I) comprising reacting the substituted aniline acetonitrile solution of formula XII and p-toluenesulfonic acid with a solution of the alcohol of formula XIII.

Description

Asymmetric synthesis of benzoxazinones via new intermediates

Technical field

The invention provides novel methods of asymmetric synthesis of (S) -6-chloro-4-cyclopropylethynyl-4-fluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one useful as a virus reverse transcriptase inhibitor human immunodeficiency (HIV).

BACKGROUND OF THE INVENTION

Reverse transcription is characteristic of retrovirus replication. Virus replication requires virus-encoded reverse transcriptase to generate DNA copies of the viral sequences by reverse transcription of the RNA genome of the virus. Thus, reverse transcriptase is a clinically significant therapeutic target for chemotherapy of retroviral infections because inhibition of the production of virus-encoded reverse transcriptase disrupts viral replication.

Multiple compounds are used to effectively treat diseases caused by the human immunodeficiency virus (HIV), a retrovirus causing progressive destruction of the human immune system, with the resultant onset of the disease termed AIDS. Effective treatment based on the inhibition of HIV reverse transcriptase is known both using nucleoside-based inhibitors and non-nucleoside-based inhibitors. Benzoxazinones have been shown to be suitable among non-nucleoside HIV reverse transcriptase inhibitors. The following compound, (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-oxoxazin-2-one of formula VI-i:

• ·

it is not only highly effective as a reverse transcriptase inhibitor, but is also effective against HIV reverse transcriptase resistance. Given the importance of this compound, (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a reverse transcriptase inhibitor, there is a need to develop economical and efficient synthetic methods for their preparation.

Thompson et al. Tetrahdron Letters 1995, 36, 937-940, report the asymmetric synthesis of enantiomeric benzoxazine by the highly enantioselective addition of acetylide followed by cyclization with a condensation agent to form benzoxazine as shown below.

AND

H

About me • ·

The starting component, p-methoxybenzylaniline, is prepared by benzylating the aniline nitrogen with p-methoxybenzyl chloride. Due to the cerium-ammonium nitrate oxidation in the debenzylation stage, a large proportion of the heavy metal-containing waste is generated in the waste component throughout the process.

European patent application 582 445 A1 discloses the synthesis of benzoxazine in a three-step process

Cl

1. 2 eq. n-BuLi / THF / 0 ° C

2. CF ₃ COOEt / 0 ° C

3. 3N HCl / reflux

R-MgBr

THF / 0 ° C to TM

1.1'-carbonyldiimidazole THF / 50 ° C

F ₃ C.

which generally comprises (1) metachlation of parachloraniline pivlamide with butyllithium followed by nucleophilic ester substitution to form ketone, (2) synthesis of tertiary carbinol by addition of Grignard reagent to ketone, and (3) cyclization of unprotected amine with carbinol by addition. The entire process requires further purification of the optical isomers using an optically active resolving agent such as (-) camphoric acid.

Young et al., PCT International Patent Application No. WO 9520389 A1 discloses the use of benzoxazinones in the inhibition of HIV reverse transcriptase, in the prevention or treatment of infection.

induced by HIV and in the treatment of AIDS. WO 9520389 A1 discloses synthetic methods comparable to those disclosed in EP 582 455 A1 above. In addition, Young et al., Antimicrobial Agents and Chemotherapy 1995, 39,

2602-2605, in clinical analysis, in vitro activity and pharmacokinetic activity of benzoxazine (VI) in the treatment of HIV where it acts as an HIV reverse transcriptase inhibitor, disclose a shortened synthesis of benzoxazine VI comparable to the synthesis of EP 582 455 A1 above, wherein tertiary carbinol is synthesized by the addition of a cyclopropylethynyl lithium reagent followed by cyclization of the unprotected amine with carbinol with the addition of a condensing agent.

Thompson et al., PCT International Patent Application No. WO 9622955 A1 discloses improved synthesis of cyclopropylacetylene suitable for the synthesis of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazine -2-one. WO 9622955A1 further discloses combinations of the synthetic methods disclosed in the publications mentioned above with significant improvements, but in the overall synthesis the process remains insufficiently effective.

The above methods of synthesizing benzoxazines employ a combination of toxic agents that are difficult to handle, relatively expensive, and use inefficient chromatographic purification steps or, in general, low yields of (S) -6-chloro-4-cyclopropyl-ethynyl in synthesis -4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one. It is therefore desirable to find novel processes for the synthesis of benzoxazines useful on an industrial scale that do not have the above limitations and will provide high yields of the desired benzoxazines.

Thus, the invention provides a novel benzylation process using acid catalyzed benzyl alcohols instead of the corresponding benzyl chloride analogs, which are more expensive and unstable. Optimization of the process allows stream processing because the product does not need to be isolated.

The invention allows the preparation of (1R, 2S) -pyrrolidinylnorephedrine in such purity that the product can be directly used as a reagent solution stream in the chiral addition step of lithium cyclopropylacetylide. The invention further enables the preparation of cyclopropylacetylene in such purity that it can also be used as a reagent stream in the chiral addition of a cyclopropylacetyl anion, for example lithium cyclopropylacetylide.

The invention provides an improved method of asymmetric synthesis of benzoxazines. The process of the invention eliminates the use of highly toxic cerium ammonium nitrate such that the waste does not contain cerium ions. The invention also provides an efficient non-chromatographic purification process to yield an enantiomerically pure product. In addition, the invention provides solid intermediates which can be purified by recrystallization.

None of the above cited works disclose methods of the invention for the synthesis of benzoxazines useful as HIV reverse transcriptase.

SUMMARY OF THE INVENTION

The present invention relates to novel processes for the preparation of benzoaxazinone compounds useful as inhibitors of HIV reverse transcriptase. The process provides a novel benzylation process for primary amines using acid catalyzed benzyl alcohols. The process of the invention provides high yields, can be performed on a kilogram scale, and provides stable intermediates. Further, the process does not require chromatographic separation to improve overall yield.

• · • ·

The present invention provides a process for preparing 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 process comprises one or more of the following.

(1) (addition) by contacting a compound of formula I

with a compound of formula

VII or formula

VIII:

(VII)

where:

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 ² 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 ^7, R ⁸ and R ⁸ are independently selected from the group consisting of H, C _L _ _g alkyl, _C1-g alkoxy and

C ₁ _ ₆ alkylthio;

R ¹² is H, C ^ g alkyl, C-j__g -alkoxy or C ₁ _G alkylthio, · Y is - _{(CH2) n} or O and n is 0, 1, 2 or 3;

in the presence of methanesulfonic acid, p-toluenesulfonic acid or other suitable acid catalysts to form a compound of formula II

(II) wherein P is

(2) (chiral addition) (a) contacting IR, 2S-pyrrolidinyl norephedrine with n-hexyl lithium or other suitable alkyllithium and cyclopropylacetylene to form a mixture, (b) contacting the mixture of step (2) (a) with a compound of formula II to to form a compound of formula III:

(III)

- 8 • 9 9 99 99

999 999 9 · 99

999 999 999

9 9 9 99 99 99 ·

999,999 9 9

(999) 99 99 99 (3) (oxidative cyclization) by contacting a compound of formula III with p-chloroanil or another suitable oxidizing agent to form a compound of formula IV:

where P is

(4) (debenzylation) by contacting a compound of formula IV with potassium hydroxide, sodium hydroxide, or other suitable cleaving agent in the presence of sodium borohydride or other scavenger to form the compound

(5) (cyclizing) contacting a compound of Formula V with phosgene or other suitable cyclizing agent to form a compound of Formula VI.

In a first embodiment, the present invention provides a novel process for preparing compounds of Formula VI:

• ·

- 9 * · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···············

Λ where:

X is Cl or F, and

A is -CF 2, -C ₂ F ₅ or -C ₂ F ₇ ;

said process comprising: (1) contacting a compound of formula I:

with a compound of formula VII or formula VIII:

(VII)

where:

R ¹ is H or C 1-6 alkyl or 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, and} R, R6, R _t 8 _and R 9 are independently selected from the group consisting of H, C ^ g alkyl, C- ^ g alkoxy, and • · ·

- C 10 -C 18 alkylthio;

R ¹² is H, C _x _6 alkyl, C ₁ _ _g C ^ alkoxy or alkylthio g; Y is - (CH ₂ ) _n or O and n is 0, 1, 2 or 3;

in a suitable solvent, in the presence of a suitable acid catalyst to form a compound of formula II:

(II) wherein P, the amine protecting group is

(2) (a) contacting a compound of formula IX:

wherein R ¹⁰ and R ¹¹ are independently C ₁ _ ₄ alkyl or -NR ¹ R ^{1O: L} is pyrrolidinyl, piperidinyl or morpholinyl;

with alkyllithium and cyclopropylacetylene, in a suitable solvent, to form a mixture, and (b) contacting the mixture of step (2) (a) with a compound of formula II to form a compound of formula III:

(3) contacting a compound of formula III in a suitable form

where P is

or

(4) contacting a compound of formula IV with a suitable cleaving agent, in a suitable solvent, in the presence of a suitable scavenger to form a compound of formula V:

(A) aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa contacting the compound of Formula V with a suitable cyclizing agent, in a suitable solvent, to form a compound of Formula VI.

In a preferred embodiment, the process for preparing a compound of formula VI, wherein

X is Cl, and

A is -CF ₃ ;

includes:

(1) contacting a compound of formula I with a compound of formula VII, wherein:

R ¹ is H or 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 ⁵ , R ^4a , R ^5a and R 6 are independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxy and

C 1-6 alkylthio; and

R ¹² is H, C ^ g alkyl, C-j__g -alkoxy or C ₁ _G alkylthio;

in a suitable solvent, in the presence of a suitable acid catalyst, to form a compound of formula II;

(2) (a) contacting IR, 2S-pyrrolidinyl norephedrine with n-hexyl lithium and cyclopropylacetylene in a suitable solvent to form a mixture, and (b) contacting the mixture of step (2) (a) with a compound of formula II to form a compound of formula III;

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

* 99 99 99

9 99 9 9 9 9 9 9 999 999

9 9 9 9 9 9

(4) contacting a compound of formula IV with a suitable cleaving agent, in a suitable solvent, in the presence of a suitable scavenger to form a compound of formula V; and (5) contacting a compound of Formula V with a suitable cyclizing agent, in a suitable solvent, to form a compound of Formula VI.

In a more preferred embodiment, a process for preparing a compound of formula VI-i:

includes:

(1) contacting a compound of formula I wherein X is Cl and A is trifluoromethyl, with p-methoxybenzyl alcohol, in a suitable solvent, in the presence of a suitable acid catalyst, to form a compound of formula II-i:

OMe (2) (a) contacting IR, 2S-pyrrolidinyl norephedrine with n-hexyllithium and cyclopropylacetylene, in a suitable solvent, to form a mixture,

(b) contacting the mixture of step (2) (a) with a compound of formula

II-i to form a compound of formula III-i:

an oxidizing agent, in a suitable solvent, to form a compound of formula IV-i:

(4) contacting a compound of formula IV-i with a suitable cleaving agent, in a suitable solvent, in the presence of a suitable scavenger, to form a compound of formula V-i:

(5) contacting a compound of formula V-i with a suitable cyclizing agent, in a suitable solvent, to form a compound of formula VI-i.

In an even more preferred embodiment in the process of preparing a compound of formula VI:

a suitable acid catalyst is selected from:

HCl, methanesulfonic acid, benzenesulfonic acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, trichloroacetic acid and p-toluenesulfonic acid, a suitable oxidizing agent is selected from:

MnO ₂ , 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, p-tetrachlorobenzoquinone, o-tetrachlorobenzoquinone and iodosobenzene diacetate, a suitable cleavage agent selected from the group of:

C _1-4 alkoxide, sodium _L _ C ₄ alkoxide, lithium C _1-4 alkoxide, NaOH, LiOH, KOH and Ca (OH) _2, the suitable trapping agent is NaBH _4, NaHSO _3, hydroxylamine, tosyl hydrazide or H ₂ O ₂ , and a suitable cyclizing agent is phosgene.

In another even more preferred embodiment of the process for preparing a compound of formula VI, the compounds of steps (2) (a) and (b) are independently prepared and mixed as a solution stream.

In a second embodiment, the present invention provides a process for preparing compounds of Formula II:

where:

(II)

X is Cl or F,

A is -CF 2, -C ₂ F ₅ or -C ₂ F ₅ ;

P is

R ² is H, -CH ₃ , -CH ₂ CH _3, or phenyl substituted with 0-3 R ¹² ,

R 6 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 ^7, R ⁸ and R ⁹ are independently selected from the group consisting of H, C _L _G alkyl, C- _L _G alkoxy and C - ^ - 6 alkylthio;

R ¹² is H, C ^ g alkyl, C- _L _G alkoxy or C ^ g -alkylthio;

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

said process comprising:

contacting a compound of formula I:

with a compound of formula VII or line VIII:

R ⁹ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Wherein R ¹ is H, C 1-6 alkyl or C 1-6 alkylcarbonyl, in a suitable solvent, in the presence of a suitable acid catalyst to form a compound of formula II.

In a preferred embodiment, the compound of formula VII is

R ¹ is H or methyl,

R ² is H or phenyl substituted with H or methoxy,

R is H or phenyl substituted with H or methoxy,

R ⁴ is H or methoxy, and r ⁵ is H or methoxy.

In another 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-toluenesulfonic acid.

In a third embodiment, the present invention provides a process for preparing compounds of Formula IV:

where:

X is Cl or F,

A is -CF 4, -C ₂ F 8 or -C ₃ F ₇ ; P is

R ² is H, -CH 1, -CH ₂ CH _3, or phenyl substituted with 0-3 R ¹² ,

R ^4, R ^5, R ^4a, R ^5a, R 6, R ^7, R 8 and R ^ are independently selected from the group consisting of H, C ^ g alkyl, C ₁ _G alkoxy and C ^ g -alkylthio;

R ¹² is H, C ₁ _G alkyl, C ₁ _G alkoxy or C ^ g -alkylthio;

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

wherein said process comprises:

contacting the compound

where

R ² is H,

in a non-aqueous solvent with a suitable oxidizing agent to form a compound of formula IV.

In a preferred embodiment, the compound is of formula III

In a more preferred embodiment, the suitable oxidizing agent is selected from the group consisting of MnO ₂ , 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, p-tetrachlorobenzoquinone, o-tetrachlorobenzoquinone, and iodosobenzene diacetate.

In a fourth embodiment, the present invention provides a process for preparing compounds of Formula V:

X is Cl or F and

A is -CF _3, -C ₂ ^F 5 ° to ^{not _c} 3 ^F 7 '· said method comprising contacting a compound of formula IV:

(IV) wherein P is

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

R ^4, R ^5, R ^4a, R ^5a, R ^6, R ^7, R ⁸ and R ⁹ are independently selected from the group consisting of H, C ₁ _G alkyl, C ₁ _G alkoxy and alkylthio;

R ¹² is H, C ₁ _G alkyl, C- ^ g alkoxy, or C ₁ _G alkylthio;

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

with a suitable resolving agent, in a suitable solvent, in the presence of a suitable scavenger, to form a compound of formula V.

In a preferred embodiment, the compound of formula IV is

or

About me

. ,,

R is phenyl substituted with H or methoxy,

R ⁴ is H or methoxy, and

R ⁵ is H or methoxy.

In a more preferred embodiment the suitable cleaving agent is selected from the group: 0 _1-4 alkoxide, 0 _1-4 alkoxide, lithium C ₄ _ ₄ alkoxide, NaOH, LiOH, KOH and Ca (OH) _2, and the suitable trapping agent is selected from the group: NaBH ₄ , NaHSO ₃ , hydroxylamine, tosylhydrazide and H ₂ O ₂ ·

In a fifth embodiment, the present invention further provides a process for preparing a compound of Formula VI:

where

X is Cl or F, and

A is -CF ₃ , -C ₂ F ₅ or -C ₃ F;

said process comprising:

(1) contacting a compound of formula I

with a compound of formula VII:

where:

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

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

R ² is -CH 2, -CH ₂ CH _3, or phenyl substituted with 0-3 R ¹² ,

R ^4, R 5, R ^{4a, and} R, R6, RV, R 8 and R ^ are independently selected from the group consisting of H, C ₁ _G alkyl, C alkoxy and C j__g _L _G alkylthio;

R ¹² is H, C L_g-alkyl, C-alkoxy or j__g _x _G alkylthio;

in a suitable solvent, in the presence of a suitable acid catalyst to form a compound of formula II:

R ⁵ R ⁶ (II) (2) (a) contacting a compound of formula IX

wherein R ¹⁰ and R ¹¹ are independently alkyl or -NR ¹⁴ R ¹² pyrrolidinyl, piperidinyl or morpholinyl;

Φ 9 · Φ · · «« «« «« «« «« φ φ φ φ φ

Alky ΦΦΦ ΦΦΦ ΦΦ ΦΦ ΦΦ with alkylllithium and cyclopropylacetylene, in a suitable solvent, to form a mixture, and (b) contacting the mixture of step (2) (a) with a compound of formula II to form a compound of formula III:

(3) contacting a compound of formula III with a suitable deprotecting agent, in a suitable solvent, to form a compound of formula V:

(4) contacting a compound of formula V with a suitable cyclizing agent, in a suitable solvent, to form a compound of formula VI.

In a seventh embodiment, the present invention provides a novel compound of formula IV-i:

OMe or a pharmaceutically acceptable salt thereof.

In an eighth embodiment, the present invention provides a process for preparing a compound of Formula II-i:

(II-i) comprising:

(1) heating the substituted aniline acetonitrile solution of formula XII:

and p-toluenesulfonic acid at a temperature of about 65 ° C to about 85 ° C and with stirring;

(2) addition of acetonitrile solution of benzyl alcohol of formula XIII:

* · · * · ···························································· ·· ·· ··

within about 2 hours to about 10 hours to a heated acetonitrile solution of substituted aniline and p-toluenesulfonic acid; and (3) stirring the heated reaction mixture for about 30 minutes to 2 hours to obtain the compound of formula II-i.

In a preferred embodiment, the process for preparing the crystalline compound of formula II-i:

includes:

(1) heating and stirring the substituted aniline acetonitrile solution of formula XII:

and p-toluenesulfonic acid at a temperature of about 65 ° C to about 85 ° C;

(XII)

9 9 9 9

9

99 99 9 999

9 9 9

99 99 (2) adding an acetonitrile solution of the benzyl alcohol of formula XIII

OH ⁱⁿ OCH ₃ (XIII) over about 2 hours to about 10 hours to a heated acetonitrile solution of substituted aniline and p-toluenesulfonic acid;

(3) heating and stirring the reaction mixture for about 30 minutes to about 4 hours to obtain a crude solution of the compound of formula II-i;

(4) cooling the crude solution of the compound of formula II-i;

(5) adding seed crystals at a temperature of about 20 ° C to about 30 ° C;

(6) slowly adding water while stirring at a temperature of about 30 ° C to about 35 ° C to form a slurry of the crystalline compound of formula II-i;

(7) stirring the slurry for about 2 hours to about 12 hours at room temperature;

(8) filtering a slurry of the crystalline compound of formula II-i to isolate the crystalline compound of formula II-i;

(9) washing the crystalline material with a mixture of acetonitrile and water in a volume ratio of about 60:40 to about 40:60; and (10) drying the material in an inert atmosphere at a temperature of about 50 ° C.

In a ninth embodiment, the present invention provides a process for preparing an amino alcohol compound of formula V-i:

(V-i) comprising (1) adding a toluene solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to a toluene solution of formula III-i:

wherein the reaction temperature is maintained in the range of about 0 ° C to about 10 ° C;

(2) maintaining a reaction temperature of about 0 ° C for about 1 hour to form a slurry of 2,3-dichloro-5,6-dicyano-1,4-dihydroxybenzene and a compound of formula IV-i:

9 * 9 9 99 99 99 99 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

9 <9 9 * 9 * 9

(3) filtering the slurry to remove 2,3-dichloro-5,6-dicyano-1,4-dihydroxybenzene;

(4) washing the filter cake paste with 2,3-dichloro-5,6-dicyano-1,4-dihydroxybenzene with toluene;

(5) combining the filtrate and toluene wash liquids;

(6) concentrating the filtrate and toluene solution of the compound of formula IV-i with methanol in vacuo to remove most of the toluene;

(7) adding to the compound of formula IV-i in methanol at a temperature of about 40 ° C to about 45 ° C dropwise with aqueous sodium hydroxide solution to form a clear solution of aminoalcohol and p-methoxybenzaldehyde;

(8) adding to the clear amino alcohol solution dropwise a solution of NaBH ₄ in aqueous sodium hydroxide solution, maintaining the reaction temperature in the range of about 40 ° C to about 45 ° C;

(9) stirring the reaction mixture for about 30 minutes;

(10) neutralizing the reaction mixture with glacial acetic acid to a pH of about 8 to about 9;

(11) adding water to form a slurry;

(12) cooling the slurry to about -15 ° C to about 0 ° C for 1 hour; and (13) filtering the cooled amino alcohol slurry and washing with water to obtain the crude crystalline amino alcohol as a yellow solid.

In a preferred embodiment, the present invention provides a process for preparing a pure amino alcohol compound of formula V-i, comprising the following additional steps:

(1) dissolving the crude amino alcohol in toluene at a temperature of about 60 ° C;

(2) adding heptane to a toluene solution of the crude amino alcohol to form a slurry of pure amino alcohol;

(3) cooling the amino alcohol slurry to a temperature of about 0 ° C and maintaining at 0 ° C for about 1 hour;

(4) filtering the pure crystalline amino alcohol;

(5) washing the pure crystalline amino alcohol with heptane; and (6) drying the pure crystalline amino alcohol in vacuo.

In a more preferred embodiment, the present invention provides a process for preparing a pure crystalline amino alcohol compound of formula V-i comprising the following additional steps:

(1) dissolving the crude amino alcohol in the MTBE-toluene mixture at a temperature from about 20 ° C to about 30 ° C;

(2) distilling the MTBE from the MTBE-toluene solution of the crude amino alcohol in vacuo;

(3) adding heptane to a toluene solution of the crude amino alcohol to form a slurry of pure amino alcohol;

(4) cooling the amino alcohol slurry to a temperature of about 0 ° C and holding at 0 ° C for about 1 hour;

(5) filtering the pure crystalline amino alcohol;

(6) washing the pure crystalline amino alcohol with heptane; and (7) drying the pure crystalline amino alcohol in vacuo.

The process of the present invention is useful for preparing (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one useful as an HIV reverse transcriptase inhibitor and compounds which are useful as intermediates in the preparation of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one. Such HIV reserve transcriptase inhibitors are useful for inhibiting HIV and treating HIV infection. Such HIV reverse transcriptase inhibitors are also useful for inhibiting HIV in HIV-containing ex vivo samples or where exposure to HIV is likely. Thus, these HIV reverse transcriptase inhibitors can be used to inhibit HIV present in a body fluid sample (e.g., a body fluid sample or semen sample) where the sample is believed to contain it, or

has been exposed to HIV. These HIV reverse transcriptase inhibitors are also useful as standards or reference compounds in assays or assays to determine the ability of a candidate composition to inhibit viral and / or HIV reverse transcriptase replication, for example, in a pharmaceutical research program. Thus, these HIV reverse transcriptase inhibitors can be used as control or reference compounds in these assays and as standards for quality control purposes.

The terms and abbreviations used herein have the following meanings.

Abbreviation:

The THF used herein means tetrahydrofuran,

DMSO used in this text means dimethylsulfoxide, DMAC used in this text means dimethylacetamide, MTBE used in this text means methyl-tert.- butyl ether, BuLi used in this text butyllithium,

NaH as used herein means sodium hydride,

LDA used herein means lithium diisopropylamide,

TsOH as used herein means p-toluenesulfonic acid,

TMEDA as used herein means Ν, Ν, Ν'Ν'-tetramethylethylenediamine, and

DDQ as used herein means 2,3-dichloro-4,5-dicyanobenzoquinone.

The reactions in the synthesis methods described and in the claims are carried out in suitable solvents which are readily selected by one skilled in the art of organic synthesis, generally suitable solvents include any solvent that does not substantially react with the starting components (components entering the reaction), intermediates or products, at

the temperatures at which the reactions proceed, i.e. at temperatures which may range from the freezing point to the boiling point of these solvents. The reaction may be carried out in a single solvent or in a mixture of more than one solvent. Suitable solvents for a particular reaction step may be selected depending on the reaction step.

Suitable halogenated solvents include chlorobenzene, fluorobenzene or dichloromethane.

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

Suitable protic solvents may 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, isobutyl alcohol, tert-butyl alcohol,

2-ethoxyethanol, diethylene glycol, 1-, 2- or 3-pentanol, neopentyl alcohol, t-pentanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol benzyl alcohol, phenol or glycerol.

Suitable aprotic solvents may include, but are not limited to, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMAC),

1,3-dimethyl-3,4,5,6-tetrahydro-2 (1 H) -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, N, N - dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene or

hexamethylphosphoramide.

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

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

The term amino protecting group as used herein means any group known in the art for protecting amino groups. The amino protecting groups include those listed in Greene Wuts, Protective Groups in Organic Synthesis by John Wiley & Sons, New York (1991), which is incorporated herein by reference. Examples of, but not limited to, amino-protecting groups include alkyl type groups such as benzyl, α-methylbenzyl, diphenylmethyl (benzhydryl), dimethoxybenzhydryl, triphenylmethyl (trityl), 9-fluorophenyl, phenylfluorophenyl, dihydroanthracenyl, monomethoxytrityl, p-methoxybenzyl, 3 4-dimethoxybenzyl,

2,4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl.

The term chiral induction agent or chiral induction agent used herein means a non-reactive chiral agent that selectively induces the formation of a chiral center in enantiomeric excess upon addition of a non-chiral substrate at the prochiral center. Examples of means for chiral induction include, but are not limited to, IR, 2S-N-substituted norephedrines, such as IR, 2S-N-methylephedrine, IR, 2S-N-pyrrolidinylnorephedrine,

IR, 2S-N-piperidinylnorephedrine and IR, 2S-morpholinylnorephedrine.

The term acid catalyst as used herein means any acid addition catalyst

an alkyl type alcohol derivative of an amino protecting group such as benzyl alcohol, benzhydrol or trityl alcohol to the 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, phosphoric acid and polyphosphoric acid.

The term oxidizing agent as used herein means any agent oxidizing a benzyl-protected amine to the corresponding imine and thereby forming compound IV from compound III by intramolecular cyclization. Examples of oxidizing agents include, but are not limited to, manganese dioxide, KMnO ₄ , KSOg, KHSO ₅ , DDQ, p-chloroanil, o -chloroanil, and iodosobenzene diacetate.

The term deprotecting agent as used herein means any acidic means allowing removal of an alkyl type protecting group, such as benzyl, benzhydryl, trityl, to liberate the amine as a free base such as compound IV. Examples of deprotecting agents include, but are not limited to, HCl, HBr, methanesulfonic acid, benzenesulfonic acid, trichloroacetic acid, trifluoroacetic acid, phosphoric acid, and p-toluenesulfonic acid.

The term "cleavage agent" as used herein refers to any means allowing the formation of compound V by removal or debenzylation of P from the hemiaminal of formula IV. These resolving agents are strong bases and include, but are not limited to, for example, metal hydroxides and metal alkoxides: NaOH, KOH, LiOH, Ca (OH) ₂ , NaOCH ₃ , NaOC ₂ H ₅ , NaOC ₃ Hg, NaOC ₄ H ₁₀ , koch ₃ , koc ₂ h ₅ and koc ₄ h ₁₀ .

The term capture means used herein

includes any means for converting the by-product to a component not reacting with the desired product, compound V, wherein the by-product is, depending on the nature of P, an aromatic aldehyde or ketone resulting from the removal or debenzylation of P from the hemiaminal compound of formula IV. Separation agents commonly used by those skilled in the art are standard reducing agents, derivatizing agents or oxidizing agents; they are all used for selective reactions of one type of compounds in a solution containing the other type of compounds. Examples of separating agents that reduce aromatic aldehyde or ketone to aldehyde include, but are not limited to, sodium borohydride, lithium borohydride, potassium borohydride, sodium bisulfite, and sodium hydrotrimethoxoborate; a preferred composition is sodium borohydride. Examples of derivatizing separators that derivatize an aromatic aldehyde or ketone to an oxime or hydrazone include, but are not limited to, hydrazine, dimethylhydrazine, hydroxylamine, and tosylhydrazide. Examples of the aromatic aldehyde oxidizing agent to the aromatic carboxylic acid include, but are not limited to, hydrogen peroxide, tert-butyl hydrogen peroxide, K ₂ SO 4 and KHSO 4.

The term cyclizing agent as used herein means any agent allowing the formation of benzoxazinone from an aminocarbinol compound of formula V. Examples of cyclizing agents include, but are not limited to, phosgene,

1,1-carbonyldiimidazole, methyl chloroformate, dimethyl carbonate.

The term lithium or alkyllithium means an organolithic composition which allows the quantitative conversion of an alkyne to an alkyllithium. Examples of lithiation agents include, but are not limited to, hexyllithium, octyllithium, butyllithium, tert-butyllithium, sec-butyllithium, isobutyllithium, lithium diisopropylamide, and the like. 99. Phenyllithium and triphenylmethyllithium. &Lt; tb &gt;

The term halo or halogen as used herein means fluoro, chloro and bromo.

The term alkyl as used herein denotes straight or branched chain saturated hydrocarbon groups of one to twelve carbon atoms. The term alkoxy as used herein means an alkyl group having the indicated number of carbon atoms attached through an oxygen bridge; the term alkylthio means an alkyl group having the indicated number of carbon atoms attached through a sulfur bridge.

The compounds disclosed herein may have asymmetric centers. All chiral, diastereomeric and racemic forms of the present invention are included. It will be appreciated that certain compounds of the invention contain an asymmetrically substituted carbon atom and can be isolated in optically active or racemic forms. Methods for preparing optically active forms, such as resolution of racemic forms and / or synthesis from optically active starting materials, are well known in the art. Unless a specific stereochemical or isomeric form is specified, all possible chiral, distereomeric and racemic forms and all forms of geometric isomers are contemplated.

Only those combinations of substituents and / or variables that result in stable compounds are acceptable. By stable compound or structure is meant that the compound is sufficiently robust to be isolated at a suitable degree of purity from the reaction mixture.

Application of the method according to the invention is envisaged at least on a multi-gram scale, on a kilogram scale, on a multi-kilogram scale or on an industrial scale. By multigram scale is meant herein a scale at which at least one feedstock is used in an amount of 10 g or more, more preferably at least 50 g or more, and even more preferably at least 100 g or more. By multi-kilogram scale, it is meant herein that at least one feedstock is used in an amount greater than 1 kg. Industrial scale means a scale different from the laboratory scale, and at this scale production produces an amount of product that is sufficient for either clinical trials or distribution to consumers.

In order to further understand the methods of the invention, Scheme 1 is given below and is not to be construed as limiting the invention. Scheme 1 illustrates in detail the method for the asymmetric synthesis of compounds of formulas I-VI, wherein X is Cl and A is trifluoromethyl.

It will be appreciated that one skilled in the art of organic synthesis may prepare homologues of compounds of formulas I-VI, wherein X is Cl or F and A is trifluoromethyl, pentafluoroethyl or heptafluoropropyl, by a suitable combination of p-chloroaniline or p- fluoroaniline with CF ₃ CO ₂ Et, CF ₃ CF ₂ CO ₂ Et or CF ₃ CF ₂ CF ₂ CO ₂ Et.

Scheme 1

Cl

NH ₂ pivaloyl-CI

NaOH

Solvent

1) Alkyl lithium CF ₃ CO ₂ Et

2) HCl / Solvent

Stage 1

IN

VI

It is an object of the present invention to provide an improved process for the asymmetric synthesis of benzoxazinones that are useful as HIV reverse transcriptase inhibitors.

Step 1: Preparation of Compound of Formula II

This step is carried out by reacting the compound of formula I, after conversion to the free base, in a suitable solvent and at a suitable temperature, with a benzyl alcohol, a benzyl ether, a benzhydryl alcohol or a benzyhydryl ether in the presence of

99

9 9 9

9 9 9

999 999 9

99 of a suitable acid catalyst to form a compound of formula II. The compound of formula I in an aqueous organic solvent may be neutralized with a base at about pH 7 at room temperature, contacted with about 1 molar equivalent of benzyl alcohol, benzyl ether, benzhydryl alcohol or benzhydryl ether, further contacted with about 0.1 to about 5.0 mol . % of a suitable acid catalyst and heated to a temperature sufficient to form a compound of Formula II. The compound of formula (II) can be separated from the reaction mixture by standard processing methods as a stable solid. An example of a standard treatment is given in Example 3. The compound of formula II may optionally be used to prepare a compound of formula III.

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

Preferred acid catalysts for step 1 include HCl, methanesulfonic acid, sulfuric acid, trifluoroacetic acid, trichloroacetic acid, and p-toluenesulfonic acid. More 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.

The preferred temperature range for step 1 is from about room temperature to about 120 ° C. More preferably, P is p-methoxybenzyl and a temperature range of about 60 to about 90 ° C.

It will be appreciated that one skilled in the art can determine the preferred reaction time for Step 1, depending on the temperature, the acid catalyst, and the Group P. In general, the reaction time is 0.5 to 12 hours.

Step 2: Chiral Induction: Preparation of Compound of Formula III 999

This step, chiral induction, comprises alkylating the achiral ketone carbonyl compound of formula II in the presence of a chiral inducing agent of formula IX in a suitable solvent with preferably at least about two equivalents of cyclopropenylethynylithium, wherein said cyclopropylethynylithium is generated in situ cyclopropylacetylene with a suitable alkyllithium, for a suitable period of time, at a temperature sufficient to form a compound of formula III. Generating about two equivalents of cyclopropylethyllithium in situ can be accomplished by contacting about two equivalents of cyclopropylacetylene with about four equivalents of a suitable alkyllithium in a suitable solvent at a temperature below about -0 ° C for about 1 to about 3 hours. One of skill in the art will appreciate that about four equivalents of alkyl lithium are needed to produce about two equivalents of cyclopropylethynyl lithium since about two equivalents of lithium react with two equivalents of the chiral inducing agent. About two equivalents of the chiral inducer of formula IX, about four equivalents of the appropriate alkyllithium and about two equivalents of cyclopropylacetylene are independently added in the solution stream and aged until sufficient cyclopropylethynylithium is formed, followed by about one equivalent of the compound of formula II in a suitable solvent temperature below -30 ° C for 1 to 3 hours to give the compound of formula III. Compound III can be separated from the reaction as a stable solid by standard workup methods. An example of standard processing is given in Example 4.

It is preferred, but not desirable, that the reactants in this step be added as a solution stream; that is, they are prepared separately as individual solutions before contact with each other. Reagents that can be easily handled, such as solids, can be added to the reaction mixture as such; for example, compounds of formula II or chiral inducing agents.

The preferred chiral reagent for step 2 is IR, 2S-pyrrolidinyl norephedrine.

Preferred alkylithium reagents for step 2 include n-butyllithium, sec-butyllithium, tert-butyllithium, isobutyllithium, n-hexyllithium and octyllithium. A more preferred alkylithium reagent is n-hexyllithium.

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

Preferred reaction times for step 2 are about two hours to generate cyclopropylethynyl lithium and about 1-2 hours to add compound II to IR, 2S-pyrrolidinyl norephedrine / cyclopropylethinyllithium.

Preferred temperature ranges for step 2 are from about -50 to about 0 ° C to generate cyclopropylethynyl lithium and from about -60 to about -40 ° C to add compound II to cyclopropylethynyl lithium / 1R, 2S-pyrrolidinyl norephedrine solution.

Step 3: Oxidative Cyclization: Preparation of Compound of Formula IV

This step comprises reacting the carbinol compound of formula III in a suitable solvent with preferably at least one equivalent of a suitable oxidizing agent at a sufficient temperature for a suitable reaction time to form a compound of formula IV. The compound of formula III in a suitable non-aqueous solvent is contacted with about one molar equivalent of a suitable oxidizing agent and heated to a temperature of about one to about six hours sufficient to form compound IV. Compound IV can be separated from the reaction mixture as a stable solid by cooling with a suitable non-aqueous solvent, followed by standard processing techniques. An example of a standard treatment is given in Example 5. Further, compound IV can be converted without isolation to step 4 to prepare compound V, as shown in Example <.

· · E e e · e e e e e e e e e e e e e e e e e e e * · ·· ·· * ·

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, methyl tert-butyl ether, tetrahydrofuran, dichloromethane and cyclohexane. When 2,3-dichloro-5,6-dicyano-1,4-benzoquinone is used in the reactions, ethanol and methanol are suitable.

The reaction time of step 3 depends on the solvent and the temperature. The preferred reaction time for step 3 when heptane / ethyl acetate is used as a solvent followed by the addition of the oxidizing agent is about four to about six hours.

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

Step 4: Debenzylation: Preparation of Compound of Formula V

This step involves reacting a compound of Formula IV in a suitable solvent with a suitable strong base at a temperature sufficient to form Compound V. Since the hemiaminal debenzylation product is an aromatic aldehyde or ketone, depending on the P structure, the aldehyde or ketone must be captured or converted with a suitable capture agent. that does not react with compound V.

Three different methods of capturing the aromatic aldehyde or ketone by-product are feasible. First, after the reaction of hemiaminal IV with a strong base to form a compound of formula V and an aromatic aldehyde or ketone by-product, the by-product is reduced to the corresponding alcohol with a suitable reducing agent; The amine V is isolated by neutralization of the reaction mixture and filtration.

Alternatively, and secondly, the by-product may be trapped • * * 9 9 · ··

9 99 99

9 9 9 9 9

9 9 9 9 9 9 9 999

9 9 9 9 9 9

999 999 99 99 99 with a reagent with greater affinity for the by-product than for the free amine V, for example by reacting the by-product with hydroxylamine to give the corresponding oxime, or more preferably by reacting the by-product with tosylhydrazide to give the corresponding tosylhydrazone adjusting the pH of the solution to crystallize or precipitate the desired amine product V. Alternatively and thirdly, the by-product, if it is an aromatic aldehyde, may be captured by a reagent that oxidizes the aldehyde to the corresponding acid but which does not react with the amine or acetylene moiety V; such a scavenger is hydrogen peroxide under basic conditions.

Compound IV in an aqueous / organic solvent is contacted with a suitable strong base, preferably sodium hydroxide or potassium hydroxide, at a temperature sufficient for a suitable reaction time to initially form a compound of formula V, followed by addition of a suitable scavenger, preferably sodium borohydride, at which is sufficient to quantitatively form Compound V by converting the aldehyde or ketone to its corresponding alcohol. Compound V can be separated from the reaction mixture as a stable solid by cooling the scavenger followed by adjusting the pH of the solution and standard processing methods.

An example of a standard work-up is given in Example 6. Alternatively, compound V can be converted to the synthesis of compounds VI.

Preferred strong bases for step 4 include sodium, potassium, lithium or calcium hydroxides as well as metal alkoxides. Most preferably, the strong base is sodium hydroxide or potassium hydroxide.

Preferred scavengers are those that reduce the aromatic aldehyde or ketone by-product to an alcohol, but which do not react with the amine of compound V or the acetylene of Compound V. Of the scavengers that are reducing agents, sodium borohydride is a suitable reagent.

Preferred solvents for step 4 are alcohol. 9 9 9 9 9

9 9 9 9 9

9 9 9 9 9 9 9 999 999

9 9 9 9 9 9

999 999 99 · <99 mixed with water. The most preferred solvent is methanol and water.

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

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

Step 5: Cyclization: Preparation of Compound of Formula VI

This step involves cyclizing the chiral compound of formula V by contacting the cyclizing agent in a suitable solvent at a temperature sufficient to form the compound of formula VI. About one equivalent of Compound V is contacted with about two equivalents of the cyclizing agent and stirred at about 20-25 ^° until the reaction is quantitative. Compound VI can be separated from the reaction as a stable solid by standard workup methods. Examples of standard processing are given in Example 7.

The preferred cyclizing agent for step 5 is phosgene.

Preferred solvents for step 5 are heptanes, toluene and tetrahydrofuran. The most preferred solvent is heptanes / tetrahydrofuran.

The preferred temperature range for adding the cyclizing agent in step 5 is less than about 5 ° C.

In the judicious choice of reagents by one skilled in the art of organic synthesis, the claimed process can be carried out in a direct manner to obtain compounds of formulas II, III, IV, V and VI.

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

Scheme 2

Cl

Pivaloyl-CI

NaOH

- 45 Cl

1) BuLi / EtTFA

2) HCI / HOAc · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

OMe pyrrolidinyl norephedrine ^: n-hexyllithium

VI-i

The methods of the present invention, by way of example and without limitation, may be further understood by reference to Scheme 2a. This scheme details another embodiment of a general synthetic method for preparing a compound of formula II-i. The process of Scheme 2a provides excellent conversion to compound II-i and facilitates product crystallization.

Scheme 2a

xii xm

The substituted aniline of formula XII and p-toluenesulfonic acid are heated and stirred in acetonitrile to a temperature of about 65 ° C to about 85 ° C and then over a period of about 2 to about 10 hours, more preferably about 3 to about 8 hours, most preferably about 3 to about about 6 hours, acetonitrile solution of benzyl alcohol of formula XIII is added. The molar ratio of substituted aniline to p-toluenesulfonic acid is about 1: 0.010 to about 1: 0.030, more preferably about 1: 0.015. The molar ratio of substituted aniline to substituted benzyl alcohol is about 1: 1 to about 1: 1.2, more preferably about 1: 1.1. After the addition of benzyl alcohol, the reaction mixture is heated and stirred for about an additional 30 minutes to about 4 hours to give a crude solution of the compound of formula ΙΙ-i. The crude solution of the compound of formula ΙΙ-i is cooled to a temperature of about 20 ° C to about 30 ° C, preferably about 25 ° C; then seed crystals II-i are added. After the seed crystals are added, water is slowly added to form a slurry of crystalline Compound II-1 while stirring at about 30 ° C to about 35 ° C. The slurry is stirred for about 2 to about 12 hours at room temperature and then the slurry is filtered to isolate crystalline compound sloučeniny-i. The crystalline material is washed with a mixture of acetonitrile and water in a volume ratio of about 60:40 to about 40:60; preferably in a volume ratio of acetonitrile to water of about 50:50. Finally, the crystalline material is dried in an inert atmosphere at a temperature of about 50 ° C.

The methods of the present invention, by way of example and without limitation, may be further understood by reference to Scheme 2b. This scheme details another embodiment of a general synthetic method for preparing a compound of formula V-i. The method of Scheme 2b allows complete recovery

2,3-dichloro-5,6-dicyano-1,4-dihydroxybenzene, allows the use of less NaBH ₄ and allows recrystallization at a much lower temperature. This method thus allows crystallization of the valuable intermediate.

Scheme 2b

A toluene solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone is added to a toluene solution of the compound of formula III-i, maintaining the reaction temperature in the range of about 0 ° C to about 10 ° C, and then the reaction temperature was maintained at 0 ° C for 1 hour to form a toluene slurry

2,3-dichloro-5,6-dicyano-1,4-dihydroxybenzene and compounds of formula IV-i. Filter the slurry to remove

2,3-dichloro-5,6-dicyano-1,4-dihydroxybenzene; The resulting 2,3-dichloro-5,6-dicyano-1,4-dihydroxybenzene waste cake was washed with toluene. The filtrate and toluene washings were combined and concentrated in vacuo at about 40 ° C to about 45 ° C with the addition of methanol to remove most of the toluene to give the compound of formula IV-i in methanol. To this solution was added aqueous sodium hydroxide solution dropwise to form a clear solution of aminoalcohol Vi and p-methoxybenzaldehyde, followed by dropwise addition of a solution of NaBH ₄ in aqueous sodium hydroxide solution, maintaining the reaction temperature at an interval of about 40 ° C to · · ···

about 45 ° C. After adding a solution of NaBH ₄ in aqueous sodium hydroxide solution, the reaction solution is stirred for about 30 minutes and then glacial acetic acid is added to neutralize the reaction to a pH of about 8 to about 9. After neutralization, water is added to form a slurry and the slurry is cooled to about 1 hour to about -15 ° C to about 0 ° C. The cooled amino alcohol VI slurry was filtered and washed with water to give the crude crystalline amino alcohol Vi as a pale yellow solid.

It is preferred to recrystallize V-1 in toluene or in MBTE-toluene mixture. When the recrystallization is carried out in toluene, the crude crystalline amino alcohol is dissolved in toluene at a temperature of about 60 ° C, after which heptane is added to form a slurry of pure amino alcohol. The amino alcohol slurry is cooled to about 0 ° C and held at about 0 ° C for 1 hour, and then the pure crystalline amino alcohol is filtered. The pure crystalline amino alcohol was washed with heptane and dried in vacuo.

When recrystallization is carried out in MTBE-toluene, the crude crystalline amino alcohol is dissolved in MBTE-toluene at a temperature of about 20 ° C to about 30 ° C, then the MTBE is distilled off in vacuo from the MTBE-toluene solution. Heptane was added to form a slurry of pure amino alcohol. The amino alcohol slurry is cooled to about 0 ° C and the temperature is maintained at about 0 ° C for about 1 hour, and then the pure crystalline amino alcohol is filtered. The pure crystalline amino alcohol was washed with heptane and dried in vacuo.

The methods of the present invention, by way of example and without limitation, may be further understood by reference to Scheme 3 wherein in the example of the compound of Formula VII neither R ² nor R ³ is H. This scheme details in detail another embodiment of the general synthetic method for utilization of a very acid labile amine protecting group. In addition to achieving high yields of excess enantiomers at the chiral induction stage, the subsequent isolation of compound V is carried out without chromatography in a one-step process, quickly and at a high rate.

mild temperature conditions.

Scheme 3

Grade 7 pyrrolidinyl nerephedrine ·

Step 6: Addition: Preparation of a compound of formula II wherein R ² and R ^{3 of} compounds VII and 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 of formula VII or VIII, wherein neither R ² nor R ³ is H, in the presence of a suitable acid catalyst. Compound I in an aqueous / organic solvent is neutralized to about pH 7 at about room temperature, contacted with about 1 molar equivalent of compound VII or VIII, where none

R ² or R ³ is not H, preferably with trityl alcohol, and is further contacted with about 0.1 to about 5 moles. % of a suitable acid catalyst and heated to a temperature sufficient to form compound II. Compound II can be separated from the reaction mixture as a stable solid by standard workup methods. An example of a standard work-up is given in Example 11. Alternatively, compound II can lead to the synthesis of compounds of formula III.

Compound VII or VIII wherein neither R ² nor R ³ is H is preferably trityl alcohol or methoxy substituted trityl alcohol.

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

It will be appreciated that one skilled in the art can determine the preferred reaction time for Step 1, depending on the temperature, the acid catalyst, and the Group P. In general, the reaction time is 0.5 to 12 hours.

Step 7: The chiral induction step in Scheme 3 is similar to the chiral induction step in Scheme 1; an example of the preparation of a compound of formula III wherein P is a trityl group is given in Example 12.

Step 8: Detritylation: Preparation of Compound of Formula V

This step involves the reaction of a compound of formula III wherein the amine protecting group is very acid labile

a group, for example trityl, in a suitable solvent with about 0.1 to about 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 which need not subsequently be captured as in step 4 of Scheme 1 above . Compound V can be separated from the reaction mixture as a stable solid by adjusting the pH of the solution and standard processing methods. An example of a standard work-up is given in Example 13. Alternatively, compound V can lead to the synthesis of compounds of formula VI.

Acceptable amino protecting groups for step 8 are trityl, p-methoxytrityl, 4,4'-dimethoxytrityl as well as non-trityl groups, such as 2,4-dimethoxybenzyl and 4,4 -dimethoxybenzhydryl ^1. A preferred amine protecting group is trityl.

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

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

The preferred temperature range for the acid addition to compound III in step 8 is from about 0 to about 50 ° C; a more preferred temperature range is from about 0 to about 30 ° C.

The preparation of cyclopropylacetylene X, which is the reactant to form the compound of formula III, is shown in Scheme 4.

Scheme 4

Μ «« * * * * * * * * · · · · · · ·

1. alkyl-Li THF 0 ° C

2. Vacuum dest.

(XI)

TO_ - Li I.NH4CI (aqueous) 2.Separation of phases IN to AND 3. sieves II

4. Fractional distillation (X)

The preparation of cyclopropylacetylene X according to Scheme 4 is further illustrated in Example 15. This preparation of cyclopropylacetylene provides about 100% conversion of chlorpentine XI and greater than about 90% yield of cyclopropylacetylene so that product X can be used in the solution stream to prepare the compound of formula III.

The following examples describe the present invention in more detail. These examples are illustrative only and in no way limit the scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of N- (4-chlorophenyl) -2,2-dimethylpropanamide

4-Chloroaniline (52.7 kg, 413 mol) was dissolved in a mixture of tert-butyl methyl ether (180 kg), 30% aqueous sodium hydroxide (61.6 kg, 463 mol) and water (24.2 kg), and then cooled to 15 ° C. To the slurry was added trimethylacetyl chloride (52.2 kg, 448 mol) over 1 hour while maintaining the temperature below 40 ° C. After stirring at 30 ° C for 30 minutes, the slurry was cooled to -10 ° C and held at this temperature for 2 hours. The product was collected by filtration, washed with 90/10 water / methanol (175 kg) and then dried in vacuo to give 85 kg (97% yield) of the title compound as a crystalline solid: mp 152-153 ° C ; NMR (300 MHz, CDCl ₃ ) δ 7.48 (d, J = 9Hz, 2H), 7.28 (d, J = 9Hz, 2H), ¹³ ° C • · · · »· · · · · · *» * · · · ··· »· • · · · and« «• · · · · ·« · · · · _β

NMR (75 MHz, CDCl ₃ ) d 176.7, 136.6, 129.1, 128.9, 121.4,

39.6, 27.6.

Preparation of N- (4-fluorophenyl) -2,2-dimethylpropanamide

It will be appreciated that one skilled in organic synthesis can readily replace 4-chloroaniline with 4-fluoroaniline to prepare the above compound.

Example 2

Preparation of 4-chloro-2-trifluoroacetylaniline hydrate 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 tert-butyl methyl ether (271.5 kg) and cooled at -20 ° C. To the cold slurry was added 2.7 N n-butyllithium in hexane (101.9 kg, 393 mol) maintaining the temperature below 5 ° C. After aging at 0-5 ° C for 2 hours, the solution is cooled to -15 ° C and then rapidly reacted with ethyl trifluoroacetate (34.5 kg, 243 mol). After 30 minutes, the resulting solution was cooled in 3 N HCl (196 L, 589 mol) maintaining the temperature below 25 ° C. After removal of the aqueous phase, the organic solution is concentrated by distilling about 200 L of solvent. Acetic acid (352 kg) was added and 325 kg of solvent 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 was heated at 65-70 ° C for 4 hours. The resulting slurry was cooled to 5 ° C and the product was collected by filtration, washed with ethyl acetate (50.5 kg) and dried in vacuo to give 42.1 kg (87%) of the title compound as a white crystalline solid: mp 159 up to 162 ° C (dec); ¹ H NMR (300 MHz, DMSO-d 6) d 7.65-7.5 complex, 2H), 7.1 (d, J = 8 Hz, 1H), 7.0 (brs,

3H); ¹⁹ F NMR (282 MHz, DMSO-d 6) δ -69.5.

9 9

9 · 9 9 9 9 9 9 9 9 9 9 9 9 9 9

98 «9 ·« · «·

It will be appreciated that one skilled in organic synthesis can readily replace ethyltrifluoroacetate with CF ₃ CF ₂ CO ₂ Et or CF ₃ CF ₂ CF ₂ CO ₂ Et to obtain additional homologs.

Example 3-a

Preparation of 4-chloro-2-trifluoroacetylaniline

4-Chloro-2-trifluoroacetylaniline hydrate 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 saturated NaHCO ₃ . The organic phase was concentrated in vacuo and the residue was recrystallized from heptane to give 12.5 g (91%) of the title compound as yellow needles: mp 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) 1 H, 6.44 (brs, 2H); ¹³ C NMR (75 MHz CDCl 3) δ 180.0, 151.6, 136.9, 130.1, 120.9, 119.0, 116.8, 111.4; ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ -70.3.

Example 3

Preparation of N - ((4 ^1-methoxy) benzyl) -4-chloro-2-trifluoroacetylaniline. Compound II-i:

To a slurry of 4-chloro-2-trifluoroacetylaniline hydrate hydrochloride (40.0 kg, 144 mmol) in toluene (140 kg) and water (50 L) was added 30% NaOH (18 kg) to pH 7.0. After removal of 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 the water / toluene azeotrope distilled. The solution was cooled to room temperature and washed with saturated brine (80 kg). The organic phase was concentrated in vacuo to a volume of 30 to 40 L and then diluted with THF (52 kg). The weight percent of the title compound in the toluene / THF mixture determined by HPLC was 43%.

The yield obtained by HPLC was 47.7 kg (96%). An analytical sample is obtained by removing the solvent under vacuum.

55 and recrystallization from heptane: mp 82-84 ° C; Those ^ NMR (300 MHz, CDC1 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 H NMR (75 MHz, CDCl ₃ ) δ 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-1- (cyclopropylethynyl) -2 - [(4-methoxyphenyl) methyl] amino] - (trifluoromethyl) benzenemethanol. Compound

To a toluene solution of (IR, 2S) -pyrrolidinyl norephedrine (80 kg containing 60.7 moles of (IR, 2S) -pyrrolidinyl norephedrine) was added triphenylmethane (100 g). Concentrate the solution under vacuum to about half the original volume. Anhydrous THF (35 kg) was added and the solution was cooled using a -50 ° C cooling jacket. When the temperature reached -20 ° C, n-hexyllithium (33 wt% in hexanes, 33.4 kg, 119.5 mol) was added while keeping the temperature below 0 ° C. To the resulting yellow solution was added a solution of cyclopropylacetylene (30 wt% in THF / hexanes / toluene; containing about 4 kg, 65 mol of cyclopropylacetylene) while maintaining the internal temperature below -20 ° C. The resulting solution was left at -45 to -50 ° C for 1 hour. To the cold solution was added a solution

N- ((4 ^1-methoxy) benzyl) -4-chloro-2-trifluoroacetylaniline (43 wt.% In THF / toluene; containing about 10 kg, 28.8 mol of N- ((4'-Methoxy) benzyl) (4-chloro-2-trifluoroacetylaniline) while maintaining the reaction temperature below -40 ° C. The mixture is kept at -43 +/- 3 ° C for 1 hour and then the reaction mixture is cooled in 140 kg of 1 N HCl, previously cooled to 0 ° C. Separate the organic layer and extract twice with 25 kg 1 N HCl, twice with 40 kg water, then concentrate in vacuo to a volume of about 25 L. Add toluene (47 kg) and concentrate the solution to a volume of 28 to 30 L. heptane and the mixture was cooled to -5 ° C and held at this temperature for 4 hours. The product was filtered, washed twice with 10 kg of heptane and dried in vacuo to give 10 kg (85%) of the title compound as an off-white solid: mp 163-165 ° C; [α] ²⁵ D + 8.15 ° (c 1.006, MeOH); ¹ H NMR (300 MHz, CDCl ₃ ) δ

7.55 (brs, 1H), 7.23 (d, J = 8Hz, 2H), 7.13 (dd, J = 3.9Hz, 1H), 6.86 (d, J = 8Hz, 2H), 6.59 (d, J = 8Hz, 1H), 4.95 (bs, 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 5

Preparation of (S) -6-chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2- (4'-methoxyphenyl) -3,1-benzoxazine. Compound IV-i:

To a solution of heptane (295.5 kg) and ethyl acetate (32.5 kg) was added p-chloroanil (57 kg, 232 mmol) and (S) -5-chloro-1- (cyclopropylethynyl) -2 - [(4 (methoxyphenyl) methyl] amino-.alpha .- (trifluoromethyl) benzenemethanol (89 kg, 217 mol). The mixture was heated to reflux with stirring for 5.5 hours and then diluted with ethyl acetate (64.1 kg) and cooled to 30 ° C. Tetrachlorohydroquinone was removed by filtration and washed with a mixture of heptane (104.7 kg) and ethyl acetate (31 kg). The filtrate was partially concentrated by distilling off 260 L of solvent and then diluted with heptane (177 kg) and cooled to -10 to -15 ° C. The resulting slurry was filtered and the product washed with heptane (41 kg) and dried to less than 20% heptane (loss on drying). Yield IV as determined by HPLC is 71 kg (80%). An analytical sample was obtained by triturating the sample with 1 N NaOH, followed by recrystallization from hexane / ethyl acetate: mp 130-131.7 ° C; ^{Χ Η} NMR (300 MHz, DMSO-d₆) δ

7.46 (d, J = 9Hz, 2H), 7.28-7.21 (m, 2H), 6.85 (d, J = 9Hz, 1H), 5.52 (s, 1.52) -1.47 (m, 1 H), 0.90-0.84 (m, 2 H),

3H), 7.0 (d, J = 9Hz, 1H), 3.78 (s, 3H),

0.72-0.68 (m, IH); ¹³ C

NMR (75 MHz, DMSO-d6) 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 6

Preparation of compound V-i: (S) -5-chloro-α- (cyclopropylethynyl) -2-amino-α- (trifluoromethyl) benzenemethanol

Crude (S) -5-chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2- ⁽¹ 4-methoxyphenyl) -3,1-benzoxazine (71 kg calculated dry weight) was added to a mixture of methanol (301 kg), 30% NaOH (121 kg) and water (61 L). The mixture was heated to 60 ° C to give a clear solution, which was then cooled to 30 ° C. Sodium borohydride solution (3.2 kg, 84.2 mol) was then added to the methanolic solution over 20 minutes, maintaining the temperature below 35 ° C. After 30 minutes the excess borohydride was cooled with acetone (5.8 kg) and the solution was diluted with water (175 L) and neutralized with acetic acid to pH 8-9. The resulting slurry was cooled to about 0 °, filtered and the product washed water and then dried under vacuum at 40 ° C. The crude product was slurried in a mixture of toluene (133 kg) and heptanes (106 kg), initially at 25 ° C and then with cooling at -10 ° C. The product was filtered, washed with heptanes (41 kg) and dried under vacuum at 40 ° C to give 44.5 kg (88%) of an off-white, pale yellow crystalline solid. An analytical sample was recrystallized from tert-butyl methyl ether / heptane: mp 141-143 ° C;

[α] ²⁵ D -28.3 ° (c 0.106, MeOH); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.54 (d, J = 2 Hz, 1 H), 7.13 (dd, J = 9, 2 Hz, 1 H), 6.61 (d, J = 9) Hz, 1H), 4.61 (brs, 1H), 4.40 (brs, 1H), 1.44-1.35 (m, 1H), 0.94-0.78 (m, 2H): ¹³ C NMR (75 MHz, 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 III-i without isolation of compound IV-i in the previous synthesis step:

(S) -5-chloro-α- (cyclopropylethynyl) -2-amino-α- (trifluoromethyl) benzenemethanol

To a slurry of DDQ (9.42 g, 41.5 mmol) in tert-butyl methyl ether (33 mL) at 10 ° C was added a solution of (S) -5-chloro-α- (cyclopropylethynyl) -2 - [(4- methoxyphenyl) methyl] amino] - N - (trifluoromethyl) benzenemethanol (16.38 g, 40 mmol). After 5 minutes, the resulting slurry was filtered at 30 ° C and the resulting solid was washed with 5 mL of tert-butyl methyl ether. The filtrate was washed with 5% aqueous sodium bicarbonate and then partially concentrated by distilling off 70 ml of solvent. Methanol (25 mL) was added, followed by distilling off 25 mL of solvent. Methanol (25 mL) and 6 N NaOH (4 mL) were added again, followed by distilling off 20 mL of solvent. 4 N NaOH (26 mL) was added and the mixture was briefly heated to 58 ° C and then cooled to 30 ° C. A solution of sodium borohydride (0.60 g, 15.9 mmol) in 0.5 N NaOH (6 mL) was then added. After 15 minutes, water (45 mL) and acetone (1 mL) were added. After 0.5 h, acetic acid (12 mL, 210 mmol) was added to pH 7.5. The resulting slurry was cooled to about 0 ° C, filtered, and the product washed with water and dried under vacuum at 40 ° C. The crude product was slurried again with methylcyclohexanone at temperature, cooled to about 0 ° C, and filtered. This material was further purified by recrystallization from tert-butyl methyl ether / hexanes to give 9.95 g (86%) as a white solid. The physical characteristics are the same as the product prepared by the two step (p-chloroanil / NaBH ₄ ) procedure (Example 6 above).

Example 7 99

9 9 9

9 9 9

999 999 • ·

99

Preparation of (S) -6-chloro-4-cyclopropylethynyl) -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 heptanes (32 kg) and THF (52 kg) below -10 ° C. Phosgene (about 8.0 kg, 80 mol) was directly fed under the surface for about one hour while maintaining the temperature below 0 ° C. The resulting slurry was heated to 20-25 ° C and held at this temperature for 1 hour. Methanol (6.5 kg, 203 mol) was added and the solution was stirred for about 30 minutes. Heptanes (97 kg) were added and about 140 L of solvent was distilled off under reduced pressure. Heptanes (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 ° C and filtered into a clean reactor, followed by elution of 40 kg of heptanes. The solution was concentrated under reduced pressure, diluted with heptanes (22 kg) and cooled below -10 ° C. The product was filtered, washed with heptanes (37 kg) and dried under vacuum at 90-100 ° C to give 16.0 kg (95%) of an off-white to pale pink solid. HPLC:% region 99.8: mp 139-141 ° C; [α] ²⁵ D -94.1 ° (c 0.300, MeOH); 1 H 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, 1 H), 1.58 (m, 1 H), 0.92 (m, 2 H), 0.77 (m, 2 H); 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 8

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

4-Chloro-2-trifluoroacetylaniline (4.96 g, 40 mmol) and • Ch · · · · · 4 4 4 4 ··· ♦ ♦ · ·· ♦ · ·

3,4-Dimethoxybenzyl alcohol (7.39 g, 44 mmol) was added to 2-propanol (40 mL). TsOH (76 mg, 0.4 mmol) was added and the mixture was heated to 60 ° C for 3.5 h. Concentrate the solution in vacuo to 1/2 of the original volume, dilute with water (10 mL) and stir at room temperature. The resulting slurry was filtered and the product dried under vacuum at 30 ° C to give 10.16 g (68%) of the title compound as a yellow powder. An analytical sample was obtained by recrystallization from acetonitrile: mp 82-84 ° C; NMR (CDC1 ₃₎ δ 9.05 (brs, 1H), 7.75 (br t, J = 2 Hz, 1H), 7.35 (dd, J = 2, 8Hz,

1H), 6.8 (d, J = 8Hz, 3H), 6.75 (d, J = 8Hz, 1H), 4.43 (d,

J = 5Hz, 2H), 3.88 (s, 3H), 3.87 (s, 3H); ¹³ C NMR (CDCl ₃ ) 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 (CDCl ₃ ) δ -69.61.

Example 9

Preparation of (S) -5-chloro-α- (cyclopropylethynyl) -2 - [(3,4-dimethoxyphenyl) methyl] amino] -α- (trifluoromethyl) benzenemethanol

A 17.2% (IR, 2S) solution of pyrrolidinyl norephedrine (254 g, 213 mmol) was concentrated by distilling off 160 mL of solvent at atmospheric pressure. Triphenylmethane (0.2 g, 0.8 mmol) was added and the solution was cooled at room temperature. THF (130 mL) was added and the solution was cooled to -20 ° C. Add n-hexyllithium (2.0 M solution in hexane, 203 mL, 0.406 mol) maintaining the temperature below 0 ° C. The mixture becomes red upon addition of 108 ml. 16 wt. solution of cyclopropylacetylene (103 g, 0.25 mol) until the solution decolorized. The solution is stirred at -5 ° C to 0 ° C for 20 minutes and then cooled to -45 ° C when N - ((3 ', 4'-dimethoxy) benzyl-4-chloro-2-trifluoroacetylaniline is added (29.7 g,

81.8 mmol), which was previously dissolved in 50 mL of THF. After 1 h at 45 ° C, the mixture was cooled in 2 N HCl (400 mL).

· * · · * * * * * * * * · · · · · · · · · · · · · · ·

The organic layer was washed twice with 2N HCl (100 mL) and then concentrated in vacuo. Toluene (150 mL) was added and the mixture was concentrated to a volume of 80 mL. Heptane (100 mL) was added and the solvent ratio (determined by GC analysis) of heptane: toluene was adjusted to 60:40 by adding 43 mL of toluene. After crystallization, the product was filtered and recrystallized from toluene: heptane (3: 1) to give 23.1 g (64%) as a pale yellow solid:

[a] ²⁵ D , +11,00 ^O (c 0.300, MeOH); 7.56 (m, IH), 7.13 (dd, J = 9, (d, J = 9 Hz, 1H), 4.24 (m, 2H) 1.34 (m, IH), 0.90-0.74 (m, 4H) 148,8, 147,8, 146.3, 131.4, 128 118,9, 118,2, 113.4, 111.8, 110 55.3, 46.5, 8 , 2, 8.1, -1.1; 19 _p

the title compound, m.p. 128-129 ° C;

¹ H NMR (300 MHz, CDCl ₃ ) δ 3 Hz, 1H), 6.84 (m, 3H), 6.58, 3.85 (s, 3H), 3.83 (s, 3H),; ¹³ C NMR (75 MHz, DMSO-d6) δ, 9, 129.4, 124.3, 119.1, 9, 92.7, 73.8, 70.9, 55.5, NMR (282 MHz) CDCl ₃ ) δ -80.0.

Example 10

Preparation of (S) -6-chloro-4-cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2- ⁽¹ 3, ¹ 4-dimethoxyphenyl) -3,1-benzoxazine

To a solution of (S) -5-chloro-α- (cyclopropylethynyl) -2 - [(3,4-dimethoxyphenyl) methyl] amino] -? - (trifluoromethyl) benzenemethanol (2.68 g, 6.1 mmol) in of methanol (10 mL) at 40 ° C was added DDQ (1.40 g, 6.1 mmol). The resulting slurry was cooled in an ice bath for 30 minutes and then 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: mp 172-175 ° C; ¹ H NMR (300 MHz, CDCl 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 = 7 Hz, 1H), 6.70 (d, J = 9Hz, 1H), 5.62 (d,

J = 4Hz, 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 NMR (282 MHz, CDCl 3) δ -79.2.

Example 11

Preparation of N-triphenylmethyl-4-chloro-2-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 added. Dissolve in DMF (50 mL) and hold at 60 ° C for 14 h. The resulting slurry 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 is obtained by recrystallization from acetonitrile:

melting point 165 až 167 [deg.] C .; ¹ H NMR (cdci ₃ ) δ 10.4 (brs, 1H), 7.71 (brt, J = 2 Hz, 1H), 7.3 (brs, 15 H) 6.9 (dd, J = 2.8 Hz, 1H), 6.27 (d, J = 8 Hz, 1H); ¹³ C NMR (75 MHz, CDC1 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.

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

4-Chloro-2-trifluoroacetylaniline hydrate hydrochloride (84.4 g, 304 mmol), cyclohexane (350 mL) MTBE (95 mL) and water (100 mL) were stirred at room temperature. The resulting slurry was neutralized with 30 mL of 10 N NaOH. To the organic phase was added trityl alcohol (91.0 g, 350 mmol) and TsOH (0.36 g, 1.9 mmol). The mixture was heated to reflux and 300 ml of solvent was distilled off. Acetonitrile (350 mL) and diisopropylethylamine (0.5 mL) were added and distillation 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 spectral and physical properties as the sample prepared in Method A.

··

·· ·· • 9 9 9

999 999

9

99

Example 12

Preparation of 5-chloro-1- (cyclopropylethynyl) -2-triphenylmethyl] amino] -α- (trifluoromethyl) benzenemethanol

To a solution of cyclopropylacetylene (3.15 g, 48 mmol) and (1R, 2S) -pyrrolidinyl norephedrine (10.9 g, 53 mmol) in THF (50 mL) was added 2 N n-hexyllithium (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 THF (20 mL) and the temperature was maintained at -45 to -50 ° C for 1 hour and then quench with 1 N citric acid (92 mL). The organic layer was separated, dried with sodium sulfate, and concentrated to an oil. Crystallization from heptane / toluene gave 6.34 g (60%) of the title compound: mp 180-182 ° C; [α] ²⁵ D + 7.77 ° (c

1.004, CH ₃ CN); ^{Χ Η} NMR (300 MHz, CDC1 ₃₎ δ 7.53 (d, J = 2 Hz, 1H), 7.4-7.1 (complex, 16H), 6.67 (dd, J = 2.7 Hz 1H, 6.05 (d, J = 7Hz, 1H), 3.17 (brs, 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 13

Preparation of (S) -5-chloro-α- (cyclopropylethynyl) -2-amino-α- (trifluoromethyl) benzenemethanol. A One-stage debenzylation.

5-Chloro-α- (cyclopropylethynyl) -2- (triphenylmethyl) amino-α- (trifluoromethyl) benzenemethanol (5.32 g, 10 mmol) was dissolved in methanol (25 mL) and treated at room temperature with 12 N HCl ( 0.5 ml). After 15 minutes, 2 N NaOH (2 mL) and water (20 mL) were added. The aqueous methanolic solution was extracted

99 99

9

9

9 9 99

9 9 9

999 99 with cyclohexane (22 ml) and then hexanes (20 ml) and then partially concentrated in vacuo and neutralized with acetic acid to pH 7. The product was filtered, washed with water and dried to give 2.65 g (92%). mp: 140-143 ° C.

The spectroscopic properties are identical to the material prepared in Example 6.

Example 14

Preparation of (IR, 2S) -pyrrolidinyl norephedrine

To a mixture of n-butanol (227 kg), water (144 kg) and potassium carbonate (144 kg, 1043 mol) was added (IR, 2S) -norephedrine (68.6 kg, 454 mol). The mixture was heated to 90 ° C and 1,4-dibromobutane (113.4 kg, 525 mol) was added over 2 hours. The reaction mixture was heated to reflux for 5 hours and then cooled to 40 ° C. Water (181 kg) was added and the phases were separated at 30 ° C. To the organic phase was added 12 N HCl (54.3 kg, 543 mol). The solution was heated to reflux and 150 L of distillate was removed at 200-300 mm. Toluene (39.5 kg) was added at 70 ° C and the resulting slurry was cooled to -5 ° C for crystallization. The product was collected, washed twice with toluene (39 kg each) and dried under nitrogen purge to give 83.6 kg of the title compound as its hydrochloride salt. The hydrochloride salt is taken up in toluene (392 kg) and water (42 kg) and treated with 30% NaOH (approximately 55 kg, 414 mol) to a pH greater than 12. After removal of the lower aqueous phase, the organic solution is partially concentrated by distilling off 140 l of solvent and 20 wt. solution of the title compound in toluene. The calculated yield is 50 kg (75%). An analytical sample was obtained by concentrating the toluene solution of the title compound in vacuo and then recrystallizing from heptane: mp 46-48 ° C.

Example 15> «· ·« ·· ···

Preparation of cyclopropylacetylene X.

1. n-hexyl Li hexane THF 0 ° C

I.NH 4 Cl (aqueous) 2.Separation

Toluene

Vacuum distillation

3. sieves

4. Fractional distillation (XI) (X)

A mixture of 5-chloro-1-pentine XI, (23.0 kg, 224 mol) and anhydrous THF (150 kg) was cooled to -20 ° C. N-Hexyllithium (2.3 eq; 158 kg, 30 wt%) in hexane was added to the reaction mixture at a rate such that the temperature did not exceed 5 ° C (about 2 hours). During the second half of the n-hexyllithium addition, the temperature must be below -5 ° C to avoid accumulation of organolithium and a dangerous exothermic reaction. The reaction mixture is left at -5 to 0 ° C for 2 hours until GC analysis indicates at least 99% conversion.

Toluene (35-40 kg) was then added and the reaction mixture was concentrated in vacuo until the volume was reduced to approximately 1/3 of the original volume. During the concentration, the mixture is heated (about 40 ° C) to allow distillation to proceed at a good rate. The mixture was then cooled to 15 to -20 ° C and a solution of ammonium chloride (11-12 kg) in 50 L of water was added at a rate such that the temperature did not exceed 10 ° C. After separation of the aqueous layer (about 70 kg), the reaction mixture is circulated through a tower containing 15 kg of molecular sieves 3A until the water content is about 300 ppm or less as determined by Karl Fischer analysis. The dry organic solution is then distilled through a column of steel wool at atmospheric pressure to give cyclopropylacetylene X as a solution in THF / toluene / hexane. The calculated yield is 14.0 kg.

Example 16

Preparation of p-methoxybenzyl ketoaniline, II-i.

** · · · · # # # # # # # # # # # # # # # # # # # # # ·· ··· · · · · · · · · ·

XII-a

XII

Il-i

Materials mol. wt amount mol. equiv. Ketoaniline-HCl 278.05 3000 g 10.14 (94%) XII-a terč.Butylmethyl- ether (MTBE) 18 1 Sodium acetate 82.03 1,419 g 17.3 1.7 D.I. water 7.2 + 11 + 10 1 Ketoaniline, XII 223.57 2,245 g 10,04 1.00 4-Methoxybenzyl- alcohol 138.17 1,526 g 11.04 1.10 p-Toluenesulfonic acid-H ₂ O 190.22 28.65 0.15 0.015 Acetonitrile 28 + 3 + 10 1 Product Theory Il-i 343.73 3.541 g 10,04 1.00 Stage A: Preparation of ketoaniline, XII To a 50 L extractor was charged inserts D.I. water (3.6 1) and acetate

sodium (1419 g). The mixture was stirred at room temperature for 5 to 10 minutes until the sodium acetate had dissolved. Then, tert-butyl methyl ether (18 L) was added, followed by the addition of substrate XII-a (3000 g). The heterogeneous mixture is stirred at room temperature for 20 to 30 minutes or until the solid disappears

• • • • · · • · · · • • • • · • • · · · • • • · • · • · • · · · · · • • • • · • • · • • • · · • · · · · • · · ·

substance. The aqueous layer should have a pH in the range of 4.0-6.0, otherwise it is adjusted to the desired range with HCl (6 N) or NaOH (5 N). The batch is allowed to settle and the two layers are separated. The organic layer was washed with D.I. water (3.6 L) and transferred to a 50 L three-necked round bottom flask equipped with a mechanical stirrer and thermocouple. Concentrate the solution to about 6-7 L, rinse with acetonitrile (2 x 12 L) and adjust the final batch volume to 8 to 8.5 L with acetonitrile. Ketoaniline XII in acetonitrile (KF solution <300 mM) is assayed by HPLC: after neutralization yielded a total of 2245 g (10.04 mol) of XII, representing a 99% yield.

Stage B:

Preparation II-i

In a 50 L flask under nitrogen was added p-toluenesulfonic acid monohydrate (28.65 g, 0.15 mol) to a solution of ketoaniline XII in acetonitrile (8-8.5 L, 10.04 mol). The reaction mixture was heated to 70 ° C with stirring. 4-Methoxybenzyl alcohol (1526 g, 11.04 mol) acetonitrile (3 L) was then added over 5 hours maintaining the temperature at 68-72 ° C. The reaction is monitored by HPLC and is usually complete 2 hours after addition of the alcohol.

The batch was cooled to room temperature and seeded. Gradually, light yellow crystals begin to form. The slurry was then allowed to stand with stirring at room temperature for 1 to 2 hours. Water was slowly added over 2 hours at 35 ° C. The mixture was allowed to stand at room temperature for 1-2 hours, the solid was filtered off, washed with a 50/50 mixture of acetonitrile and water (2 x 10 L). The wet cake was dried under vacuum (50 ° C, 711 mm for 24 hours) to give the product IL-1 (3354 g, 99% wt, 95% yield based on LC assay and 99.5 + LC area%). The KF of the dry cake is less than 0.5 mol. %.

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- 68 Example 17

Preparation of p-methoxybenzyl ketoahilin, II-i

Materials mol. wt. amount mol. equiv Ketoaniline, XII 223.57 250 g 1.12 1.00 4-Methoxybenzyl- 138.17 170 g 1,23 1.10 alcohol, XIII p-Toluenesulfone 190.22 3.19 g 0.017 0.015 acid-H ₂ O Acetonitrile 1,7 1 Water 1,5 1 Product Theorie Il-i 343.73 384.3 g 1.12 1.00 Into 3 l three - necked flasks round bottom, provided

acetonitrile (900 mL), ketoaniline XII (250 g, 1.12 mol) and p-toluenesulfonic acid monohydrate (3.19 g, 0.017 mol) were charged under nitrogen with a mechanical stirrer and a separating funnel and a thermocouple. The reaction mixture is then heated to reflux with stirring. From a separatory funnel, 4-methoxybenzyl alcohol (170 g, 1.23 mol) in acetonitrile was added over 4 hours. The batch is then kept under reflux at 85 ° C. The reaction is monitored by HPLC and is usually complete 1 hour after the addition of 4-methoxybenzyl alcohol.

The batch is cooled to 45-50 ° C and seeded. Water (1.1 L) was added with stirring over 30-40 minutes and the batch was charged

becomes cloudy. During the process, yellow crystals are embarrassingly formed. The batch was allowed to stand at room temperature with stirring for a further 1-2 hours. The solid was collected by filtration and the wet cake was washed with 50/50 acetonitrile / water (800 mL). After drying, the product II-i (361 g, 96.3% by weight, 90% yield and> 99.5 A%) is obtained. The water content of the cake is 0.6 mol. %.

Example 18

Preparation of amino alcohol, V-i

III-i

Materials mol. wt. amount mol. PMB-protected amino- 409.8 1,14 kg 2.78 alcohol II-i DDQ (99%) 227 0,64 kg 2.78 Toluene 12 1 NaHCO ₃ (5%) 84 2,50 1 MeOH 14,0 1 5 N NaOH 40 2,50 1 12.51 NaBH ₄ (97%) 37.8 29,5 g 0.76 0.5 N NaOH 295.0 ml Glacial acetic acid 779 ml Water 7,51 1 Heptane 4,2 1

Stage A:

· · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Preparation of amino alcohol V-i

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is dissolved in toluene (3.42 L) at about 30 ° C and is added dropwise to a slurry of PMB protected alcohol in toluene under nitrogen. (5.7 L) at 0 ° C, maintaining the temperature of the reaction mixture between 0 and 10 ° C. The resulting mixture was left at room temperature for 2 hours and then filtered. The solid paste was washed with toluene (3 x 0.8 L). Combine the filtrate and wash, wash with aqueous 5% NaHCO 3 and concentrate in vacuo to ca. 2 L at ca. 40 ° C. Add MeOH (91) portion wise and concentrate to ca. 2 L with methanol. The solution is heated to 40 ° C and 5 N NaOH (2.5 L) is added over about 10 minutes. The resulting clear solution is kept at 40 ° C for 30 minutes. A solution of NaBH ₄ in 0.5 N NaOH was added dropwise while maintaining the temperature between 40-45 ° C. The mixture was stirred at ambient temperature for 15 minutes, cooled to about 19 ° C and neutralized with glacial acetic acid to pH about 4 while maintaining the temperature at 20-25 ° C using an external cooling bath.

Water was added over 15 minutes. The mixture was kept at 23 ° C for 1 hour and filtered. The solid was washed with water and dried in vacuo to give a pale yellow solid: 832 g.

Stage B:

Recrystallization of amino alcohol, V-i

The crude product was taken up in toluene (2.78 L) and heated rapidly to 60-64 ° C to give a clear solution.

The solution was allowed to cool to room temperature and heptane (4.17 L) was added slowly over 1 hour. The resulting slurry was cooled to 0 ° C and held at this temperature for 1 hour. The solid was collected by filtration, washed with heptane (1 volume solid) and dried in vacuo to give 734.2 g of the desired product.

71 compounds as a white solid.

Alternative method B:

Recrystallization of V-i

The crude product was taken up in toluene (1.6 L) at 20-25 ° C. MTBE (0.66 L) was added to the clear solution. Concentrate the solution in vacuo to about 1.6 L. Add toluene (0.5 L). The solution was again concentrated to about 1.6 L to give a slurry. Heptane (2.4 L) was added to the slurry over 1 hour. The resulting mixture was cooled to 0 ° C, left for 1 hour and filtered. The solid was washed with heptane (1 volume solid) and dried in vacuo to give the desired product as a white solid.

Although the present invention has been described with respect to specific embodiments, the details of these embodiments are not limiting. Various embodiments and modifications do not affect the scope of the present invention and these equivalent embodiments are part of the invention.

Claims (12)

A process for preparing a compound of formula II-i: O (II-i) characterized by comprising: (1) heating the substituted aniline acetonitrile solution of formula XII: and p-toluenesulfonic acid at a temperature of about 65 ° C to about 85 ° C; (2) addition of acetonitrile of formula XIII: a solution of benzyl alcohol (XIII) within about 2 hours to about 10 hours to a heated acetonitrile solution of substituted aniline; and 73 p-toluenesulfonic acid; and (3) stirring the heated reaction mixture for about 30 minutes to about 4 hours to obtain a crude solution of the compound of formula II-i. Process for preparing a crystalline compound of formula II-i: (II-i) characterized by comprising: (1) heating and stirring the substituted aniline acetonitrile solution of formula XII: (XII) and p-toluenesulfonic acid at a temperature of about 65 ° C to about 85 ° C; (2) addition of acetonitrile solution of benzyl alcohol of formula XIII: OH OCH ₃ (XIII) over about 2 hours to about 10 hours to a heated acetonitrile solution of substituted aniline and p-toluenesulfonic acid; and (3) heating and stirring the reaction mixture for about 30 minutes to about 4 hours to obtain a crude solution of the compound of formula II-i. (4) cooling the crude solution of the compound of formula II-i; (5) adding seed crystals at a temperature of about 20 ° C to about 30 ° C; (6) slowly adding water while stirring at a temperature of about 30 ° C to about 35 ° C to form a slurry of the crystalline compound of formula II-i; (7) stirring the slurry for about 2 hours to about 12 hours at room temperature; (8) filtering a slurry of the crystalline compound of formula II-i to isolate the crystalline compound of formula II-i; (9) washing the crystalline material with a mixture of acetonitrile and water in a volume ratio of about 60:40 to about 40:60; and (10) drying the material in an inert atmosphere at a temperature of about 50 ° C. The process as recited in claim 2, wherein the molar ratio of substituted aniline to toluenesulfonic acid is about 1: 0.010 to about 1: 0.030. The process as recited in claim 3, wherein the molar ratio of substituted aniline to substituted benzyl alcohol is about 1: 1 to about 1: 1.2. 5. The process as recited in claim 4, wherein the reaction time in step 2 is about 2 to about 8 hours. A process as recited in claim 5 wherein the molar ratio of substituted aniline to toluenesulfonic acid is about 1: 0.015. The process as recited in claim 6, wherein the molar ratio of substituted aniline to substituted benzyl alcohol is about 1: 1.1. 8. The process as recited in claim 7, wherein the reaction time in step 2 is about 3 to about 6 hours. 9. The method as recited in claim 8, wherein the temperature used in step 5 is about 25 ° C. 10. The process as recited in claim 9, wherein the volume to volume ratio of acetonitrile to water used in step 9 is about 50:50. A process for preparing an amino alcohol compound of formula V-i: (V-i) comprising: (1) adding a toluene solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to a toluene solution of a compound of formula III-i: wherein the reaction temperature is maintained in the range of about 0 ° C to about 10 ° C; (2) maintaining a reaction temperature of about 0 ° C for about 1 hour to form a slurry of 2,3-dichloro-5,6-dicyano-1,4-dihydroxybenzene and a compound of formula IV-i: (IV-i) (3) filtering the slurry to remove 2,3-dichloro-5,6-dicyano-1,4-dihydroxybenzene; (4) washing the filter cake paste 2,3-dichloro-5,69 9 9 9 9 9 9 ··· • 9 9 9999 999 999 • 99 999 9 9 ·· ··· 999 99 «9 99 - 77-dicyano-1,4-dihydroxybenzene with toluene; (5) combining the filtrate and toluene wash liquids; (6) concentrating the filtrate and toluene solution of the compound of formula IV-i with methanol in vacuo to remove most of the toluene; (7) adding to the compound of formula IV-i in methanol at a temperature of about 40 ° C to about 45 ° C dropwise with aqueous sodium hydroxide solution to form a clear solution of aminoalcohol and p-methoxybenzaldehyde; (8) adding to the clear amino alcohol solution dropwise a solution of NaBH ₄ in aqueous sodium hydroxide solution, maintaining the reaction temperature in the range of about 40 ° C to about 45 ° C; (9) stirring the reaction mixture for about 30 minutes; (10) neutralizing the reaction mixture with glacial acetic acid to a pH of about 8 to about 9; (11) adding water to form a slurry; (12) cooling the slurry to about -15 ° C to about 0 ° C for 1 hour; and (13) filtering the cooled amino alcohol slurry and washing with water to obtain the crude crystalline amino alcohol as a yellow solid. A process for the preparation of a pure crystalline amino alcohol compound of formula V-i as set forth in claim 11, comprising: (1) dissolving the crude amino alcohol in toluene at a temperature of about 60 ° C; (2) adding heptane to a toluene solution of the crude amino alcohol to form a pure amino alcohol slurry; (3) cooling the amino alcohol slurry to a temperature of about 0 ° C and holding at 0 ° C for about 1 hour; * (4) filtration of pure crystalline amino alcohol; (5) washing the pure crystalline amino alcohol with heptane; and (6) drying the pure crystalline amino alcohol in vacuo. A process for preparing a pure crystalline amino alcohol compound of formula V-i as set forth in claim 11, comprising the following additional steps: (1) dissolving the crude amino alcohol in the MTBE-toluene mixture at a temperature from about 20 ° C to about 30 ° C; (2) vacuum distillation of MTBE from the MTBE-toluene solution of the crude amino alcohol; * (3) adding heptane to a toluene solution of the crude amino alcohol to form a slurry of pure amino alcohol; (4) cooling the amino alcohol slurry to a temperature of about 0 ° C and holding at 0 ° C for about 1 hour; (5) filtering the pure crystalline amino alcohol; (6) washing the pure crystalline amino alcohol with heptane; and (7) drying the pure crystalline aminoalcohol under vacuum.