WO2008054857A1 - Process for the preparation of intermediates useful in the treatment of hiv infection - Google Patents

Abstract

The present invention is directed to processes for the synthesis of intermediates useful in the preparation of non-nucleoside reverse transcriptase inhibitors.

Description

Process for the Preparation of Intermediates Useful in the Treatment of

HIV Infection Field of the Invention

The present invention provides a process for the preparation of compounds useful in the preparation of non-nucleoside reverse transcriptase inhibitors.

Background of the Invention

The human immunodeficiency virus ("HIV") is the causative agent for acquired immunodeficiency syndrome ("AIDS"), a disease characterized by the destruction of the immune system, particularly of CD4⁺ T-cells, with attendant susceptibility to opportunistic infections, and its precursor Al DS-related complex ("ARC"), a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss. HIV is a retrovirus; the conversion of its RNA to DNA is accomplished through the action of the enzyme reverse transcriptase. Compounds that inhibit the function of reverse transcriptase inhibit replication of HIV in infected cells. Such compounds are useful in the prevention or treatment of HIV infection in humans.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs), in addition to the nucleoside reverse transcriptase inhibitors gained a definitive place in the treatment of HIV-1 infections. The NNRTIs interact with a specific site of HIV-1 reverse transcriptase that is closely associated with, but distinct from, the nucleoside binding site on reverse transcriptase. NNRTIs, however, are notorious for rapidly eliciting resistance due to mutations of the amino acids surrounding the NNRTI-binding site (E. De Clercq, // Famaco 54, 26-45, 1999). Failure of long-term efficacy of NNRTIs is often associated with the emergence of drug-resistant virus strains (J. Balzarini, Biochemical Pharmacology, VoI 58, 1-27, 1999). Moreover, the mutations that appear in the reverse transcriptase enzyme frequently result in a decreased sensitivity to other reverse transcriptase inhibitors, which results in cross-resistance.

WO 00117982 discloses a series of benzophenone derivatives that when administered in vivo provide compounds that are useful as inhibitors of both wild type and mutant variants of HIV reverse transcriptase. Current methods for the preparation of certain intermediates useful in the synthesis of benzophenone compounds involve multi-step processes that are difficult to perform on large-scale and therefore are unsuitable for manufacture.

One process that is known for the cyanation of aryl halides and useful in the synthesis of potential non-nucleoside reverse transcriptase inhibitors is palladium catalyzed cyanation. This process requires a palladium source and a compatible ligand. During large-scale development of the palladium catalyzed cyanation of aryl halides, such reactions are often often lengthy and produce low yields, requiring multiple charges of catalyst and ligand to effect completion. Further, palladium catalyzed cyanation of aryl halides often results in stalled reactions. Many of these stalled reactions may be attributed to contamination from low-level amounts of oxygen, resulting in the need to rigorously remove oxygen by degassing of solvents completing the reaction in the presence of nitrogen, increasing time and cost associated with the manufacture of certain aryl compounds.

Summary of the Invention

Briefly, in one aspect, the present invention features a process for the preparation of a compound of formula (I)

wherein m is 0 or 1 ; R² is selected from halogen, -CF₃, C_1-8alkyl, C_1-8alkylamino, C_1-8 alkoxy, Cs^cycloalkylC^alkenyl, C_6-i₄arylC₂-₆alkenyl, -CN, -NO₂, -NH₂, -SR⁶, - S(O)₂R⁶, -S(O)R⁷, -S(O)₂R⁷, -C(O)R⁷, -C(O)OR⁷, or N(H)C(O)R⁷; R⁶ is C_1-8alkyl, optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, -CF₃, aryl, and heterocycle; R⁷ is Ci_-8 alkyl, optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, aryl, C_3-6cycloalkyl and heterocycle; -NH₂, or heterocycle; comprising the steps of reacting a compound of formula (II)

wherein R¹ is a halogen, and R² and m are as defined with respect to formula (I) with at least one silyl hydride reagent reagent in the presence of a palladium catalyst and a ligand to form the compound of formula (I).

In one aspect of the invention, the silyl hydride reagent is a silane. In one aspect of the invention, the silane is alkylsilane. In one aspect of the invention, the alkylsilane is selected from the group consisting of triethylsilane and triisopropylsilane. In yet another aspect of the invention, the alkylsilane is triethylsilane.

In one aspect of the invention, the silyl hydride reagent is siloxane. In one aspect of the invention, the siloxane is polyalkylsiloxane. In one aspect of the invention, the polyalkylsiloxane is selected from the group consisting of polymethylhydrosiloxane.

In yet another aspect of the invention, the palladium catalyst is Pd(OAc)₂. In yet another aspect of the present invention, the palladium catalyst is Pd₂(dba)₃. In yet another aspect of the present invention, the palladium catalyst is PdCI₂. In one aspect of the invention, the ligand is DPPF.

In one aspect, the invention features a process for the preparation of a compound of formula (I)

wherein m is O or 1 ; R² is selected from halogen, -CF₃, C_1-8alkyl, C_1-8alkylamino, C_1-8 alkoxy, Cs^cycloalkylC^alkenyl, C_6-i₄arylC₂-₆alkenyl, -CN, -NO₂, -NH₂, -SR⁶, - S(O)₂R⁶, -S(O)R⁷, -S(O)₂R⁷, -C(O)R⁷, -C(O)OR⁷, or N(H)C(O)R⁷; R⁶ is C_1-8alkyl, optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, -CF₃, aryl, and heterocycle; R⁷ is Ci_-8 alkyl, optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, aryl, C_3-6cycloalkyl and heterocycle; -NH₂, or heterocycle, comprising the steps of reacting a compound of formula (II)

wherein R¹ is a halogen, and R² and m are as defined with respect to formula (I), with polymethylhydrosiloxane in the presence of a palladium catalyst and phosphine ligand to form a compound of Formula (I).

Detailed Description of the Invention As used herein, the term "alkyl", alone or in combination with any other term, refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon radical containing the specified number of carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, n-hexyl and the like.

As used herein, the term "silyl hydride reagent(s)" includes, among others, siloxanes and silanes. Examples of silanes include trialkylsilanes. Examples of siloxanes include polyalkylhydrosiloxanes, alkylhydrosiloxanes, alkylsiloxanes, and polyalkylsiloxanes.

The term trialkylsilane includes silane compounds of the formula HSi(R)3, wherein R is an alkyl as defined herein.

The term polyalkylhydrosiloxanes includes compounds of the formula

wherein n denotes a polymer of varying length.

The present invention features a process for preparing compounds of formula

(I)

wherein m is 0 or 1 ; R² is selected from halogen, -CF₃, C_1-8alkyl, C_1-8alkylamino, C_1-8 alkoxy, Cs^cycloalkylC^alkenyl, C_6-i₄arylC₂-₆alkenyl, -CN, -NO₂, -NH₂, -SR⁶, - S(O)₂R⁶, -S(O)R⁷, -S(O)₂R⁷, -C(O)R⁷, -C(O)OR⁷, or N(H)C(O)R⁷; R⁶ is C_1-8alkyl, optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, -CF₃, aryl, and heterocycle; R⁷ is C_1-8 alkyl, optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, aryl, C_3-6cycloalkyl and heterocycle; -NH₂, or heterocycle; comprising the steps of reacting compounds of formula (II)

(II) wherein R¹ is a halogen, with at least one silyl hydride reagent in a palladium catalyzed cyanation reaction to form a compound of Formula (I).

The palladium source may be any suitable palladium catalyst. Palladium catalysts suitable for the process of the present invention include, but are not limited to, PdCI₂, Pd(OAc)₂ and PdCI₂. In one aspect of the invention the palladium source is Pd(OAc)₂ or PdCI₂. Any suitable phosphine ligand typically used in palladium catalyzed cyanation reactions may be incorporated with the palladium catalyst. Such ligands include, but are not limited to, PPh₃, DPPE, DPPF, DPPP, DPPB, and BINAP. The cyanide source may be any cyanide suitable for palladium catalyzed reactions. Suitable cyanides include, but are not limited to, sodium cyanide, potassium cyanide and copper cyanide.

The reaction can be run in a wide variety of solvents that are generally compatible with the reaction conditions. Suitable solvents include, but are not limited to, N-methylpyrrolidinone, dimethylacetamide, dimethylformamide, dimethoxyethane, tetrahydrofuran, dioxane, and combinations thereof.

In one aspect of the invention, the silyl hydride reagent is a polysiloxane or a silane. In another aspect of the invention, the polysiloxane is polyalkylhydrosiloxane. In a further aspect of the invention, the silyl hydride reagent is polymethylhydrosiloxane (PMHS). In yet another aspect of the invention, the silyl hydride reagent is triethylsilane.

The silyl hydride reagent may be present in as low amounts as 1 (one) weight percent or as much as 100 weight percent silyl hydride reagent to the reaction. The silyl hydride reagent may be present in catalytic or stoicheometric amounts. In one aspect of the invention, the silyl hydride reagent is added just prior to the palladium catalyst. In another aspect of the invention, the silyl hydride reagent is added after the addition of the palladium catalyst. It is understood that the process of the present invention is not limited to a specific step-wise procedure, but that the silyl hydride reagent may be added to the reaction prior to or following the addition of the palladium catalyst.

The addition of the silyl hydride reagent may allow the reaction to progress without stalling, even when fully exposed to air and therefore reduce or remove the need for stringent degassing and oxygen removal. Further, the addition of silyl hydride reagent may impart a protective effect on the catalyst from oxidative inactivation.

The addition of silyl hydride reagents, such as silanes including triethylsilane, or siloxanes including PMHS allows conversion of aryl halides to aryl cyanides while exposed to air. Either reaction may be completed without the use of nitrogen inerting or solvent degassing unlike previously known palladium catalyzed cyanation reactions.

The following scheme, Scheme A, represents the process according to a feature of the present invention and is not intended to limit the scope of the invention but is provided for illustration only. Scheme A

wherein R¹, R² and m are as defined hereinabove.

The following scheme, Scheme B, represents one aspect of the invention, wherein the palladium catalyst is Pd₂(dba)₃ in DPPF and NMP as the solvent. Scheme B

wherein R¹, R² and m are as defined hereinabove.

The following scheme, Scheme C, represents one aspect of the invention, wherein the palladium catalyst is Pd(OAc)₂ in DPPF and NMP as the solvent. Scheme C

wherein R¹, R² and m are as defined hereinabove.

The following scheme, Scheme D, represents one aspect of the invention, wherein the palladium catalyst is Pd(CI)₂ in DPPF and NMP as the solvent. Scheme D (^R )

wherein R¹, R² and m are as defined hereinabove.

Examples

Abbreviations:

As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams);

L (liters); ml. (milliliters); μl_ (microliters); psi (pounds per square inch);

M (molar); mM (millimolar);

Hz (Hertz); MHz (megahertz); mol (moles); mmol (millimoles);

RT (room temperature); h (hours); min (minutes); TLC (thin layer chromatography); mp (melting point); RP (reverse phase);

TEA (triethylamine); THF (tetrahydrofuran); atm (atmosphere); DMSO (dimethylsulfoxide);

EtOAc (ethyl acetate); CHCI₃ (chloroform);

HCI (hydrochloric acid); Ac (acetyl);

DMF (N,N-dimethylformamide); Me (methyl);

MeOH (methanol) EtOH (ethanol);

Et (ethyl); tBu (tert-butyl);

Pd(OAC)₂( Palladium acetate) Pd₂(dba)₃

(Tris(dibenzylidenaceton)dipalladium(O)); PMHS (polymethylhydrosiloxane); PPh₃ (Triphenylphosphine); DPPE ( 1 ,2-Bis(diphenylphosphino)ethane); DME ( Dimethoxyethane);

DPPP ( 1 ,3-Bis(diphenylphosphino)propane); DPPB (1 ,4-Bis(diphenylphosphino)butane); BINAP(2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl); DPPF (1 ,1 '-Bis(diphenylphosphino)ferrocene);

NMP (N-methyl pyrrolidinone); CDCI₃ (deuterochloroform);

Example 1

3-bromoacetophenone (1.Og, 5.3 mmol), zinc cyanide (0.32g, 2.7 mmol), NMP (5 ml) and water (0.5 ml) were stirred in a one neck round bottom flask fitted with vigeroux reflux condenser open to atmosphere. The contents were heated to 80⁰C and treated with PMHS (0.1 Og) followed by a slurry of Pd(OAc)₂ (11.3mg, 0.05 mmol) and DPPF (36.2 mg, 0.0065 mmol) in NMP (0.5 ml). The contents were heated at 80⁰C for approximately two hours and monitored for completeness by HPLC. The reaction was cooled and the contents placed on a silica gel column eluted with 50% heptane/ethyl acetate. The purified product was isolated as an off white solid, (596 mg, 78%) by evaporation of volatiles. All products were fully characterized by H-NMR, 13C-NMR and HPLC. This exercise was also conducted on up to one kilogram scale in fixed equipment where the reaction was conducted without the use of nitrogen inerting or solvent degassing.

Table 1 lists the aryl bromides that were subjected to cyanation reactions using PMHS additive and conducted generally according to the method described herein in Example 1 , with the exception of starting materials, which are provided in Table 1.

Table 1

Entry Starting material? Time Temp Isolated Yield

1 hr 12O⁰C 97

1: ¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (d, j=8.2Hz, 2H) 7.95 (d, J=8.2 Hz, 2H). ¹³C NMR(IOOMHz, DMSOd₆) δ 134.1, 127.05, 125.32, 122.61, 118.31, 116.20.

2: ¹H NMR (400 MHz, DMSOd₆) δ 8.07 (d, j=8.4Hz, 2H) 7.98 (d, J=8.4 Hz, 2H), 2.61 (s, 3H). ¹³C NMR (100 MHz, DMSOd₆) δ 198.00, 140.49, 133.43, 129.43, 118.84, 122.61, 115.82,27.67.

3: ¹H NMR (400 MHz, CDCI₃) δ 8.13 (d, j=8.7Hz, 2H) 7.74 (d, J=8.7 Hz, 2H), 3.95 (s, 3H). ¹³C NMR(IOO MHZ, CDCI₃) δ 165.65, 134.13, 132.45, 130.32, 118.19, 116.61, 52.97.

4: ¹H NMR (400 MHz, DMSOd₆) δ 10.37 (s, 1H), 7.75 (m, 4H) 2.09 (s, 3H). ¹³C NMR(IOOMHz, DMSOd₆) δ 169.84, 144.13, 133.90, 132.45, 119.76, 119.56, 105.34,24.87.

5: ¹H NMR (400 MHz, CDCI₃) δ 7.58 (d, j-9.1 Hz, 2H) 6.94 (d, j-9.1 Hz, 2H) 3.85 (s, 3H). ¹³C NMR(IOO MHZ, CDCI₃) δ 163.05, 134.21, 119.47, 114.96, 104.61, 55.78 6: ¹H NMR (400 MHz, CDCI₃) δ 7.38-7.34 (m, 1 H) 7.24-7.22 (m, 1 H) 7.15-7.08 (m, 2H) 3.82 (s, 3H). ¹³C NMR (I OO MHZ, CDCI₃) δ 159.83, 130.55, 124.70, 119.53, 118.98, 117.05, 1 13.39, 55.76.

7: ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (s, 1 H) 8.21 (d, j=7.9Hz, 1 H) 8.08 (d, j=7.6Hz, 1 H) 7.72 (dd, j=7.9Hz, 1 H) 2.61 (s, 3H) ¹³C NMR (100 MHz, DMSOd₆) δ 197.36, 138.11 , 137.06, 138.08, 133.00, 130.73, 1 18.86, 112.62, 27.54

8: ¹H NMR (400 MHz, CDCI₃) δ 9.04 (s, 1 H) 8.54 (d, j=2.1 Hz, 1 H) 8.17 (d, J=4.7Hz, 1 H) 7.89 (m, 1 H) 7.68 (m, 1 H) 7.26 (s, 1 H). ¹³C NMR (I OO MHZ, CDCI₃) δ 149.97, 149.01 , 141.72, 133.02, 130.08, 128.74, 128.49, 126.42, 117.34, 106.80

Example 2

S-chloro-S-flS-chloro^-fmethyloxyJphenyllcarbonytybenzonitrile

Under a nitrogen atmosphere, a reactor was charged with (3-bromo-5- chlorophenyl)[5-chloro-2-(methyloxy)phenyl]methanone (1.0 wt, 1.0 eq) and zinc cyanide (0.20 wt, 0.60 equiv.), and 90% 1 ,2-dimethoxyethane/water (5 vol). The reactor contents were heated to approximately 80⁰C under nitrogen. A slurry of 1 ,1- bis(diphenylphosphino) ferrocene (DPPF, 0.01 wt, 0.0065 equiv) and palladium acetate (.0031 wt, .005 equiv.) in DME (0.15 vol) was added in a single portion and washed into reactor with additional DME (0.05 vol). PMHS (0.01 wt, 0.06 equiv) in DME (0.1 vol) was added in a single portion. The reaction was stirred at approximately 80⁰C for 2 hours. The second half of the catalyst, ligand, and PMHS was charged by adding a slurry of 1 ,1-bis(diphenylphosphino)ferrocene (DPPF, 0.01 wt, 0.0065 equiv) and palladium acetate (.0031 wt, .005 equiv.) in DME (0.15 vol) and washed into reactor with additional DME (0.05 vol). PMHS (0.01 wt, 0.06 equiv) in DME (0.1 vol) was added in a single portion. The reaction was allowed to heat at approximately 80⁰C for an additional two hours at which point remaining starting material is <1 % by standard LC method. The mixture was cooled to 20⁰C and a prepared solution of concentrated NH₄OH (1 vol), saturated aqueous NH₄CI (4 vol), and water (5 vol) was added at such a rate that internal temperature was maintained below 30⁰C. After stirring for 1 hour the reaction mixture was filtered through filter cloth and the reactor rinsed with water (2 vol) through the filter cake. The filter cake was then washed with additional water (4 X 2 vol) and suctioned dry. The resulting solid was placed back in the reactor and disolved in acetone (8 vol) with warming to 50° C. The contents were filtered through celite pad and washed with acetone (0.1 vol). The filtrate was maintained at 50° C and treated with water (0.9 vol) while maintaining solution. The reactor was cooled to 10⁰C over a one hour period and maintained at 10⁰C for 1 to 2 hours. The solids were then filtered through filter cloth and the cake rinsed with cold 9:1 acetone:water (2x1 vol). The solid was transferred to a drying oven and dried under vacuum at 50⁰C for 24 hours. ¹H NMR (400 MHz, DMSOd₆) δ 8.31 (s, 1 H) 8.02 (s, 1 H) 7.94 (s, 1 H) 7.63 (d, J=8.8Hz, 1 H) 7.45 (s, 1 H) 7.22 (d, J=9.0Hz, 1 H) 3.65 (s, 3H).

Claims

1. A process for the preparation of a compound of formula (I)

wherein m is 0 or 1 ; R² is selected from halogen, -CF₃, Ci_-8alkyl, Ci_-8alkylamino, Ci_-8 alkoxy, Cs-ecycloalkylC^ealkenyl, C_6-i₄arylC₂-6alkenyl, -CN, -NO₂, -NH₂, -SR⁶, - S(O)₂R⁶, -S(O)R⁷, -S(O)₂R⁷, -C(O)R⁷, -C(O)OR⁷, or N(H)C(O)R⁷; R⁶ is C_1-8alkyl, optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, -CF₃, aryl, and heterocycle; R⁷ is Ci_-8 alkyl, optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, aryl, C_3-6cycloalkyl and heterocycle; -NH₂, or heterocycle, comprising the steps of reacting a compound of formula (II)

wherein R¹ is a halogen, and R² and m are as defined with respect to formula (I), with at least one silyl hydride reagent in the presence of a palladium catalyst and a ligand to form the compound of formula (I).

2. The process according to claim 1 wherein the silyl hydride reagent is a silane.

3. The process according to claim 2 wherein the silane is alkylsilane.

4. The process according to claim 3 wherein the alkylsilane is triethylsilane.

5. The process according to claim 1 wherein the silyl hydride reagent is a siloxane.

6. The process according to claim 5 wherein the siloxane is polyalkylsiloxane.

7. The process according to claim 5 wherein the siloxane is polymethylhydrosiloxane.

8. The process according to any of claims 1-7 wherein the palladium catalyst is Pd(OAc)₂.

9. The process according to any of claims 1-7 wherein the palladium catalyst is Pd₂(dba)₃.

10. The process according to any of claims 1-7 wherein the palladium catalyst is PdCI₂.

11. The process according to any of claims 1-10 wherein the ligand is DPPF.

12. A process for the preparation of a compound of formula (I)

wherein m is 0 or 1 ; R² is selected from halogen, -CF₃, Ci_-8alkyl, Ci_-8alkylamino, Ci_-8 alkoxy, C₃-₆cycloalkylC_2-6alkenyl, C₆-i₄arylC_2-6alkenyl, -CN, -NO₂, -NH₂, -SR⁶, - S(O)₂R⁶, -S(O)R⁷, -S(O)₂R⁷, -C(O)R⁷, -C(O)OR⁷, or N(H)C(O)R⁷; R⁶ is C_1-8alkyl, optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, -CF₃, aryl, and heterocycle; R⁷ is Ci_-8 alkyl, optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, aryl, C_3-6cycloalkyl and heterocycle; -NH₂, or heterocycle, comprising the steps of reacting a compound of formula (II)

wherein R¹ is a halogen, and R² and m are as defined with respect to formula (I), with polymethylhydrosiloxane in the presence of a palladium catalyst and phosphine ligand to form a compound of formula (I).