ASYMMETRIC HYDROGENATION OF ENAMIDES

SUMMARY OF THE INVENTION The present invention relates to a process for the efficient preparation of enantiomerically enriched acyl amine derivatives. The product chiral acyl amine derivatives are frequent constituents of drug candidates and are also useful in the asymmetric synthesis of other biologically active molecules. The process comprises an enantioselective hydrogenation of a prochiral enamide in the presence of a rhodium metal precursor complexed with a chiral mono- or bidentate phosphine ligand.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention provides a process for the preparation of acyl amines of formula I:

enantiomerically enriched at the carbon atom marked with an *; wherein

Y is N or CH;

Rl and R2 are independently selected from H, halogen, Ci_4alkyl, OH, OCi_4alkyl, OSO2CH3, OSO2CF3, NO2, and phenyl optionally substituted with 1 to 3 substituents independently selected from

CN, halogen, Ci_4alkyl optionally substituted with 1 to 5 halogen atoms, OH, OCi_4alkyl, CO2-

Ci_4alkyl, and OCi_4alkyl optionally substituted with 1 to 5 halogen atoms; and

R3 is C(O)H, C(O)C i-4alkyl optionally substituted with 1 to 5 halogen atoms, C(O)aryl, C(O)CH2-aryl,

C(0)0-Ci-ioalkyl, C(O)O-aryl; or C(O)OCH2-aryl; which comprises hydrogenating in the presence of hydrogen gas a prochiral enamide of formula II:

(H)

in a suitable organic solvent in the presence of a rhodium metal precursor complexed to a chiral mono- or bidentate phosphine ligand.

In one embodiment of the process the phosphine ligand is selected from ROPHOS (R = H, Me, Et), BINAPINE, Malphos (or catASium when X = O) and NMe-Malphos (or catASium MN when X = N-Me), alk-Butiphane, CARBOPHOS, alk-DuPHOS, alk-BPE, Ph-BPE, BisP (R' = t-butyl, 1,1- diethylpropyl, adamantyl, isopropyl, 1-methylcyclohexyl, cyclohexyl, cyclopentyl and isopropyl), BICP, DiPamp, alk-FerroTane, (l,2-diethylphospholanyl)ferrocene, TangPhos, Binaphane, Josiphos and Me- ketalphos, wherein alk is Ci_4alkyl, Me is methyl, Et is ethyl and Ph is phenyl. Structures of the ligands are as shown below.

NMe-Malphos (X = N-Me)

Phos

In another embodiment the acyl amine and the enamide have the formulas (Ia) and (Ha), respectively.

³

(Ia) (Ha)

In one subset of this embodiment R.2 is F. In another subset, R3 is C(O)-C i_4alkyl. In yet another subset Rl is Br, R2 is F, and R3 is C(O)-C i_4alkyl.

In another embodiment Y of the compounds of formula (I) and (II), and (Ia) and (Ila) is CH and the phosphine ligand is selected from alk-DuPhos, alk-BPE, BINAPHANE, TangPhos, Josiphos, DiPamp, Me-Ketalphos, and alk-Butiphane. In one subset of this embodiment R3 is C(O)C i_4alkyl, and the phosphine ligand is selected from alk-DuPhos, alk-BPE, Tangphos, DiPamp, Me-ketalphos and alk- Butiphane; in another subset R3 is C(O)C i-4alkyl and the phosphine ligand is selected from N-Me- DuPhos, Me-BPE, Tangphos and Me-ketalphos. In yet another subset, R3 is C(O)OC i_4alkyl, and the phosphine ligand is selected from Me-DuPhos, Et-DuPhos, Me-BPE, Tangphos, BINAPHANE, Josiphos, and diPamp.

In another embodiment Y of the compounds of formula (I) and (II), and (Ia) and (Eta) is N and the phosphine ligand is selected from Rophos, BINAPINE, malphos, CARBOPHOS, DuPhos, BPE, BisP, DiPamp, and Ferrotane. In one subset R3 is C(O)C i_4alkyl, and the phosphine ligand is selected from Tangphos, Rophos, BINAPINE, malphos, N-Me-malphos, iPr-Butiphane, CARBOPHOS, iPr-Duphos, Me-BPE, Et-BPE, Ph-BPE, Me-DuPhos, Et-DuPhos, l,2-(diethylphospholanyl)ferrocene, BisP, DiPamp and Et-Ferrotane, where Me is methyl, iPr is isopropyl, Et is ethyl, Ph is phenyl..

In another embodiment the process provides for the preparation of a compound of formula (Ib), which comprises hydrogenating in the presence of hydrogen gas a prochiral compound of

formula (lib) in a suitable organic solvent in the presence of a rhodium metal precursor complexed to a chiral mono- or bidentate phosphine ligand, wherein said phosphine ligand is selected from Me-DuPhos, Me-BPE, Tangphos and Me-ketalphos.

(Ib) (Hb)

In another embodiment the process provides for the preparation of a compound of formula (Ic), which comprises hydrogenating in the presence of hydrogen gas a prochiral compound of formula (lie) in a suitable organic solvent in the presence of a rhodium metal precursor complexed to a chiral mono- or bidentate phosphine ligand, wherein said phosphine ligand is selected from Tangphos, Rophos, BINAPINE, N-Me-malphos, CARBOPHOS, Me-BPE, Me-DuPhos, Et-DuPhos, and BisP.

(Ic) (Hc)

The process of the present invention contemplates that the catalytic complex of the rhodium metal precursor and the chiral phosphine ligand may be either (a) generated in situ by the sequential or contemporaneous addition of the rhodium metal precursor and chiral phosphine ligand to the reaction mixture or (b) pre-formed with or without isolation and then added to the reaction mixture. The asymmetric hydrogenation reaction of the present invention is carried out in a suitable organic solvent. Suitable organic solvents include lower alkanols, such as methanol, ethanol, and isopropyl alcohol; 2,2,2-trifluoroethanol (TFE); hexafluoroisopropyl alcohol; ethers such as tetrahydrofuran and methyl f-butyl ether; esters such as ethyl acetate and isopropyl acetate; aromatic and non-aromatic hydrocarbons such as hexane, heptane, benzene, and toluene; halogenated hydrocarbons such as dichloromethane; and mixtures thereof. The reaction temperature for the reaction may be in the range of about -50 ⁰ C to about

120 ⁰ C. A suitable temperature range for the reaction is about 0 ⁰ C to about 65 °C.

The hydrogenation reaction can be performed at a hydrogen pressure range of about 0 psig to about 1000 psig. A suitable hydrogen pressure range is about 20 psig to about 200 psig.

The rhodium metal precursor is [Rh(monoolefϊn)2X]2, [Rh(diene)X]2, [Rh(monoolefin)2acetylacetonate], [Rh(diene)acetylacetonate], [Rh(monoolefm)4]X, or [Rh(diene)2]X wherein X is an anion selected from halogen, methanesulfonate, trifluoromethanesulfonate (OTf), tetrafluoroborate (BF4), hexafluorophosphate (PFg), hexafluoroantimonate (SbFo) or BARF

(tetrakis(3,5-bis(trifluoromethyl)phenyl)borate. In one embodiment the rhodium metal precursor is [Rh(cod)Cl]2, [Rh(norbornadiene)Cl]2, [Rh(cod)2]X, or [Rh(norbornadiene)2]X, wherein cod = 1,5- cyclooctadiene. In a subset of this embodiment, the rhodium metal precursor is [Rh(cod)2]X. The ratio of rhodium metal precursor to substrate is about 0.01 to about 10 mol %. A suitable ratio of the rhodium metal precursor to the substrate is about 0.05 mol % to about 0.4 mol %. A second aspect of the present invention provides a process for the preparation of an enamide of formula (II) which comprises reaction an aryl nitrile of formula (III)

(III)

with a methylating agent selected from methylmagnesium bromide, methylmagnesium chloride, methyllithium and methyllithium-lithium bromide complex, in a suitable organic solvent and in the presence of R3-C1 or (R3)2θ, wherein Rl, R2 and R^ are as defined above. Suitable solvents for the reaction are for examples ethers such as ethyl ether, methyl t-butyl ether, aromatic hydrocarbons such as toluene, and mixtures thereof. The reaction may be carried out from about -50 ⁰ C to about 25°C.

Throughout the instant application, the following terms have the indicated meanings: The term "% enantiomeric excess" (abbreviated "ee") shall mean the % major enantiomer less the % minor enantiomer. Thus, a 70% enantiomeric excess corresponds to formation of 85% of one enantiomer and 15% of the other. The term "enantiomeric excess" is synonymous with the term "optical purity."

The process of the present invention provides compounds of structural foπnula I with high optical purity, typically in excess of 50% ee. In one embodiment, compounds of formula I are obtained with an optical purity in excess of 70% ee. In a class of this embodiment, compounds of

formula I are obtained with an optical purity in excess of 80% ee. In a subclass of this class, compounds of formula I are obtained with an optical purity in excess of 90% ee.

The term "enantioselective" shall mean a reaction in which one enantiomer is produced (or destroyed) more rapidly than the other, resulting in the predominance of the favored enantiomer in the mixture of products.

The alkyl groups specified above are intended to include those alkyl groups of the designated length in either a straight or branched configuration. Exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, and the like. The term "halogen" is intended to include the halogen atoms fluorine, chlorine, bromine, and iodine.

The term "aryl" includes phenyl or naphthyl. Unless specified, "aryl" is unsubstituted or substituted with one to five substituents independently selected from phenyl, halogen, hydroxy, amino, carboxy, Cχ_4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylsulfonyl, and Cμ4 alkyloxycarbonyl, wherein the alkyl moiety of each is unsubstituted or substituted with one to five fluorines.

Representative experimental procedures utilizing the novel process are detailed below. The following Examples are for the purposes of illustration only and are not intended to limit the process of the present invention to the specific conditions for making these particular compounds.

REFERENCE EXAMPLE

1. N-[I -(5-Bromo-3 -fluoropyridin-2-yl)vinyl] acetamide

Step 1. 2,5-Dibromo-3-nitropyridine.

2-Hydroxy-3-nitro-5-bromopyridine (1 eq) was suspended in toluene (3 vol) and N ₁ N- dimethylformamide (DMF, 0.1 eq) was added. The mixture was protected from light. A solution of phosphorus oxybromide (1.2 eq) in toluene (2 vol) was added to the pyridine mixture over 1.5 h at about 90 ⁰ C and the reaction was aged for about 14 h at 90 ⁰ C. The reaction mixture was cooled to room temperature and water (10 vol) and toluene (5 vol) were added. The layers were cut and the organic layer was washed with IN NaOH (2 x 10 vol) and H2O (5 vol). The batch was concentrated under reduced pressure to yield the desired product.

Step 2. 5-Bromo-3-nitropyridine-2-carbonitrile.

The compound of Step 1 (1 eq) was suspended in propionitrile (3 vol). Copper cyanide (1.1 eq) was added and the mixture was heated to 90 ⁰ C and aged for about 17 h. The reaction mixture was cooled to room temperature and isopropyl acetate (12 vol) and saturated brine (8 vol) were added.

The mixture was stirred for 15 min and the layers were cut. The top organic layer was washed with brine (4 x 6 vol). The batch concentrated under reduced pressure to yield the desired product.

Step 3. 5-Broino-3-fluoropyridine-2-carbonitrile. Sulfuric acid (0.02 eq) was added to a solution of tetrabutylammonium fluoride (3 eq) in

DMF (5 vol) and the mixture cooled to -40 ⁰ C. A solution of the compound of Step 2 (1 eq) in DMF (2 vol) was added maintaining the temperature < -35 ⁰ C. After about 20 minutes 2N HCl (3 vol) was added followed by IN HCl (15 vol). The precipitated product was collected by filtration to give the desired product.

Step 4. N-[l-(5-Bromo-3-fluoropyridin-2-yl)vinyl]acetamide.

Compound of Step 3 (1 eq) was dissolved in toluene (10 vol). The batch was cooled to - 10 ⁰ C and MeMgCl (1.5 eq) was added maintaining the temperature < 0 ⁰ C. The mixture was aged for 1 h and acetic anhydride was added over approximately 30 min maintaining the temperature <0 ⁰ C. The reaction was aged for 18 h at -10 ⁰ C. The mixture was quenched with half-saturated ΝaHC03 (6 vol) and aged at 20-25 ⁰ C for 30 min. The layers were separated and the organic layer was washed with water (5 vol), 10% aqueous Na2SO4 (2 x 5 vol) and water (2 x 5 vol). The batch was concentrated under vacuum to give the title compound.

2. N-[l-(4'-Bromo-2'-fluorophenyl)vinyl]acetamide

To a solution of 4-bromo-2-fluorobenzonitrile (1.0 eq) in methyl t-butyl ether (MTBE, 200 g/L) at room temperature methylmagnesium bromide (1.1 eq, 1.4 M in toluene/tetrahydrofuran) was slowly charged while maintaining a maximum temperature of <35 ⁰ C. The solution was aged for 2.5 hours at room temperature. The reaction was re-cooled to -10 °C, and added to a solution of 2.5 M acetic anhydride in MTBE (2.0 eq) while maintaining the internal temperature <-5 ⁰ C. The reaction was aged for 2 hours at -10 ⁰ C; the resulting yellow slurry was added to 1.0 M acetic acid solution (1.0 eq) that was pre-cooled to 0 ⁰ C. After separation, the organic layer was washed with 1 M acetic acid and Na2SO4 (1% aqueous), and stirred over KOH (2M, 12 h). The organics were separated and washed with Na2SO4 (1% aqueous). The organic stream was concentrated to approximately 100g/L and was seeded with authentic enamide product. After a seed bed was maintained, the slurry was further concentrated while adding toluene until a final solvent composition of 2:1 heptane/toluene was reached with a 2-5 g/L supernatant concentration. Filtration of the slurry and washing with 4:1 heptane/toluene afforded the title compound.

EXAMPLE 1

iV-r(li?)-l-f5-Bromo-3-fluoropyridin-2-yl)ethyllacetamide

In a nitrogen filled glovebox (<10 ppm O2), (S,S,R,R)-Tangphos (1.05 equivalents relative to Rh) was combined with (COD)2RhBF4 and dissolved in methanol to make a solution that was

0.107M in Rh. The catalyst solution was aged for Ih.

In an nitrogen filled glovebox the catalyst solution (((S,S,R,R)-Tangphos)Rh(COD)BF4,

0.00284 eq, S/C = 352) was transferred to a stainless steel cylinder (see figure) along with methanol rinse (1 volume). To a separate stainless steel cylinder an additional charge of methanol (1 volume) was added. These two cylinders were connected via a ball-valve (see figure).

connect here to autoclave via flexible hosing

MeOH rinse catalyst solution

The enamide of Reference Example 1 (54 wt% in MeOH) was drawn into a stirred autoclave via vacuum followed by a methanol (10 mL/g enamide) rinse. The solution was then degassed with nitrogen (3 X). The stainless steel vessels containing the catalyst solution were connected to the autoclave via flexible tubing. The autoclave was placed under partial vacuum and the catalyst solution was drawn into the autoclave followed by the MeOH rinse. The solution was degassed with H2 (100 psig) 3X and the final pressure adjusted to 20 psig. The reaction temperature was set to 25 ⁰ C and agitation initiated. The reaction pressure was increased to 98 psig after 20 minutes. The mixture was hydrogenated for an additional 4h. Enantiomeric excess was 99.5%.

The batch was removed from the autoclave and concentrated under vacuum and solvent switched to isopropyl acetate (IPAc) to a final concentration of 10 mL/g. The IPAc solution was filtered through silica gel (300 wt%), and washed with 1 volume of BPAc. Darko KB-B (50 wt%) was added and

the mixture aged for 16 h at 20-25 ⁰ C. The batch was filtered through Solka Floe and the cake washed with IPAc (1.1 volumes). The batch was concentrated under vacuum to give the title compound.

EXAMPLE 2 N-rriiZVl-^-Bromo-Σ-fluorophenvDethvnacetamide

A solution of Rh(COD)2θTf (0.34 mol %) and degassed isopropyl alcohol (IPA, 0.05 M) was aged for 10 min followed by the slow addition of (-)-l,2-bis((2i?,5i?j-2,5-dimethylphospholano)- ethane (0.37 mol %) and the mixture was then aged overnight.

A stirred autoclave was charged with a solution of enamide of Reference Example 2 (1 eq) in IPA (6 vol) and this was repeatedly pressurized with nitrogen, followed by evacuation (3 times).

The catalyst solution was added to the autoclave under an inert atmosphere. The autoclave was sealed and vacuum/Ν2-purged again (three times). Without agitation, the vessel was pressure-purged with H2

(three times). The vessel was pressurized to 40 psig H2 and agitation was started. The reaction was aged

2.5 h. Enantiomeric excess was 96 - 97%.

In a 72-L round-bottom flask, the crude acetamide streams were combined. The vessel was purged with nitrogen before Darco G-60 (33 wt% based on enamide) was added. The contents were heated to 50 ⁰ C for 6 hours, cooled to room temperature, and the slurry was then filtered through solka floe. The product stream was clarified by passing through a 5μ in-line filter, concentrated to 280 g/L, and then heated to 65 ⁰ C. Water was slowly added (0.75 batch volumes), cooled to room temperature, additional H2O was added (0.5 batch volume), and the resulting slurry was cooled to 2.5 ⁰ C. The crystalline title compound was filtered and washed with water/TPA (4:1) with a typical mother liquor loss of 4-6%.