# US 8,785,674 B2 · Process for hydrogenation of halogenoalkenes without dehalogenation

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- Number: US 8,785,674 B2
- Document ID: US8785674B2
- Status: Granted
- Kind: B2
- Application number: 13/379,171
- Filed: 2010-06-18
- Published: 2012-08-30
- Granted: 2014-07-22
- Earliest claimed: 2009-06-19
- Assignees: Lek Pharmaceuticals D.D.
- Applicants: Ivana Gazic Smilovic; Zdenko Casar
- Inventors: Ivana Gazic Smilovic; Zdenko Casar
- Web page: https://patentgrep.com/patent/US8785674B2

## CPC

- C07F 5/025: {Boronic and borinic acid compounds}
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

A process for preparing a compound of formula VI wherein R1 and R6 is hydrogen, substituted or unsubstituted alkyl substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; R5 is B(OR2)(OR3), or wherein R2 and R3 independently from each other represent substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; or R2 and R3 cooperatively form a part of a 5- to 10-membered fused or unfused ring, optionally a chiral 5- to 10-membered fused or unfused ring; X is selected from Cl, Br, I; and * indicates a chiral center; is described.

## Claims

### Claim 1

A process for preparing a compound of formula VI
wherein
R1 and R6 is hydrogen, substituted or unsubstituted alkyl substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
R5 is B(OR2)(OR3);
wherein R2 and R3 independently from each other represent substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; or R2 and R3 cooperatively form a part of a 5- to 10-membered fused or unfused ring, optionally a chiral 5- to 10-membered fused or unfused ring;
X is selected from Cl, Br, I; and
* indicates a chiral center;
by hydrogenation of a compound of formula V
wherein R1, R5, R6 and X are as defined above;
wherein hydrogenation is conducted in the presence of a catalyst selected from complexes comprising at least one transition metal, and said catalyst is used at a molar substrate to catalyst ratio in the range of 5:1 to 100:1, and wherein dehalogenation occurs in less than 10 molar % relative to the molar amount of the compound of formula VI.

### Claim 2 (depends on 1)

The process according to claim 1, wherein R1 or/and R6 is/are (independently from each other) selected from hydrogen or a group consisting of substituted or unsubstituted linear C1-C5-alkyl, substituted or unsubstituted branched C1-C5-alkyl and substituted or unsubstituted C3-C8-cycloalkyl, preferably R1 or/and R6 is/are (independently from each other) selected from hydrogen or unsubstituted linear or branched C1-C5-alkyl, more preferably R1 and/or R6 is/are hydrogen or isopropyl; and/or wherein either R1 or R6 is hydrogen, preferably R6 is hydrogen; and/or wherein R2 and R3 are selected from a group consisting of linear substituted or unsubstituted C1-C5-alkyl, substituted or unsubstituted branched C1-C5-alkyl, or R2 and R3 form a part of a 5- to 10-membered fused or unfused ring, optionally a chiral 5- to 10-membered fused or unfused ring; wherein R2 and R3 cooperatively form a part of a 5-membered ring representing 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane.

### Claim 3 (depends on 1)

The process according to claim 1, wherein said catalyst is a catalyst for homogeneous catalysis; and/or
wherein said the catalyst comprises at least one ligand containing electron-rich species such as various double bonded compounds and/or free electron pair containing O, N, S, or P species.

### Claim 4 (depends on 1)

The process according to claim 1, wherein the catalyst has chirality in the ligand and/or at the transition metal atom, or the transition metal complex having chirality is formed in situ by using an achiral procatalyst comprising the transition metal together with a cocatalyst having chirality, preferably, the chiral components selected from ligand(s) and/or transition metal atom(s) or transition metal catalyst formed in situ are in enantiontiopure or diastereomerically pure form, more preferably, at least one of said ligands has chirality, wherein said ligand(s) is/are in enantiopure or diasteriomerically pure form.

### Claim 5 (depends on 1)

The process according to claim 1, wherein the catalyst comprises ligand(s) selected from (S)-2-(1-(bis(2,6-dimethylphenyl)phosphino)-2-methylpropan-2-yl)-4-tert-butyl-4,5-dihydrooxazole; (S)-4-tert-butyl-2-(2-(diphenylphosphino)phenyl)-4,5-dihydrooxazole; (4S,5S)-4-(2-(dicyclohexylphosphinooxy)-1,3-diphenylpropan-2-yl)-5-methyl-2-phenyl-4,5-dihydrooxazole; (R,R)-P,N-ferrocene oxazoline; (R,R)-P,N-ferrocene imidazoline; Benzoyl-(R,R)-P,N-ferrocene imidazoline; (R)-(+)-2,2′,6,6′-tetramethoxy-4,4′-bis(diphenylphosphino)-3,3′-bipyridine; (S)-2,2′,6,6′-tetramethoxy-bis[di(3,5-dimethylphenyl) phosphino]-3,3′-bipyridine; (R)-4,12-bis(diphenylphosphino)-[2.2]-paracyclophane; 1-(S)—N-methyl-N-(diphenyl-phosphino)-1-[(R)-(diphenylphosphino)-ferrocenyl]ethylamine; (R)-2-(1-naphthyl)-8-diphenylphosphino-1-(S)-3,5-dioxa-4-phosphacyclohepta[2,1-1;3,4-a′]di-naphthalen-4-yl)-1,2-dihydroquinoline toluene aduct; (S)-(+)-4,12-bis[di(3,5-dimethylphenyl)phosphino]-[2.2]paracyclophane; (R)-2,2′-bis(diphenyl-phosphinoamino)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl; preferably, the ligand(s) are selected from (S)-2-(1-(bis(2,6-dimethylphenyl)phosphino)-2-methylpropan-2-yl)-4-tert-butyl-4,5-dihydro-oxazole; (S)-4-tert-butyl-2-(2-(diphenylphosphino)phenyl)-4,5-dihydrooxazole, (4S,5S)-4-(2-(dicyclohexyl-phosphinooxy)-1,3-diphenylpropan-2-yl)-5-methyl-2-phenyl-4,5-dihydrooxazole, (R,R)-P,N-ferrocene oxazoline, (R,R)-P,N-ferrocene imidazoline and benzoyl-(R,R)—P,N-ferrocene imidazoline.

### Claim 6 (depends on 1)

The process according to claim 1, wherein at least one transition metal of the catalyst is selected from the group consisting of Cu, Co, Ni, Rh, Ru, Pd and Ir.

### Claim 7 (depends on 1)

The process according to claim 1, wherein the catalyst is selected from the group consisting of (1,5-cyclooctadiene) (pyridine)(tricyclohexyl-phosphine) iridium(1) hexafluorophosphate; (1,5-cyclooctadiene)iridium(1)tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (S)-2-(1-(bis(2,6-dimethylphenyl)phosphino)-2-methylpropan-2-yl)-4-tert-butyl-4,5-dihydrooxazole; (1,5-cyclooctadiene)iridium(I)tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (S)-4-tert-butyl-2-(2-(diphenylphosphino)phenyl)-4,5-dihydro-oxazole; (1,5-cyclooctadiene)iridium(I)tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (4S,5S)-4-(2-(dicyclohexylphosphinooxy)-1,3-diphenylpropan-2-yl)-5-methyl-2-phenyl-4,5-dihydrooxazole; (1,5-cyclooctadiene)iridium(1)tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (R,R)-P,N-ferrocene oxazoline; (1,5-cyclooctadiene)iridium(I)tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (R,R)-P,N-ferrocene imidazoline, (1,5-cyclooctadiene)iridium(I)tetrakis[3,5-bis-(trifluoromethyl)phenyl]borate benzoyl-(R,R)—P,N-ferrocene imidazoline, bis(1,5-cyclooctadiene)diiridium(I)dichloride(R)-(+)-2,2′,6,6′-tetramethoxy-4,4′-bis(diphenylphosphino)-3,3′-bipyridine, bis(1,5-cyclooctadiene)diiridium(1)dichloride (S)-2,2′,6,6′-tetramethoxy-bis[di(3,5-dimethylphenyl)phosphino]-3,3′-bipyridine; bis(1,5-cyclooctadiene)dirhodium (I)dichloride (S)-2,2′,6,6′-tetramethoxy-bis[di(3,5-dimethylphenyl) phosphino]-3,3′-bipyridine; bis(cycloocta-1,5-diene)rhodium(I)tetrafluoroborate (R)-4,12-bis(diphenylphosphino)-[2.2]-paracyclophane; and benzeneruthenium(II)dichloride dimer 1-(S)—N-methyl-N-(diphenylphosphino)-1-[(R)-(diphenylphosphino)-ferrocenyl]ethylamine and bis(2-methylallyl)(1,5-cyclooctadien)ruthenium (II) (S)-(+)-4,12-bis[di(3,5-dimethylphenyl)phosphino]-[2.2]paracyclophane.

### Claim 8 (depends on 1)

The process according to claim 1, wherein hydrogenation is carried out at a temperature from about 10° C. to 80° C., and/or
wherein hydrogenation is carried out at a pressure of hydrogen of about 5 to 20 bar; and/or
wherein the reaction time is about 1 to 20 days; and/or
wherein a solvent for the halogenation reaction is selected from the group consisting of THF, CH2Cl2, 1,2-dichloroethane and toluene.

### Claim 9 (depends on 1)

The process according to claim 1, wherein the dehalogenation occurs in less than 5 molar %, relative to the molar amount of the compound of formula VI.

### Claim 10 (depends on 1)

The process according to claim 1 further comprising formulating the compound of formula VI with pharmaceutically acceptable excipients into a pharmaceutically active compound.

### Claim 11 (depends on 6)

The process according to claim 6, wherein at least one transition metal of the catalyst is selected from the group consisting of Rh, Ru, Pd and Ir.

### Claim 12 (depends on 11)

The process according to claim 11, wherein at least one transition metal of the catalyst is selected from the group consisting of Ru and Ir.

### Claim 13 (depends on 12)

The process of claim 12, wherein said metal of the catalyst is Ir.

### Claim 14 (depends on 8)

The process according to claim 8, wherein hydrogenation is carried out at a temperature from about 45° C. to 55° C., wherein the reaction time is about 10 days.

### Claim 15 (depends on 14)

The process of claim 14, wherein hydrogenation is carried out at a temperature of about 50° C.

### Claim 16 (depends on 9)

The process according to claim 9, wherein the dehalogenation occurs in less than 3 molar % relative to the molar amount of the compound of formula VI.

### Claim 17 (depends on 16)

The process according to claim 16, wherein the dehalogenation occurs in less than 1 molar % relative to the molar amount of the compound of formula VI.