Synthetic route for the preparation of α-amino boronic acid derivatives via substituted alk-1-ynes

1. A process for producing bortezomib N-(pyrazin-2-yl)carbonyl-L-phenylalanine-L-leucine boronic acid), comprising the steps of:

a) providing a compound of formula VI

wherein:

R 1 is isopropyl;

R 2 and R 3 cooperatively form a part of a 5-membered ring representing 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane;

X is a halogen selected from the group consisting of CI, Br and I; and

* indicates a chiral center;

wherein said process of providing said compound of formula VI comprises the steps of:

(i) providing a compound of formula V

wherein R 1 , R 2 , R 3 and X are defined as above;

(ii) converting said compound of formula V to compound of formula VI by hydrogenation, and

(iii) optionally applying enantiomeric resolution in order to obtain enantiomerically pure compound of formula VI;

b) converting said compound of formula VI to compound of formula VIII

wherein R 1 , R 2 and R 3 and R′ are defined as above;

A is an anion selected from the group of anions consisting of Cl − , Br − , HSO 4 − , CH 3 COO − , CF 3 COO − and R′SO 3 − , wherein R′ represents alkyl or aryl; and

* indicates a chiral center; or free amine thereof,

by a process comprising the steps of:

(i) converting the compound of formula VI to compound of formula VII

wherein R 1 , R 2 and R 3 are defined as above, and

PM is an amino group protecting moiety, wherein PM is selected from the group consisting of tert-butanesulfinyl, tosyl, p-nitrobenzenesulfonyl, carbobenzyloxy, t-butyloxycarbonyl, benzyl, p-methoxybenzyl, dimethoxybenzyl, p-hydroxybenzyl, 9-phenylfluoren-9-yl, fluorenyl, diphenylmethyl, ferrocenylmethyl and 4-methyltrityl, and x=1 and y=1, or PM is SiR″ 3 , wherein R″ represents alkyl and x=0 and y=2; and

* indicates a chiral center;

by substituting X of the compound of formula VI with a protected amino group, and

(ii) subjecting the compound of formula VII to cleavage of protection groups to yield the compound of formula VIII;

c) obtaining an enantiomerically pure compound of formula VIII by enantiomeric resolution,

d) converting the enantiomerically pure compound of formula VIII to a compound of formula XII:

by a process comprising the steps of either:

(i) coupling the enantiomerically pure compound of formula VIII with the compound of formula XI

 to give the compound of formula XII;

or

(i)′ coupling the enantiomerically pure compound of formula VIII with the compound of formula XIII

to give the compound of formula XIV

(ii)′ deprotecting the amino group moiety to yield the compound of formula XV

and,

(iii)′ coupling the compound of formula XV with a compound of formula XVI

to give the compound of formula XII; and

e) deprotecting the compound of formula XII to yield bortezomib.

2. The process according to claim 1 , wherein said hydrogenation is conducted in the presence of a catalyst, wherein said catalyst is a catalyst for homogeneous catalysis; and/or

wherein the catalyst is a complex comprising at least one transition metal.

3. The process according to claim 2 , wherein the ligands of said complex are at least one ligand containing electron-rich species with various double bonded compounds and/or free electron pair containing O, N, S, or P species, wherein transition metal 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.

4. The process according to claim 2 , wherein the catalyst is/are ligand(s) selected from the group consisting of (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′-tetramethoxy4,4′-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 adduct; (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.

5. The process according to claim 2 , wherein the transition metal is selected from the group consisting of Cu, Co, Ni, Rh, Ru, Pd and Ir.

6. The process according to claim 2 , wherein the catalyst is selected from the group consisting of (1,5-cyclooctadiene) (pyridine)(tricyclohexyl-phosphine)iridium(I)hexafluorophosphate; (1,5-cyclooctadiene)iridium(I)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(I)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 and (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(I)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; 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.

7. The process according to claim 2 , wherein dehalogenation is essentially avoided during hydrogenation, wherein dehalogenation occurs in less than 10 molar %, relative to the molar amount of compound of formula VI.

8. A process for producing a pharmaceutical composition comprising the steps of:

(i) preparing bortezomib N-(pyrazin-2-yl)carbonyl-L-phenylalanine-L-leucine-boronic acid) or ester or anhydride or salt thereof according to claim 7 , and

(ii) mixing said bortezomib with at least one excipient.