Process for Making Hydroisoindoline Tachykinin Receptor Antagonists

1 . A process of making hydroisoindoline tachykinin receptor antagonists of Formula (I)

and pharmaceutically acceptable salts thereof, wherein

R1 is selected from the group consisting of

(1) hydrogen

(2) C 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,

(3) cyclopentenone, which is unsubstituted or substituted with halogen, hydroxyl or methyl,

(4) —(CO)—C 1-6 alkyl,

(5) —(CO)—NH 2 ,

(6) —(CO)—NHC 1-6 alkyl, and

(7) —(CO)—N(C 1-6 alkyl)(C 1-6 alkyl);

X is independently selected from the group consisting of:

(1) hydrogen,

(2) fluorine, and

(3) methyl;

comprising:

Step (a) reacting a phenyl acetic acid of Formula (2)

with SOCl 2 in an aprotic solvent optionally in the presence of a first catalyst to provide a compound of Formula (3)

Step (b) reacting the compound of Formula (3) with NHMeOMe in the presence of an aqueous inorganic base to provide a Weinreb amide of Formula (4)

Step (c) reacting the Weinreb amid of Formula 4 with a suitable Grignard reagent in an second aprotic solvent followed by a first quenching with Ac 2 O and a second quenching with an aqueous inorganic acid to provide an enone of Formula (5)

Step (d) reacting the enone of Formula (5) with a silane reagent in a third aprotic solvent and an organic base to provide a diene of Formula (6)

Step (e) reacting a diene of Formula (6) with a fumarate of Formula (7)

wherein R is (−)-menthyl

and a Lewis acid in a non-polar solvent to provide a compound of Formula (8)

Step (f) hydrolyzing a compound of Formula (8) with suitable hydrolysis reagents in an organic polar solvent to provide a compound of Formula (9)

Step (g) reducing the ketone functionality of the compound of Formula (9) with a first reducing agent, followed by reduction of CO 2 R with a second reducing agent in an aprotic solvent to provide a triol of Formula (10)

Step (h) reacting the triol of Formula (10) with an alkylsulfonyl chloride in the presence of an organic base to provide a compound of Formula (11)

wherein R 2 is methyl, ethyl or propyl,

Step (i) reacting the compound of Formula (11) with compound of Formula (12)

in the presence of an acid catalyst in an aprotic solvent to produce a compound of Formula (13)

Step (j) cyclizing the compound of Formula (13) with allylamine in a polar solvent to provide a compound of Formula (14)

Step (k) reacting the compound of Formula (14) with third catalyst followed by addition of acid to provide a compound of Formula (15)

optionally as an acid salt;

Step (l) reacting the acid salt of the compound of Formula (15) with a functionalizing reagent in a polar solvent to provide the compound of Formula (I)

2 . A process according to claim 1 , wherein the compound of Formula (I) is

3 . A process according to claim 1 wherein

Steps (a) and Step (b) is carried out in a single pot without intermediate isolation.

4 . A process according to claim 1 wherein

in Step (a) the aprotic solvent is toluene or benzene; and the first catalyst is Di-methylformamide;

in Step (c) the second aprotic solvent is THF or Methyl-t-butyl ether or a mixture of toluene and THF; the Grignard reagent is vinyl magnesium or vinyl magnesium bromide;

in Step (d) the silane reagents is chlorotriethylsilane, chlorotrimethylsilane, or t-butyldimethylchlorosilane; the organic base is triethylamine, ethyldiisopropylamine, or DBU; the solvent is THF, MeCN, toluene, benzene or ether or a mixture thereof;

in Step (e), the Lewis acid catalysts is Et 2 AlCl, iBu 2 AlCl, or EtAlCl 2 ; the solvent is toluene, methylene chloride, 1,2-dichloroethane, or benzene;

in Step (f) the hydrolysis agents is aqueous HCl, HBr, HF, or HI; the solvent is MeCN or THF;

in Step (g) the first reducing agent is LiAl(OtBu) 3 H or NaBH 4 ; the second reducing agent is LiAlH 4 and LiBH 4 ; the solvent is THF or diglyme;

in Step (h), the alkanesulfony chlorides is propanesulfonyl chloride, ethanesulfonyl chloride, or methanesulfonyl chloride; the organic base is 2,4,6-collidine, ethyldiisopropylamine, tetramethylpiperidine, pentamethylpiperidine, 2,6-lutidine, or triethylamine; the solvent is MeCN, THF, methylene chloride, EtOAc, or iProAc, 1,2-dichloroethane;

in Step (i) the acid catalyst is HBF 4 , BF 3 , or CF 3 SO 3 H; the solvent is methylene chloride, 1,2-dichloroethane, toluene, trifluorotoluene, cyclohexane;

in Step (j) the solvent is 2-propanol, MeOH, EtOH or i-PrOAc;

in Step (k) the solvent is THF or MTBE; and

in Step (l) the solvents is 2-propanol or toluene and the functionalizing reagent is

an alkyl(aryl)halide, an alkyl(aryl)triflate, a dialkyl(aryl)carbonic anhydride, an acyl halide, an alkyl(aryl)chloroformate, alkyl(aryl)sulfonylhalide, a haloaklyl(aryl)sulfonylhalide, an alkanoyl halide, a benzylic halide, a halo-CON(alkyl or aryl)2, an alkyl(aryl) aldehyde or ketone in the presence of a reducing agent, or sulfonylate.

5 . A process of making a compound of Formula (I) comprising:

and pharmaceutically acceptable salts thereof, wherein

R1 is selected from the group consisting of

(1) hydrogen

(2) C 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,

(3) cyclopentenone, which is unsubstituted or substituted with halogen, hydroxyl or methyl,

(4) —(CO)—C 1-6 alkyl,

(5) —(CO)—NH 2 ,

(6) —(CO)—NHC 1-6 alkyl, and

(7) —(CO)—N(C 1-6 alkyl)(C 1-6 alkyl);

X is independently selected from the group consisting of:

(1) hydrogen,

(2) fluorine, and

(3) methyl;

comprising

optionally as an acid salt;

Step (l) reacting the acid salt of the compound of Formula (15)

with a functionalizing agent in a polar solvent to provide the compound of Formula (I)

6 . A process according to claim 5 , wherein the compound of Formula (I) is

7 . A process according to claim 5 comprising

Step (k) reacting the compound of Formula (14)

with third catalyst followed by addition of acid to provide a compound of Formula (15)

optionally as an acid salt;

Step (l) reacting the acid salt of the compound of Formula (15) with an alkylating reagent? in a polar solvent to provide the compound of Formula (I)

8 . A process according to claim 7 comprising

Step (j) cyclizing the compound of Formula (13)

wherein R 2 is methyl, ethyl or propyl,

with allylamine in a polar solvent to provide a compound of Formula (14)

Step (k) reacting the compound of Formula (14) with third catalyst followed by addition of acid to provide a compound of Formula (15)

as an acid salt;

Step (l) reacting the acid salt of the compound of Formula (15) with a functionalizing reagent in a polar solvent to provide the compound of Formula (I)

9 . A process according to claim 8 comprising

Step (i) reacting the compound of Formula (11) with compound of Formula (12)

in the presence of an acid catalyst in an aprotic solvent to produce a compound of Formula (13)

Step (j) cyclizing the compound of Formula (13) with allylamine in a polar solvent to provide a compound of Formula (14)

Step (k) reacting the compound of Formula (14) with third catalyst followed by addition of acid to provide a compound of Formula (15)

as an acid salt;

Step (l) reacting the acid salt of the compound of Formula (15) with a functionalizing reagent in a polar solvent to provide the compound of Formula (I).

10 . A process according to claim 9 wherein

in Step (i) the acid catalyst is HBF 4 , BF 3 , or CF 3 SO 3 H; the solvent is methylene chloride, 1,2-dichloroethane, toluene, trifluorotoluene, cyclohexane;

in Step (j) the solvent is 2-propanol, MeOH, EtOH or i-PrOAc;

in Step (k) the solvent is THF or MTBE; and

in Step (l) the solvents is 2-propanol or toluene.

11 . A process of making a compound of Formula 13

wherein R 2 is methyl, ethyl or propyl,

Step (i) reacting the compound of Formula (11)

with compound of Formula (12)

in the presence of an acid catalyst in an aprotic solvent to produce a compound of Formula (13).

12 . A process according to claim 11 wherein R 2 is propyl,

the acid catalyst is HBF 4 , BF 3 , or CF 3 SO 3 H; and the solvent is methylene chloride, 1,2-dichloroethane, toluene, trifluorotoluene or cyclohexane.

13 . A process of making a compound of Formula 14

comprising:

Step (j) cyclizing the compound of Formula (13)

wherein R 2 is methyl, ethyl or propyl,

with allylamine in a polar solvent to provide a compound of Formula (14).

14 . A process according to claim 13 wherein

R2 is propyl, and

in Step (j) the solvent is 2-propanol, MeOH, EtOH or i-PrOAc.