Synthesis of (2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile

1. A process for preparing the L-malic acid salt of a compound of formula (I),

comprising the steps of:

(a) treating a compound of formula (XVIII) wherein X 2 is Cl, Br, I, methanesulfonate or p-toluenesulfonate, with a compound of formula (XIX) or salts thereof wherein P 1 is an acid protecting group, potassium iodide, and milled potassium phosphate, in an aprotic organic solvent, to provide a compound of formula (XX)

(b) treating the compound of formula (XX) with D-tartaric acid in a 1:1 ratio to provide the D-tartrate salt of the compound of formula (XX);

(c) deprotecting the D-tartrate salt of step (b) to provide a compound of formula (I); and

(d) treating an aqueous solution of the compound of formula (I) with a C 1-6 alcoholic solution of L-malic acid in a 1:1.1 ratio to form the L-malic acid salt of the compound of formula (I);

wherein the compound of formula (XVIII) is prepared by a process comprising:

(a)

(i) asymmetric reduction of a compound of formula to a compound of formula (XXXVII), wherein P 2 is an amine-protecting group, R 1 is an acid protecting group, and R 2 is C 1-6 alkyl

(ii) activating the compound of formula (XXXVII) to provide a compound of formula (XXXVIII), wherein R 4 is trihaloacetyl, methanesulfonyl, benzenesulfonyl or p-toluenesulfonyl

(iii) deprotecting and cyclizing the compound of formula (XXXVIII) to provide a compound of formula (XXXVI) or salt thereof

(iv) saponifying a compound of formula (XXXVI) or salts thereof to provide a compound of formula (XXXIX), wherein R 1 is an acid protecting group and R 2 is C 1-6 alkyl

(v) treating the compound of formula (XXXIX) or salts thereof with a reagent having formula X 2 CH 2 COY 2 to provide a compound of formula (XL), wherein X 2 and Y 2 are independently Cl or Br

(vi) treating the compound of formula (XL) with ammonia in the presence of a coupling reagent and a base to provide a compound of formula (XLI)

and

(vii) dehydrating the compound of formula (XLI) to provide a compound of formula (XVIII)

or

(b)

(i) treating the compound of formula (XXX) with an acid and a reducing agent, in a solvent, to provide a compound of formula (XXXI)

(ii) treating the compound of formula (XXXI) with a base, followed by treatment with an acid, to provide a compound of formula (XXXII)

(iii) treating the compound of formula (XXXII) with ammonia in the presence of a coupling reagent and a base, to provide a compound of formula (XXXIII);

(iv) treating the compound of formula (XXXIII) with a dehydrating agent to provide a compound of formula (XXXIV);

(v) deprotecting the compound of formula (XXXIV) to provide a compound of formula (XXXV) or salts thereof

and

(vi) treating the compound of formula (XXXV) or salts thereof with a reagent having formula X 2 CH 2 COY 2 wherein X 2 and Y 2 are independently Cl or Br, to provide a compound of formula (XVIII)

2. The process according to claim 1 , wherein the compound of formula (XVIII) is prepared by a process comprising:

(a) asymmetric reduction of a compound of formula (XXX) to a compound of formula (XXXVII), wherein P 2 is an amine-protecting group, R 1 is an acid protecting group, and R 2 is C 1-6 alkyl

(b) activating the compound of formula (XXXVII) to provide a compound of formula (XXXVIII), wherein R 4 is trihaloacetyl, methanesulfonyl, benzenesulfonyl or p-toluenesulfonyl

(c) deprotecting and cyclizing the compound of formula (XXXVIII) to provide a compound of formula (XXXVI) or salt thereof

(d) saponifying a compound of formula (XXXVI) or salts thereof to provide a compound of formula (XXXIX), wherein R 1 is an acid protecting group and R 2 is C 1-6 alkyl

(e) treating the compound of formula (XXXIX) or salts thereof with a reagent having formula X 2 CH 2 COY 2 to provide a compound of formula (XL), wherein X 2 and Y 2 are independently Cl or Br

(f) treating the compound of formula (XL) with ammonia in the presence of a coupling reagent and a base to provide a compound of formula (XLI)

and

(g) dehydrating the compound of formula (XLI) to provide a compound of formula (XVIII)

3. The process according to claim 1 wherein the solvent is selected from the group consisting of acetonitrile, lactams, N,N-dimethylamides of formic acid and aliphatic C 1-6 carboxylic acids, sulfoxides, ethers, aliphatic ketones, and mixtures thereof.

4. The process according to claim 1 wherein the solvent is selected from the group consisting of acetonitrile, 1-methyl-2-pyrrolidinone, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dioxane, and mixtures thereof.

5. The process according to claim 1 wherein an acid selected from the group consisting of trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, hydrogen chloride, and phosphoric acid is added in step (c).

6. The process according to claim 5 wherein the acid is phosphoric acid.

7. The process according to claim 1 , wherein the compound of formula (XVIII) is prepared by a process comprising:

(a) treating the compound of formula (XXX) with an acid and a reducing agent, in a solvent, to provide a compound of formula (XXXI)

(b) treating the compound of formula (XXXI) with a base, followed by treatment with an acid, to provide a compound of formula (XXXII)

(c) treating the compound of formula (XXXII) with ammonia in the presence of a coupling reagent and a base, to provide a compound of formula (XXXIII)

(d) treating the compound of formula (XXXIII) with a dehydrating agent to provide a compound of formula (XXXIV)

(e) deprotecting the compound of formula (XXXIV) to provide a compound of formula (XXXV) or salts thereof

and

(f) treating the compound of formula (XXXV) or salts thereof with a reagent having formula X 2 CH 2 COY 2 wherein X 2 and Y 2 are independently Cl or Br, to provide a compound of formula (XVIII)

8. (2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile, L-malic acid salt.