Synthesis of 1:1:1 co-crystal of 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene, L-proline and water

1. A process for the manufacture of final intermediate (FI) comprising the steps:

(a) reacting intermediate I1, wherein X is I, with at least one metalation agent, and subsequently adding the reaction product of such metalation to intermediate I2, wherein PG is a protection group, to yield intermediate I3;

(b) methylating intermediate I3 to yield intermediate I4;

(c) reducing intermediate I4 with a reduction agent to yield intermediate I5; and

(d) acetylating intermediate I5 to yield final intermediate FI;

wherein the intermediates I3, I4 and I5 are not isolated and/or purified before performing steps (b), (c) and/or (d), respectively:

2. The process according to claim 1 , wherein PG is trimethylsilyl (TMS).

3. The process according to claim 1 , wherein the at least one metalation agent comprises Turbo-Grignard (iPrMgCl*LiCl).

4. The process according to claim 1 , wherein the reduction agent comprises trimethylsilane.

5. A process for the manufacture of final intermediate (FI) comprising the steps:

(a) reacting intermediate I1, wherein X is I, with at least one metalation agent, and subsequently adding the reaction product of such metalation to intermediate I2, wherein PG is a protection group, to yield intermediate I3;

(b) methylating intermediate I3 to yield intermediate I4;

(c) acetylating intermediate I4 to yield intermediate I6;

(d) reducing intermediate I6 with a reduction agent to yield final intermediate FI;

wherein all of the intermediates I3, I4 and I6 are not isolated and/or purified before performing steps (b), (c) and/or (d), respectively:

6. The process according to claim 5 , wherein PG is trimethylsilyl (TMS).

7. The process according to claim 5 , where the at least one metalation agent comprises Turbo-Grignard (iPrMgCl*LiCl).

8. The process according to claim 5 , wherein the reduction agent comprises trimethylsilane.

9. A process for the manufacture of the crystalline compound 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene L-proline monohydrate according to formula (I)

comprising the following steps:

(a) 2-fluoro-4-bromobenzonitrile is reacted with isopropylmagnesium chloride and iodine to yield 2-fluoro-4-iodobenzonitrile;

(b) 2-fluoro-4-iodobenzonitrile is then coupled with ethyl-4-bromophenylacetate and subsequently decarboxylated to yield 2-(4-bromobenzyl)-4-iodo-benzonitrile;

(c) 2-(4-bromobenzyl)-4-iodo-benzonitrile is then reacted with intermediate “I2” [PG=trimethylsilyl (TMS)] and reduced and acetylated in a chemical synthesis sequence of halogen-metal exchange/lactone addition/acidic reduction/acetylation according to claim 4 , steps (b) and (c), with involved intermediates I3, I4 and I5 carrying a bromo substitution instead of the displayed cyclopropyl substitution at the distal benzyl moiety, wherein the intermediates I3, I4 and I5 are not isolated and/or purified before further processing;

(d) subsequently the cyclopropyl moiety is installed in the corresponding bromo analogue of final intermediate (FI) by means of a transition metal catalyzed reaction with a cyclopropyl species to obtain final intermediate (FI);

(e) final intermediate (FI) is then subjected to the process for the manufacture of the crystalline compound 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene L-proline monohydrate according to formula (I) according to the following steps:

(e.1) deacetylating the final intermediate (FI); and

(e.2) forming the crystalline compound according to formula (I) by reacting the deacetylated final intermediate of step (e.1) with L-proline and water to enable isolation of the final reaction product

10. The process according to claim 9 comprising the steps according to the following synthesis route:

wherein the above abbreviations have the following meanings:

iPrMgCl=isopropylmagnesium chloride; I2=iodine; THF=tetrahydrofuran; MeTHF=2-methyl tetrahydrofuran; tBuOK=potassium tert-butoxide; DMF=dimethylformamide; NaOH=sodium hydroxide; iPrMgCl.LiCl=isopropylmagnesium chloride lithium chloride; TMS=trimethylsilyl; MeSO 3 H=methanesulfonic acid; MeOH=methanol; Et 3 SiH=triethylsilane; BF 3 .OEt=boron trifluoride etherate; Ac 2 O=acetic anhydride; NMM=N-methylmorpholine; DMAP=4-dimethylaminopyridine; Ac=Acetyl; PdOAc2=palladium(II) acetate; PCy3=tricyclohexylphosphine; PhMe=toluene; iPrOH=isopropanol.

11. The process according to claim 9 , wherein the cyclopropyl species comprises cyclopropylboronic acid.