Login| Sign Up| Help| Contact|

Patent Searching and Data


Title:
SYNTHESIS OF THE 1 :1 :1 CO-CRYSTAL OF 1 -CYANO-2-(4-CYCLOPROPYL-BENZYL)-4-(BETA-D-GLUCOPYRANOS-1 -YL)-BENZENE, L-PROLINE AND WATER
Document Type and Number:
WIPO Patent Application WO/2019/121509
Kind Code:
A1
Abstract:
The invention relates to a process for the manufacture of the crystalline compound according to formula (I) comprising the steps (a) deacetylating the final intermediate (FT), (b) forming the crystalline compound according to formula (I) by reacting the deacetylated final intermediate of step (a) with L-proline and water and isolating the final reaction product, processes for manufacturing intermediates thereof, process intermediates and their uses in the processes according to the present invention.

Inventors:
ECKHARDT MATTHIAS (DE)
BRINK MONIKA (DE)
HIMMELSBACH FRANK (DE)
SAHLI STEFAN (CH)
SHU CHUTIAN (CN)
WANG XIAO-JUN (US)
WEBER BEAT (CH)
YANG BING-SHIOU (US)
Application Number:
PCT/EP2018/085193
Publication Date:
June 27, 2019
Filing Date:
December 17, 2018
Export Citation:
Click for automatic bibliography generation   Help
Assignee:
BOEHRINGER INGELHEIM VETMEDICA GMBH (DE)
International Classes:
C07D309/10; C07C69/614; C07C253/30; C07C255/35; C07D207/08; C07D309/30
Domestic Patent References:
WO2014016381A12014-01-30
WO2007128749A12007-11-15
WO2007093610A12007-08-23
WO2007128749A12007-11-15
WO2014016381A12014-01-30
Foreign References:
Other References:
WOLFE J P ET AL: "Improved Functional Group Compatibility in the Palladium-Catalyzed Amination of Aryl Bromides", TETRAHEDRON LETTERS, vol. 38, no. 36, 8 September 1997 (1997-09-08), pages 6359 - 6362, XP004087936, ISSN: 0040-4039, DOI: 10.1016/S0040-4039(97)01463-9
HYNES J B ET AL: "Further studies on the synthesis of quinazolines from 2-fluorobenzonitriles", JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 28, no. 5, August 1991 (1991-08-01), pages 1357 - 1363, XP055546483, ISSN: 0022-152X, DOI: 10.1002/jhet.5570280530
UNSINN A ET AL: "A Convenient Alumination of Functionalized Aromatics by Using the Frustrated Lewis Pair Et 3 Al and TMPMgCl.LiCl", CHEMISTRY, A EUROPEAN JOURNAL, vol. 19, no. 43, 18 October 2013 (2013-10-18), pages 14687 - 14696, XP055546491, ISSN: 0947-6539, DOI: 10.1002/chem.201301869
LI-YUAN BAO ET AL., CHEM. COMMUN., vol. 32, 2015, pages 6884 - 6900
Attorney, Agent or Firm:
ELKE, Anna Maria et al. (DE)
Download PDF:
Claims:
CLAIMS

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

(a) deacetylating the final intermediate (FI);

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

H20

2. The process according to claim 1, wherein the deacetylation step (a) comprises the following steps:

(al) reacting the final intermediate (FI) dissolved in at least one organic solvent, preferably methyl tetrahydrofuran (MeTHF), in the presence of a base, preferably NaOH, and water;

(a2) optionally, swapping the at least one organic solvent of the organic phase yielded in step (al), preferably methyl tetrahydrofuran (MeTHF), to at least one different organic solvent, preferably 2-propanol, and optionally adding water.

3. The process according to any one of claims 1 to 2, wherein the crystalline compound forming step (b) further comprises the following steps:

(bl) adding L-proline, which is dissolved in the at least one different organic solvent, preferably 2- propanol, and water, to the water-organic phase mixture, preferably 2-propanol and water, yielded in step (al) or optionally step (a2), and incubating such reaction mixture;

(b2) isolating the crystalline compound l-cyano-2-(4-cyclopropyl-benzyl)-4-( -D-glucopyranos-l- yl)-benzene L-proline monohydrate according to formula (I) from the reaction mixture of step (bl).

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

(a) reacting intermediate II, wherein X is Br or I, with at least one metalation agent, preferably Turbo- Grignard (iPrMgCl*LiCl), and subsequently adding the reaction product of such metalation to intermediate 12, wherein PG is a protection group, preferably trimethylsilyl (TMS), to yield intermediate 13;

(b) methylating intermediate 13 to yield intermediate 14;

(c) reducing intermediate 14 with a reduction agent, preferably a silane, more preferably triethylsilane, to yield intermediate 15;

(d) acetylating intermediate 15 to yield final intermediate FI;

wherein preferably at least one, more preferably all, of intermediates 13, 14 and/or 15 is/are not isolated and/or purified before further processing, i.e., performing steps (b), (c) and/or (d), respectively.

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

(a) reacting intermediate II, wherein X is Br or I, with at least one metalation agent, preferably Turbo- Grignard (iPrMgCl*LiCl), and subsequently adding the reaction product of such metalation to intermediate 12, wherein PG is a protection group, preferably trimethylsilyl (TMS), to yield intermediate 13;

(b) methylating intermediate 13 to yield intermediate 14;

(c) acetylating intermediate 14 to yield intermediate 16;

(d) reducing intermediate 16 with a reduction agent, preferably a silane, more preferably triethylsilane, to yield final intermediate FI;

wherein preferably at least one, more preferably all, of intermediates 13, 14 and/or 16 is/are not isolated and/or purified before further processing, i.e., performing steps (b), (c) and/or (d), respectively.

6. The process according to any one of claims 4 to 5, wherein X is I and/or PG is trimethylsilyl (TMS), preferably X is I and PG is trimethylsilyl (TMS).

7. A process for the manufacture of intermediate II comprising the steps:

(a) reacting intermediate 17 with intermediate 18, wherein X is Br or I and wherein Hal is F or Cl, in the presence of a base, preferably potassium t-butoxide (KOtBu), to yield intermediate II;

(b) isolating intermediate II from the reaction mixture of step (a).

8. The process according to claim 7, wherein X is I and/or Hal is F, preferably X is I and Hal is F.

9. An intermediate compound selected from the group consisting of:

(1) (2)

(3) (4)

(11) (12) (13)

10 An intermediate compound according to claim 9 selected from the group consisting of:

(1) (2)

11. An intermediate compound according to claim 10 obtainable by the process according to any one of claims 4 to 8.

12. The use of an intermediate compound according to any one of claims 9 to 11 in the process according to any one of claims 1 to 8.

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

comprising, preferably consisting of, 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“12” [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 13, 14 and 15 carrying a bromo substitution instead of the displayed cyclopropyl substitution at the distal benzyl moiety;

(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 an appropriate cyclopropyl species, such as cyclopropylboronic acid, to obtain final intermediate (FI);

(e) final intermediate (FI) is then subjected to the process for the manufacture of the crystalline

compound l-cyano-2-(4-cyclopropyl-benzyl)-4-( -D-glucopyranos-l-yl)-benzene L-proline monohydrate according to formula (I) according to any one of claims 1 to 3.

14. The process according to claim 13 comprising, preferably consisting of, the steps according to the following synthesis route:

wherein the above abbreviations have the following meanings:

iPrMgCl = isopropylmagnesium chloride; 12 = iodine; THF = tetrahydrofuran; MeTHF = 2-methyl tetrahydrofuran; tBuOK = potassium tert-butoxide; DMF = dimethylformamide; NaOH = sodium hydroxide; iPrMgCl.LiCl = isopropylmagnesium chloride lithium chloride; TMS = tetramethylsilane; MeSOd I = methanesulfonic acid; MeOH = methanol; FhSil I = triethylsilane; BFs.OEt = boron trifluoride etherate; AC2O = acetic anhydride; NMM = N-methylmorpholine; DMAP = 4-dimethylaminopyridine; Ac = Acetyl; PdOAc2 = palladium(II) acetate; PCy3 = tricyclohexylphosphine; PhMe = toluene; iPrOH = isopropanol.

Description:
SYNTHESIS OF THE 1 :1 :1 CO-CRYSTAL OF

1 -CYANO-2-(4-CYCLOPROPYL-BENZYL)-4-(BETA-D-GLUCOPYRANOS-1 -YL)-BENZENE, L-PROLINE AND WATER

FIELD OF THE INVENTION

The invention relates to the field of chemistry, particularly synthetic chemistry. In particular, the invention relates to the synthesis of crystalline l-cyano-2-(4-cyclopropyl-benzyl)-4-( -D-glucopyranos-l-yl)-benzene L-proline monohydrate, more particular to the 1:1: 1 co-crystal of all three crystal components 1 -cyano-2-(4- cyclopropyl-benzyl)-4-( -D-glucopyranos-l-yl)-benzene, L-proline and water.

BACKGROUND OF THE INVENTION

WO 2007/093610 describes glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their medical uses as well as processes for their manufacture. It discloses among many other compounds also l-cyano-2-(4-cyclopropyl-benzyl)-4-( -D-glucopyranos-l-yl)- benzene.

WO 2007/128749 relates to glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their medical uses as well as processes for their manufacture. Among many other compounds it also discloses l-cyano-2-(4-cyclopropyl-benzyl)-4-( -D-glucopyranos-l- yl)-benzene.

WO 2014/016381 describes crystalline complexes of I -cyano-2-(4-cyc lopropy I -benzyl )-4-((i-D- glucopyranos-l-yl) -benzene with natural amino acids, methods for the preparation thereof as well as the use thereof for preparing medicaments. Although the WO publication describes crystalline l-cyano-2-(4- cyclopropyl-benzyl)-4-( -D-glucopyranos-l-yl)-benzene L-proline it does not explicitly mention l-cyano-2- (4-cyclopropyl-benzyl)-4-( -D-glucopyranos- 1 -yl)-benzene L-proline monohydrate.

Further prior art is as follows:

Li-Yuan Bao et al. (Chem. Commun. 2015, 32: 6884-6900), who review the progress and developments in the turbo Grignard reagent i-PrMgCl*LiCl.

The disadvantages of the prior art are as follows:

l-cyano-2-(4-cyclopropyl-benzyl)-4-( -D-glucopyranos-l-yl)-benzene as a crude substance is an amorphous oil, which cannot be handled technically and in commercial scale without further processing/modification

complex synthesis l-cyano-2-(4-cyclopropyl-benzyl)-4-( -D-glucopyranos-l-yl)-benzene with numerous intermediate steps

non-commercially available starting material requires synthesis of precursors for the final synthesis of 1 -cyano-2-(4-cyclopropyl-benzyl)-4-( -D-glucopyranos- 1 -yl)-benzene

The objective underlying the present invention is therefore to provide a synthesis process which overcomes the problems of the prior art as described above. SUMMARY OF THE INVENTION

The present invention concerns in one aspect a process for the manufacture of the crystalline compound 1- cyano-2-(4-cyclopropyl-benzyl)-4-( -D-glucopyranos-l-yl)-benzene L-proline monohydrate according to formula (I) comprising the steps:

(a) deacetylating the final intermediate (FI);

(b) forming the crystalline compound according to formula (I) by reacting the deacetylated final

intermediate of step (a) with L-proline and water to enable isolation of the final reaction product.

H 2 0

In another aspect the present invention concerns a process for the manufacture of final intermediate (FI) comprising the steps:

(a) reacting intermediate II, wherein X is Br or I, with at least one metalation agent, preferably Turbo- Grignard (iPrMgCl*LiCl), and subsequently adding the reaction product of such metalation to intermediate 12, wherein PG is a protection group, preferably trimethylsilyl (TMS), to yield intermediate 13;

(b) treating intermediate 13 with methanol to yield intermediate 14;

(c) reducing intermediate 14 with a reduction agent, preferably a silane, more preferably triethylsilane, to yield intermediate 15;

(d) acetylating intermediate 15 to yield final intermediate FI;

wherein preferably at least one, more preferably all, of intermediates 13, 14 and/or 15 is/are not isolated and/or purified before further processing, i.e. performing steps (b), (c) and/or (d), respectively.

In a further aspect the present invention concerns a process for the manufacture of final intermediate (FI) comprising the steps:

(a) reacting intermediate II, wherein X is Br or I, with at least one metalation agent, preferably Turbo- Grignard (iPrMgCl*LiCl), and subsequently adding the reaction product of such metalation to intermediate 12, wherein PG is a protection group, preferably trimethylsilyl (TMS), to yield intermediate 13;

(b) treating intermediate 13 with methanol to yield intermediate 14;

(c) acetylating intermediate 14 to yield intermediate 16;

(d) reducing intermediate 16 with a reduction agent, preferably a silane, more preferably triethylsilane, to yield final intermediate FI; wherein preferably at least one, more preferably all, of intermediates 13, 14 and/or 16 is/are not isolated and/or purified before further processing, i.e. performing steps (b), (c) and/or (d), respectively.

In yet another aspect the present invention concerns a process for the manufacture of intermediate II comprising the steps:

(a) reacting intermediate 17 with intermediate 18, wherein X is Br or I and wherein Hal is F or Cl, in the presence of a base, preferably potassium t-butoxide (KOtBu), to yield intermediate II;

(b) isolating intermediate II from the reaction mixture of step (a).

In yet another aspect the present invention concerns crystalline compound l-cyano-2-(4-cyclopropyl-benzyl)- 4-((14)-glucopyranos- 1 -yl)-bcn/cne L-proline monohydrate according to formula (I)

H 2 0

In yet a further aspect the present invention concerns an intermediate compound selected from the group consisting of intermediates (1) to (13):

(1) (2)

In yet another aspect the present invention concerns an intermediate compound selected from intermediate compounds (1) to (13) as herein disclosed obtainable by one or more processes according to the present invention as herein disclosed.

In yet a further aspect the present invention concerns the use of an intermediate compound selected from intermediate compounds (1) to (13) as herein disclosed in one or more processes according to the present invention as herein disclosed.

The advantages of the synthesis processes according to the present invention are as follows: 1: 1:1 co-crystal can be technically handled in contrast to the oil form of the free compound, i.e.

crystallized, isolated, characterized and further processed in commercial scale

“non-obvious” chemistry: it was very difficult to develop a synthesis strategy comprising a molecule with a benzonitrile moiety - employing an organomagnesium or lithium compound as for the synthesis of non- cyanated glucosides can be troublesome since the nitrile moiety may interfere with the halogen-metal exchange and subsequent addition reaction

shorter/more efficient/more economic synthesis route due to incorporating the cyano group in the aglycon from the beginning instead of introducing it afterwards from a halogenated, brominated or chlorinated, precursor in an extra synthesis step

commercially available starting materials or starting materials that can be prepared easily.

DETAILED DESCRIPTION OF THE INVENTION

Before the embodiments of the present invention are described in further details it shall be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise.

Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. All given ranges and values may vary by 1 to 5 % unless indicated otherwise or known otherwise by the person skilled in the art, therefore, the term“about” was usually omitted from the description and claims. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described. All publications mentioned herein are incorporated herein by reference for the purpose of describing and disclosing the substances, excipients, carriers, and methodologies as reported in the publications which might be used in connection with the invention. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

In the course of the present invention crystalline compound I -cyano-2-(4-cyc lopropy I -benzyl )-4-((i-D- glucopyranos-l-yl) -benzene L-proline monohydrate is herewith understood to be the 1: 1:1 co-crystal of all three crystal components l-cyano-2-(4-cyclopropyl-benzyl)-4-( -D-glucopyranos-l-yl)-benzene, L-proline and water, as represented by formula (I):

Such 1 : 1 : 1 co-crystal is physicochemically characterized in WO 2014/016381.

In a preferred embodiment the present invention provides for a process for the manufacture of the crystalline compound l-cyano-2-(4-cyclopropyl-benzyl)-4-( -D-glucopyranos-l-yl)-benzene L-proline monohydrate according to formula (I) comprising the steps

(a) deacetylating the final intermediate (FI);

(b) forming the crystalline compound according to formula (I) by reacting the deacetylated final

intermediate of step (a) with L-proline and water and isolating the final reaction product;

wherein the deacetylation step (a) comprises the following steps:

(al) reacting the final intermediate (FI) dissolved in at least one organic solvent, preferably methyl

tetrahydrofuran (MeTHF), in the presence of a base, preferably NaOH, and water;

(a2) optionally, swapping the at least one organic solvent of the organic phase yielded in step (al),

preferably methyl tetrahydrofuran (MeTHF), to at least one different organic solvent, preferably 2- propanol, and optionally adding water.

Preferably, the crystalline compound forming step (b) further comprises the following steps:

(bl) adding L-proline, which is dissolved in the at least one different organic solvent, preferably 2- propanol, and water, to the water-organic phase mixture, preferably 2-propanol and water, yielded in step (al) or optionally step (a2), and incubating such reaction mixture;

(b2) isolating the crystalline compound l-cyano-2-(4-cyclopropyl-benzyl)-4-( -D-glucopyranos-l-yl)- benzene L-proline monohydrate according to formula (I) from the reaction mixture of step (bl).

In another preferred embodiment the present invention provides for a process for the manufacture of final intermediate (FI) comprising the steps:

(a) reacting intermediate II, wherein X is Br or I, with at least one metalation agent, preferably Turbo- Grignard (iPrMgCl*LiCl), and subsequently adding the reaction product of such metalation to intermediate 12, wherein PG is a protection group, preferably trimethylsilyl (TMS), to yield intermediate 13;

(b) treating intermediate 13 with methanol to yield intermediate 14;

(c) reducing intermediate 14 with a reduction agent, preferably a silane, more preferably triethylsilane, to yield intermediate 15;

(d) acetylating intermediate 15 to yield final intermediate FI;

wherein preferably at least one, more preferably all, of intermediates 13, 14 and/or 15 is/are not isolated and/or purified before further processing, i.e., performing steps (b), (c) and/or (d), respectively; and wherein X is I and/or PG is trimethylsilyl (TMS), preferably X is I and PG is trimethylsilyl (TMS).

In another preferred embodiment the present invention provides for a process for the manufacture of final intermediate (FI) comprising the steps:

(a) reacting intermediate II, wherein X is Br or I, with at least one metalation agent, preferably Turbo- Grignard (iPrMgCl*LiCl), and subsequently adding the reaction product of such metalation to intermediate 12, wherein PG is a protection group, preferably trimethylsilyl (TMS), to yield intermediate 13;

(b) treating intermediate 13 with methanol to yield intermediate 14;

(c) acetylating intermediate 14 to yield intermediate 16;

(d) reducing intermediate 16 with a reduction agent, preferably a silane, more preferably triethylsilane, to yield final intermediate FI;

wherein preferably at least one, more preferably all, of intermediates 13, 14 and/or 16 is/are not isolated and/or purified before further processing, i.e., performing steps (b), (c) and/or (d), respectively; and wherein X is I and/or PG is trimethylsilyl (TMS), preferably X is I and PG is trimethylsilyl (TMS).

In principle, any suitable protection group known to the person skilled in the art can be employed. Exemplary protection groups (PG) according to the present invention are trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS, TBDMS), tert-butyldiphenylsilyl (TBDPS), benzyl (Bn), 4-methoxybenzyl (PMB), 2-naphthylmethyl (Nap), 2-methoxyethoxymethyl (MEM), 2,2,2- trichloroethyl carbonyl (Troc), methyl and the like. Preferred protection group (PG) according to the present invention is trimethylsilyl (TMS).

With regard to the reduction agent, in principle any suitable reduction agent known to the person skilled in the art can be employed. Exemplary reduction agents according to the present invention are silanes, such as triethylsilane, tripropylsilane, triisopropylsilane or diphenylsilane, sodium borohydride, sodium

cyanoborohydride, zinc borohydride, boranes, lithium aluminum hydride, diisobutylaluminum hydride and the like. Preferred reduction agent is a silane, more preferably triethylsilane.

In yet another preferred embodiment the present invention provides for a process for the manufacture of intermediate II comprising the steps:

(a) reacting intermediate 17 with intermediate 18, wherein X is Br or I and wherein Hal is F or Cl, in the presence of a base, preferably potassium t-butoxide (KOtBu), to yield intermediate II ;

(b) isolating intermediate II from the reaction mixture of step (a);

wherein X is I and/or Hal is F, preferably X is I and Hal is F.

In yet another preferred embodiment the present invention provides for an intermediate compound selected from the group consisting of:

EXAMPLES

The following examples serve to further illustrate the present invention; but the same should not be construed as a limitation of the scope of the invention disclosed herein.

Example 1 - Preparation of l-cyano-2-(4-cyclopn>pyl-benzyl)-4-(|i-I)-gliicopyranos-l -yl)-benzene L- proline monohydrate according to formula (I) starting from final intermediate FI

30 g Intermediate FI was dissolved in 130 g 2-methyltetrahydrofuran. 9.3 g NaOH (30 % in water ) was added and the resulting solution was heated to 50°C for 3 hours, cooled to 5°C and the pH adjusted to 9.3 using 1 M aqueous HCl-solution. The phases were separated and the organic phase was washed with water. The organic solvent was swapped to 2-propanol and 3.3 g water was added at room temperature. A solution of 6.3 g L-proline in 8.5 g water and 42 g 2-propanol was added at 23°C within 4 h, and seeded during the addition. The resulting suspension was cooled to 5°C, stirred for 1 h, and the product filtered. After washing with a solvent mixture of 60 g 2-propanol and 3.5 g water, and drying in vacuo, the final crystalline compound had a purity of 100 % (analyzed by HPLC) and overall yield was 87 %.

Example 2 - Preparation of final intermediate FI starting from intermediates II and 12 - variant A

628 mg Intermediate II, X = Br, dissolved in 8 mL tetrahydrofuran (THF), was reacted during 15 minutes with 2.4 mL tert-butyllithium (1.7 M in pentane) at -100°C. 934 mg of intermediate 12 (PG = trimethylsilyl, TMS) dissolved in 5 mL THF was added and the reaction mixture has been kept at -80°C. After 1 hour the reaction was quenched with 14 mL saturated aqueous of ammonium chloride-solution followed by extraction with ethyl acetate, drying over magnesium sulfate and concentration of the solution. The residue was dissolved in 9.4 mL solvent mixture methanol and 0.32 mL methanesulfonic acid added the mixture kept at 55°C. After 16 hours the pH was adjusted to 8 by addition of saturated sodium bicarbonate solution, concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and concentrated in vacuo to get intermediate 14. 1400 mg residue containing intermediate 14 was reduced with 1.17 g triethylsilane and 1.6 g boron trifluoride diethyl etherate in a mixture of 4.5 g dicholormethane and 5 g acetonitrile at 22°c for 1 h. The reaction mixture was added to 12 hg 2 N aqueous sodium hydroxide solution an extracted with TBME. The organic phase was concentrated in vacuo and treated trice with 7 g MeOH and evaporated to 1/5 volume. The residue was then dissolved in 8 g THF and the intermediate FI was obtained by acetylation with 2.2 g acetic anhydride, 2.5 g N-methylmorpholine and a catalytic amount of 4-(dimethylamino)-pyridine. Isolation and crystallization from aqueous methanol (1: 1) gave the intermediate 11 at a purity of 98.4% and a total overall yield of 26 %.

Example 3 - Preparation of final intermediate FI starting from intermediates II and 12 - variant B

Intermediate 14 has been obtained as described in example 2.

220 mg of intermediate 14 have been acetylated with 0.24 mL acetic anhydride, 390 mg N,N- diisopropylethylamine, and a catalytic amount of 4-(dimethylamino)-pyridinein 5 mL dichloromethane. After extractive aqueous work-up, drying over magnesium sulfate and evaporation in vacuo, 320 mg of the acetylated intermediate 16 was reduced in 4 mL acetonitrile with 0.19 mL triethylsilane, 0.11 mL boron trifluoride diethyl etherate and 1 equivalent water. Purity of intermediate FI was >85% and yield was 26 %.

Example 4a - Preparation of intermediate II starting from intermediates 17 and 18

In 6.6 g of intermediate 17, 8 g of intermediate 18 (Hal = F, X = I) were dissolved in 28.5 g tetrahydrofuran and 6.2 g dimethylformamide, and a solution of 8 g potassium tert-butoxide in 59 g tetrahydrofuran was added to the mixture at -20°C and stirred for 1 h . The reaction was quenched by addition of 27.2 g water and 13.2 g 30% aqueous sodium hydroxide solution. The resulting mixture was then stirred at 55°c for 16 h and cooled to 22°C. 10 g acetic acid and 25 g water were added, the phases separated and 67.5 g isopropyl acetate added to the organic phase. The organic phases was washed with 67 g 5% aqueous sodium chloride solution, and the solvent swapped to 2-propanol. The product was crystallized from 2-propanol by seeding and cooling to 15°C. The product was filtered and washed with 2-propanol to yield intermediate II in 97% purity and 50% yield.

Example 4b - Preparation of intermediate II starting from intermediates 17 and 18

Example 4a has been repeated using intermediate 18 (Hal = F, X = Br). Overall yield is 47 % and purity of the intermediate was >90%.

Example 5 - Preparation of intermediate 17

Intermediate 17 has been prepared by mixing cyclopropyl magnesium bromide (1.0 eq.), zinc chloride (1.3 eq.) and ethyl 2-(4-bromophenyl)acetate (1.0 eq.) in presence of triphenylphosphine (0.06 eq.) and palladium(II) acetate (0.05 eq.) in tetrahydrofuran at a temperature of 50°C. Extractive workup using ethyl acetate and water gave the crude product that was purified by distillation. Yield 70%. Purity >97.0 %. Example 6 - Alternative synthesis route

Abbreviations:

iPrMgCI = isopropylmagnesium chloride; 12 = iodine; THF = tetrahydrofuran; MeTHF = 2-methyl tetrahydrofuran; tBuOK = potassium tert-butoxide; DMF = dimethylformamide; NaOH = sodium hydroxide; iPrMgCI.LiCI = isopropylmagnesium chloride lithium chloride; TMS = tetramethylsilane; Me OH I = methanesulfonic acid; MeOH = methanol; FhSil I = triethylsilane; BFs.OEt = boron trifluoride etherate; AC2O = acetic anhydride; NMM = N-methylmorpholine; DMAP = 4-dimethylaminopyridine; Ac = Acetyl; PdOAc2 = palladium(II) acetate; PCy3 = tricyclohexylphosphine; PhMe = toluene; iPrOH = isopropanol.

Alternatively, final intermediate FI can by synthesized by installing the cyclopropyl moiety at a later stage in the synthesis as shown in the scheme above. Instead of employing compound 2, the corresponding aryl bromo iodobenzonitrile may be used. The aryl bromo iodobenzonitrile can be prepared by a nucleophilic aromatic substitution / decarboxylation coupling between 2-fluoro-4-iodobenzonitrile and ethyl-4- bromophenylacetate. The aryl bromo iodobenzonitrile can then be subjected to the same chemistry sequence of halogen-metal exchange / lactone addition / acidic methanol / reduction / acetylation. It is then necessary to install the cyclopropyl moiety of the isolated product from this sequence by a transition metal catalyzed reaction with an appropriate cyclopropyl species, such as cyclopropylboronic acid, to obtain final intermediate FI.

In detail, 2-fluoro-4-bromobenzonitrile is reacted with isopropylmagnesium chloride and iodine to yield 2- fluoro-4-iodobenzonitrile. Such yielded intermediate compound is then coupled with ethyl-4- bromophenylacetate and subsequently decarboxylated to yield 2-(4-bromobenzyl)-4-iodo-benzonitrile. 2-(4- bromobenzyl)-4-iodo-benzonitrile is then reacted with intermediate“12” [PG = trimethylsilyl (TMS)] and reduced and acetylated in a chemical synthesis sequence of halogen-metal exchange / lactone addition / acidic reduction / acetylation analogously to the herein described and claimed process for the manufacture of final intermediate (FI), steps (b) and (c), with involved intermediates 13, 14 and 15 carrying a bromo substitution instead of the displayed cyclopropyl substitution at the distal benzyl moiety. At the end of this chemical synthesis sequence the cyclopropyl moiety is installed in the corresponding bromo analogue of final intermediate (FI) by means of a transition metal catalyzed reaction with an appropriate cyclopropyl species, such as cyclopropylboronic acid, to obtain final intermediate (FI). The final intermediate (FI) is then subjected to the process for the manufacture of the crystalline compound l-cyano-2-(4-cyclopropyl-benzyl)- 4-((i-l)-glucopyranos- 1 -ylpbenzene L-proline monohydrate according to formula (I) as herein described and claimed.

REFERENCES

(1) WO 2007/093610

(2) WO 2007/128749

(3) WO 2014/016381

(4) Li-Yuan Bao et al., Chem. Commun. 2015, 32: 6884-6900