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

Abstract

To provide a method for synthesizing a 1:1:1 co-crystal of 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene, L-proline, and water.SOLUTION: The present invention relates to a method for producing a crystalline compound according to formula (I), the method including: (a) a step of deacetylating a final intermediate (FT); and (b) a step of forming the crystalline compound according to formula (I) by reacting the deacetylated final intermediate of step (a) with L-proline and water, and isolating a final reaction product.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to the field of chemistry, in particular to the field of synthetic chemistry. In particular, the present invention relates to crystalline 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene L-proline monohydrate, and more particularly to the synthesis of a 1:1:1 co-crystal consisting of all of 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene, L-proline and water, which are three crystal components.

Background Art

[0002] WO2007 / 093610 describes glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their medical uses, and methods for their manufacture. The above patent document discloses 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene among a number of other compounds. WO2007 / 128749 relates to glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their medical uses, and methods for their manufacture. Among a number of other compounds, the above patent document also discloses 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene.

[0003] WO2014 / 016381 describes a crystalline complex of 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene with a natural amino acid, a method for its preparation, and its use for pharmaceutical preparation. This international patent application describes crystalline 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene L-proline, but this application does not clearly describe 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene L-proline monohydrate. Furthermore, the prior art is as follows: Li-Yuan Bao et al. (Chem. Commun. 2015, 32: 6884-6900), which outlined the progress and development in the turbo Grignard reagent i-PrMgCl*LiCl. The drawbacks of the prior art are as follows: - 1-Cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene as a crude substance is an amorphous oil, and this oily substance cannot be handled on a technical and commercial scale without further treatment / modification. - The complex synthesis of 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene involving numerous intermediate steps - For the final synthesis of 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene, since the starting materials are not commercially available, the synthesis of precursors is required.

Summary of the Invention

[0004] Therefore, the objective of the present invention underlying is to provide a synthesis method that overcomes the above-mentioned problems of the prior art. In one aspect, the present invention relates to a method for producing the crystalline compound 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene L-proline monohydrate according to formula (I), comprising: (a) A step of deacetylating the final intermediate (FI), (b) A step of reacting the deacetylated final intermediate of step (a) with L-proline and water to form a crystalline compound according to formula (I) by enabling the isolation of the final reaction product relates to a method.

[0005]

Chemical Formula

[0006] In another aspect, the present invention is as follows: (a) Reacting intermediate I1 (where X is Br or I) with at least one metalating agent, preferably turbo-Grignard (iPrMgCl·LiCl), and then adding the reaction product of such metalation to intermediate I2 (where PG is a protecting group, preferably trimethylsilyl (TMS)) to obtain intermediate I3 (b) Treating intermediate I3 with methanol to obtain intermediate I4 (c) Reducing intermediate I4 with a reducing agent, preferably a silane, more preferably triethylsilane, to obtain intermediate I5 (d) Acetylating intermediate I5 to obtain the final intermediate FI A process for producing a final intermediate (FI), comprising: Preferably at least one, more preferably all, of intermediates I3, I4 and / or I5 are not isolated and / or purified before further treatment, i.e., before performing steps (b), (c) and / or (d) respectively.

[0007]

Chemical formula

[0008] In a further aspect, the present invention is as follows: (a) Reacting intermediate I1 (where X is Br or I) with at least one metalating agent, preferably turbo-Grignard (iPrMgCl·LiCl), and then adding the reaction product of such metalation to intermediate I2 (where PG is a protecting group, preferably trimethylsilyl (TMS)) to obtain intermediate I3 (b) Treating intermediate I3 with methanol to obtain intermediate I4 (c) Acetylating intermediate I4 to obtain intermediate I6 (d) Reducing intermediate I6 with a reducing agent, preferably a silane, more preferably triethylsilane, to obtain the final intermediate FI A process for producing a final intermediate (FI), comprising: Regarding a production method, preferably at least one, more preferably all, of intermediates I3, I4, and / or I6 are not isolated and / or purified before further processing, i.e., before performing steps (b), (c), and / or (d) respectively.

[0009]

Chemical formula

[0010] In yet another aspect, the present invention relates to the following: (a) A step of reacting intermediate I7 with intermediate I8 (where X is Br or I and Hal is F or Cl) in the presence of a base, preferably potassium t-butoxide (KOtBu), to obtain intermediate I1 (b) A step of isolating intermediate I1 from the reaction mixture of step (a) Regarding a production method of intermediate I1, which includes the above steps.

[0011]

Chemical formula

[0012] In yet another aspect, the present invention relates to the crystalline compound 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene L-proline monohydrate represented by formula (I).

Chemical formula

[0013] In a further aspect, the present invention relates to an intermediate compound selected from the group consisting of intermediates (1) to (13).

Chemical formula

[0014] In yet another aspect, the present invention relates to an intermediate compound selected from intermediate compounds (1) to (13) disclosed herein, which can be obtained by one or more methods according to the present invention disclosed herein.

[0015] In a further aspect, the present invention relates to the use of an intermediate compound selected from intermediate compounds (1) to (13) disclosed herein in one or more methods according to the present invention disclosed herein.

[0016] The advantages of the synthesis method according to the present invention are as follows: - The 1:1:1 co-crystal can be technically handled, i.e., crystallized, isolated, identified, and further processed on a commercial scale, in contrast to the oily form which is the free compound. - "Non-obvious" chemical properties: The development of a synthetic strategy involving molecules with a benzonitrile moiety has been very difficult. Regarding the synthesis of non-cyanated glucosides, the use of organomagnesium or lithium compounds can be difficult because the nitrile moiety may interfere with halogen-metal exchange and subsequent addition reactions. - Instead of introducing a cyano group after a halogenated, brominated, or chlorinated precursor in an extra synthetic step, the cyano group is incorporated into the aglycone from the beginning, resulting in a shorter / more efficient / more economical synthetic route. - It is a commercially available starting material or a starting material that can be easily prepared.

DETAILED DESCRIPTION OF THE INVENTION

[0017] Before describing the embodiments of the present invention in more detail, it is noted that, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All given ranges and values are subject to a variation of 1 to 5% unless otherwise indicated or not particularly known to one of ordinary skill in the art, and thus, the term "about" is usually omitted from the description and claims. Any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, but the preferred methods, devices, and materials are described herein. All publications mentioned herein are hereby incorporated by reference herein for the purpose of describing and disclosing the substances, additives, carriers, and methods reported in the publications that can be used in connection with the present invention. Nothing in this specification should be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention.

[0019] In the process of the present invention, the crystalline compound 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene L-proline monohydrate is, according to this specification, of formula (I):

Chemical formula

[0020] Such a 1:1:1 co-crystal is physically and chemically characterized in WO2014 / 016381. In a preferred embodiment, the present invention comprises (a) a step of deacetylating a final intermediate (FI), (b) a step of forming a crystalline compound of formula (I) by reacting the deacetylated final intermediate of step (a) with L-proline and water and isolating the final reaction product A process for producing the crystalline compound 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene L-proline monohydrate of formula (I), comprising: The deacetylation step (a) is as follows: (a1) Reacting the final intermediate (FI) dissolved in at least one organic solvent, preferably methyltetrahydrofuran (MeTHF), with water in the presence of a base, preferably NaOH; (a2) Optionally, at least one organic solvent of the organic phase obtained in step (a1), preferably methyltetrahydrofuran (MeTHF), may be exchanged with at least one different organic solvent, preferably 2-propanol, and water may be added. A production method is provided that includes the above.

[0021] Preferably, the step (b) of forming the crystalline compound is as follows: (b1) Adding L-proline dissolved in at least one different organic solvent, preferably 2-propanol and water, obtained in step (a1) or optionally step (a2) to a water-organic phase mixture, preferably 2-propanol and water, and allowing such a reaction mixture to stand; (b2) Isolating the crystalline compound 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene L-proline monohydrate of formula (I) from the reaction mixture of step (b1). It further includes the above.

[0022] In another preferred embodiment, the present invention provides the following: (a) Reacting intermediate I1 (X is Br or I) with at least one metalating agent, preferably turbo-Grignard (iPrMgCl·LiCl), and then adding the reaction product of such metalation to intermediate I2 (PG is a protecting group, preferably trimethylsilyl (TMS)) to obtain intermediate I3; (b) Treating intermediate I3 with methanol to obtain intermediate I4. (c) A step of reducing intermediate I4 with a reducing agent, preferably a silane, more preferably triethylsilane, to obtain intermediate I5. (d) A step of acetylating intermediate I5 to obtain the final intermediate FI. A method for producing a final intermediate (FI), comprising: Preferably at least one, more preferably all, of intermediates I3, I4, and / or I5 are not isolated and / or purified before further processing, i.e., before performing steps (b), (c), and / or (d) respectively, X is I, and / or PG is trimethylsilyl (TMS), preferably X is I and PG is trimethylsilyl (TMS). Provided is a production method.

[0023] In another preferred embodiment, the present invention provides the following: (a) Reacting intermediate I1 (where X is Br or I) with at least one metalating agent, preferably turbo-Grignard (iPrMgCl·LiCl), and then adding the reaction product of such metalation to intermediate I2 (where PG is a protecting group, preferably trimethylsilyl (TMS)) to obtain intermediate I3. (b) A step of treating intermediate I3 with methanol to obtain intermediate I4. (c) A step of acetylating intermediate I4 to obtain intermediate I6. (d) A step of reducing intermediate I6 with a reducing agent, preferably a silane, more preferably triethylsilane, to obtain the final intermediate FI. A method for producing a final intermediate (FI), comprising: Preferably at least one, more preferably all, of intermediates I3, I4, and / or I6 are not isolated and / or purified before further processing, i.e., before performing steps (b), (c), and / or (d) respectively, X is I, and / or PG is trimethylsilyl (TMS), preferably X is I and PG is trimethylsilyl (TMS). Provided is a production method.

[0024] In principle, any suitable protecting group known to those skilled in the art can be used. Exemplary protecting groups (PGs) 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-trichloroethylcarbonyl (Troc), methyl, and the like. A preferred protecting group (PG) according to the present invention is trimethylsilyl (TMS). Regarding the reducing agent, in principle, any suitable reducing agent known to those skilled in the art can be used. Exemplary reducing agents according to the present invention are silanes such as triethylsilane, tripropylsilane, triisopropylsilane or diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane, lithium aluminum hydride, diisobutylaluminum hydride, and the like. A preferred reducing agent is silane, more preferably triethylsilane. In yet another preferred embodiment, the present invention provides the following: (a) Reacting intermediate I7 with intermediate I8 (where X is Br or I and Hal is F or Cl) in the presence of a base, preferably potassium t-butoxide (KOtBu), to obtain intermediate I1; (b) Isolating intermediate I1 from the reaction mixture of step (a). A process for producing intermediate I1, comprising: wherein X is I and / or Hal is F, preferably X is I and Hal is F. A production method is provided.

[0025] In yet another preferred embodiment, the present invention provides the following:

Chemical formula

Examples

[0026] The following examples serve to further illustrate the present invention, but these examples should not be construed as limiting the scope of the present invention disclosed herein.

[0027] (Example 1) Preparation of 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene L-proline monohydrate according to formula (I), starting from the final intermediate FI 30 g of intermediate FI was dissolved in 130 g of 2-methyltetrahydrofuran. 9.3 g of NaOH (in water, 30%) was added, and the resulting solution was heated at 50°C for 3 hours, cooled to 5°C, and the pH was adjusted to 9.3 using 1M aqueous HCl. These phases were separated, and the organic phase was washed with water. The organic solvent was exchanged with 2-propanol, and 3.3 g of water was added at room temperature. A solution of 6.3 g of L-proline in 8.5 g of water and 42 g of 2-propanol was added within 4 hours at 23°C, and seed crystals were added during the addition. The resulting suspension was cooled to 5°C and stirred for 1 hour, and the product was filtered. After washing with a solvent mixture consisting of 60 g of 2-propanol and 3.5 g of water and drying in vacuo, the final crystalline compound had a purity of 100% (analysis by HPLC) and a total yield of 87%.

[0028] (Example 2) Preparation of the final intermediate FI starting from intermediates I1 and I2 - Variant A 628 mg of Intermediate I1 (X = Br) dissolved in 8 mL of tetrahydrofuran (THF) was reacted with 2.4 mL of tert-butyllithium (1.7 M in pentane) at -100 °C for 15 minutes. 934 mg of Intermediate I2 (PG = trimethylsilyl, TMS) dissolved in 5 mL of THF was added, and the reaction mixture was maintained at -80 °C. After 1 hour, the reaction was quenched with 14 mL of saturated aqueous ammonium chloride solution, then extracted with ethyl acetate, dehydrated over magnesium sulfate, and the solution was concentrated. The residue was dissolved in 9.4 mL of a solvent mixture of methanol and 0.32 mL of methanesulfonic acid, and this mixture was maintained at 55 °C. After 16 hours, the pH was adjusted to 8 by adding saturated sodium bicarbonate solution and concentrated in vacuo. This residue was partitioned between ethyl acetate and saturated sodium chloride solution. The organic phase was dehydrated over magnesium sulfate and concentrated in vacuo to give Intermediate I4.

[0029] 1400 mg of the residue containing Intermediate I4 was reduced at 22 °C for 1 hour with 1.17 g of triethylsilane and 1.6 g of boron trifluoride diethyl etherate in a mixture consisting of 4.5 g of dichloroethane and 5 g of acetonitrile. The reaction mixture was added to 12 hg of 2N aqueous sodium hydroxide solution and extracted with TBME. The organic phase was concentrated in vacuo, treated twice with 7 g of MeOH, and the solvent was evaporated until the volume was reduced to 1 / 5. Next, this residue was dissolved in 8 g of THF, and Intermediate FI was obtained by acetylation using 2.2 g of acetic anhydride, 2.5 g of N-methylmorpholine, and a catalytic amount of 4-(dimethylamino)-pyridine. Isolation and crystallization from aqueous methanol (1:1) gave Intermediate I1 in 98.4% purity and 26% overall yield.

[0030] (Example 3) Preparation of Final Intermediate FI Starting from Intermediates I1 and I2 - Variant B Intermediate I4 can be obtained as described in Example 2. In 5 mL of dichloromethane, 220 mg of Intermediate I4 was acetylated using 0.24 mL of acetic anhydride, 390 mg of N,N - diisopropylethylamine, and a catalytic amount of 4 - (dimethylamino) - pyridine. After workup extraction with water, dehydration with magnesium sulfate, and evaporation of the solvent in vacuo, 320 mg of acetylated Intermediate I6 was reduced in 4 mL of acetonitrile containing 0.19 mL of triethylsilane, 0.11 mL of boron trifluoride diethyl etherate, and 1 equivalent of water. The purity of Intermediate FI was >85%, and the yield was 26%.

[0031] (Example 4a) Preparation of Intermediate I1 Starting from Intermediates I7 and I8 6.6 g of Intermediate I7 and 8 g of Intermediate I8 (Hal = F, X = I) were dissolved in 28.5 g of tetrahydrofuran and 6.2 g of dimethylformamide. To this mixture, a solution of 8 g of potassium tert - butoxide in 59 g of tetrahydrofuran was added at - 20 °C, and the mixture was stirred for 1 hour. The reaction was quenched by adding 27.2 g of water and 13.2 g of 30% aqueous sodium hydroxide solution. Next, the resulting mixture was stirred at 55 °C for 16 hours and cooled to 22 °C. 10 g of acetic acid and 25 g of water were added, and the phases were separated. 67.5 g of isopropyl acetate was added to the organic phase. The organic phase was washed with 67 g of 5% aqueous sodium chloride solution, and the solvent was exchanged to 2 - propanol. The product was crystallized from 2 - propanol by adding seed crystals and cooling to 15 °C. The product was filtered and washed with 2 - propanol to obtain Intermediate I1 with a purity of 97% and a yield of 50%.

[0032] (Example 4b) Preparation of Intermediate I1 Starting from Intermediates I7 and I8 Example 4a was repeated using Intermediate I8 (Hal = F, X = Br). The overall yield was 47%, and the purity of the intermediate was >90%.

[0033] (Example 5) Preparation of Intermediate I7 In tetrahydrofuran, in the presence of triphenylphosphine (0.06 equivalent) and palladium(II) acetate (0.05 equivalent), cyclopropylmagnesium bromide (1.0 equivalent), zinc chloride (1.3 equivalents) and ethyl 2-(4-bromophenyl)acetate (1.0 equivalent) were mixed at a temperature of 50 °C to prepare Intermediate I7. Aftertreatment by extraction using ethyl acetate and water gave a crude product, which was purified by distillation. Yield = 70%. Purity > 97.0%.

[0034] (Example 6) Alternative synthetic route

Chemical formula

[0035] Alternatively, the final intermediate FI can be synthesized by introducing a cyclopropyl moiety at a later stage of the synthesis, as shown in the scheme above. Instead of using compound 2, the corresponding aryl bromoiodobenzonitrile may be used. The aryl bromoiodobenzonitrile can be obtained by nucleophilic aromatic substitution / decarboxylative coupling between 2-fluoro-4-iodobenzonitrile and ethyl 4-bromophenylacetate. Next, the same chemical sequence of halogen-metal exchange / lactone addition / acidic methanol / reduction / acetylation can be applied to the aryl bromoiodobenzonitrile. It is then necessary to introduce the cyclopropyl moiety of the product isolated from the above sequence by a transition metal-catalyzed reaction with a suitable cyclopropyl species such as cyclopropylboronic acid to obtain the final intermediate FI.

[0036] Specifically, 2-fluoro-4-bromobenzonitrile is reacted with isopropylmagnesium chloride and iodine to obtain 2-fluoro-4-iodobenzonitrile. Next, the intermediate compound thus obtained is coupled with ethyl 4-bromophenylacetate and then decarboxylated to obtain 2-(4-bromobenzyl)-4-iodo-benzonitrile. Next, with respect to the production of the final intermediate (FI), using intermediates I3, I4 and I5 involved having a bromo substitution instead of the cyclopropyl substitution shown in the distal benzyl moiety, the method described and claimed herein, i.e., in the same chemical synthesis sequence of halogen-metal exchange / lactone addition / acidic reduction / acetylation as in steps (b) and (c), 2-(4-bromobenzyl)-4-iodo-benzonitrile is reacted with the intermediate "I2" [PG = trimethylsilyl (TMS)], reduced, and acetylated. At the end of this chemical synthesis sequence, the cyclopropyl moiety is introduced into the corresponding bromo analog of the final intermediate (FI) by a transition metal catalyzed reaction with a suitable cyclopropyl species such as cyclopropylboronic acid to obtain the final intermediate (FI). Next, the final intermediate (FI) is subjected to the method for producing the crystalline compound 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene L-proline monohydrate of formula (I) described and claimed herein

[0037] 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

Claims

1. A method for the preparation 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 steps of: (a) deacetylating the final intermediate (FI); (b) forming a crystalline compound according to formula (I) by reacting the deacetylated final intermediate of step (a) with L-proline and water to allow for isolation of the final reaction product. A method comprising: 【Chemistry 1】

2. The deacetylation step (a) comprises the steps of: (a1) reacting the final intermediate (FI), dissolved in at least one organic solvent, preferably methyltetrahydrofuran (MeTHF), with water in the presence of a base, preferably NaOH; (a2) optionally exchanging at least one organic solvent, preferably methyltetrahydrofuran (MeTHF), of the organic phase obtained in step (a1) for at least one different organic solvent, preferably 2-propanol, and optionally adding water; The method of claim 1 , comprising:

3. The step (b) of forming a crystalline compound comprises: (b1) adding L-proline obtained in step (a1) or, optionally, in step (a2), dissolved in at least one different organic solvent, preferably 2-propanol and water, to an aqueous-organic phase mixture, preferably 2-propanol and water, and incubating such reaction mixture. (b2) isolating the crystalline compound 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene-L-proline monohydrate according to formula (I) from the reaction mixture of step (b1). The method of claim 1 or 2, further comprising:

4. below: (a) reacting intermediate I1 (X is Br or I) with at least one metallation agent, preferably turbo-Grignard (iPrMgCl*LiCl), and then adding the reaction product of such metallation to intermediate I2 (PG is a protecting group, preferably trimethylsilyl (TMS)) to obtain intermediate I3; (b) methylating intermediate I3 to obtain intermediate I4. (c) reducing intermediate I4 with a reducing agent, preferably a silane, more preferably triethylsilane, to obtain intermediate I5; (d) acetylation of intermediate I5 to give final intermediate FI. A process for the preparation of a final intermediate (FI), comprising: A process for the preparation, wherein preferably at least one, more preferably all, of intermediates I3, I4 and / or I5 are not isolated and / or purified prior to further processing, i.e., prior to carrying out steps (b), (c) and / or (d), respectively. 【Chemistry 2】

5. below: (a) reacting intermediate I1 (X is Br or I) with at least one metallation agent, preferably turbo-Grignard (iPrMgCl*LiCl), and then adding the reaction product of such metallation to intermediate I2 (PG is a protecting group, preferably trimethylsilyl (TMS)) to obtain intermediate I3; (b) methylating intermediate I3 to obtain intermediate I4. (c) acetylating intermediate I4 to obtain intermediate I6. (d) reducing intermediate I6 with a reducing agent, preferably a silane, more preferably triethylsilane, to obtain the final intermediate FI. A process for the preparation of a final intermediate (FI), comprising: A process for the preparation, wherein preferably at least one, more preferably all, of intermediates I3, I4 and / or I6 are not isolated and / or purified prior to further processing, i.e., prior to carrying out steps (b), (c) and / or (d), respectively. 【Chemistry 3】

6. 6. The method according to claim 4 or 5, wherein X is I and / or PG is trimethylsilyl (TMS), preferably X is I and PG is trimethylsilyl (TMS).

7. below: (a) reacting intermediate I7 ​​with intermediate I8 (X is Br or I, Hal is F or Cl) in the presence of a base, preferably potassium t-butoxide (KOtBu), to obtain intermediate I1; (b) isolating intermediate I1 from the reaction mixture of step (a). A method for preparing intermediate I1, comprising: 【Chemistry 4】

8. 8. The method 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: 【Chemistry 5】 【change】

10. 10. The intermediate compound of claim 9, selected from the group consisting of: 【Chemistry 6】

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

12. Use of an intermediate compound according to any one of claims 9 to 11 in a method according to any one of claims 1 to 8.

13. below: (a) reacting 2-fluoro-4-bromobenzonitrile with isopropylmagnesium chloride and iodine to obtain 2-fluoro-4-iodobenzonitrile; (b) then coupling the 2-fluoro-4-iodobenzonitrile with ethyl-4-bromophenylacetate followed by decarboxylation to give 2-(4-bromobenzyl)-4-iodo-benzonitrile; (c) then reacting 2-(4-bromobenzyl)-4-iodo-benzonitrile with intermediate "I2" [PG = trimethylsilyl (TMS)] to reduce and acetylate using participating intermediates I3, I4 and I5, which have a bromo substitution instead of the cyclopropyl substitution shown on the distal benzyl moiety, in a chemical synthesis sequence of halogen-metal exchange / lactone addition / acidic reduction / acetylation as described in steps (b) and (c) of claim 4; (d) then introducing the cyclopropyl moiety into the corresponding bromo analogue of final intermediate (FI) by transition metal catalyzed reaction with an appropriate cyclopropyl species, such as cyclopropylboronic acid, to give final intermediate (FI). (e) then subjecting the final intermediate (FI) to the process for the preparation of the crystalline compound 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene-L-proline monohydrate according to formula (I) as claimed in any one of claims 1 to 3. The crystalline compound 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene L-proline monohydrate according to formula (I) comprises, preferably consists of 【Chemistry 7】 Manufacturing method.

14. The steps according to the following synthetic route: 【Chemistry 8】 (The above abbreviations have the following meanings: iPrMgCl = isopropylmagnesium chloride; I2 = iodine; THF = tetrahydrofuran; MeTHF = 2-methyltetrahydrofuran; tBuOK = potassium tert-butoxide; DMF = dimethylformamide; NaOH = sodium hydroxide; iPrMgCl.LiCl = isopropylmagnesium chloride lithium chloride; TMS = tetramethylsilane; 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) 14. The method of claim 13, comprising, preferably consisting of:

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