EA044433B1 - SYNTHESIS OF A 1:1:1 CO-CRYSTAL OF 1-CYANO-2-(4-CYCLOPROPYLBENZYL)-4-(β-D-Glucopyranose-1-YL)BENZENE, L-PROLINE AND WATER - Google Patents

Description

Field of technology to which the invention relates

The invention relates to the field of chemistry, in particular synthetic chemistry. In particular, the invention relates to the synthesis of crystalline L-proline 1-cyano-2-(4-cyclopropylbenzyl)-4-(β-Oglucopyranos-1-yl)benzene monohydrate, more preferably a 1:1:1 co-crystal of all three crystalline components 1-cyano-2-(4-cyclopropylbenzyl)-4-(in-O-glucopyranos-1-yl)benzene, L-proline and water.

Prerequisites for creating the invention

WO 2007/093610 describes glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their medical uses, as well as methods for their preparation. Among many other compounds, 1-cyano-2-(4-cyclopropylbenzyl)-4-(β-Dglucopyranos-1-yl)benzene has also been described.

WO 2007/128749 relates to glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their medicinal uses, as well as methods for their preparation. Among many other compounds, 1-cyano-2-(4cyclopropylbenzyl)-4-(β-D-glucopyranos-1-yl)benzene has also been described.

WO 2014/016381 describes crystalline complexes of 1-cyano-2-(4-cyclopropylbenzyl)-4-(β-Dglucopyranos-1-yl)benzene with natural amino acids, methods for their preparation, as well as their use in the preparation of medicinal products. Although the WO publication describes crystalline 1-cyano-2-(4-cyclopropylbenzyl)-4-(β-D-glucopyranos-1-yl)benzene L-proline, this reference does not explicitly mention the monohydrate 1 -cyano-2-(4-cyclopropylbenzyl)-4-(β-Dglucopyranose-1 -yl)benzene L-proline.

Another prior art source is the following document: Li-Yuan Bao et al. (Chem. Commun. 2015, 32: 6884-6900), which provides an overview of the progress and developments for the i-PrMgCl-LiCl turbo Grignard reagent.

The known level of technology is characterized by the following disadvantages:

1-cyano-2-(4-cyclopropylbenzyl)-4-(in-O-glucopyranos-1-yl)benzene is present as a crude substance in an amorphous oil, which cannot be processed technically and on an industrial scale without additional processing/modification , complex synthesis of 1-cyano-2-(4-cyclopropylbenzyl)-4-(in-O-glucopyranos-1-yl)benzene with various intermediate steps, commercially unavailable suitable starting material required for the synthesis of precursors for the final synthesis of 1- cyano-2-(4-cyclopropylbenzyl)-4-(in-O-glucopyranos-1-yl)benzene.

Thus, the object underlying the present invention is to provide a synthesis method that overcomes the problems of the prior art described above.

The essence of the invention

The present invention provides, in one aspect, a method for preparing the crystalline compound L-proline 1-cyano-2-(4-cyclopropylbenzyl)-4-(β-D-glucopyranos-1-yl)benzene monohydrate according to formula (I), which includes the following stages:

(a) deacetylation of the final intermediate (FI);

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

H ₂ O

In another aspect, the present invention provides a method for preparing the final intermediate (FI), which includes the following steps:

(a) reacting intermediate I1, where 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 I2, where PG

- 1044433 represents a protecting group, preferably trimethylsilyl (TMS), giving 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, yielding intermediate I5;

(d) acetylation of intermediate I5, yielding the final intermediate FI;

where 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., steps (b), (c) and/ or (d) respectively.

N

(V)

In a further aspect, the present invention provides a method for preparing the final intermediate (FI), which includes the following steps:

(a) reacting intermediate I1, where 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 I2, where PG is a protecting group, preferably trimethylsilyl (TMS), giving intermediate I3;

(b) treating intermediate I3 with methanol to obtain intermediate I4;

(c) acetylation of intermediate I4, yielding intermediate I6;

(d) reducing intermediate I6 with a reducing agent, preferably a silane, more preferably triethylsilane, yielding the final intermediate FI;

wherein 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. steps (b), (c) and/ or (d) respectively.

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In one aspect, the present invention provides a method for preparing an intermediate

In yet another compound I1, which includes the following steps:

(a) reacting intermediate I7 with intermediate I8, where X is Br or I and where Hal is F or Cl, in the presence of a base, preferably potassium tert-butoxide (KOtBu), producing intermediate I1;

(b) isolating intermediate I1 from the reaction mixture from step (a).

In yet another aspect, the present invention provides a crystalline L-proline 1-cyano-2-(4-cyclopropylbenzyl)-4-(in-O-glucopyranos-1-yl)benzene monohydrate compound according to Formula (I)

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In yet another aspect, the present invention provides an intermediate selected from the group consisting of intermediates (1)-(13)

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In yet another aspect, the present invention provides an intermediate selected from intermediates (1)-(13) as described herein, prepared by one or more methods in accordance with the present invention as described herein.

In a still further aspect, the present invention provides the use of an intermediate selected from intermediates (1)-(13) as described herein in one or more methods in accordance with the present invention as described herein.

The synthetic methods of the present invention have the following advantages: the 1:1:1 cocrystal can be technically processed, unlike the oil form of the free compound, i.e. crystallized, isolated, characterized and further processed on an industrial scale, non-obvious chemistry: it is extremely difficult to develop a strategy synthesis involving a molecule with a benzonitrile component - using an organomagnesium or lithium compound, as for the synthesis of non-cyanated glycosides, can be problematic since the nitrile component may interfere with the halogen-metal exchange reaction and the subsequent addition reaction, a shorter/more efficient/more economical synthesis route due to the incorporation of the cyano group into the aglycone from the very beginning, instead of its incorporation subsequently from a halogenated, brominated or chlorinated precursor in an additional synthetic step, commercially available starting materials or starting materials that can be easily prepared.

Detailed Description of the Invention

Before embodiments in accordance with the present invention are described in detail, it should be noted that, as used in this application and in the appended claims, the singular forms include references to the plural unless the context clearly indicates otherwise.

Unless otherwise specified, all technical and scientific terms used in this application have the same meanings as commonly understood by one of ordinary skill in the art to which

- 5 044433 relates to the present invention. All ranges and values given may vary from 1 to 5% unless otherwise stated or otherwise known to one skilled in the art, so the term approximately is generally omitted from the specification and claims. Although any methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention, preferred methods, devices and materials will be described below. All publications mentioned herein are incorporated herein by reference for the purpose of describing and disclosing substances, excipients, carriers and techniques as described in the publications that may be used in connection with the present invention. Nothing in this application should be construed to imply that the invention is not entitled to backdate such disclosure by virtue of a prior invention.

In the context of the present invention, the crystalline compound 1-cyano-2-(4cyclopropylbenzyl)-4-(β-D-glucopyranos-1-yl)benzene L-proline monohydrate is herein understood as a 1:1:1 co-crystal of all three crystalline components 1-cyano-2-(4-cyclopropylbenzyl)-4-(β-Dglucopyranos-1-yl)benzene, L-proline and water, as represented by formula (I)

Such a 1:1:1 cocrystal is physicochemically characterized in WO 2014/016381.

In a preferred embodiment, the present invention provides a method for preparing a crystalline L-proline 1-cyano-2-(4-cyclopropylbenzyl)-4-(in-O-glucopyranos-1yl)benzene monohydrate compound according to formula (I), which comprises the following stages:

(a) deacetylation of the final intermediate (FI);

(b) forming a crystalline compound according to formula (I) by reacting the deacetylated final intermediate from step (a) with L-proline and water and isolating the final reaction product;

where the deacetylation step (a) includes the following steps:

(a1) reacting the final intermediate (FI) dissolved in at least one organic solvent, preferably methyltetrahydrofuran (MeTHF), in the presence of a base, preferably NaOH, and water;

(a2) optionally replacing at least one organic solvent of the organic phase used in step (a1), preferably methyltetrahydrofuran (MeTHF), with at least one different organic solvent, preferably 2-propanol, and optionally adding water.

Preferably, step (b) of forming a crystalline compound further includes the following steps:

(b1) adding L-proline, which is dissolved in at least one different organic solvent, preferably 2-propanol, and water, to the water-organic phase mixture, preferably 2-propanol and water, used in step (a1) or optionally step (a2), and incubating such reaction mixture;

(b2) isolating the crystalline compound 1-cyano-2-(4-cyclopropylbenzyl)-4-(inD-glucopyranos-1-yl)benzene L-proline monohydrate according to formula (I) from the reaction mixture of step (b1).

In another preferred embodiment, the present invention provides a method for preparing the final intermediate (FI), which includes the following steps:

(a) reacting intermediate I1, where 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 I2, where PG is a protecting group, preferably trimethylsilyl (TMS), giving 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, yielding intermediate I5;

- 6 044433 (d) acetylation of intermediate I5, yielding the final intermediate

FI;

where 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., carrying out steps (b), (c) and/ or (d), respectively; and where 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 a method for preparing the final intermediate (FI), which includes the following steps:

(a) reacting intermediate I1, where 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 I2, where PG is a protecting group, preferably trimethylsilyl (TMS), giving intermediate I3;

(b) treating intermediate I3 with methanol to obtain intermediate I4;

(c) acetylation of intermediate I4, yielding intermediate I6;

(d) reducing intermediate I6 with a reducing agent, preferably a silane, more preferably triethylsilane, yielding the final intermediate FI;

where 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., steps (b), (c) and/ or (d), respectively; and where X is I and/or PG is trimethylsilyl (TMS), preferably X is I and PG is trimethylsilyl (TMS).

In principle, any protecting group known to one skilled in the art can be used. Typical protecting 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 ( RMV), 2-naphthylmethyl (Nap), 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethylcarbonyl (Troc), methyl and others. A preferred protecting group (PG) in accordance with the present invention is trimethylsilyl (TMS).

With regard to the reducing agent, in principle, any suitable reducing agent known to one skilled in the art can be used. Typical reducing agents in accordance with 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 others. The preferred reducing agent is silane, more preferably triethylsilane. In yet another preferred embodiment, the present invention provides a method for preparing intermediate I1, which includes the following steps:

(a) reacting intermediate I7 with intermediate I8, where X is Br or I and where Hal is F or Cl, in the presence of a base, preferably potassium tert-butoxide (KOtBu), producing intermediate I1;

(b) isolating intermediate I1 from the reaction mixture from step (a);

where 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 an intermediate selected from the group consisting of

Examples

The following examples are presented to further illustrate the present invention; but at the same time they should not be construed as limiting the scope of the invention disclosed in this application.

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Example 1 Preparation of 1-cyano-2-(4-cyclopropylbenzyl)-4-(β-D-glucopyranos-1yl)benzene L-proline monohydrate according to formula (I), using intermediate FI as starting material.

g of intermediate FI was dissolved in 130 g of 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. The phases were separated and the organic phase was washed with water. The organic solvent was replaced with 2-propanol and 3.3 g of 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. over 4 hours, and seeded during addition. The resulting suspension was cooled to 5°C, stirred for 1 hour, and the product was filtered. After washing with a solvent mixture of 60 g of 2-propanol and 3.5 g of water, and drying in vacuo, the final crystalline compound was 100% pure (assayed by HPLC) and the overall yield was 87%.

Example 2 Preparation of the final intermediate FI using intermediates I1 and I2 as starting materials - option A.

628 mg of intermediate I1, X = Br, dissolved in 8 ml of tetrahydrofuran (THF), were reacted for 15 minutes with 2.4 ml of tert-butyllithium (1.7 M in pentane) at -100°C. 934 mg of intermediate I2 (PG = trimethylsilyl, TMS) dissolved in 5 ml THF was added and the reaction mixture was kept at -80°C. After 1 hour, the reaction was quenched with 14 ml of saturated aqueous ammonium chloride, followed by extraction with ethyl acetate, drying over magnesium sulfate and concentration of the solution. The residue was dissolved in 9.4 ml of a mixture of methanol solvents and 0.32 ml of methanesulfonic acid was added, maintaining the mixture at 55°C. After 16 h, the pH was adjusted to 8 by adding saturated sodium bicarbonate solution and 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 give intermediate I4.

1400 mg of the residue containing intermediate I4 was reduced with 1.17 g of triethylsilane and 1.6 g of boron trifluoride diethyl etherate in a mixture of 4.5 g of dichloromethane and 5 g of acetonitrile at 22° C. for 1 hour. The reaction mixture was added to 12 g 2n. aqueous sodium hydroxide solution and extracted with TVME. The organic phase was concentrated in vacuo and treated twice with 7 g of MeOH and evaporated to 1/5 volume. The residue was then dissolved in 8 g THF to prepare intermediate FI by acetylation with 2.2 g acetic anhydride, 2.5 g Nmethylmorpholine and a catalytic amount of 4-(dimethylamino)pyridine. Isolation and crystallization from aqueous methanol (1:1) afforded intermediate I1 in 98.4% purity and 26% overall yield.

Example 3 Preparation of the final intermediate FI using intermediates I1 and I2 as starting materials - option B.

Intermediate I4 was prepared as described in Example 2. 220 mg of intermediate I4 was acetylated with 0.24 ml acetic anhydride, 390 mg N,N-diisopropylethylamine, and a catalytic amount of 4-(dimethylamino)pyridine in 5 ml dichloromethane. After aqueous extractive workup, drying over magnesium sulfate and evaporation in vacuo, 320 mg of acetylated intermediate I6 was reconstituted in 4 ml of acetonitrile using 0.19 ml of triethylsilane, 0.11 ml of boron trifluoride diethyl etherate and 1 equivalent of water. The purity of the FI intermediate was >85% and the yield was 26%.

Example 4a. Preparation of intermediate I1 using intermediates I7 and I8 as starting materials.

In 6.6 g of intermediate I7, 8 g of intermediate I8 (Hal = F, X = I) was dissolved in 28.5 g of tetrahydrofuran and 6.2 g of dimethylformamide, and a solution of 8 g of potassium tert-butoxide in 59 g of tetrahydrofuran was added to the mixture at -20°C and 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. After this, 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, the phases were separated and 67.5 g of isopropyl acetate was added to the organic phase. The organic phases were washed with 67 g of 5% aqueous sodium chloride solution and the solvent was replaced with 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, yielding intermediate I1 in 97% purity and 50% yield.

Example 4b. Preparation of intermediate I1 using intermediates I7 and I8 as starting materials.

Example 4a was repeated using intermediate I8 (Hal=F, X=Br). The overall yield was 47% and the purity of the intermediate was >90%.

Example 5 Preparation of intermediate I7.

Intermediate I7 was prepared by mixing cyclopropylmagnesium bromide (1.0 eq), zinc chloride (1.3 eq) and ethyl 2-(4-bromophenyl) acetate (1.0 eq) in the presence of triphenylphosphine ( 0.06 equiv.) and palladium(P) acetate (0.05 equiv.) in tetrahydrofuran at a temperature of 50°C. Extractive workup using ethyl acetate and water provided a crude product, which was purified by distillation. Yield 70%. Purity >97.0%.

Example 6. Alternative synthesis route.

Abbreviations:

iPrMgCl = isopropyl magnesium chloride; I2 = iodine; THF = tetrahydrofuran; MeTHF = 2methyltetrahydrofuran; tBuOK = potassium tert-butoxide; DMF = dimethylformamide; NaOH = sodium hydroxide; iPrMgCl-LiCl = isopropyl magnesium 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(P) acetate; PCy3 = tricyclohexylphosphine; PhMe = toluene; iPrOH = isopropanol.

Alternatively, the final FI intermediate can be synthesized by incorporating a cyclopropyl moiety at the last step of the synthesis, as shown in the scheme above. Instead of using compound 2, the corresponding arylbromiodobenzonitrile can be used. Arylbromoiodobenzonitrile can be prepared by nucleophilic aromatic substitution/decarboxylation coupling between 2-fluoro-4-iodobenzonitrile and ethyl 4-bromophenylacetate. The arylbromoiodobenzonitrile can then be subjected to a similar sequence of halogen-metal exchange/lactone addition/acid methanol/reduction/acetylation reactions. Then, if necessary, to incorporate the cyclopropyl component of the isolated product from this sequence via a transition metal catalyzed reaction with suitable cyclopropyl species such as cyclopropylboronic acid, yielding the final FI intermediate.

In more detail, 2-fluoro-4-bromobenzonitrile is reacted with isopropylmagnesium chloride and iodine to produce 2-fluoro-4-iodobenzonitrile. This resulting intermediate is then coupled with ethyl 4-bromophenylacetate and then decarboxylated to yield 2-(4-bromobenzyl)-4-iodobenzonitrile. 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/acid reduction/acetylation , similar to the method described and claimed herein for the preparation of the final intermediate (FI), steps (b) and (c), involving intermediates I3, I4 and I5 bearing a bromine substitution in place of the shown cyclopropyl substitution on the distal benzyl moiety. After completion of this chemical synthesis sequence, the cyclopropyl moiety is incorporated into the appropriate bromine analogue of the final intermediate (FI) via a transition metal catalyzed reaction with suitable cyclopropyl species such as cyclopropylboronic acid, yielding the final intermediate (FI). The final intermediate (FI) is then subjected to the process for the preparation of crystalline 1-cyano-2-(4-cyclopropylbenzyl)-4-(in-O-glucopyranos-1yl)benzene L-proline monohydrate compound according to formula (I) as described and claimed in this application.

Links.

(1) WO 2007/093610.

(2) WO 2007/128749.

(3) WO 2014/016381.

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

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Claims (13)

CLAIM 1. A method for obtaining the final intermediate (FI), which includes the following steps: (a) reacting intermediate I1, where X is I, with at least one metalation agent, and then adding the product of such metalation reaction to intermediate I2, where PG is a protecting group, producing intermediate I3; (b) methylating intermediate I3 to produce intermediate I4; (c) reducing intermediate I4 with a reducing agent to yield intermediate I5; (d) acetylation of intermediate I5, yielding the final intermediate FI; wherein all intermediates I3, I4 and I5 are not isolated and/or purified before further processing, i.e. steps (b)-(d), respectively 2. The method according to claim 1, wherein in step (a) the metalation agent is the Turbo-Grignard reagent, which is iPrMgCl-LiCl, and PG is trimethylsilyl (TMS), and in step (c) the reducing agent is silane or preferably triethylsilane. 3. A method for obtaining the final intermediate (FI), which includes the following steps: (a) reacting intermediate I1, where X is I, with at least one metalation agent, and then adding the product of such metalation reaction to intermediate I2, where PG is a protecting group, producing intermediate I3; (b) methylating intermediate I3 to produce intermediate I4; (c) acetylation of intermediate I4, yielding intermediate I6; (d) reducing intermediate I6 with a reducing agent to yield the final intermediate FI; wherein all intermediates I3, I4 and I6 are not isolated and/or purified before further processing, i.e. steps (b)-(d), respectively - 10 044433 4. The method according to claim 3, wherein in step (a) the metalation agent is the Turbo-Grignard reagent, which is iPrMgCl-LiCl, and PG is trimethylsilyl (TMS), and in step (d) the reducing agent is silane or preferably triethylsilane. 5. Method according to one of claims 1 to 4, wherein PG is trimethylsilyl (TMS). 6. Intermediate connection (2), which is 7. Intermediate connection (8), which is - 11 044433 8. The use of intermediate compound (2), which is to obtain the final intermediate (FI) in accordance with the method according to one of claims 1 to 5. 9. The use of intermediate compound (5), (6) or (8), which is the final intermediate (FI) in accordance with, respectively, for obtaining according to one of claims 1 to 5. 10. Method for preparing crystalline compound of 1-cyano-2-(4cyclopropylbenzyl)-4-(β-D-glucopyranos-1-yl)benzene L-proline monohydrate according to formula (I) including the following stages: (a) 2-fluoro-4-bromobenzonitrile is reacted with isopropylmagnesium chloride and iodine to give 2-fluoro-4-iodobenzonitrile; (b) 2-fluoro-4-iodobenzonitrile is then coupled with ethyl 4-bromophenylacetate and thereafter decarboxylated to give 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 the chemical synthesis sequence - 12 044433 halogen-metal exchange reactions/lactone addition/acid reduction/π acetylation. 1, steps (b) and (c), involving intermediates 13,14 and 15 bearing a bromine substitution instead of the shown cyclopropyl substitution on the distal benzyl moiety; (d) the cyclopropyl moiety is then incorporated into the corresponding bromine analogue of the final intermediate (FI) via a transition metal catalyzed reaction with cyclopropylboronic acid to produce the final intermediate (FI); (e) the final intermediate (FI) is then converted to the crystalline compound 1-cyano-2-(4-cyclopropylbenzyl)-4-(P-P-glucopyranos-1-yl)benzene L-proline monohydrate according to formula (I ), implementation of the following stages (A) and (B): (A) deacetylation of the terminal intermediate (FI); (B) forming a crystalline compound according to formula (I) by reacting the deacetylated final intermediate from step (A) with L-proline and water to permit isolation of the final reaction product 11. The method according to claim 10, where the deacetylation step (A) includes the following steps: (A1) reacting the final intermediate (FI) dissolved in at least one organic solvent, preferably methyltetrahydrofuran (MeTHF), in the presence of a base, preferably in the presence of NaOH, and water; and (A2) optionally replacing at least one organic solvent of the organic phase used in step (A1), preferably methyltetrahydrofuran (MeTHF), with at least one different organic solvent, preferably 2-propanol, and optionally adding water. 12. The method according to claim 10, where step (B) of forming a crystalline compound further includes the following steps: (B1) adding L-proline, which is dissolved in at least one different organic solvent, preferably 2-propanol, and water, to the water-organic phase mixture, preferably to the mixture of 2-propanol and water, used in step (A1) or optionally step (A2), and incubating such reaction mixture; and (B2) isolating the crystalline compound of 1-cyano-2-(4-cyclopropylbenzyl)-4-(3D-r lucopyranos-1-yl)benzene L-proline monohydrate according to formula (I) from the reaction mixture of step (B1). 13. Method according to one of pi. 10-12, including steps in accordance with the following synthesis route - 13 044433 where the above abbreviations have the following meanings: iPrMgCl = isopropyl magnesium chloride; 12 = iodine; THF = tetrahydrofuran; MeTHF = 2methyltetrahydrofuran; tBuOK = potassium tert-butoxide; DMF = dimethylformamide; NaOH = sodium hydroxide; iPrMgCl-LiCl = isopropyl magnesium chloride lithium chloride; TMS = trimethylsilyl; MeSO ₂ H = methanesulfonic acid; MeOH = methanol; EtaSiH = triethylsilane; BPz-E1: ₂ O = boron trifluoride etherate; Ac ₂ O = acetic anhydride; NMM = N-methylmorpholine; DMAP = 4-dimethylaminopyridine; Ac = acetyl; PdOAc ₂ = palladium(P) acetate; PCy3 = tricyclohexylphosphine; PhMe = toluene; iPrOH = isopropanol. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2