METHOD FOR PRODUCING DIPHENYLMETHANE DERIVATIVE

• US 20190169174A1
• Filed: 06/15/2017
• Published: 06/06/2019
• Est. Priority Date: 06/17/2016
• Status: Active Grant

• Current Assignee: Daewoong Pharmaceutical Company Limited, Green Cross Corporation (Green Cross Holdings Corporation)
• Original Assignee: Daewoong Pharmaceutical Company Limited, Green Cross Corporation (Green Cross Holdings Corporation)
• Inventors: YOON, Hee-kyoon, PARK, Se-Hwan, YOON, Ji-Sung, CHOI, Soongyu, SEO, Hee Jeong, PARK, Eun-Jung, KONG, Younggyu, SONG, Kwang-Seop, KIM, Min Ju, PARK, So Ok
• Granted Patent: US 10,640,496 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: B01D 9/005 Selection of auxiliary, e.g. for control of crystallisation nuclei, of crystal growth, of adherence to walls; Arrangements for introduction thereof
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07B 51/00 Introduction of protecting groups or activating groups, not provided for in the preceding groups
• CPC Class Codes: C07D 307/78 Benzo [b] furans; Hydrogenated benzo [b] furans
• CPC Class Codes: C07D 407/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention relates to an improved method for producing a diphenylmethane derivative which is effective as a sodium-dependent glucose cotransporter (SGLT) inhibitor, the method being carried out by means of a convergent synthesis method in which each major group is separately synthesized and then coupled. As such, in comparison to a linear synthesis method disclosed in existing documents, the synthesis pathway is compact and yield can be increased, and risk factors inherent in the linear synthesis pathway can be reduced. Furthermore, the crystal form of the compound produced according to the method has superb physicochemical characteristics, and thus can be effectively utilized in fields such as pharmaceutical manufacturing.

Claims

1. A method for producing a compound of the following Formula 1a, the method comprising the steps of:

(1) reacting a compound of the following Formula 2 with a compound of the following Formula 3 and subjecting the resultant to a cyclization reaction, to obtain a compound of the following Formula 4;

(2) subjecting the compound of Formula 4 to aldehydation or amidation, followed by reacting the resultant with a compound of the following Formula 5 and performing reduction, to obtain a compound of the following Formula 6; and

(3) reacting the compound of Formula 6 with a compound of the following Formula 7, and performing deprotection and reduction,

2. The method for producing the compound of Formula 1a according to claim 1,

wherein the step (1) includes the steps of:

(i) reacting the compound of Formula 2 with the compound of Formula 3 to obtain a compound of the following Formula 3a;

(ii) subjecting an allyl group of the compound of Formula 3a to a rearrangement reaction and subjecting the resultant to an oxidation or ozonation reaction followed by performing reduction, to obtain a compound of the following Formula 3d; and

(iii) subjecting the compound of Formula 3d to a cyclization reaction, to obtain the compound of Formula 4,

3. The method for producing the compound of Formula 1a according to claim 2,

wherein the cyclization reaction is a cyclization reaction using a Vilsmeier reagent, a cyclization reaction using a leaving group, a cyclization reaction using a halide, or a cyclization reaction using a Mitsunobu reaction.

4. The method for producing the compound of Formula 1a according to claim 1,

wherein the step (2) includes subjecting the compound of Formula 4 to aldehydation, to obtain a compound of the following Formula 4a, and then reacting the compound of Formula 4a with the compound of Formula 5,

5. The method for producing the compound of Formula 1a according to claim 1,

wherein the step (2) includes subjecting the compound of Formula 4 to amidation, to obtain a compound of the following Formula 4b, and then reacting the compound of Formula 4b with the compound of Formula 5,

6. The method for producing the compound of Formula 1a according to claim 1,

wherein the method further comprises an alkylation reaction after the step (3), and X′

is C_1-7 alkyl.

7. The method for producing the compound of Formula 1a according to claim 1,

wherein the step (3) further includes isolating only a compound in which glucose is in a β

-form, after or during the deprotection and reduction process.

8. The method for producing the compound of Formula 1a according to claim 1,

wherein the step (3) is carried out by the method comprising the steps of:

(3a-1) reacting the compound of Formula 6 with the compound of Formula 7 in the presence of n-butyllithium, sec-butyllithium, t-butyllithium, or i-propylmagnesium chloride, to obtain a compound of the following Formula 7a;

(3a-2) subjecting the compound of Formula 7a to deprotection and methylation reactions under an acid condition in the presence of methanol, to obtain a compound of the following Formula 7d;

(3b) reducing the compound of Formula 7b to obtain a compound of the following Formula 7e; and

(3c) introducing a protecting group into the compound of Formula 7e, heating the resultant in alcohol, ethyl acetate, or dichloromethane, and isolating and deprotecting the resulting precipitate, to obtain only a β

-form,

9. The method for producing the compound of Formula 1a according to claim 1,

wherein the step (3) is carried out by the method comprising the steps of:

(3a′

) reacting the compound of Formula 6 with the compound of Formula 7 in the presence of n-butyllithium, sec-butyllithium, t-butyllithium, or i-propylmagnesium chloride, and subjecting the resultant to deprotection and methylation reactions under an acid condition in the presence of methanol without a separate purification, to obtain a compound of the following Formula 7d;

(3b′

) reducing the compound of Formula 7d to obtain a compound of the following Formula 7e; and

(3c′

) introducing a protecting group into the compound of Formula 7e to isolate only a (3-form, and performing deprotection,

10. The method for producing the compound of Formula 1a according to claim 1,

wherein the step (3) is carried out by the method comprising the steps of:

(3a″

) reacting the compound of Formula 6 with the compound of Formula 7 in the presence of n-butyllithium, sec-butyllithium, t-butyllithium, or i-propylmagnesium chloride, and subjecting the resultant to deprotection and methylation reactions under an acid condition in the presence of methanol without a separate purification, to obtain a compound of the following Formula 7d;

(3b″

) introducing a protecting group into the compound of Formula 7d to obtain a compound of the following Formula 7f; and

(3c″

) isolating only a β

-form of the compound of Formula 7f and performing reduction, and then performing deprotection,

11. The method for producing the compound of Formula 1a according to claim 9, wherein each of the compound of Formula 7 and n-butyllithium is used in an amount of 1.5 to 2.5 equivalents with respect to 1 equivalent of the compound of Formula 6.

12. The method for producing the compound of Formula 1a according to claim 1,

wherein the method further comprises a step of performing crystallization using a solvent selected from the group consisting of toluene, ethyl acetate, dichloromethane, a mixture of tetrahydrofuran and dichloromethane, and a mixture of tetrahydrofuran and n-hexane, after the step (3).

13. The method for producing the compound of Formula 1a according to claim 1,

wherein n is 1.

14. The method for producing the compound of Formula 1a according to claim 1,

wherein A is oxygen;

n is 1;

X′

is halogen; and

B is phenyl which is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C_1-7 alkyl, C_3-10 cycloalkyl, and C_1-7 alkoxy.

21. The method for producing the compound of Formula 1a according to claim 10, wherein each of the compound of Formula 7 and n-butyllithium is used in an amount of 1.5 to 2.5 equivalents with respect to 1 equivalent of the compound of Formula 6.

15. A method for producing a compound of the following Formula 1b, the method comprising the steps of:

(1) reacting a compound of the following Formula 2 with a compound of the following Formula 3 and subjecting the resultant to a cyclization reaction, to obtain a compound of the following Formula 4;

(2) subjecting the compound of Formula 4 to aldehydation or amidation, followed by reacting the resultant with the compound of Formula 5 and performing reduction, to obtain a compound of the following Formula 6;

(3) reacting the compound of Formula 6 with a compound of the following Formula 8 and then performing reduction, to obtain a compound of the following Formula 9;

(4) forming a furanose ring of the compound of Formula 9 into a pyranose ring under an acidic condition and then introducing a protecting group thereinto, to obtain a compound of the following Formula 10; and

(5) treating the compound of Formula 10 with thiourea, reacting the resultant with C_1-7 alkyl halide, and then performing reduction,

16. A crystalline form of a compound of the following Formula c28.

17. The crystalline form according to claim 16,

wherein the crystalline form has an X-ray diffraction (XRD) spectrum which includes peaks at diffraction angles (2θ

) of 6.2°

±

0.2°

, 7.2°

±

0.2°

, 8.8°

±

0.2°

, 17.6°

±

0.2°

, 19.0°

±

0.2°

, 22.5°

±

0.2°

, and 25.1°

±

0.2°

in a case of being irradiated using a Cu—

K_α

light source.

18. The crystalline form according to claim 16,

wherein the crystalline form has an X-ray diffraction (XRD) spectrum which includes peaks at diffraction angles (2θ

) of 7.0°

±

0.2°

, 14.9°

±

0.2°

, 17.7°

±

0.2°

, 18.8°

±

0.2°

, 20.6°

±

0.2°

, 21.8°

±

0.2°

, and 23.5°

±

0.2°

in a case of being irradiated using a Cu—

K_α

light source.

19. The crystalline form according to claim 16,

wherein the crystalline form has an X-ray diffraction (XRD) spectrum which includes peaks at diffraction angles (2θ

) of 5.6°

±

0.2°

, 7.3°

±

0.2°

, 15.7°

±

0.2°

, 17.2°

±

0.2°

, 18.9°

±

0.2°

, 21.2°

±

0.2°

, and 21.9°

±

0.2°

in a case of being irradiated using a Cu—

K_α

light source.

20. The crystalline form according to claim 16,

wherein the crystalline form has an X-ray diffraction (XRD) spectrum which includes peaks at diffraction angles (2θ

) of 5.5°

±

0.2°

, 7.2°

±

0.2°

, 15.3°

±

0.2°

, 17.2°

±

0.2°

, 17.6°

±

0.2°

, 18.9°

±

0.2°

, and 21.1°

±

0.2°

in a case of being irradiated using a Cu—

K_α

light source.