KR20230060921A - Novel ertugliflozin prodrug - Google Patents

Abstract

The present invention relates to a novel precursor of ertugliflozin. According to the precursor of the present invention, the physicochemical properties of ertugliflozin can be supplemented.

Description

Novel precursor of ertugliflozin {NOVEL ERTUGLIFLOZIN PRODRUG}

The present invention relates to an ertugliflozin precursor and a method for preparing the same. Specifically, it relates to a novel ertugliflozin precursor having improved bioavailability compared to the conventional main component of ertugliflozin and a method for preparing the same.

[Ertogliflozin]

Ertugliflozin of Formula 1 is a compound disclosed in Korean Patent Registration No. 10-1338540, and is an active ingredient used as an oral antidiabetic agent.

[Formula 1]

Ertugliflozin is known to inhibit the reabsorption of glucose in the kidneys and excrete glucose in the urine, thereby suppressing the rise in blood sugar.

[Conventional main ingredient of ertugliflozin]

Ertugliflozin is sold as Steglatro tablets. Steglatro tablets contain ertugliflozin L-pyroglutamic acid of Formula 2 as a main component.

[Formula 2]

Ertugliflozin L-pyroglutamic acid is disclosed in Korean Patent Registration No. 10-1446454, and is a co-crystal of ertugliflozin and L-pyroglutamic acid. This is the main ingredient proposed to improve the solubility of ertugliflozin.

Republic of Korea Patent Registration No. 10-1338540 Republic of Korea Patent Registration No. 10-1446454

Co-crystal refers to a state in which an active ingredient (API) and a co-crystal former are combined. A similar concept is the salt compound of FIG. 1 . However, salts refer to a state in which an active ingredient and a salt-former are bonded by an ionic bond, whereas a co-crystal is a state in which two ingredients are bonded by a weak mutual bond such as a hydrogen bond, a pi-pi bond, or a van der Waals bond.

There is no strict distinction between a salt and a co-crystal, but it is generally considered that a salt is formed when the pKa difference between the active ingredient and the forming material is 2 or more, and a co-crystal is formed when it is 2 or less.

The use of co-crystals can compensate for the physicochemical disadvantages of existing active ingredients. However, since the co-crystal is composed of weak mutual bonds, a special process is required for the bonding, and there is a limit in that there is a possibility that the intermolecular bonds may be broken after the co-crystal is successfully manufactured. If the bond between the active ingredient and the forming body is broken in the co-crystal, it becomes the active ingredient itself and the physicochemical disadvantages are exposed again as they are.

In the prior art, an attempt was made to manufacture a co-crystal with L-pyroglutamic acid or L-proline in order to compensate for the insufficient physicochemical disadvantages of an active ingredient called ertugliflozin. However, in order to overcome the limitations of the co-crystal, the present inventors have changed the conventional idea and started to develop a new precursor rather than a co-crystal.

1. Ertugliflozin precursor of Formula 3.

[Formula 3]

2. Ertugliflozin precursors of Formula 4.

[Formula 4]

The ertugliflozin precursor of the present invention exhibits better solubility and intestinal permeability than ertugliflozin. In addition, it has excellent stability compared to conventional ertugliflozin L-pyroglutamic acid co-crystals, and can maintain constant physicochemical properties.

1 is a diagram showing a conceptual explanation of a salt and a co-crystal.

Hereinafter, a preferred embodiment is presented to aid understanding of the present invention. However, it should be noted that the following examples are only reference information provided to more easily understand the present invention, and the scope of the present invention is not limited thereto.

[Synthesis method 1]

The ertugliflozin precursor of the present invention can be prepared according to Scheme 1.

Scheme 1

The reaction of Scheme 1 is as follows.

The compound of Formula 5 is synthesized by protecting the 4 hydroxyl groups of the compound of Formula 1 (Ertugliflizin) with 4 TMS protecting groups using chlorotrimethylsilane.

Subsequently, the compound of Formula 6 was synthesized by selectively deprotecting only the TMS protecting group attached to the terminal primary alcohol under acid conditions, followed by a nucleophilic acyl substitution reaction between cyclopropanecarboxylic acid anhydride and alcohol Use to introduce the desired ester functional group.

Thereafter, the ertugliflozin precursor of Chemical Formula 3 may be synthesized by removing the remaining four TMS protecting groups at once using tetra n -butyl ammonium fluoride.

In addition, after synthesizing an ester by treating the common compound of Formula 6 with chloroacetic anhydride, removing the remaining protecting group with tetra n -butyl ammonium fluoride, Ertuglifl of Formula 4 Rosin precursors can also be synthesized.

Specific examples according to Scheme 1 are as follows.

((( 1R , 2S ,3S, 4R , 5S )-5-(4- chloro -3-(4-ethoxybenzyl)phenyl)-1-(((trimethylsilyl)oxy)methyl)-6, Preparation of 8-dioxabicyclo[3.2.1]octane-2,3,4-triyl)tris(oxy))tris(trimethylsilane) (compound of Formula 5)

To a solution of 1.00 g and 2.29 mmol of the compound of formula 1 (Ertugliflizin) in 10 mL of dichloromethane, 1.91 mL of triethylamine and 13.73 mmol were added.

After stirring the reaction solution for 10 minutes, the temperature of the reaction solution was lowered to 0 °C, and then 1.74 mL of chlorotrimethylsilane, 13.73 mmol was added.

After stirring the reaction solution at room temperature for 12 hours, 20 mL of a saturated aqueous ammonium chloride solution was added thereto to terminate the reaction.

After extraction with dichloromethane (20 mL X 3), magnesium sulfate is added to remove water.

After removing solids through filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to column chromatography to obtain the desired compound of Formula 5. 1.48g, 89% was obtained.

((1 S ,2 S ,3 S ,4 R ,5 S )-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-tris((trimethylsilyl)oxy)-6 ,8-dioxabicyclo[3.2.1]octan-1-yl)methanol (Compound of Formula 6) Preparation

After dissolving 1.00 g, 1.38 mmol of the compound of formula 5 in dichloromethane/purified water 2:1, 4 mL mixed solution, 35 mg, 0.14 mmol of pyridinium p -toluenesulfonate was added thereto at 0 °C. give.

After stirring the reaction solution at 0 °C for 2 hours, the reaction is terminated by adding saturated aqueous sodium bicarbonate solution (10 mL).

After extraction using dichloromethane (10 mL X 3), magnesium sulfate is added to remove water.

After removing solids through filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to column chromatography to obtain the desired compound of Formula 6. 0.84 g, 93% was obtained.

(( 1R , 2S , 3S , 4R , 5S )-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-tris((trimethylsilyl)oxy)-6 Preparation of ,8-dioxabicyclo[3.2.1]octan-1-yl)methyl cyclopropanecarboxylate (compound of Formula 3)

Compound of Formula 6 Add 0.28 mL, 1.99 mmol of triethylamine to a 5 mL solution of 0.65 g, 0.99 mmol of dichloromethane.

After stirring the reaction solution for 10 minutes, the temperature of the reaction solution was lowered to 0 °C, and then 0.23 g of cyclopropanecarboxylic anhydride and 1.49 mmol were added.

After stirring the reaction solution at room temperature for 4 hours, a saturated aqueous solution of ammonium chloride (10 mL) was added to terminate the reaction.

After extraction using dichloromethane (10 mL X 3), magnesium sulfate is added to remove water.

After removing solids through filtration, the residue obtained by concentrating the filtrate under reduced pressure was again dissolved in 10 mL of THF.

After lowering the temperature of the reaction solution to 0 °C, tetra n-butyl ammonium fluoride 1 M in THF, 6 mL, 6 mmol is added.

After stirring the reaction solution at room temperature for 4 hours, 10 mL of water was added to terminate the reaction.

After extraction using ethyl acetate (10 mL X 3), magnesium sulfate is added to remove water.

After removing solids through filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to column chromatography to obtain 0.43 g, 85% of the desired compound of Formula 3.

NMR (500 MHz, DMSO-d ₆ ) δ 7.39 (d, J = 3.9 Hz, 1H), 7.39 (d, J = 6.6 Hz, 1H), 7.29 (dd, J = 8.3, 2.1 Hz, 1H), 7.08 (dt, J = 8.6, 2.8 Hz, 2H), 6.82 (dt, J = 8.6, 2.9 Hz, 2H), 5.48 (d, J = 5.0 Hz, 1H), 5.07 (d, J = 5.1 Hz, 1H) , 4.98 (d, J = 6.1 Hz, 1H), 4.26 (d, J = 12.4 Hz, 1H), 4.10 (d, J = 12.4 Hz, 1H), 4.05 (d, J = 7.4 Hz, 1H), 3.99 (s, 2H), 3.96 (q, J = 7.0 Hz, 2H), 3.57 (t, J = 6.4 Hz, 1H), 3.49 (dd, J = 7.5, 1.2 Hz, 1H), 3.46–3.39 (m, 2H), 1.63 (dq, J = 7.9, 4.7 Hz, 1H), 1.28 (t, J = 7.0 Hz, 3H), 0.89–0.84 (m, 2H), 0.84–0.80 (m, 2H).

(( 1R , 2S ,3S, 4R , 5S )-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2 .1] octan-1-yl) methyl 2-chloroacetate (compound of Formula 4) Preparation

Compound of Formula 6 Add 0.28 mL, 1.99 mmol of triethylamine to a 5 mL solution of 0.65 g, 0.99 mmol of dichloromethane.

After stirring the reaction solution for 10 minutes, the temperature of the reaction solution was lowered to 0 °C, and 0.25 g, 1.49 mmol of chloroacetic anhydride was added thereto.

After stirring the reaction solution at room temperature for 4 hours, a saturated aqueous solution of ammonium chloride (10 mL) was added to terminate the reaction.

After extraction using dichloromethane (10 mL X 3), magnesium sulfate is added to remove water.

After removing solids through filtration, the residue obtained by concentrating the filtrate under reduced pressure was again dissolved in 10 mL of THF.

After lowering the temperature of the reaction solution to 0 °C, tetra n-butyl ammonium fluorine 1 M in THF, 6 mL, 6 mmol is added.

After stirring the reaction solution at room temperature for 4 hours, 10 mL of water was added to terminate the reaction.

After extraction using ethyl acetate (10 mL X 3), magnesium sulfate is added to remove water.

After removing solids through filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to column chromatography to obtain 0.41 g, 80% of the desired compound of Formula 4.

NMR (500 MHz, DMSO-d ₆ ) δ 7.39 (d, J = 2.1 Hz, 1H), 7.38 (d, J = 8.3 Hz, 1H), 7.29 (dd, J = 8.3, 2.2 Hz, 1H), 7.08 (dt, J = 8.7, 3.0 Hz, 2H), 6.82 (d, J = 8.7, 3.0 Hz, 2H), 5.17 (d, J = 5.3 Hz, 1H), 4.94 (d, J = 5.4 Hz, 1H) , 4.86 (d, J = 6.5 Hz, 1H), 4.73 (t, J = 5.9 Hz, 1H), 3.98 (s, 2H), 3.98–3.96 (m, 1H), 3.96 (q, J = 7.0 Hz, 2H), 3.62 (dd, J = 12.4, 5.8 Hz, 1H), 3.53 (dd, J = 7.1, 5.4 Hz, 1H), 3.49 (dd, J = 12.4, 5.9 Hz, 1H), 3.45 (dd, J = 7.1, 1.3 Hz, 1H), 3.44–3.37 (m, 2H), 1.29 (t, J = 7.0 Hz, 3H).

[Synthesis method 2]

The ertugliflozin precursor of the present invention can be prepared according to Scheme 2.

Scheme 2

The reaction of Scheme 2 is as follows.

A desired compound can be synthesized in one step by selectively carrying out a nucleophilic acyl substitution reaction only on the terminal primary alcohol having the least steric hindrance among the four hydroxyl groups present in the compound of Formula 1 (Ertugliflizin).

The compound of formula 3 can be synthesized by dissolving the compound of formula 1 (Ertugliflizin) in an appropriate solvent, adding a base, and then adding cyclopropanecarboxylic anhydride slowly for a long time.

A compound of Formula 4 can also be synthesized by dissolving the compound of Formula 1 (Ertugliflizin) in an appropriate solvent using the same method, adding a base, and then slowly adding chloroacetic anhydride thereto over a long period of time.

Specific examples according to Scheme 2 are as follows.

(( 1R , 2S , 3S , 4R , 5S )-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-tris((trimethylsilyl)oxy)-6 Preparation of ,8-dioxabicyclo[3.2.1]octan-1-yl)methyl cyclopropanecarboxylate (compound of Formula 3)

0.37 mL of pyridine and 4.58 mmol of pyridine were added to a solution of 1.00 g and 2.29 mmol of the compound of Formula 1 (Ertugliflizin) in 10 mL of toluene.

After stirring the reaction solution for 10 minutes, the temperature of the reaction solution is lowered to -10 °C.

Meanwhile, 0.37 g of 2.40 mmol of cyclopropanecarboxylic anhydride was dissolved in 5 mL of toluene using another reaction container, and then slowly added dropwise to the reaction solution in which the compound of Formula 1 was dissolved over 12 hours.

After stirring the reaction solution at -10 °C for an additional 12 hours, the reaction was terminated by adding 30 mL of saturated aqueous ammonium chloride solution.

After extraction with dichloromethane (30 mL X 3), magnesium sulfate is added to remove water.

After removing solids through filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to column chromatography to obtain 0.83 g, 72% of the desired compound of Formula 3.

NMR (500 MHz, DMSO-d ₆ ) δ 7.39 (d, J = 3.9 Hz, 1H), 7.39 (d, J = 6.6 Hz, 1H), 7.29 (dd, J = 8.3, 2.1 Hz, 1H), 7.08 (dt, J = 8.6, 2.8 Hz, 2H), 6.82 (dt, J = 8.6, 2.9 Hz, 2H), 5.48 (d, J = 5.0 Hz, 1H), 5.07 (d, J = 5.1 Hz, 1H) , 4.98 (d, J = 6.1 Hz, 1H), 4.26 (d, J = 12.4 Hz, 1H), 4.10 (d, J = 12.4 Hz, 1H), 4.05 (d, J = 7.4 Hz, 1H), 3.99 (s, 2H), 3.96 (q, J = 7.0 Hz, 2H), 3.57 (t, J = 6.4 Hz, 1H), 3.49 (dd, J = 7.5, 1.2 Hz, 1H), 3.46–3.39 (m, 2H), 1.63 (dq, J = 7.9, 4.7 Hz, 1H), 1.28 (t, J = 7.0 Hz, 3H), 0.89–0.84 (m, 2H), 0.84–0.80 (m, 2H).

(( 1R , 2S ,3S, 4R , 5S )-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2 .1] octan-1-yl) methyl 2-chloroacetate (compound of Formula 4) Preparation

0.37 mL of pyridine and 4.58 mmol of pyridine were added to a solution of 1.00 g and 2.29 mmol of the compound of Formula 1 (Ertugliflizin) in 10 mL of toluene.

After stirring the reaction solution for 10 minutes, the temperature of the reaction solution is lowered to -10 °C.

Meanwhile, 0.41 g of chloroacetic anhydride and 2.40 mmol of anhydrous chloroacetic acid were dissolved in 5 mL of toluene in another reaction vessel, and then slowly added dropwise to the reaction solution in which the compound of Formula 1 was dissolved over 12 hours.

After stirring the reaction solution at -10 °C for an additional 12 hours, the reaction was terminated by adding 30 mL of saturated aqueous ammonium chloride solution.

After extraction with dichloromethane (30 mL X 3), magnesium sulfate is added to remove water.

After removing solids through filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to column chromatography to obtain 0.71 g of the desired compound of Formula 4 (60%).

NMR (500 MHz, DMSO-d ₆ ) δ 7.39 (d, J = 2.1 Hz, 1H), 7.38 (d, J = 8.3 Hz, 1H), 7.29 (dd, J = 8.3, 2.2 Hz, 1H), 7.08 (dt, J = 8.7, 3.0 Hz, 2H), 6.82 (d, J = 8.7, 3.0 Hz, 2H), 5.17 (d, J = 5.3 Hz, 1H), 4.94 (d, J = 5.4 Hz, 1H) , 4.86 (d, J = 6.5 Hz, 1H), 4.73 (t, J = 5.9 Hz, 1H), 3.98 (s, 2H), 3.98–3.96 (m, 1H), 3.96 (q, J = 7.0 Hz, 2H), 3.62 (dd, J = 12.4, 5.8 Hz, 1H), 3.53 (dd, J = 7.1, 5.4 Hz, 1H), 3.49 (dd, J = 12.4, 5.9 Hz, 1H), 3.45 (dd, J = 7.1, 1.3 Hz, 1H), 3.44–3.37 (m, 2H), 1.29 (t, J = 7.0 Hz, 3H).

Claims (2)

An ertugliflozin precursor of Formula 3.
[Formula 3]

An ertugliflozin precursor of Formula 4.
[Formula 4]

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