WO2021121270A1

WO2021121270A1 - Method for purifying sglts inhibitor and application thereof

Info

Publication number: WO2021121270A1
Application number: PCT/CN2020/136812
Authority: WO
Inventors: 王元; 何训贵; 王海边
Original assignee: 上海研健新药研发有限公司
Priority date: 2019-12-19
Filing date: 2020-12-16
Publication date: 2021-06-24
Also published as: CN113330017A; CN113330017B

Abstract

A method for purifying an SGLTs inhibitor and an application thereof. The SGLTs inhibitor is (1S,2S,3S,4R,5S)-5-(3-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4- ethyl phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol. Nitrobenzoic acid or a derivate thereof is used to react with a compound of formula (A), and then is hydrolyzed to obtain a high-purity compound. Further reacting the purified compound to obtain a diethylamine amine solvate is further disclosed, and the solvate is expected to be developed into a new generation of SGLTs inhibitor.

Description

A purification method of SGLTs inhibitor and its application

Technical field

The invention belongs to the field of drug synthesis, and specifically relates to a purification method and application of SGLTs inhibitors.

Background technique

Diabetes is a metabolic disorder, recurrent or persistent hyperglycemia. In the early stages of diabetes treatment, diet control and exercise therapy are the first choice for blood sugar control. When these methods are difficult to achieve blood sugar control, insulin or oral hypoglycemic drugs are needed for treatment. Studies have found that the regulation of glucose transport by cells is mainly achieved by two protein family members, glucose-promoting transporters (GLUTs) (passive transport) and sodium-dependent glucose cotransporters (SGLTs) (active transport). Among them, members of the SGLTs family with glucose transport function are mainly distributed in the proximal tubules of the intestine and kidney, and it is inferred that they play a key role in the process of intestinal glucose absorption and renal glucose reuptake. It has become one of the ideal potential targets for the treatment of diabetes. If an SGLTs inhibitor can be developed, it is possible to regulate its glucose transport function, on the one hand, it can control the absorption of intestinal glucose, and on the other hand, it can inhibit kidney glucose. The re-intake of diabetics strengthens the excretion of glucose from the urine and exerts a more systematic hypoglycemic effect, thus becoming an ideal medicine for the treatment of diabetes. In summary, as a new type of diabetes treatment drugs, SGLTs inhibitors have good development prospects. Therefore, there is an urgent need to develop a compound with good efficacy, pharmacokinetic properties and high safety for the treatment of diabetes and related metabolic disorders.

In 2015, Jiangsu Hausen Pharmaceutical Group Co., Ltd. disclosed a series of compounds that inhibit sodium-dependent glucose cotransporters (SGLTs) in its patent application WO2015/032272A1. The structure of the most representative compound of formula (A) is as follows :

Its chemical name is: (1S,2S,3S,4R,5S)-5-(3-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl )-4-ethylphenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol, this compound is effective for SGLT2 and SGLT1 Both have a very obvious inhibitory effect and are expected to be developed as a SGLT2 single inhibitor or SGLT2/SGLT1 dual inhibitor. However, in view of the structural characteristics of the series of compounds, and due to the large amount of impurities, they are generally oily or foamy solids. An amorphous compound of formula (A) is disclosed in Example 9 of patent application WO2015/032272A1. It contains many impurities and is difficult to remove in subsequent development. Therefore, there is an urgent need to develop a method that can purify the compound of formula (A) for industrial production, and prepare qualified APIs to meet the needs of clinical research and the production of marketed pharmaceutical preparations.

Summary of the invention

The purpose of the present invention is to provide a purification method for SGLTs inhibitors, so as to meet the needs of clinical research and the production of marketed pharmaceutical preparations.

The first aspect of the present invention provides a method for purifying a compound of formula (A), which comprises the following steps:

Step 1) The compound of formula (A) is reacted to produce the compound of formula (B);

Step 2) The compound of formula (B) is hydrolyzed to produce the compound of formula (A), and the reaction route is as follows:

As a preferred solution, in step 1) of the purification method, the compound of formula (A) is reacted with p-nitrobenzoic acid or its derivative to produce the compound of formula (B).

As a further preferred solution, in step 1) of the purification method, the p-nitrobenzoic acid derivative is p-nitrobenzoyl chloride, p-nitrobenzoyl chloride or p-nitrobenzoic anhydride.

As a further preferred solution, in step 1) of the purification method, the molar ratio of the compound of formula (A) to p-nitrobenzoic acid is 1.0: (1.0-6.0).

As a further preferred solution, in step 1) of the purification method, the molar ratio of the compound of formula (A) to p-nitrobenzoic acid is 1.0: (3.0-4.0).

As a further preferred solution, in step 1) of the purification method, the molar ratio of the compound of formula (A) to p-nitrobenzoic acid is 1.0:4.0.

As a preferred solution, in step 1) and/or step 2) of the purification method, the organic layer is washed with sodium bicarbonate during the treatment after the reaction is completed. In the step 1) and/or step 2), adding sodium bicarbonate solution to wash can remove the excess or generated p-nitrobenzoic acid or its derivatives as much as possible.

As a preferred solution, in step 1) of the purification method, the product of formula (B) is obtained and then purified with acetonitrile, isopropanol, dichloromethane or a mixture thereof.

As a further preferred solution, in step 1) of the purification method, the product of formula (B) is obtained and then purified with acetonitrile and/or isopropanol.

As a further preferred solution, in step 1) of the purification method, the product of the compound of formula (B) is obtained and then purified with dichloromethane.

The second aspect of the present invention provides an intermediate compound of formula (B) in the method for purifying the compound of formula (A), the structure is as follows:

The third aspect of the present invention provides a method for preparing a compound of formula (I), which comprises the following steps:

Step 1) Contacting the compound of formula (A) prepared by the aforementioned purification method with diethylamine;

Step 2) Add seed crystals and/or anti-solvent until the solution appears turbid or a combination, and continue to crystallize;

Step 3) solid-liquid separation to obtain the compound of formula (I), the reaction route is as follows:

As a preferred solution, the diethylamine described in step 1) in the method for preparing the compound of formula (I) is pure liquid diethylamine, an aqueous solution of diethylamine or a mixed liquid of diethylamine and an organic solvent.

As a preferred solution, in step 1) of the method for preparing the compound of formula (I), the compound of formula (A) is dissolved in diethylamine or the compound of formula (A) is dissolved in an organic solvent, and then the two Ethylamine.

As a preferred solution, in step 2) of the method for preparing the compound of formula (I), the anti-solvent is selected from water, n-heptane, n-hexane, isooctane, pentane, cyclohexane, and cyclopentane. Alkane, ether and mixtures thereof.

As a preferred solution, in the method for preparing the compound of formula (I), the organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, acetone, methyl ethyl ketone, tetrahydrofuran, and dioxane. Six-ring, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, dichloromethane, trichloroethane, carbon tetrachloride, methyl tert-butyl ether, isopropyl acetate Propyl ether, benzene, toluene, xylene and mixtures thereof.

As a further preferred solution, in the method for preparing the compound of formula (I), step 3) after solid-liquid separation further includes the step of further drying to obtain the compound of formula (I), and the drying process specifically includes drying at room temperature. Then, the temperature is controlled at 30-60°C and dried, preferably at 35-45°C.

Compared with the prior art, the present invention has the following technical advantages:

1. The present invention is an industrialized purification method that solves the problem of drug accessibility.

2. The present invention adopts simple raw materials or reagents, mild reaction conditions and strong operability.

3. The present invention develops a key intermediate compound of formula (B), which has stable physical and chemical properties and is not easily degraded.

4. Adding a recrystallization step in step 1) of the purification method can increase the purity of the compound of formula (B), thereby increasing the purity of the compound of formula (I) and improving the appearance of the product.

5. By changing the drying method of the compound of formula (I) in the present invention, a product suitable for clinical application is obtained, and various indicators such as moisture, solvent residue and ignition residue meet the clinical requirements.

Detailed ways

After extensive and in-depth research, the inventor of the present application developed a purification method for the SGLTs inhibitor of the compound structure of formula (A) for the first time. In the present invention, p-nitrobenzoic acid or its derivatives are used to react the compound of formula (A), and the compound of formula (A) with high purity is obtained after post-treatment. It is further studied to react the purified high-purity compound of formula (A) to obtain diethylamine amine solvate (compound of formula (I)), which can be widely used in the treatment or delay of diabetes and diabetic retina Disease, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, Diabetes complications, atherosclerosis or hypertension and other diseases are expected to be developed into a new generation of SGLTs inhibitors. On this basis, the present invention has been completed.

Hereinafter, the present invention will be further described in detail and completely in conjunction with the embodiments, but it is by no means limiting the present invention, and the present invention is not limited to the content of the embodiments.

The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR). The NMR chemical shift (δ) is given in units of parts per million (ppm). NMR was measured with Bruker BioSpin Gmbh 600 nuclear magnetic resonance instrument, the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ) and deuterated acetone ((CD ₃ ) ₂ CO), and the internal standard was tetramethylsilane ( TMS).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specifications used by TLC are 0.15mm～0.20mm.

The starting materials in the examples of the present invention are known and can be bought on the market, or can be synthesized by using or following methods known in the art.

Unless otherwise specified, all the reactions of the present invention are carried out under a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the unit of the reaction temperature is degrees Celsius (°C).

Example 1

Add 12.64kg of tetrahydrofuran to the reaction kettle, add 2.83kg (6.37mol) of the oily compound of formula (A), 4.11Kg N,N-diisopropylethylamine (DIPEA) and 0.387kg 4-dimethylamino under stirring at room temperature. Pyridine (DMAP). Cool the above reaction system to below 15°C, add 4.72kg (25.44mol) of p-nitrobenzoyl chloride to 12.64kg of tetrahydrofuran, stir to dissolve until clear, add the above clear solution dropwise to the reaction system of the reactor, dropwise During the addition, the temperature is controlled at 15-40°C. After the dripping is completed, the temperature is raised to 45-50° C. and the reaction is kept and stirred for about 3.5 hours. TLC detects that the reaction is complete. Add 28.29 kg of water and 12.26 kg of ethyl acetate, stir and stand to separate the layers, and collect the organic layer and the water layer respectively. The aqueous layer was extracted with 12.26 kg of ethyl acetate, and the organic layer was collected. Combine all the organic layers, add 8% sodium bicarbonate solution 14.14 kg*2, stir and stand to separate the layers, collect the organic layer, add anhydrous sodium sulfate and dry. After filtration, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to dryness to obtain an oily compound of formula (B).

Add 8.96 kg of acetonitrile to the oily compound of formula (B) obtained above, stir to dissolve, and add 13.39 kg of isopropanol. Heat up to reflux and dissolve, keep stirring at 75-80°C for 10-15 minutes, then lower the temperature to 15-25°C and continue stirring for 3 hours. After filtering, the filter cake is washed once with a mixed solvent (2.26 kg acetonitrile and 3.39 kg isopropanol), sucked dry, and the filter cake is dried.

The above-mentioned dried product was added to 30.08kg of dichloromethane, stirred to dissolve, filtered, and eluted with 37.63kg of dichloromethane. The filtrate was concentrated to dryness to obtain 2.17 kg of the product compound of formula (B) (yield 32.7%).

¹ HNMR(400MHz,DMSO-d ₆ )δ8.34(d,2H),δ8.21(m,10H),δ7.93(dd,4H),δ7.42(d,1H),δ7.39( s,1H),δ7.19(d,1H),δ6.46(d,1H),δ6.25(t,2H),δ6.19(m,1H),δ6.00(s,2H), δ5.01(d,1H),δ4.80(d,1H),δ4.64(d,1H),δ4.13(d,1H),δ4.09(s,4H),δ3.79(s ,2H),δ2.38(q,2H),δ0.93(t,3H).

Example 2

Add 2.16 kg of the compound of formula (B) into the reaction kettle, add 8.64 kg of acetonitrile, heat to reflux, and stir to dissolve. Slowly add 8.64 kg of isopropanol, and then slowly lower the temperature to 20-25°C after the addition, continue to control the temperature and stir for 1.5 hours, filter, and wash the filter cake once with a mixed solvent (acetonitrile and isopropanol), drain it, and The filter cake was dried to obtain 2.12 kg of a yellow solid compound of formula (B) (yield 98.15%, purity 99.3%).

Example 3

Add 2.80 kg (2.69 mol) of the compound of formula (B) into the reaction kettle, add 11.95 kg of tetrahydrofuran, and stir until clear. 0.565kg (13.46mol) of lithium hydroxide monohydrate was added to 13.45kg of water and stirred until clear. The above-mentioned lithium hydroxide solution is added to the reaction kettle reaction system at 20-30°C, the temperature is controlled and the reaction is stirred for 3 hours, and TLC detects that the reaction is complete. Concentrate the reaction solution to remove tetrahydrofuran, add 16.02kg of dichloromethane to the remaining materials, stir and stand for separation, collect the organic layer and the water layer separately, add 16.02kg of dichloromethane to extract the aqueous layer, stir and stand for separation, collect the organic Floor. Combine the organic layers, concentrate to dryness, add 10.83kg ethyl acetate to the residue, then add 7.6% sodium bicarbonate solution 6.2kg*4, stir and stand for separation, collect the organic layer, add anhydrous sodium sulfate to dry, and filter , The filter cake was washed once with 1.40kg ethyl acetate. 6.72 kg of absolute ethanol was added to the above filtrate, and concentrated under reduced pressure to dryness to obtain 1.24 kg of a solid compound of formula (A) (yield 100%, purity 99.0%).

Example 4

1.2 kg (2.70 mol) of the compound of formula (A) was added to 4.28 kg of diethylamine, and stirred to dissolve. The above solution was pressure filtered into a reaction kettle, and water was added dropwise to the above reaction solution at a temperature of 20-30°C, and the dripping was stopped when the reaction solution appeared turbid. The amount of water added was 25.6kg. 1.2 g of seed crystals of the compound of formula (I) (form I) are added, and the temperature is controlled and stirred for crystallization for 24 hours. After filtering, the filter cake was washed once with 5.64 kg of 14.9% diethylamine aqueous solution. The filter cake was vacuum dried at room temperature for 24 hours, and then heated to 35-40° C. and vacuum dried for 24 hours to obtain 1.12 kg of a white powder of formula (I) compound (yield 80.2%).

¹ HNMR(400MHz, (CD ₃ ) ₂ CO)δ7.37(m,2H),δ7.17(d,1H),δ6.71(d,1H),δ6.62(m,2H),δ4. 18(s,4H),δ4.15(d,1H),δ3.92(s,2H),δ3.85(m,2H),δ3.73(m,2H),δ3.64(d,1H) ), δ3.59(d,1H), δ2.60(q,2H), δ2.56(q,3H), δ1.11(t,3H), δ1.03(t,5H).

All documents mentioned in the present invention are cited as references in this application, as if each document was individually cited as a reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

A method for purifying a compound of formula (A), which is characterized in that it comprises the following steps:

Step 1) The compound of formula (A) is reacted to produce the compound of formula (B);

Step 2) The compound of formula (B) is hydrolyzed to produce the compound of formula (A), and the reaction route is as follows:
The purification method according to claim 1, wherein in step 1), the compound of formula (A) is reacted with p-nitrobenzoic acid or a derivative thereof to produce a compound of formula (B); preferably, the p-nitrobenzoic acid The derivative is p-nitrobenzoyl chloride, p-nitrobenzoyl chloride or p-nitrobenzoic anhydride, and the molar ratio of the compound of formula (A) to p-nitrobenzoic acid or its derivatives is 1.0: (1.0～6.0) , More preferably 1.0: (3.0 to 4.0); most preferably 1.0: 4.0.
The purification method according to claim 1, wherein the organic layer is washed with sodium bicarbonate during the treatment after the reaction in step 1) and/or step 2).
The purification method according to claim 1, characterized in that in step 1), the product of formula (B) is obtained and then purified with acetonitrile, isopropanol, dichloromethane or a mixture thereof.
The purification method according to claim 4, characterized in that in step 1) the product of the compound of formula (B) is obtained and then purified with acetonitrile and/or isopropanol.
The purification method according to claim 4, characterized in that in step 1), the product of the compound of formula (B) is obtained and then purified with dichloromethane.
Compound of formula (B):
A method for preparing a compound of formula (I), which is characterized in that it comprises the following steps:

Step 1) Contacting the compound of formula (A) prepared by the purification method of claim 1 with diethylamine;

Step 2) Add seed crystals and/or anti-solvent until the solution appears turbid or a combination, and continue to crystallize;

Step 3) solid-liquid separation to obtain the compound of formula (I), the reaction route is as follows:
The method for preparing a compound of formula (I) according to claim 8, wherein the diethylamine in step 1) is a pure liquid diethylamine, an aqueous solution of diethylamine or a mixture of diethylamine and an organic solvent liquid.
The method for preparing a compound of formula (I) according to claim 8, wherein in step 1), the compound of formula (A) is dissolved in diethylamine or the compound of formula (A) is dissolved in an organic solvent first, and then Add diethylamine.
The method for preparing the compound of formula (I) according to claim 8, wherein the anti-solvent in step 2) is selected from water, n-heptane, n-hexane, isooctane, pentane, cyclohexane, Cyclopentane, ether and mixtures thereof.
The method for preparing the compound of formula (I) according to claim 9 or 10, wherein the organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, acetone, methyl ethyl ketone, Tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, methylene chloride, trichloroethane, carbon tetrachloride, methyl tert-butyl Base ether, isopropyl ether, benzene, toluene, xylene and mixtures thereof.
The method for preparing the compound of formula (I) according to claim 8, characterized in that, after step 3) solid-liquid separation, further drying is included to obtain the compound of formula (I), and the drying process is specifically drying at room temperature. , And then control the temperature to dry at 30-60 ℃, preferably at 35-45 ℃.