Preparation method of difluoromethyl building block (1R, 3R)-3-((t-butyloxycarboryl) amino)-1-(2, 2-difluoroethyl) cyclopentane-1-methyl formate

Abstract

The invention discloses a preparation method of a difluoromethyl building block (1R, 3R)-3-((t-butyloxycarbonyl) amino)-1-(2, 2-difluoroethyl) cyclopentane-1-methyl formate. According to the preparation method, 1S, 3R)-3-((dibenzylidene) amino) cyclopentane-1-methyl formate is taken as an initial raw material, and a target compound (1R, 3R)-3-((t-butyloxycarboryl) amino)-1-(2, 2-difluoroethyl) cyclopentane-1-methyl formate is obtained through a difluoromethylation reaction, a deprotection reaction, a ring closing reaction and a Boc protection reaction. The preparation method is short in process route, convenient to operate, mild in reaction condition, easy to control, low in cost, suitable for process amplification, easy in product purification and high in yield.

Description

Technical Field

[0001] The present invention relates to the technical field of the synthesis of pharmaceutical intermediates, and more particularly to a method for preparing a difluoromethyl building block (1R,3R)-3-((tert-butoxycarbonyl)amino)-1-(2,2-difluoroethyl)cyclopentane-1-carboxylic acid methyl ester. Background Art

[0002] Fluorine-containing building blocks refer to a class of organic compounds containing fluorine elements. Although the abundance of fluorine in the earth's crust ranks 13th, it is the most abundant halogen in nature. Due to the strong electronegativity, small atomic radius and low polarizability of fluorine atoms, fluorine-containing building blocks usually have unique physical, chemical and physiological properties. Such as trifluoromethyl (TFM), difluoromethyl (DFM). Incorporating fluorine atoms or fluorinated alkyl groups into organic molecules to regulate their physical and chemical properties, such as stability, reactivity, lipophilicity and acidity, with minimal steric perturbation, and can be helpful in the identification of lead compounds. In addition, compared with their non-fluorinated counterparts, fluorine-containing building blocks show higher thermal stability. Therefore, the preparation and application of fluorinated compounds have attracted extensive interest of scientists and are widely used in materials chemistry, medicinal chemistry, organic chemistry and biochemistry.

[0003] In the past decade, the research on difluoromethyl compounds has developed rapidly, mainly for the following reasons: (1) The hydrogen atom in difluoromethyl, as a hydrogen bond donor, can effectively improve the membrane permeability of drugs, promote drug absorption, and further improve drug efficacy; (2) Containing a weakly acidified C—H bond, it can be used as an electron isostere of hydroxyl, mercapto and hydroxymethyl groups, and can regulate the biological activity, metabolic stability, etc. of molecules; (3) Difluoromethyl has similar polarity and volume to hydroxyl groups, and can mimic hydroxyl groups in proteins, enzymes and certain substances to produce a metabolic hindrance effect.

[0004] Due to the wide use of difluoromethyl-containing drugs, derivatives of difluoromethyl compounds can be applied to the synthesis of some pharmaceutical and pesticide intermediates or bulk drugs. However, so far, there are more reports on trifluoromethyl building blocks, while there are fewer reports on difluoromethyl building blocks. Therefore, designing a new class of difluoromethyl building blocks and studying their reactions will be of great significance. Summary of the Invention

[0005] Aiming at the deficiencies of the prior art, the present invention provides a method for preparing a difluoromethyl building block (1R,3R)-3-((tert-butoxycarbonyl)amino)-1-(2,2-difluoroethyl)cyclopentane-1-carboxylic acid methyl ester. The preparation method of the present invention has a short process route, convenient operation, mild and easy-to-control reaction conditions, low cost, is suitable for process amplification, the product is easy to purify, and the yield is relatively high.

[0006] The technical solution of the present invention is as follows:

[0007] A preparation method of a difluoromethyl building block (1R,3R)-3-((tert-butoxycarbonyl)amino)-1-(2,2-difluoroethyl)cyclopentane-1-carboxylic acid methyl ester, and the preparation method is carried out according to the following process:

[0008]

[0009] It includes the following steps:

[0010] (1) Using compound 1 as the starting material, adding compound 2, and through a difluoromethylation reaction, a mixture of compound 3 and compound 3' is prepared;

[0011] (2) The mixture of compound 3 and compound 3' undergoes a deprotection reaction under the action of an acid to obtain a mixture of compound 4 and compound 4';

[0012] (3) Placing the mixture of compound 4 and compound 4' under alkaline conditions to carry out a ring-closing reaction to obtain a mixture of compound 4 and compound 5;

[0013] (4) Without separation and purification, the mixture of compound 4 and compound 5 is directly subjected to Boc protection reaction and then purified to obtain the (1R,3R)-3-((tert-butoxycarbonyl)amino)-1-(2,2-difluoroethyl)cyclopentane-1-carboxylic acid methyl ester.

[0014] Furthermore, in step (1), the specific process of the difluoromethylation reaction is as follows:

[0015] Dissolve compound 1 in solvent I, add LDA at -78 to -40 °C and react for 1 to 5 h, then add 1,1-difluoro-2-iodoethane and continue to react for 1 to 5 h; then raise the temperature to room temperature and react for 1 to 24 h, quench with saturated ammonium chloride solution, and extract and concentrate with ethyl acetate to obtain the mixture of compound 3 and compound 3'.

[0016] Furthermore, the solvent I is selected from one or more of diethyl ether, tetrahydrofuran, and DME; the concentration of compound 1 in solvent I is 0.1 to 1 mol / L; the dosage of LDA is 1 to 5 equivalents of compound 1; the dosage of 1,1-difluoro-2-iodoethane is 1 to 5 equivalents of compound 1.

[0017] Furthermore, in step (2), the specific process of the deprotection reaction is as follows:

[0018] Dissolve the mixture of compound 3 and compound 3' in solvent II, add an acid solution, and react at room temperature for 1 to 24 h. First, extract with dichloromethane, adjust the pH of the aqueous phase to 10 with sodium hydroxide solution, and then extract and concentrate with ethyl acetate to obtain the mixture of compound 4 and compound 4'.

[0019] Further, the solvent II is selected from any one of tetrahydrofuran, acetonitrile, and dichloromethane; the ratio of the total mass of the mixture of compound 3 and compound 3' to the volume of the solvent II is 1 g: 1 - 10 mL; the acid solution is any one of hydrochloric acid aqueous solution, sulfuric acid aqueous solution, and trifluoroacetic acid aqueous solution; the concentration of the acid solution is 1 - 3 mol / L; the volume ratio of the acid solution to the solvent II is 1: 1 - 3.

[0020] Further, in step (3), the specific process of the ring - closing reaction is as follows:

[0021] Dissolve the mixture of compound 4 and compound 4' in solvent III, add a base, heat to 50 - 120 °C and react for 1 - 24 h, cool and then filter the reaction solution by suction, and concentrate the mother liquor to obtain a mixture of compound 4 and the ring - closing reaction product compound 5.

[0022] Further, the solvent III is selected from any one of acetonitrile, 1,2 - dichloroethane, and 1,4 - dioxane; the ratio of the total mass of the mixture of compound 4 and compound 4' to the volume of the solvent II is 1 g: 1 - 10 mL; the base is selected from any one of cesium carbonate, potassium carbonate, and sodium carbonate; the molar ratio of the mixture of compound 4 and compound 4' to the base is 1: 1 - 10.

[0023] Further, in step (4), the specific process of the Boc - protection reaction is as follows:

[0024] Dissolve the mixture of compound 4 and compound 5 in solvent IV, add DIEA and Boc₂O, react at room temperature for 1 - 24 h, quench with water, extract with dichloromethane and concentrate to obtain a crude product, and purify the crude product by silica gel column chromatography to obtain the difluoromethyl building block (1R,3R) - 3 - ((tert - butoxycarbonyl)amino) - 1 - (2,2 - difluoroethyl)cyclopentane - 1 - carboxylic acid methyl ester.

[0025] Further, the solvent IV is selected from one or more of dichloromethane, tetrahydrofuran, DMF, and acetonitrile; the ratio of the total mass of the mixture of compound 4 and compound 5 to the volume of the solvent IV is 1.0 g: 1 - 10 mL; the ratio of the total mass of the mixture of compound 4 and compound 5 to the mass of DIEA is 1: 1 - 5; the molar ratio of DIEA to Boc₂O is 3: 2.

[0026] The beneficial technical effects of the present invention are as follows:

[0027] The present invention uses methyl (1S,3R)-3-((diphenylmethylene)amino)cyclopentane-1-carboxylate as the starting material for the reaction. Through difluoromethylation reaction and deprotection reaction, two configurational substances, namely a mixture of compound 4 and compound 4', are obtained. Then, by ingeniously designing a ring-closing reaction, compound 4' undergoes a ring-closing reaction to obtain compound 5, and compound 4 is further Boc-protected and then separated and purified to obtain the target compound, avoiding the problem of difficult direct separation of compound 4 and compound 4'.

[0028] The synthesis method of the present invention is reported for the first time. The reaction conditions are mild, easy to operate, with low cost, simple purification, high purity of the obtained product, and good stability, suitable for process scale-up. Therefore, this difluoromethyl building block is expected to become an important building block for a class of pharmaceutical and pesticide intermediates or bulk drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 It is a schematic diagram of the reaction process of the present invention.

[0030] Figure 2 1H NMR spectrum of methyl (1R,3R)-3-((tert-butoxycarbonyl)amino)-1-(2,2-difluoroethyl)cyclopentane-1-carboxylate prepared in Example 1 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0031] The present invention will be specifically described below in conjunction with the drawings and examples.

[0032] Example 1

[0033] A preparation method of methyl (1R,3R)-3-((tert-butoxycarbonyl)amino)-1-(2,2-difluoroethyl)cyclopentane-1-carboxylate, comprising the following steps:

[0034] (1) Add tetrahydrofuran (300 mL) to a 1 L three-necked flask. While stirring, add compound 1, methyl (1S,3R)-3-((diphenylmethylene)amino)cyclopentane-1-carboxylate (30.7 g, 0.1 mol, 1 eq). Cool the temperature to -78 °C. Under nitrogen protection, slowly dropwise add LDA / THF (2 mol / L, 250 mL, 0.5 mol, 5 eq) to the reaction solution, and then add 1,1-difluoro-2-iodoethane (96.0 g, 0.5 mol, 5 eq) to the reaction solution. Continue the reaction at -78 °C for 5 h, then warm up to room temperature and react for 24 h. Quench with saturated ammonium chloride solution, extract 3 times with ethyl acetate (100 mL). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 32 g of a mixture of compound 3 and compound 3'. The mixture of compound 3 and compound 3' can be directly put into the next reaction.

[0035] (2) Add tetrahydrofuran (320 mL) to a 1-L single-necked flask. While stirring, add a mixture of Compound 3 and Compound 3' (32 g, crude product). Then add aqueous hydrochloric acid solution (1 mol / L, 107 mL). React at room temperature for 3 h. First, extract impurities with dichloromethane (60 mL) three times. Then adjust the pH of the aqueous phase to 10 with sodium hydroxide solution, and extract with ethyl acetate (100 mL) three times. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 17 g of a mixture of Compound 4 and Compound 4'. The product can be directly used in the next reaction step.

[0036] (3) Add acetonitrile (50 mL) to a 250-mL single-necked flask. While stirring, add a mixture of Compound 4 and Compound 4' (17 g, crude product). Then add cesium carbonate (53.5 g, 164 mmol). Heat to 70 °C and react for 3 h. After cooling, filter the reaction solution by suction. Concentrate the mother liquor to obtain 15 g of a mixture of Compound 4 and Compound 5. The product can be directly used in the next reaction step.

[0037] (4) Add dichloromethane (150 mL) to a 250-mL single-necked flask. While stirring, add a mixture of Compound 4 and Compound 5 (15 g, crude product). Then add DIEA (75 g, 580 mmol) and Boc2O (84.4 g, 387 mmol). React at room temperature for 3 h. Quench with water, extract with dichloromethane (100 mL) three times. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. Purify the crude product by silica gel column chromatography (200 - 300 mesh) to obtain a yellow oily substance (11.1 g, overall yield of four steps is 36%), namely methyl (1R,3R)-3-((tert-butoxycarbonyl)amino)-1-(2,2-difluoroethyl)cyclopentane-1-carboxylate.

[0038] The structure characterization data of the product in this example are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 5.83 (tt, J = 56.2, 4.8 Hz, 1H), 4.50 (s, 1H), 4.08 (d, J = 7.2 Hz, 1H), 3.69 (s, 3H), 2.64 (dd, J = 13.6, 7.2 Hz, 1H), 2.35–2.07 (m, 4H), 1.72 (ddd, J = 12.8, 8.8, 6.4 Hz, 1H), 1.42 (s, 11H).

[0039] Example 2

[0040] A preparation method of methyl (1R,3R)-3-((tert-butoxycarbonyl)amino)-1-(2,2-difluoroethyl)cyclopentane-1-carboxylate, comprising the following steps:

[0041] (1) Add anhydrous diethyl ether (200 mL) to a 1 L three-necked flask. With stirring, add compound 1, methyl (1S,3R)-3-((diphenylmethylene)amino)cyclopentane-1-carboxylate (30.7 g, 0.1 mol, 1 eq). Cool the temperature to -60 °C. Under nitrogen protection, slowly add LDA / THF (2 mol / L, 150 mL, 0.3 mol, 3 eq) dropwise to the reaction solution. Keep it at -60 °C for 3 h. Then add 1,1-difluoro-2-iodoethane (57.6 g, 0.3 mol, 3 eq) to the reaction solution. Continue the reaction at -60 °C for 3 h. Then warm up to room temperature and react for 12 h. Quench with saturated ammonium chloride solution and extract 3 times with ethyl acetate (100 mL). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 29 g of a mixture of compound 3 and compound 3'. The product can be directly used in the next reaction.

[0042] (2) Add acetonitrile (145 mL) to a 1 L single-necked flask. With stirring, add the mixture of compound 3 and compound 3' (29 g, crude product). Add sulfuric acid aqueous solution (2 mol / L, 72 mL). React at room temperature for 12 h. First, extract impurities 3 times with dichloromethane (60 mL). Then adjust the pH of the aqueous phase to 10 with sodium hydroxide solution and extract 3 times with ethyl acetate (100 mL). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 15 g of a mixture of compound 4 and compound 4'. The product can be directly used in the next reaction.

[0043] (3) Add 1,2-dichloroethane (105 mL) to a 250 mL single-necked flask. With stirring, add the mixture of compound 4 and compound 4' (15 g, crude product). Add potassium carbonate (50.0 g, 362 mmol). Heat up to 90 °C and react for 12 h. After cooling, filter the reaction solution by suction. Concentrate the mother liquor to obtain 13 g of a mixture of compound 4 and compound 5. The product can be directly used in the next reaction.

[0044] (4) Add tetrahydrofuran (78 mL) to a 250 mL single-necked flask. With stirring, add the mixture of compound 4 and compound 5 (13 g, crude product). Add DIEA (39 g, 301 mmol) and Boc2O (43.9 g, 201 mmol). React at room temperature for 12 h. Quench with water and extract 3 times with dichloromethane (100 mL). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. The crude product is subjected to silica gel column chromatography with 200 - 300 mesh to obtain a yellow oil (9.5 g, overall yield of four steps is 31%), namely methyl (1R,3R)-3-((tert-butoxycarbonyl)amino)-1-(2,2-difluoroethyl)cyclopentane-1-carboxylate.

[0045] Example 3

[0046] A preparation method of methyl (1R,3R)-3-((tert-butoxycarbonyl)amino)-1-(2,2-difluoroethyl)cyclopentane-1-carboxylate, comprising the following steps:

[0047] (1) Add DME (100 mL) to a 1 L three-necked flask. While stirring, add compound 1, methyl (1S,3R)-3-((diphenylmethylene)amino)cyclopentane-1-carboxylate (30.7 g, 0.1 mol, 1 eq). Cool the temperature to -40 °C. Under nitrogen protection, slowly add LDA / THF (2 mol / L, 50 mL, 0.1 mol, 1 eq) to the reaction solution. Then add 1,1-difluoro-2-iodoethane (19.2 g, 0.1 mol, 1 eq) to the reaction solution. Continue the reaction at -40 °C for 1 h, then warm up to room temperature and react for 3 h. Quench with saturated ammonium chloride solution, extract 3 times with ethyl acetate (100 mL). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 25 g of a mixture of compound 3 and compound 3'. The product can be directly put into the next reaction.

[0048] (2) Add dichloromethane (75 mL) to a 250 mL single-necked flask. While stirring, add the mixture of compound 3 and compound 3' (25 g, crude product). Add trifluoroacetic acid aqueous solution (3 mol / L, 75 mL). React at room temperature for 24 h. First, extract impurities 3 times with dichloromethane (60 mL). Then adjust the pH of the aqueous phase to 10 with sodium hydroxide solution, extract 3 times with ethyl acetate (100 mL). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 12 g of a mixture of compound 4 and compound 4'. The product can be directly put into the next reaction.

[0049] (3) Add 1,4-dioxane (120 mL) to a 250 mL single-necked flask. While stirring, add the mixture of compound 4 and compound 4' (12 g, crude product). Add sodium carbonate (61.4 g, 579 mmol). Heat up to 120 °C and react for 24 h. After cooling, filter the reaction solution by suction. Concentrate the mother liquor to obtain 10 g of a mixture of 4 and 5. The product can be directly put into the next reaction.

[0050] (4) Acetonitrile (30 mL) was added to a 250 mL single-necked bottle, and a mixture of compound 4 and compound 5 (10 g, crude product) was added under stirring. DIEA (10 g, 77 mmol) and Boc2O (11.3 g, 51 mmol) were added, and the mixture was reacted at room temperature for 24 h. The mixture was quenched with water, and extracted with dichloromethane (100 mL) three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was chromatographed on a 200-300 mesh silica gel column to obtain a yellow oil (8 g, four-step combined yield 26%), i.e., methyl (1R, 3R)-3-((tert-butoxycarbonyl)amino)-1-(2,2-difluoroethyl)cyclopentane-1-carboxylate.

[0051] The above is only a preferred embodiment of the present invention, and the present invention is not limited to the above embodiments. It is understood that other improvements and changes directly derived or associated by those skilled in the art without departing from the spirit and concept of the present invention should be considered to be included in the protection scope of the present invention.

Claims

1. A method for preparing difluoromethyl building block (1R, 3R)-3-((tert-butyloxycarbonyl)amino)-1-(2,2-difluoroethyl)cyclopentane-1-carboxylic acid methyl ester, characterized in that: The preparation method is carried out according to the following process: The steps include: (1) Compound 1 is used as a starting material, compound 2 is added, and a mixture of compound 3 and compound 3' is prepared through a difluoromethylation reaction; (2) The mixture of compound 3 and compound 3' undergoes a deprotection reaction under the action of an acid to obtain a mixture of compound 4 and compound 4'; (3) placing the mixture of compound 4 and compound 4' under alkaline conditions to perform a ring-closing reaction to obtain a mixture of compound 4 and compound 5; (4) The mixture of compound 4 and compound 5 is not separated or purified, but directly subjected to Boc protection reaction and then purified to obtain the (1R, 3R)-3-((tert-butoxycarbonyl)amino)-1-(2,2-difluoroethyl)cyclopentane-1-carboxylic acid methyl ester.

2. The preparation method according to claim 1, characterized in that: In step (1), the specific process of the difluoromethylation reaction is: Compound 1 is dissolved in solvent I, LDA is added at -78 to -40°C for reaction for 1 to 5 hours, and 1,1-difluoro-2-iodoethane is added for reaction for 1 to 5 hours; then the temperature is raised to room temperature for reaction for 1 to 24 hours, quenched with saturated ammonium chloride solution, extracted and concentrated with ethyl acetate to obtain a mixture of compound 3 and compound 3'.

3. The preparation method according to claim 2, characterized in that: The solvent I is selected from one or more of diethyl ether, tetrahydrofuran, and DME; the concentration of the compound 1 in the solvent I is 0.1 to 1 mol / L; the amount of the LDA is 1 to 5 equivalents of the compound 1; the amount of the 1,1-difluoro-2-iodoethane is 1 to 5 equivalents of the compound 1.

4. The preparation method according to claim 1, characterized in that: In step (2), the specific process of the deprotection reaction is: The mixture of compound 3 and compound 3' is dissolved in solvent II, acid solution is added, and the mixture is reacted at room temperature for 1 to 24 hours. The mixture is first extracted with dichloromethane, the pH of the aqueous phase is adjusted to 10 with sodium hydroxide solution, and then extracted and concentrated with ethyl acetate to obtain the mixture of compound 4 and compound 4'.

5. The preparation method according to claim 4, characterized in that: The solvent II is selected from any one of tetrahydrofuran, acetonitrile, and dichloromethane; the ratio of the total mass of the mixture of compound 3 and compound 3' to the volume of solvent II is 1g:1-10mL; the acid solution is any one of hydrochloric acid aqueous solution, sulfuric acid aqueous solution, and trifluoroacetic acid aqueous solution; the concentration of the acid solution is 1-3 mol / L; the volume ratio of the acid solution to solvent II is 1:1-3.

6. The preparation method according to claim 1, characterized in that: In step (3), the specific process of the ring-closure reaction is: The mixture of compound 4 and compound 4' is dissolved in solvent III, a base is added, the temperature is raised to 50-120°C and the reaction is carried out for 1-24 hours. The reaction solution is filtered after cooling, and the mother liquor is concentrated to obtain a mixture of compound 4 and the ring-closure reaction product compound 5.

7. The preparation method according to claim 6, characterized in that: The solvent III is selected from any one of acetonitrile, 1,2-dichloroethane, and 1.4-dioxane; the ratio of the total mass of the mixture of compound 4 and compound 4' to the volume of solvent II is 1g:1-10mL; the base is selected from any one of cesium carbonate, potassium carbonate, and sodium carbonate; the molar ratio of the mixture of compound 4 and compound 4' to the base is 1:1-10.

8. The preparation method according to claim 1, characterized in that: In step (4), the specific process of the upper Boc protection reaction is: The mixture of compound 4 and compound 5 was dissolved in solvent IV, DIEA and Boc2O were added, the reaction was carried out at room temperature for 1 to 24 hours, water was added to quench, and the crude product was extracted with dichloromethane and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain the difluoromethyl building block (1R, 3R)-3-((tert-butoxycarbonyl)amino)-1-(2,2-difluoroethyl)cyclopentane-1-carboxylic acid methyl ester.

9. The preparation method according to claim 8, characterized in that: The solvent IV is selected from one or more of dichloromethane, tetrahydrofuran, DMF, and acetonitrile; the ratio of the total mass of the mixture of compound 4 and compound 5 to the volume of solvent IV is 1.0 g: 1 to 10 mL; the ratio of the total mass of the mixture of compound 4 and compound 5 to the mass of DIEA is 1: 1 to 5; the molar ratio of DIEA to Boc2O is 3:2.

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