Method for preparing β-aminopyrazine acetic acid ester

Abstract

The present disclosure relates to a method for preparing β-aminopyrazine acetate. Specifically, a method for preparing 2-amino-2-(pyrazinyl) acetate and the use of the intermediate in preparing DPP-IV inhibitors, such as relagliptin, are provided. The method is simple to operate, low in cost, and suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of medicine and relates to a method for preparing β-aminopyrazine acetic acid ester. Background Art

[0002] Retagliptin is a type of DPP-IV inhibitor used to treat type 2 diabetes. Sitagliptin, a similar drug, was approved for marketing by the U.S. FDA in October 2006.

[0003] 3-(Trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester is an important intermediate for the preparation of retagliptin.

[0004] .

[0005] WO2009082881 discloses that 2-cyanopyrazine is used as a starting material, and 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine is obtained through cyano reduction, amidation, ring closure and other steps. R )-3-tert-butyloxycarbonylamino-4-(2,4,5-trifluorophenyl)-butyric acid is reacted, and then the carboxylate group is reconstructed. The overall process yield is low, and the expensive catalyst, such as octacarbonyl dicobalt, has a high production cost, which is not conducive to large-scale production.

[0006] .

[0007] CN106892926B discloses a method for preparing 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester, and synthesizing retagliptin by using the method, which includes cyclization of 2-(pyrazine-2-yl)-2-(2,2,2-trifluoroacetamide)acetic acid methyl ester under the condition of a dehydrating agent such as POCl3, and a reduction step.

[0008] Among them, 2-(pyrazin-2-yl)-2-(2,2,2-trifluoroacetamide)acetic acid methyl ester is obtained by reacting commercially available N-(diphenylmethylene)glycine ethyl ester with 2-chloropyrazine under the conditions of potassium carbonate and tetra-n-butylammonium bromide, followed by hydrolysis and amidation. (See J. Med. Chem. 1994,37, 4567-4571). Summary of the invention

[0009] In one aspect, the present disclosure provides a method for preparing a compound of formula I or a salt thereof, , comprising the steps of converting a compound of formula D into a compound of formula E under sodium nitrite conditions, and then converting the compound of formula E into a compound of formula F under reducing agent conditions, Among them, R 2 Selected from C 1-6Alkyl or benzyl, for example methyl, ethyl or benzyl.

[0010] In some embodiments, the molar ratio of the compound of formula D to sodium nitrite is 1:1 to 1:6, including but not limited to 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5 or 1:6.

[0011] In some embodiments, the reaction of the compound of formula D with sodium nitrite further comprises acetic acid.

[0012] In some embodiments, the compound of formula D reacts under the conditions of sodium nitrite and acetic acid to generate the compound of formula E, wherein the molar ratio of the compound of formula D to sodium nitrite is 1:1 to 1:6.

[0013] In some embodiments, the reduction reaction conditions of the compound of formula E are zinc powder / acid or H2 / metal palladium. In some embodiments, the compound of formula E undergoes reduction reaction under zinc powder / acid conditions. In some embodiments, the compound of formula E undergoes reduction reaction under zinc powder / acetic acid conditions. In other embodiments, the compound of formula E undergoes reduction reaction under H2 / palladium on carbon conditions.

[0014] In some embodiments, the method further comprises the step of converting the compound of formula C into a compound of formula D, Among them, R 1 Selected from C 1-6 Alkyl or benzyl, such as methyl, ethyl or benzyl; R 2 Selected from C 1-6 Alkyl or benzyl, for example methyl, ethyl or benzyl.

[0015] In some embodiments, the method comprises the steps of converting a compound of formula C to a compound of formula D-1 under alkaline conditions, and converting the compound of formula D-1 to a compound of formula D, wherein the base (2) used in the reaction is selected from, but not limited to, sodium hydroxide or potassium hydroxide. , where R 1 Selected from C 1-6 Alkyl or benzyl, such as methyl, ethyl or benzyl; R 2 Selected from C 1-6 Alkyl or benzyl, for example methyl, ethyl or benzyl.

[0016] In some embodiments, the molar ratio of the base (2) to the compound of formula C used in the reaction is 1:1 to 4:1, including but not limited to 1:1, 2:1, 3:1 or 4:1.

[0017] In some embodiments, the decarboxylation reaction temperature of the compound of formula C is 20-100°C, preferably 30-80°C, and more preferably 40-60°C.

[0018] In some embodiments, the compound of formula D-1 is reacted with an alcohol under thionyl chloride conditions to form a compound of formula D, wherein the alcohol is C 1-6 Alkyl alcohol or benzyl alcohol.

[0019] In some embodiments, the compound of formula D-1 reacts with methanol under thionyl chloride conditions to form the corresponding methyl ester compound. In some embodiments, the compound of formula D-1 reacts with ethanol under thionyl chloride conditions to form the corresponding ethyl ester compound.

[0020] On the other hand, the method of the present disclosure further comprises the step of reacting the compound of formula A with the compound of formula B under alkaline conditions to form a compound of formula C, wherein the base (1) used in the reaction is selected from but not limited to cesium carbonate, Among them, R 1 Selected from C 1-6 alkyl or benzyl, such as methyl, ethyl or benzyl; X is halogen, such as chlorine.

[0021] In some embodiments, the molar ratio of the compound of formula A to the compound of formula B is 1:1 to 6:1, preferably 1:1 to 3:1, and more preferably 1:1 to 2:1.

[0022] In some embodiments, the molar ratio of the base (1) to the compound of formula B used in the reaction is 1:1 to 4:1, including but not limited to 1:1, 2:1, 3:1 or 4:1.

[0023] In some embodiments, the reaction temperature of the compound of formula A and the compound of formula B is 60-100°C, including but not limited to 60°C, 70°C, 80°C, 90°C or 100°C.

[0024] In some embodiments, the solvent for the reaction of the compound of formula A with the compound of formula B is selected from, but not limited to, N,N-dimethylformamide (DMF) or dimethyl sulfoxide (DMSO).

[0025] In some embodiments, a phase transfer catalyst may be added to the reaction of the compound of formula A with the compound of formula B. The phase transfer catalyst is selected from, but not limited to, tetrabutylammonium bromide.

[0026] In some embodiments, tetrabutylammonium bromide is added in a catalytic amount, which is 0.1 to 0.5 eq (equivalent) of the molar amount of the compound of formula B, including but not limited to 0.1 eq, 0.2 eq, 0.3 eq, 0.4 eq or 0.5 eq.

[0027] In some embodiments, the disclosed scheme comprises: a) reacting a compound of formula A with a compound of formula B under cesium carbonate conditions to form a compound of formula C, b) converting the compound of formula C into a compound of formula D, c) converting the compound of formula D into a compound of formula E under sodium nitrite conditions, and then the compound of formula E forms a compound of formula F under reducing agent conditions, Among them, R 1 Selected from C 1-6 Alkyl or benzyl, such as methyl, ethyl or benzyl; R 2 Selected from C 1-6 alkyl or benzyl, such as methyl, ethyl or benzyl; X is halogen, such as chlorine.

[0028] On the other hand, in some embodiments, the compound of formula I is The method comprises the steps of reacting compound d under sodium nitrite to form compound e, and then reacting compound e under reducing agent to form compound f. .

[0029] In other embodiments, the method further comprises the steps of reacting the compound of formula F with trifluoroacetyl chloride or trifluoroacetic anhydride to form a compound of formula G, the compound of formula G forms a compound of formula H under trifluoroacetic anhydride conditions, and then catalytically hydrogenating to form a compound of formula I, wherein the reagent used for catalytic hydrogenation is Pd / C or palladium hydroxide. Among them, R 2 Selected from C 1-6 Alkyl or benzyl, such as methyl, ethyl or benzyl. The relevant experimental procedures can be found in CN114478536, and the relevant contents are introduced into this text for illustration.

[0030] In some embodiments, the method comprises a) reacting compound a with compound b under cesium carbonate conditions to form compound c, b) reacting compound c under sodium hydroxide or potassium hydroxide conditions to form a compound of formula D-1, c) reacting the compound of formula D-1 with methanol under thionyl chloride conditions to form compound d, d) reacting compound d under sodium nitrite conditions to form compound e, and then reacting compound e under H2 / palladium carbon to form compound f, .

[0031] In some embodiments, in step a), compound a and compound b are added in a molar ratio of 1:1 to 2:1 and react under cesium carbonate conditions to form compound c.

[0032] In some embodiments, step b) compound c is decarboxylated under sodium hydroxide or potassium hydroxide conditions to form a compound of formula D-1.

[0033] In another aspect, the present disclosure also provides a method for preparing compound AA or a pharmaceutically acceptable salt thereof. , comprising the steps of preparing the compound of formula I as described above, and reacting the compound of formula I with the compound of formula II to form a compound of formula A-1, and deprotecting the compound of formula A-1 to form compound AA, Among them, R 2 Selected from C 1-6 P is an amino protecting group, such as tert-butyloxycarbonyl (BOC).

[0034] In some embodiments, the compound of formula I is reacted with the compound of formula II under N, N-carbonyldiimidazole / imidazole hydrochloride conditions to form the compound of formula A-1.

[0035] In some embodiments, the amino protecting group is removed under hydrochloric acid conditions. The relevant experimental procedures can be found in CN114478536, and the relevant contents are introduced into this text for illustration.

[0036] Pharmaceutically acceptable salts of compound AA of the present disclosure include, but are not limited to, phosphates. On the other hand, other compounds of the present disclosure may exist in the form of salts, such as hydrochlorides or sulfates. For example, compound f exists in the form of hydrochloric acid.

[0037] On the other hand, the preparation method disclosed in the present invention further comprises one or more steps of filtration, concentration, purification by column chromatography and drying.

[0038] "To form" and "to convert into" do not specifically mean that the conversion reaction between two substrates is a single step, and can be a single step or multi-step reaction between two substrates. If the intermediate contains a protecting group, the intermediate is subjected to a step of removing the protecting agent, and then reacts with the corresponding substrate to obtain the corresponding target product.

[0039] The values ​​in this disclosure are instrumental measurements, which have a certain degree of error. Generally speaking, plus or minus 10% is within the reasonable error range. Of course, the context in which the value is used needs to be considered. For example, the particle size of the active ingredient, the value is the error change after measurement does not exceed plus or minus 10%, can be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2% or plus or minus 1%, preferably plus or minus 5%.

[0040] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including alkyl groups having 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl.

[0041] "Protective group" is a suitable group for protecting amino groups known in the art, see the literature (Protective Groups in Organic Synthesis, 5Th Ed. TW Greene & P. ​​GM Wuts) in amino protecting groups. DETAILED DESCRIPTION

[0042] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0043] The experimental methods in the examples of this disclosure that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by raw material or product manufacturers. Reagents that do not specify specific sources are conventional reagents purchased from the market.

[0044] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectroscopy (MS). NMR shifts (d) are given in units of 10-6 (ppm).

[0045] NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, and the measurement solvent was deuterated chloroform (CDCl3).

[0046] MS was determined using a Waters Micromass Quattro micro API triple quadrupole mass spectrometer in positive / negative ion mode with a mass scan range of 120-1300.

[0047] HPLC column: YMC-Pack ODS-A (3μm, 4.6 mmx 150 mm) Thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 silica gel plate. The specification of silica gel plate used in thin layer chromatography (TLC) is 0.2mm±0.03mm, and the specification of thin layer chromatography separation and purification products is 0.4mm-0.5 mm. Example 1

[0048]

[0049] Step 1:

[0050] Diethyl malonate (10 g, 62.5 mmol), DMF (50 mL), cesium carbonate (60.9 g, 187 mmol, 3 eq), 2-chloropyrazine (17.9 g, 112 mmol, 1.8 eq), and TBAB (0.05 eq, 1 g) were added to a 250 mL reaction bottle, stirred to dissolve, and heated to 80-95 °C for reaction. After TLC detection, the reaction was basically complete, and the temperature was lowered to room temperature, and the solid was filtered out. The filter cake was washed with 50 mL of ethyl acetate, the organic layers were combined, 200 mL of ethyl acetate was added, and the mixture was washed with 100 mL × 3 water. The organic layer was separated, dried with anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. After purification, the product compound c12.4 g was obtained with a yield of 83%.

[0051] Step 2:

[0052] Add compound c (14.9 g, 62.5 mmol) into a 250 mL reaction bottle, add THF (100 mL), stir evenly, add 2 M sodium hydroxide (90 mL), heat to 40-50 °C for reaction, after TLC detection the reaction is almost complete, cool to room temperature, add methyl tert-butyl ether 50 mL × 2 for extraction, add 1 M hydrochloric acid to the aqueous layer to adjust the pH to 2-3, and 7.94 g of compound D-1 is obtained after purification, with a yield of 92%.

[0053] Step 3:

[0054] Compound D-1 (10 g, 72.4 mmol) was added into a 100 mL reaction bottle, and 50 mL of methanol was added and stirred to dissolve. The mixture was cooled in an ice-water bath, and thionyl chloride (12.8 g, 108 mmol) was slowly added dropwise. The temperature was slowly raised to room temperature and the reaction was continued for 5-6 h. After TLC detection, the reaction was completed. The reaction solution was concentrated to dryness under reduced pressure to obtain a light yellow solid.

[0055] Add 30 mL of acetic acid to the obtained yellow solid, stir to dissolve, cool to 0-10°C in an ice-water bath, add 28 mL of sodium nitrite aqueous solution (46 g of sodium nitrite, 140 mL of water) dropwise, stir to react at room temperature, and after TLC detection shows that the reaction is basically complete, add 50 mL of ethyl acetate for extraction, separate the organic layer, extract the aqueous layer with 25 mL of ethyl acetate × 2, combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate to dryness to obtain 10.6 g of light yellow compound e with a yield of 85.6%.

[0056] Step 4:

[0057] Compound e (8 g, 44 mmol) was added to a 500 mL reaction bottle, and methanol 240 mL and hydrochloric acid 4 mL were added, and the mixture was stirred to dissolve. 5% Pd / C 0.8 g was added, and the reaction was hydrogenated at room temperature for 16 hours. TLC detected that the reaction of the raw materials was complete. The mixture was filtered, and the filtrate was concentrated to dryness. Acetone was added and stirred for 0.5-1 h, and the mixture was filtered and dried in a vacuum at 30-40 °C to obtain 8.42 g of compound f with a yield of 93.9%. HPLC: 98.2%.

[0058] Example 2

[0059]

[0060] Step 1:

[0061] Compound D-1 (5 g, 36.2 mmol) was added to a 100 mL reaction bottle, and 50 mL of acetic acid was added, stirred to dissolve, cooled to 0-10 °C in an ice-water bath, and 15 mL of sodium nitrite aqueous solution (46 g of sodium nitrite, 140 mL of water) was added dropwise. The reaction was stirred at room temperature. After TLC detection showed that the reaction was basically complete, part of the solvent was concentrated under reduced pressure, 80 mL of water was added, stirred for 2, filtered, and dried in vacuo at 35 °C to obtain 4.2 g of light yellow compound e-1 with a yield of 69.4%.

[0062] Step 2:

[0063] Add compound e-1 (2 g, 12 mmol) into a 100 mL reaction bottle, add 20 mL of methanol and stir to dissolve, add 20 mL of acetic acid, cool to 0~10°C in an ice-water bath, add zinc powder (2 g, 30.8 mmol) in batches, react at room temperature after the addition is complete, filter, and concentrate the filtrate to dryness to obtain compound f-1 1.63, yield 89%, HPLC: 99.2%.

[0064] Example 3

[0065]

[0066] Step 1:

[0067] Compound f (40.6 g, 0.2 mol) was added to TFFA (105 g, 0.5 mol) in batches and stirred at room temperature. After the reaction was detected by TLC, the mixture was concentrated under reduced pressure to obtain an oily substance, and then water was added and stirred at room temperature for 6 h. A large amount of solid precipitated. The mixture was cooled to 10-15 °C and stirred for 5 h. The mixture was filtered and the filter cake was added with 100 mL of a mixture of isopropanol and petroleum ether for pulping. The mixture was filtered, washed and dried to obtain 66.2 g of compound g with a yield of 79.2%.

[0068] Step 2:

[0069] Compound g (15.3 g, 60 mmol) was added to tetrahydrofuran, TFAA (19 g, 90 mmol) was slowly added dropwise under an ice bath, and then stirred at room temperature for 15 h. After the reaction was completed, methanol was added dropwise to the reaction solution to quench, and an oily substance was obtained by vacuum distillation. A saturated sodium bicarbonate aqueous solution was added thereto, stirred, filtered, the filter cake was washed with water, and dried to obtain 13.5 g of compound h, with a yield of 92.0%.

[0070] Example 4

[0071]

[0072] Step 1:

[0073] Compound h (13 g, 53 mmol), ethyl acetate 150 mL, sodium bicarbonate (9 g, 106 mmol) and 10% wet palladium carbon (1.31 g, 60% water content) were hydrogenated at 40° C. for 18 h to obtain compound i 12.6 g, with a yield of 95.4%.

[0074] Step 2:

[0075] Compound j (60g, 180mmol), N,N'-carbonyldiimidazole (30.8g, 190mmol), imidazole hydrochloride (5.84g, 56mmol) were added to tetrahydrofuran (750mL), and the reaction solution was heated to 48-56°C and stirred for 50min under nitrogen protection. Compound i (47.2g, 190mmol) was added to the system, and the mixture was stirred at 52-60°C for 6h. After the reaction was basically complete as monitored by HPLC, most of the solvent was concentrated under reduced pressure, and the remaining reaction solution was added dropwise to water to precipitate a large amount of solid, which was filtered, washed with water, and dried to obtain a crude product; the crude product was added to isopropanol and heated to reflux and stirred for 2.5-3h, cooled to 15-25°C and crystallized for 14-16h, the solid was precipitated, filtered, and dried to obtain 92.5g of white solid compound k, with a yield of 91%.

[0076] Step 3:

[0077] In a 1000mL reaction bottle, add 600mL of ethyl acetate, control the temperature below 20°C, pass 40g of hydrochloric acid gas, add compound k (60g, 106mmol), stir and react at 20-30°C for 2.5-3h, and concentrate to dryness under reduced pressure to obtain an oily substance. Add 500mL of dichloromethane to dissolve it, and wash it with sodium bicarbonate solution. The pH of the aqueous layer is 7-8. The aqueous layer is extracted with dichloromethane (250mL), and the organic layers are combined, washed with purified water (400mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain 49.2g of the target product with a yield of 99.8%.

[0078] Add isopropanol (1350 mL) to 49.2 g (106 mmol) of the product from the previous step, stir and dissolve, control the temperature at 15-30°C, add the prepared isopropanol phosphate solution (preparation method: 14.5 g of 85% phosphoric acid is dissolved in 80 mL of isopropanol), stir for 1.5-2 h, filter, wash with isopropanol, add the wet product to isopropanol (360 mL), suspend and stir, filter, wash with isopropanol, and dry under reduced pressure at 45-50°C to obtain 56.0 g of an off-white phosphate product with a yield of 94%.

[0079] Example 5

[0080]

[0081] 2-((diphenylmethylene)amino)acetic acid methyl ester (2.5 g, 9.87 mmol), TBAB (3.18 g, 9.86 mmol), potassium carbonate (4.1 g), 2-chloropyrazine (2.26 g, 19.7 mmol) were added to DMF, heated to 86 ° C and stirred. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate was added, and the solid was filtered out. The filter cake was washed with a small amount of ethyl acetate, the filtrate was combined, water was added, and the organic layer was separated after stirring for 5 min. The aqueous layer was extracted with ethyl acetate 100 ml × 2, the organic layers were combined, washed with saturated sodium chloride, dried, filtered, concentrated and slurried to obtain 2.76 g of 2-((diphenylmethylene)amino)-2-(pyrazin-2-yl)acetic acid methyl ester, with a yield of 87.8%, HPLC: 83.6% (maximum single impurity 16.5%), and the actual yield was 73.4%.

[0082] 2.5 g (7.85 mmol) of methyl 2-((diphenylmethylene)amino)-2-(pyrazin-2-yl)acetate was added to acetone, and the mixture was cooled in an ice-water bath while stirring. A concentrated hydrochloric acid-acetone mixture (8.5 ml of hydrochloric acid was dissolved in 17 mL of acetone) was added. After the addition was completed, the mixture was heated to room temperature and stirred for reaction. The reaction was monitored by TLC. When the raw material disappeared, the mixture was filtered, and the filter cake was washed with 5 mL of cold acetone and dried in vacuo to obtain 1.52 g of methyl 2-amino-2-(pyrazin-2-yl)acetate hydrochloride with a yield of 95%. The yield was HPLC: 85.2% (maximum single impurity 13.8%), and the actual yield was 80.9%.

[0083] Example 6

[0084]

[0085] The effects of different conditions on nitration were investigated. The specific reaction conditions are shown in the following table. Different nitration conditions were used to prepare intermediate e with a purity of ≥98.5%.

[0086]

[0087] As can be seen from the above table, the use of sodium nitrite in the HAc-H2O system for nitration has the highest product yield and is the first choice for nitration reactions.

Claims

1. A method for preparing a compound of formula I or a salt thereof, the method comprising: a) Compound a reacts with compound b under cesium carbonate conditions to form compound c, b) Compound c reacts under sodium hydroxide conditions to form a compound of formula D-1, c) the compound of formula D-1 reacts with methanol under thionyl chloride conditions to form compound d, d) Compound d is reacted under sodium nitrite / acetic acid conditions to form compound e, and then compound e is reacted under H2 / palladium on carbon conditions to form compound f, e) Compound f reacts with trifluoroacetic anhydride to form compound g, and compound g reacts with trifluoroacetic anhydride to form compound h, f) Compound h is hydrogenated via palladium-carbon catalysis to form compound i, Wherein: in step a), compound a and compound b are added in a molar ratio of 2:1, the reaction solvent is N,N-dimethylformamide, and tetrabutylammonium bromide is added, and the reaction is carried out at a reaction temperature of 80°C to 100°C; In step b), compound c is decarboxylated under sodium hydroxide to form a compound of formula D-1, the molar ratio of sodium hydroxide to compound c used in the reaction is 2:1-3:1, and the decarboxylation reaction temperature is 40-60°C; In step d), the molar ratio of compound d to sodium nitrite is 1:1.

5.

2. A method for preparing compound AA or a pharmaceutically acceptable salt thereof, The method comprises the steps of claim 1, and the steps of reacting a compound of formula I with a compound of formula II to form a compound of formula A-1, and deprotecting the compound of formula A-1 to form compound AA. in, R 2 is selected from methyl; P is an amino protecting group.

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