CN116693437A - Synthesis method of N-Boc-3-azetidineacetic acid - Google Patents

Abstract

The invention discloses a synthesis method of N-Boc-3-azetidine acetic acid, which belongs to the technical field of chemical pharmacy, and uses N-Boc-3-azetidinone as a starting material to obtain the N-Boc-3-azetidine acetic acid through nucleophilic substitution reaction, hydrolysis, acidification and hydrogenation reaction in sequence. The synthesis method has the advantages of mild reaction conditions, high yield, low cost and high application value, can realize industrial production, can improve the utilization rate of raw materials, reduce resource waste and pollution, and furthest reduces the production cost of the whole process.

Description

A kind of synthetic method of N-Boc-3-azetidine acetic acid

technical field

The invention belongs to the technical field of chemical pharmacy and relates to a synthesis method of N-Boc-3-azetidine acetic acid.

Background technique

N-Boc-3-azetidine acetic acid is a commonly used chemical and pharmaceutical intermediate, which can be used to treat diseases related to BAF complex. The existing synthetic method is to use N-Boc-3-azetidinone as a raw material, first nucleophilic substitution with ethyl triphenylphosphonoacetate at room temperature to obtain 3-ethoxycarbonylmethylene-azetidine Alkane-1-carboxylate tert-butyl ester continues to react to obtain the target product, but the product obtained by this method is not easy to purify, the yield is low, the cost of raw materials is high, it is difficult to separate, and it is difficult to purify. Reaction, poor stability, difficult operation, poor atom economy; patent WO2021155321 on May 8, 2021 reported that the yield was only 76%, and the industrial production cost was too high. The reaction route is as follows:

Contents of the invention

Aiming at the deficiencies in the prior art, the invention provides a synthetic method of N-Boc-3-azetidine acetic acid, which also takes N-Boc-3-azetidinone as the starting material, and proceeds successively through Nucleophilic substitution, hydrolysis, acidification, and hydrogenation reactions with triethyl phosphoacetate give the target product. The method has high yield, pure product, can be produced industrially, can improve the utilization rate of raw materials, reduce waste of resources, and reduce the production cost of the overall process to the greatest extent, and has extremely high application value.

The synthetic method of N-Boc-3-azetidine acetic acid of the present invention comprises the steps:

Step 1: Add tetrahydrofuran and sodium tert-butoxide to the reaction flask, under nitrogen protection, control the temperature at -5~5°C, add triethyl phosphoroacetate dropwise under stirring, raise the temperature to 15~25°C after the addition, and keep warm for 3 Hour. Cool down to 10-15°C, then add N-Boc-3-azetidinone tetrahydrofuran solution dropwise, dissolve in tetrahydrofuran, and dissolve in advance for later use; react at room temperature for 4-6 hours after the dropwise addition, and monitor by spotting. After the reaction, the reaction solution was poured into water, extracted with ethyl acetate, and the aqueous phase was extracted once with the same amount of ethyl acetate as before. The organic phases were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain tert-butyl 3-ethoxycarbonylmethylene-azetidine-1-carboxylate.

Step 2: Add the intermediate obtained in the previous step and water into the reaction flask, stir, add sodium hydroxide, raise the temperature to 60-70°C for 1-2 hours after the addition, and monitor by spotting. After the reaction, the temperature was lowered to room temperature and extracted once with dichloromethane. The temperature of the aqueous phase was controlled below 20°C and hydrochloric acid was added dropwise to adjust the pH to 3-4. After the dropwise addition, stir at room temperature for half an hour to allow it to fully react. Suction filtration after the reaction was completed, and the filter cake was washed once with water to obtain 2-{1-[(tert-butoxy)carbonyl]azetidine-3-alkylene}acetic acid.

Step 3: Add ethanol and the intermediate obtained in the previous step to the reaction kettle, then add palladium carbon, cover the kettle lid, vacuumize nitrogen replacement, and then pass hydrogen at a pressure of 0.1-0.2 MPa, and react at room temperature for 12-20 hours. After the reaction, filter palladium carbon with suction, evaporate the ethanol from the filtrate, heat and dissolve it with ethyl acetate, then add petroleum ether to stir and crystallize, drop to room temperature, filter with suction, and dry to obtain N-Boc-3-azetidine acetic acid.

In step 1, the molar ratio of N-Boc-3-azetidinone to triethyl phosphoroacetate is 1: 1.1 to 1.3, the molar ratio to sodium tert-butoxide is 1: 1.2 to 1.4, and the molar ratio to tetrahydrofuran The mass ratio is 1:6-7.

In step 1, the developer used for spotting the plate was ethyl acetate and petroleum ether, with a volume ratio of 1:4.

In step 1, the volume ratio of water, ethyl acetate, and tetrahydrofuran in the reaction solution required for the reaction after the reaction is 1.6-2:1.6-2:1.

In step 1, the volume ratio of the saturated sodium chloride solution to the organic phase is 2:1.

In step 2, the molar ratio of 3-ethoxycarbonylmethylene-azetidine-1-carboxylic acid tert-butyl ester to sodium hydroxide is 1:1.3～1.5, and the molar ratio to hydrochloric acid is 1:1.5～ 1.7. The mass ratio with water is 1:5~6.

In step 2, the concentration of hydrochloric acid is 12mol/L, which is slowly added dropwise and continuously monitored.

In step 3, the mass ratio of 2-{1-[(tert-butoxy)carbonyl]azetidine-3-alkylene}acetic acid to ethanol is 1:6～7, and ethyl acetate and petroleum ether The volume ratio is 1:1:3.

In step 3, palladium carbon contains 5% water, and the mass ratio of palladium carbon to 2-{1-[(tert-butoxy)carbonyl]azetidine-3-alkylene}acetic acid is 1:20.

In step 3, during recrystallization, after adding ethyl acetate, the temperature was controlled at 50-60°C, and the mixture was stirred under reflux for 1 hour. After the heating was stopped, petroleum ether was slowly added under continuous stirring, and the temperature dropped to room temperature for suction filtration.

The synthetic route of the present invention is as follows:

The synthetic method of the present invention uses N-Boc-3-azetidinone as a raw material, and triethyl phosphoroacetate has a wide range of sources, and the N-Boc-3-azetidinone is obtained through nucleophilic substitution, hydrolysis, acidification, and hydrogenation reactions. Cyclobutaneacetic acid has mild reaction conditions, less side reactions, high product purity, high total yield, and a large reduction in industrial production costs.

Description of drawings

Fig. 1 is the proton nuclear magnetic resonance spectrogram of raw material of the present invention;

Fig. 2 is the proton nuclear magnetic resonance spectrogram of the product of the present invention.

Detailed ways

The technical solutions of the present invention are further illustrated below through specific examples. These examples are for illustration only, not limitation.

Example 1

The synthetic method of N-Boc-3-azetidine acetic acid in the present embodiment comprises the following steps:

1. Synthesis of tert-butyl 3-ethoxycarbonylmethylene-azetidine-1-carboxylate

Add 855 mL of tetrahydrofuran and 115 g (1.2 mol) of sodium tert-butoxide into the reaction flask, and add 247 g (1.1 mol) of triethyl phosphoroacetate dropwise under stirring at -5°C under temperature control. Hours, cool down to 10°C and add dropwise the THF solution of N-Boc-3-azetidinone (dissolve 171g (1mol) N-Boc-3-azetidinone in 340ml tetrahydrofuran, dissolve in advance and set aside) . After the dropwise addition, the reaction was carried out at room temperature for 5 hours, followed by plate monitoring (the volume ratio of ethyl acetate to petroleum ether was 1:4). After the reaction, pour the reaction solution into 2 liters of water, add 1 liter of ethyl acetate for extraction, then extract the water phase with 1 liter of ethyl acetate, combine the organic phases, wash with 1 liter of saturated saline, and wash the organic phase with anhydrous sodium sulfate Dry and evaporate to dryness under reduced pressure to obtain 235g. Yield 91%, HPLC purity 93.3%.

2. Synthesis of 2-{1-[(tert-butoxy)carbonyl]azetidine-3-alkylene}acetic acid

Add 235 g of tert-butyl 3-ethoxycarbonylmethylene-azetidine-1-carboxylate from the previous step and 1.2 L of water into the reaction flask, stir, add 60 g (1.5 mol) of sodium hydroxide, and raise the temperature after adding React at 60°C for 1.5 hours, and monitor by spotting (the volume ratio of ethyl acetate to petroleum ether is 1:4). After the reaction, the temperature was lowered to room temperature and extracted once with 1.5 L of dichloromethane. The temperature of the aqueous phase was controlled below 20°C and 125 mL of hydrochloric acid was added dropwise to adjust the pH to 3.3. After the dropwise addition, stir at room temperature for half an hour to allow it to fully react. Suction filtration after reaction finishes, filter cake is washed once with 500mL water, obtains 2-{1-[(tert-butoxy)carbonyl]azetidine-3-alkylene}acetic acid 190g, yield 92.9%, HPLC purity 98.1%.

3. Synthesis of N-Boc-3-azetidine acetic acid

Add 1.2L of ethanol and 190g of the intermediate obtained in the previous step into the reaction kettle, then add 10g of palladium carbon, cover the kettle, vacuumize nitrogen replacement, and then pass hydrogen, the pressure is 0.1MPa, and react at room temperature for 16 hours. After the reaction, filter the palladium carbon with suction, evaporate the ethanol from the filtrate, add 200mL of ethyl acetate, heat up to 50°C, heat and dissolve it, stir for 1 hour, stop heating, then add 600mL of petroleum ether in batches, stir and crystallize, cool down to room temperature and pump Filter and dry to obtain 188 g of N-Boc-3-azetidine acetic acid with a yield of 99.1% and an HPLC purity of 99.2%.

¹ H NMR (400MHz, CHLOROFORM-D) δ4.10 (t, J = 8.5Hz, 2H), 3.62 (dd, J = 8.9, 5.5Hz, 2H), 2.87 (dq, J = 11.3, 5.5, 4.0Hz ,1H),2.67(d,J=7.8Hz,2H),1.43(s,9H).

Example 2

The synthetic method of N-Boc-3-azetidine acetic acid in the present embodiment comprises the following steps:

1, Synthesis of 3-ethoxycarbonylmethylene-azetidine-1-carboxylic acid tert-butyl ester:

Add 855 mL of tetrahydrofuran and 125 g (1.3 mol) of sodium tert-butoxide into the reaction flask, and add 269 g (1.2 mol) of triethyl phosphoroacetate dropwise under controlled temperature at 5°C while stirring. , lower the temperature to 15°C, and then dropwise add the tetrahydrofuran solution of N-Boc-3-azetidinone (dissolve 171g (1mol) N-Boc-3-azetidinone in 340ml tetrahydrofuran, and dissolve in advance for later use). After the dropwise addition, the reaction was carried out at room temperature for 4.5 hours, followed by plate monitoring (the volume ratio of ethyl acetate to petroleum ether was 1:4). After the reaction, pour the reaction solution into 2 liters of water, add 1 liter of ethyl acetate for extraction, then extract the water phase with 1 liter of ethyl acetate, combine the organic phases, wash with 1 liter of saturated saline, and wash the organic phase with anhydrous sodium sulfate Dry and evaporate to dryness under reduced pressure to obtain 239g. Yield 92.6%, HPLC purity 93.4%.

2. Synthesis of 2-{1-[(tert-butoxy)carbonyl]azetidine-3-alkylene}acetic acid:

Add 239 g of tert-butyl 3-ethoxycarbonylmethylene-azetidine-1-carboxylate obtained in the previous step and 1.2 L of water into the reaction flask, stir, add 68 g (1.7 mol) of sodium hydroxide, and complete the addition Raise the temperature to 70°C and react for 1 hour, and spot plate monitoring (the volume ratio of ethyl acetate to petroleum ether is 1:4). After the reaction, the temperature was lowered to room temperature and extracted once with 1.5 L of dichloromethane. The temperature of the aqueous phase was controlled below 20°C and 132 mL of hydrochloric acid was added dropwise to adjust the pH to 3.2. After the dropwise addition, stir at room temperature for half an hour to allow it to fully react. Suction filtration after reaction finishes, filter cake is washed once with 500mL water, obtains 2-{1-[(tert-butoxy)carbonyl]azetidine-3-alkylene}acetic acid 193g, yield 92.9%, HPLC purity 98.2%.

3. Synthesis of N-Boc-3-azetidine acetic acid:

Add 1.2L of ethanol and 193g of the intermediate obtained in the previous step into the reaction kettle, then add 10g of palladium carbon, cover the kettle, vacuumize nitrogen replacement, and then pass hydrogen, the pressure is 0.2MPa, and react at room temperature for 16 hours. After the reaction, filter the palladium carbon with suction, evaporate the ethanol from the filtrate, add 200mL of ethyl acetate, heat up to 60°C, heat it to dissolve, stir for 1 hour, stop heating, then add 600mL of petroleum ether in batches, stir and crystallize, cool down to room temperature and pump Filter and dry to obtain 189 g of N-Boc-3-azetidine acetic acid with a yield of 98.8% and an HPLC purity of 99.1%.

¹ H NMR (400MHz, CDCl ₃ ) δ 4.10 (t, J = 8.5Hz, 2H), 3.62 (dd, J = 8.9, 5.5Hz, 2H), 2.87 (dq, J = 11.3, 5.5, 4.0Hz, 1H), 2.67(d, J=7.8Hz, 2H), 1.43(s, 9H).

Example 3

The synthetic method of N-Boc-3-azetidine acetic acid in the present embodiment comprises the following steps:

1, Synthesis of 3-ethoxycarbonylmethylene-azetidine-1-carboxylic acid tert-butyl ester:

Add 855 mL of tetrahydrofuran and 125 g (1.3 mol) of sodium tert-butoxide into the reaction flask, and add 247 g (1.1 mol) of triethyl phosphoroacetate dropwise under controlled temperature at 0°C while stirring. , lower the temperature to 10-15°C and then dropwise add the tetrahydrofuran solution of N-Boc-3-azetidinone (dissolve 171g (1mol) N-Boc-3-azetidinone in 340ml tetrahydrofuran, dissolve in advance ). After the dropwise addition, the reaction was carried out at room temperature for 4.8 hours, followed by plate monitoring (the volume ratio of ethyl acetate to petroleum ether was 1:4). After the reaction, pour the reaction solution into 2 liters of water, add 1 liter of ethyl acetate for extraction, then extract the water phase with 1 liter of ethyl acetate, combine the organic phases, wash with 1 liter of saturated saline, and wash the organic phase with anhydrous sodium sulfate Dry and evaporate to dryness under reduced pressure to obtain 236g. Yield 91.4%, HPLC purity 93.3%.

2. Synthesis of 2-{1-[(tert-butoxy)carbonyl]azetidine-3-alkylene}acetic acid:

Add 236 g of tert-butyl 3-ethoxycarbonylmethylene-azetidine-1-carboxylate obtained in the previous step and 1.2 L of water into the reaction flask, stir, add 68 g (1.7 mol) of sodium hydroxide, and complete the addition Raise the temperature to 60-70°C and react for 1 hour, and spot plate monitoring (the volume ratio of ethyl acetate to petroleum ether is 1:4). After the reaction, the temperature was lowered to room temperature and extracted once with 1.5 L of dichloromethane. The temperature of the aqueous phase was controlled below 20°C and 125 mL of hydrochloric acid was added dropwise to adjust the pH to 3.8. After the dropwise addition, stir at room temperature for half an hour to allow it to fully react. Suction filtration after reaction finishes, filter cake is washed once with 500mL water, obtains 2-{1-[(tert-butoxy)carbonyl]azetidine-3-alkylene}acetic acid 188g, yield 91.6%, HPLC purity 98.1%.

3. Synthesis of N-Boc-3-azetidine acetic acid:

Add 1.2L of ethanol and 188g of the intermediate obtained in the previous step into the reaction kettle, then add 9g of palladium carbon, cover the kettle, vacuumize nitrogen replacement, and then pass hydrogen, the pressure is 0.15MPa, and react at room temperature for 18 hours. After the reaction, filter the palladium carbon with suction, evaporate the ethanol from the filtrate, add 200mL of ethyl acetate, heat up to 57°C, heat and dissolve it, stir for 1 hour, stop heating, then add 600mL of petroleum ether in batches, stir and crystallize, cool down to room temperature and pump Filter and dry to obtain 186 g of N-Boc-3-azetidine acetic acid with a yield of 98% and an HPLC purity of 99.1%.

¹ H NMR (400MHz, CDCl ₃ ) δ 4.10 (t, J = 8.5Hz, 2H), 3.62 (dd, J = 8.9, 5.5Hz, 2H), 2.87 (dq, J = 11.3, 5.5, 4.0Hz, 1H), 2.67(d, J=7.8Hz, 2H), 1.43(s, 9H).

Can draw following conclusions by above-mentioned embodiment 1-3:

1. When synthesizing 3-ethoxycarbonylmethylene-azetidine-1-carboxylic acid tert-butyl ester, an excessive amount of triethyl phosphoroacetate should be added to make N-Boc-3-nitrogen The heterocyclobutanone reacts sufficiently to increase the yield of tert-butyl 3-ethoxycarbonylmethylene-azetidine-1-carboxylate.

2. When synthesizing 2-{1-[(tert-butoxy)carbonyl]azetidine-3-alkylene}acetic acid, excess sodium hydroxide should be added to make 3-ethoxycarbonylmethylene Base-azetidine-1-carboxylic acid tert-butyl ester reaction is quickened, make pH value close to 3 as far as possible during acidification, thereby improve 2-{1-[(tert-butoxy)carbonyl]azetidine-3- The yield of alkylene}acetic acid.

3. When synthesizing N-Boc-3-azetidine acetic acid, excess palladium carbon should be added to make 2-{1-[(tert-butoxy)carbonyl]azetidine-3-alkylene Base} acetic acid is accelerated and fully reacted, thereby improves the productive rate of N-Boc-3-azetidine acetic acid.

The invention provides a high-yield synthetic method of N-Boc-3-azetidine acetic acid, which uses N-Boc-3-azetidinone as a raw material and undergoes nucleophilic substitution, hydrolysis, acidification and hydrogenation The N-Boc-3-azetidine acetic acid is obtained by the reaction, the reaction conditions are mild, and the total yield is above 85%, which is improved to a certain extent compared with the yield (76%) of the patent WO2021155321, and the utilization rate of raw materials is improved at the same time , reduce resource waste, reduce pollution, and minimize the production cost of the overall process.

The above is only a preferred embodiment of the present invention, it should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, some improvements can also be made, and these improvements are also regarded as the present invention. scope of protection.

Claims (9)

1. A method for synthesizing N-Boc-3-azetidineacetic acid, which is characterized by comprising the following steps:

step 1: nucleophilic substitution reaction is carried out on the N-Boc-3-azetidinone and triethyl phosphorylacetate to generate 3-ethoxycarbonylmethylene-azetidine-1-carboxylic acid tert-butyl ester;

step 2: 3-ethoxycarbonylmethylene-azetidine-1-carboxylic acid tert-butyl ester undergoes hydrolysis reaction under alkaline condition, and is acidified after extraction to produce 2- {1- [ (tert-butoxy) carbonyl ] azetidine-3-alkylene } acetic acid;

step 3: hydrogenation of 2- {1- [ (tert-butoxy) carbonyl ] azetidin-3-ylene } acetic acid over palladium on carbon to form N-Boc-3-azetidineacetic acid;

the specific reaction route is as follows:

。

2. the method for synthesizing N-Boc-3-azetidinacetic acid according to claim 1, wherein said step 1 is specifically: adding tetrahydrofuran and sodium tert-butoxide into a reaction bottle, protecting with nitrogen, controlling the temperature at-5 ℃, dropwise adding triethyl phosphorylacetate under stirring, heating to 15-25 ℃ after the addition, preserving heat and reacting for 3 hours, cooling to 10-15 ℃, dropwise adding tetrahydrofuran solution of N-Boc-3-azetidinone, dropwise adding room temperature and reacting for 4-6 hours, monitoring by a dot plate, pouring the reaction liquid into water after the reaction is finished, extracting with ethyl acetate, extracting the water phase with ethyl acetate the same amount as the ethyl acetate, merging the organic phases, washing with saturated sodium chloride solution, drying the organic phases with anhydrous sodium sulfate, and evaporating under reduced pressure to obtain the 3-ethoxycarbonylmethylene-azetidine-1-carboxylic acid tert-butyl ester.

3. The method for synthesizing N-Boc-3-azetidineacetic acid according to claim 2, characterized in that the molar ratio of N-Boc-3-azetidinone to triethyl phosphorylacetate is 1:1.1-1.3; the mol ratio of the N-Boc-3-azetidinone to the sodium tert-butoxide is 1:1.2-1.4; the mass ratio of the N-Boc-3-azetidinone to the tetrahydrofuran is 1:6-7; the volume ratio of the saturated sodium chloride solution to the organic phase is 2:1.

4. The method for synthesizing N-Boc-3-azetidinacetic acid according to claim 1, wherein said step 2 is specifically: adding the 3-ethoxycarbonylmethylene-azetidine-1-carboxylic acid tert-butyl ester obtained in the previous step and water into a reaction bottle, stirring, adding sodium hydroxide, heating to 60-70 ℃ for reacting for 1-2 hours, monitoring by a dot board, cooling to the room temperature, extracting with methylene dichloride once, controlling the temperature of a water phase below 20 ℃, dropwise adding hydrochloric acid, adjusting the pH value to 3-4, dropwise adding room temperature, stirring for half an hour, fully reacting, filtering after the reaction is finished, washing a filter cake with water once, and obtaining 2- {1- [ (tert-butoxy) carbonyl ] azetidine-3-alkylene } acetic acid.

5. The method for synthesizing N-Boc-3-azetidineacetic acid according to claim 4, characterized in that in said step 2, the molar ratio of 3-ethoxycarbonylmethylene-azetidine-1-carboxylic acid tert-butyl ester to sodium hydroxide is 1:1.3-1.5; the mol ratio of the 3-ethoxycarbonylmethylene-azetidine-1-carboxylic acid tert-butyl ester to the hydrochloric acid is 1:1.5-1.7; the mass ratio of the 3-ethoxycarbonylmethylene-azetidine-1-carboxylic acid tert-butyl ester to water is 1:5-6.

6. The method for synthesizing N-Boc-3-azetidineacetic acid according to claim 4, wherein in said step 2, the concentration of said hydrochloric acid is 12mol/L.

7. The method for synthesizing the N-Boc-3-azetidine acetic acid according to claim 1, wherein in the step 3, ethanol and 2- {1- [ (tert-butoxy) carbonyl ] azetidine-3-alkylene } acetic acid obtained in the previous step are added into a reaction kettle, palladium carbon is added, a kettle cover is covered, vacuum nitrogen is used for replacement, hydrogen is introduced, the pressure is 0.1-0.2 MPa, the reaction is carried out at room temperature for 12-20 hours, the palladium carbon is filtered after the reaction, the ethanol is distilled off from filtrate, the ethanol is heated and dissolved by ethyl acetate, petroleum ether is added into the reaction kettle for stirring crystallization, the reaction kettle is cooled to the room temperature for vacuum filtration, and the N-Boc-3-azetidine acetic acid is obtained after drying.

8. The method for synthesizing N-Boc-3-azetidineacetic acid according to claim 7, wherein in step 3, the mass ratio of 2- {1- [ (tert-butoxy) carbonyl ] azetidin-3-ylene } acetic acid to ethanol is 1:6 to 7, and the volume ratio of 2- {1- [ (tert-butoxy) carbonyl ] azetidine-3-ylene } acetic acid to ethyl acetate and petroleum ether is 1:1:3.

9. The method for synthesizing N-Boc-3-azetidine acetic acid according to claim 7, wherein in step 3, during recrystallization, ethyl acetate is added and then the temperature is controlled at 50-60 ℃, reflux stirring is carried out for 1 hour, petroleum ether is added under continuous stirring after heating is stopped, and the temperature is reduced to room temperature and suction filtration is carried out.