Preparation method of 5, 5-difluoro-2, 7-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester
By employing a four-step synthetic route, utilizing mild reaction conditions and readily available starting materials, the problems of high cost and high temperature risk in existing technologies have been solved, and the industrial production of tert-butyl 5,5-difluoro-2,7-diazaspiro[3.5]nonane-2-carboxylic acid with high yield has been achieved.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-14
- Publication Date
- 2026-04-03
AI Technical Summary
The existing methods for synthesizing tert-butyl 5,5-difluoro-2,7-diazaspiro[3.5]nonane-2-carboxylic acid are costly, involve complicated steps, and pose a risk of high-temperature reaction, making them unsuitable for industrial production.
A four-step synthetic route was adopted, using tert-butyl 3-(cyanomethylene)azacyclobutane-1-carboxylate, ethyl difluorobromoacetate, acetic acid, copper powder, etc. as starting materials. By controlling the temperature and using sodium borohydride, p-toluenesulfonyl chloride, Raney nickel, etc., the target compound was synthesized step by step, avoiding high temperature and high pressure reactions.
It reduces production costs, increases synthesis yield, has mild reaction conditions, is suitable for industrial production, and has an overall yield of over 80%.
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Figure CN121779397A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for preparing tert-butyl 5,5-difluoro-2,7-diazaspiro[3.5]nonane-2-carboxylic acid. Background Technology
[0002] Spirocyclic compounds, due to their unique rigid structure, have high thermal stability and are widely used in pharmaceuticals, pesticides, materials and other fields, especially as intermediates in drug synthesis.
[0003] However, the main problems with existing synthetic methods are: 1. Conventional synthetic methods use reduction reactions, resulting in high synthesis costs and consequently high production costs. 2. Existing synthetic routes involve cumbersome reaction steps, low overall yields, high reaction temperatures, production risks, and are not conducive to subsequent scaling up of production capacity.
[0004] Therefore, there is an urgent need for a new synthesis method and post-processing purification method to improve yield and purity, and reduce production costs and risks. Summary of the Invention
[0005] The purpose of this invention is to provide a method for preparing 5,5-difluoro-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester, which reduces production costs and risks, increases yield, and is suitable for industrial production. The specific technical solution is as follows: A method for preparing tert-butyl 5,5-difluoro-2,7-diazaspiro[3.5]nonane-2-carboxylic acid, comprising the following steps: S1 was prepared by reacting tert-butyl 3-(cyanomethylene)azacyclobutane-1-carboxylate, ethyl difluorobromoacetate, acetic acid (HAc), and copper powder in an organic solvent. After the reaction was complete, post-treatment was performed to obtain compound I.
[0006] Specifically, tert-butyl 3-(cyanomethylene)azacyclobutane-1-carboxylate was dissolved in tetrahydrofuran (THF) with stirring. Ethyl difluorobromoacetate was added, and the temperature was controlled below 40°C. Copper powder was then added. Acetic acid was added, and the mixture was refluxed at 65°C for 12-16 hours. The molar ratio of tert-butyl 3-(cyanomethylene)azacyclobutane-1-carboxylate to ethyl difluorobromoacetate and acetic acid was 1:1.1-2:1.5-3. After the reaction was complete, the reaction solution was cooled, ammonium chloride solution was added, and the mixture was allowed to stand for separation. The aqueous phase was extracted three times with ethyl acetate (EA). The product was then dried, filtered, concentrated, and the residue was distilled to obtain the liquid product.
[0007] S2, Compound I and sodium borohydride react in an organic solvent. After the reaction is complete, post-treatment is performed to obtain Compound II.
[0008] Specifically, intermediate I is dissolved in methanol by stirring, and sodium borohydride is added in batches at a controlled temperature of 0-10 degrees Celsius. The reaction is stirred for 10-16 hours, with the molar ratio of compound I to sodium borohydride being 1:1.2-4. After the reaction is complete, the reaction solution is quenched with water, concentrated, extracted with an organic solvent (such as dichloromethane), and then dried, filtered, and concentrated to obtain a yellow solid.
[0009] S3, compound II and p-toluenesulfonyl chloride react in an organic solvent. After the reaction is complete, post-treatment is performed to obtain compound III.
[0010] Specifically, compound II was added to dichloromethane (DCM), stirred to dissolve, and then p-toluenesulfonyl chloride (TsCl) was added dropwise while cooling to 0°C. The temperature was controlled below 10°C, and the reaction was carried out at 5-10°C for 5-8 hours. The molar ratio of compound II to p-toluenesulfonyl chloride was 1:1.1-2. After the reaction was complete, the reaction solution was added to water, separated, dried, filtered, and concentrated to obtain a yellow solid, which was then added to the next step in 100% yield.
[0011] S4, compound III, and Raney nickel are reacted in an organic solvent, purged with nitrogen, and after the reaction is complete, post-treatment is performed to obtain the product.
[0012] Specifically, compound III and Raney nickel were added to methanol, purged with nitrogen three times, and reacted at room temperature for 20-24 hours. The mass ratio of compound III to Raney nickel was 1:0.1-0.3. After the reaction was complete, post-processing was performed: filtration, concentration, sand preparation, and column chromatography to obtain the product.
[0013] The synthetic route is as follows:
[0014] Compared with the prior art, the beneficial effects achieved by the present invention are as follows: The synthesis method of this invention adopts a novel route, and the product 5,5-difluoro-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester is obtained through four steps.
[0015] This invention involves no high-temperature reactions. Except for the first step, which has a reaction temperature of around 60 degrees Celsius, the temperatures of the remaining steps are relatively low. It does not require dangerous reactions such as high temperature and high pressure. The reaction conditions are mild and suitable for industrial scale-up production and industrial promotion.
[0016] The synthesis yield of this invention is high, with the yields of the second and fourth steps both exceeding 80%, resulting in a high overall yield.
[0017] The process of this invention is mild, the starting raw materials are inexpensive and readily available, there is no high-temperature reaction, the overall process is mild, green and safe to produce, and it is suitable for industrial production. Attached Figure Description
[0018] Figure 1 This is the nuclear magnetic resonance spectrum of the product of this invention. Detailed Implementation
[0019] The present invention will be further described below with reference to specific embodiments. These embodiments are only used to more clearly illustrate the technical solutions of the present invention and should not be construed as limiting the scope of protection of the present invention. Example
[0020]
[0021] First step process name molecular weight Feeding amount equivalent 3-(cyanomethylene)azacyclobutane-1-carboxylic acid tert-butyl ester 194.23 20 g 1 Ethyl difluorobromoethyl 202.98 25.08g 1.2 Copper powder 63.55 13.74g 2.1 HAc 60.05 12.37g 2 THF / 200ml 10v In a 500 mL three-necked flask, add 20 g of tert-butyl 3-(cyanomethylene)azacyclobutane-1-carboxylate and 200 mL of tetrahydrofuran, and stir to dissolve; add 25.08 g of ethyl difluorobromoacetate, and control the temperature to below 40 degrees Celsius; add 13.74 g of copper powder; add 12.37 g of acetic acid, and reflux at 65 degrees Celsius overnight for 14 h.
[0022] After the reaction was detected to be complete by TLC, the temperature was lowered to room temperature (around 30 degrees Celsius), 100 mL of ammonium chloride solution was added and stirred. The mixture was allowed to stand and separate into layers. The aqueous phase was extracted three times with 50 mL of ethyl acetate. The product was dried, filtered (with diatomaceous earth as a base), concentrated, and the residue was distilled to obtain 18 g of liquid product, with a yield of 55%.
[0023] Second step process name molecular weight Feeding amount equivalent Compound I 318.32 18g 1.0 Sodium borohydride 37.82 4.28g 2.0 methanol / 90ml Approximately 5V Add 18g of compound I and 90mL of methanol, stir to dissolve, add sodium borohydride in batches while controlling the temperature at 0-10 degrees Celsius, and stir overnight for 14 hours.
[0024] After the reaction was complete, 90 mL of water was added to quench the reaction, the mixture was concentrated, extracted three times with 50 mL of dichloromethane, dried, filtered, and concentrated to obtain 14 g of yellow solid, with a yield of 90%.
[0025] Third step of the process name molecular weight Feeding amount equivalent Compound II 276.28 14g 1.0 TsCl 190.65 10.63g 1.1 DCM / 70ml Approximately 5.0V Add 14g of compound II and 70mL of dichloromethane, stir to dissolve, cool to 0°C and add 10.63g of p-toluenesulfonyl chloride dropwise, keeping the temperature below 10°C, and react at 5-10°C for 6 hours.
[0026] After the reaction was complete, the reaction solution was added to 10 mL of water, separated, dried, filtered, and concentrated to obtain 18 g of yellow solid, which was then added to the next step at a yield of 100%.
[0027] Fourth step process name molecular weight Feeding amount equivalent Compound III 354.37 18g 1.0 Raney nickel / 3.6g 20%m methanol / 180ml 10V In a 500 mL reaction flask, add 18 g of compound III, 180 mL of methanol, and 3.6 g of Raney nickel. Purge the mixture with nitrogen three times and react at room temperature for 24 h.
[0028] After the reaction was complete, the product was filtered, concentrated, sanded, and column filtered (PE:EA = 3:1 - PE:EA = 1:1 - DCM:MeoH = 20:1) to obtain a white solid product (e.g. Figure 1 The nuclear magnetic resonance spectrum of this invention is correct, confirming the product (11g, yield 82.6%). Example
[0029] First step process name molecular weight Feeding amount equivalent 3-(cyanomethylene)azacyclobutane-1-carboxylic acid tert-butyl ester 194.23 20 g 1 Ethyl difluorobromoethyl 202.98 23g 1.1 Copper powder 63.55 16.36g 2.5 HAc 60.05 9.27g 1.5 THF / 200ml 10v In a 500 mL three-necked flask, add 20 g of tert-butyl 3-(cyanomethylene)azacyclobutane-1-carboxylate and 200 mL of THF, and stir to dissolve; add 23 g of ethyl difluorobromoacetate, and control the temperature to below 40 degrees Celsius; add 16.36 g of copper powder; add 9.27 g of HAc, and reflux at 65 degrees Celsius overnight for 12 h.
[0030] After the reaction was complete, the temperature was lowered, 100 mL of ammonium chloride solution was added, the mixture was allowed to stand and separate into layers, the aqueous phase was extracted three times with 50 mL of EA solution, dried, filtered, concentrated, and the residue was distilled to obtain 17.5 g of liquid, with a yield of 53%.
[0031] Second step process name molecular weight Feeding amount equivalent Compound I 318.32 17.5g 1.0 Sodium borohydride 37.82 2.50g 1.2 methanol / 90ml Approximately 5V Add 17.5 g of compound I and 90 mL of methanol, stir to dissolve, add sodium borohydride in batches while controlling the temperature at 0-10 degrees Celsius, and stir overnight for 10 h.
[0032] After the reaction was complete, 90 mL of water was added to quench the reaction, the mixture was concentrated, extracted three times with 50 mL of DCM, dried, filtered, and concentrated to obtain 13 g of yellow solid, with a yield of 86%.
[0033] Third step of the process name molecular weight Feeding amount equivalent Compound II 276.28 13g 1.0 TsCl 190.65 13.46g 1.5 DCM / 70ml Approximately 5.0V Add 13g of compound II and 70mL of DCM, stir to dissolve, cool to 0 degrees Celsius and add 13.46g of TsCl dropwise, keeping the temperature below 10 degrees Celsius, and react at 5-10 degrees Celsius for 5 hours.
[0034] After the reaction was complete, the reaction solution was added to 10 mL of water, separated, dried, filtered, and concentrated to obtain 16.9 g of yellow solid, which was then added to the next step at a yield of 100%.
[0035] Fourth step process name molecular weight Feeding amount equivalent Compound III 354.37 16g 1.0 Raney nickel / 1.6g 10%m methanol / 160ml 10V In a 500 mL reaction flask, add 16 g of compound III, 160 mL of methanol, and 1.6 g of Raney nickel. Purge the mixture with nitrogen three times and react at room temperature for 20 h.
[0036] After the reaction was complete, the product was filtered, concentrated, sanded, and column filtered to obtain 9.6 g of white solid, with a yield of 81.1%. Example
[0037] First step process name molecular weight Feeding amount equivalent 3-(cyanomethylene)azacyclobutane-1-carboxylic acid tert-butyl ester 194.23 20 g 1 Ethyl difluorobromoethyl 202.98 41.8g 2 Copper powder 63.55 19.63g 3 HAc 60.05 18.55g 3 THF / 400ml 20v In a 1000 mL three-necked flask, add 20 g of tert-butyl 3-(cyanomethylene)azacyclobutane-1-carboxylate and 400 mL of THF, and stir to dissolve; add 41.8 g of ethyl difluorobromoacetate, and control the temperature below 40 degrees Celsius; add 19.63 g of copper powder; add 18.55 g of HAc, and reflux at 65 degrees Celsius overnight for 16 h.
[0038] After the reaction was complete, the temperature was lowered, 200 mL of ammonium chloride solution was added, the mixture was allowed to stand and separate into layers, the aqueous phase was extracted three times with 100 mL of EA solution, dried, filtered, concentrated, and the residue was distilled to obtain 17.4 g of liquid, with a yield of 53%.
[0039] Second step process name molecular weight Feeding amount equivalent Compound I 318.32 17g 1.0 Sodium borohydride 37.82 8g 4.0 methanol / 170ml 10v Add 17g of compound I and 170mL of methanol, stir to dissolve, add sodium borohydride in batches while controlling the temperature at 0-10 degrees Celsius, and stir overnight for 16 hours.
[0040] After the reaction was complete, 150 mL of water was added to quench the reaction, the mixture was concentrated, extracted three times with 50 mL of DCM, dried, filtered, and concentrated to obtain 13.0 g of yellow solid, with a yield of 88%.
[0041] Third step of the process name molecular weight Feeding amount equivalent Compound II 276.28 13g 1.0 TsCl 190.65 17.9g 2.0 DCM / 130ml 10.0V Add 13g of compound II and 130mL of DCM, stir to dissolve, cool to 0 degrees Celsius and add 17.9g of TsCl dropwise, keeping the temperature below 10 degrees Celsius, and react at 5-10 degrees Celsius for 8 hours.
[0042] After the reaction was complete, the reaction solution was added to 10 mL of water, separated, dried, filtered, and concentrated to obtain 16.8 g of yellow solid, which was then added to the next step at a yield of 100%.
[0043] Fourth step process name molecular weight Feeding amount equivalent Compound III 354.37 16g 1.0 Raney nickel / 4.8g 30%m methanol / 160ml 10V In a 250 mL reaction flask, add 16 g of compound III, 160 mL of methanol, and 4.8 g of Raney nickel. Purge the mixture with nitrogen three times and react at room temperature for 22 h.
[0044] After the reaction was complete, the product was filtered, concentrated, sanded, and column filtered to obtain 9.7 g of white solid, with a yield of 82.0%. Example
[0045] First step process name molecular weight Feeding amount equivalent 3-(cyanomethylene)azacyclobutane-1-carboxylic acid tert-butyl ester 194.23 20 0g 1 Ethyl difluorobromoethyl 202.98 250g 1.2 Copper powder 63.55 138g 2.1 HAc 60.05 124g 2 THF / 2000ml 10v Add 200g of tert-butyl 3-(cyanomethylene)azacyclobutane-1-carboxylate and 2000mL of THF to the reaction flask and stir to dissolve; add 250g of ethyl difluorobromoacetate and control the temperature to less than 40 degrees Celsius; add 138g of copper powder; add 124g of HAc, and reflux at 65 degrees Celsius overnight for 14 hours.
[0046] After the reaction was complete, the temperature was lowered, 1000 mL of ammonium chloride solution was added, the mixture was allowed to stand and separate into layers, the aqueous phase was extracted three times with 200 mL of EA solution, dried, filtered, concentrated, and the residue was distilled to obtain 178 g of liquid, with a yield of 54%.
[0047] Second step process name molecular weight Feeding amount equivalent Compound I 318.32 178g 1.0 Sodium borohydride 37.82 42.3g 2.0 methanol / 900ml Approximately 5V Add 178g of compound I and 900mL of methanol to a reaction flask, stir to dissolve, add sodium borohydride in batches while controlling the temperature at 0-10 degrees Celsius, and stir overnight for 12 hours.
[0048] After the reaction was complete, 900 mL of water was added to quench the reaction, the mixture was concentrated, extracted three times with 100 mL of DCM, dried, filtered, and concentrated to obtain 135 g of yellow solid, with a yield of 87%.
[0049] Third step of the process name molecular weight Feeding amount equivalent Compound II 276.28 135g 1.0 TsCl 190.65 102g 1.1 DCM / 700ml Approximately 5.0V Add 135g of compound II and 700mL of DCM, stir to dissolve, cool to 0 degrees Celsius and add 102g of TsCl dropwise, keeping the temperature below 10 degrees Celsius, and react at 5-10 degrees Celsius for 6 hours.
[0050] After the reaction was complete, the reaction solution was added to 100 mL of water, separated, dried, filtered, and concentrated to obtain 176 g of yellow solid, which was then added to the next step at a yield of 100%.
[0051] Fourth step process name molecular weight Feeding amount equivalent Compound III 354.37 170g 1.0 Raney nickel / 34g 20%m methanol / 1700ml 10V In a reaction flask, 177 g of compound III, 1700 mL of methanol, and 35.4 g of Raney nickel were added. The mixture was purged with nitrogen three times and reacted at room temperature for 24 h.
[0052] After the reaction was complete, the mixture was filtered, concentrated, sanded, and passed through a column to obtain 101g of white solid, with a yield of 80.4%.
[0053] In the above Examples 1-3, the yield in the fourth step was above 81%, and the yield in the scale-up experiment in Example 4 was also above 80%. The overall yield was high, and the yield could also be maintained above 80% in the subsequent pilot production. The design route of the present invention has a high overall yield and is suitable for industrial scale-up production.
[0054] The above are merely preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the technical principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.
Claims
1. A method for preparing tert-butyl 5,5-difluoro-2,7-diazaspiro[3.5]nonane-2-carboxylic acid, characterized in that: Includes the following steps: S1, using tert-butyl 3-(cyanomethylene)azacyclobutane-1-carboxylate, ethyl difluorobromoacetate, acetic acid, and copper powder as starting materials, reacted in an organic solvent. After the reaction was complete, post-treatment was performed to obtain compound I. S2, Compound I and sodium borohydride react in an organic solvent. After the reaction is complete, post-treatment is performed to obtain Compound II. S3, compound II and p-toluenesulfonyl chloride react in an organic solvent. After the reaction is complete, post-treatment is performed to give compound III. S4, compound III and Raney nickel are reacted in an organic solvent, purged with nitrogen, and after the reaction is complete, post-treatment is performed to obtain the product; The synthetic route is as follows: 。 2. The method as described in claim 1, characterized in that: In S1, tert-butyl 3-(cyanomethylene)azacyclobutane-1-carboxylate is dissolved in tetrahydrofuran by stirring, ethyl difluorobromoacetate is added, and the temperature is controlled below 40 degrees Celsius; copper powder is added; then acetic acid is added, and the mixture is refluxed at 65 degrees Celsius for 12-16 hours. The molar ratio of tert-butyl 3-(cyanomethylene)azacyclobutane-1-carboxylate to ethyl difluorobromoacetate and acetic acid is 1:1.1-2:1.5-3.
3. The method as described in claim 2, characterized in that: The post-treatment of S1 was as follows: the reaction solution was cooled, ammonium chloride solution was added, and the mixture was allowed to stand for separation. The aqueous phase was extracted three times with ethyl acetate, and then dried, filtered, concentrated, and the residue was distilled to obtain the liquid.
4. The method as described in claim 1, characterized in that: In S2, compound I is dissolved in methanol by stirring, and sodium borohydride is added in batches at a controlled temperature of 0-10 degrees Celsius. The reaction is stirred for 10-16 hours. The molar ratio of compound I to sodium borohydride is 1:1.2-4.
5. The method as described in claim 4, characterized in that: S2 post-processing: The reaction solution was quenched with water, concentrated, extracted with an organic solution, dried, filtered, and concentrated to obtain a yellow solid.
6. The method as described in claim 1, characterized in that: In S3, compound II is added to dichloromethane, stirred and dissolved, and then p-toluenesulfonyl chloride is added dropwise at 0 degrees Celsius while maintaining the temperature below 10 degrees Celsius. The reaction is carried out at 5-10 degrees Celsius for 5-8 hours. The molar ratio of compound II to p-toluenesulfonyl chloride is 1:1.1-2.
7. The method as described in claim 6, characterized in that: After the S3 reaction is complete, post-processing is performed: the reaction solution is added to water, separated, dried, filtered, and concentrated to obtain a yellow solid, which is then added to the next step at a yield of 100%.
8. The method as described in claim 1, characterized in that: In S4, compound III and Raney nickel were added to methanol, and the mixture was purged with nitrogen three times and reacted at room temperature for 20-24 hours. The mass ratio of compound III to Raney nickel was 1:0.1-0.
3.
9. The synthesis method as described in claim 8, characterized in that: After the S4 reaction is complete, post-processing is performed: filtration, concentration, sand making, and column chromatography to obtain a white solid product.