Process for the preparation of ethyl-1-oxo-4-azaspiro[5.5]undecane-9-carboxylate and homologues thereof

Abstract

The application discloses a preparation method of ethyl-1-oxygen-4-azaspiro [5.5] undecane-9-carboxylic acid ethyl ester and homologues thereof. The method uses a compound 1 as an initial raw material, and the compound 1 is prepared into an intermediate of a compound 13 through a reaction, an epoxy ring of the compound 13 is opened, a required benzyl amine part is introduced, a cyclization reaction is then carried out, the benzyl amine part is reduced, and finally a target product is obtained. The preparation method has the advantages of low cost, simple synthesis steps, good reaction repeatability, easy separation of a target product of each step, industrial production, and high yield of the target product.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of ethyl-1-oxo-4-azaspiro[5.5]undecane-9-carboxylate and homologs thereof. BACKGROUND

[0002] The compound ethyl-1-oxo-4-azaspiro[5.5]undecane-9-carboxylate has a wide application in the fields of chemical pharmacy and organic synthesis, and is particularly widely used in nuclear medicine in recent years. For example, the patent WO2023030434A1 discloses that the compound is used for preparing an inhibitor drug of prostate-specific membrane antigen, and embodiment 9 specifically discloses a synthesis route and steps of the compound (compound V-1 ) for synthesizing a target drug compound V . The patents CN118576737A and CN118576738A also disclose the same synthesis route.

[0003] At present, there are few reports on the synthesis method of ethyl-1-oxo-4-azaspiro[5.5]undecane-9-carboxylate, and there is no suitable large-scale synthesis method. The patent CN111662245A discloses a synthesis method of ethyl-3-oxoimino-1-oxa-4-azaspiro[5.5]undecane-9-carboxylate (compound of the following formula 6). Among them, the yield of the compound of formula 6 obtained by the ring-closing reaction of the compound of formula 5 is only 17%. The compound of formula 4 is obtained from the compound of formula 3, the compound of formula 5 is obtained by halogen exchange from the compound of formula 4, and the compound of formula 6 is obtained by the ring-closing reaction of the compound of formula 5. In the prior art, the compound of formula 3 is usually prepared from the compound of formula 1 through two-step reaction, and the compound of formula 6 is subjected to reduction reaction to obtain the target product ethyl-1-oxo-4-azaspiro[5.5]undecane-9-carboxylate (compound of formula 7) of the present application. The specific reaction formula is shown in the following formula:

[0004]

[0005]

[0006]

[0007] In the synthesis route, the yield of the compound of formula 6 prepared from the compound of formula 5 is only 17%, and the yield of the compound of formula 7 prepared by reduction of the compound of formula 6 is usually only about 1%-5%, and the reduction reaction has poor repeatability and cannot be used for scale-up reaction, which is not suitable for industrial production.

[0008] Another synthesis method of ethyl-1-oxo-4-azaspiro[5.5]undecane-9-carboxylate is disclosed in patent CN115785019 A. The compound of formula 3 or its salt (such as hydrochloride) is subjected to reductive amination with the compound of formula 8 to obtain the compound of formula 9, and the compound of formula 9 is directly reacted with base and di-tert-butyl dicarbonate to obtain the compound of formula 10; the compound of formula 10 is subjected to cyclization by treatment with p-toluenesulfonyl chloride and potassium tert-butoxide to obtain the compound of formula 11, and the compound of formula 11 is subjected to removal of the Boc group under acidic conditions to obtain the hydrochloride of the compound of formula 7, i.e. ethyl-1-oxo-4-azaspiro[5.5]undecane-9-carboxylate, which is shown in the following formula:

[0009]

[0010]

[0011] The compound of formula 3 is usually prepared from the compound of formula 1 in two steps. However, this synthesis route has many steps and a long reaction route, and the post-treatment and purification of the multi-step reaction all need to use column chromatography separation. Because column chromatography produces a large amount of waste silica gel and waste mobile phase organic solvent, it is difficult to mass-produce and industrialize this reaction route. Secondly, the compound of formula 8 has a high cost, making the entire reaction route have a high cost. Finally, when the compound of formula 10 is used to prepare the compound of formula 11, the reaction repeatability is poor, and a large amount of by-product of formula 12 is easily produced .

[0012] It is difficult to synthesize this compound at a low cost, with a simple synthesis step, good reaction repeatability, easy separation of the target product of each step, and industrialized production. SUMMARY

[0013] The purpose of the present application is to overcome the shortcomings and deficiencies of the prior art, and to provide an improved preparation method of ethyl-1-oxo-4-azaspiro[5.5]undecane-9-carboxylate. The preparation method can realize low cost, simple synthesis steps, good reaction repeatability, easy separation of the target product of each step, industrialized production, and high yield of the target product.

[0014] To achieve the above purpose, the technical scheme adopted by the present application is as follows:

[0015] A preparation method of azaspirocyclic carboxylate compounds, the preparation method comprising the following steps: 1) reacting a compound of formula I with a methylene transfer reagent in the presence of a base to obtain a compound of formula II ; 2) reacting the compound of formula II with an alcohol amine compound in an organic solvent to obtain a compound of formula III ; 3) cyclizing the compound of formula III and a sulfonating reagent in the presence of a base in a solvent to obtain a compound of formula IV ; 4) reacting the compound of formula IV and a reducing agent, hydrogen chloride in the presence of a catalyst in a solvent to obtain a compound of formula V hydrochloride; wherein, in each formula, R1is selected from C1-C6alkyl.

[0016] When R1is ethyl, the compound of formula V is ethyl-1-oxo-4-azaspiro[5.5]undecane-9- carboxylate (i.e., compound 7 or V-1 in the background art, which can be used to prepare an inhibitor drug for prostate-specific membrane antigen), and when R1is other C1-C6alkyl, it can also achieve the same purpose as compound 7 (because in subsequent application to prepare the corresponding drug, the ester moiety will be hydrolyzed to carboxyl first, and then reacted).

[0017] In some embodiments, R1is selected from methyl, ethyl, propyl, n-butyl, or t-butyl.

[0018] In some embodiments, R1is selected from methyl, ethyl, or butyl.

[0019] In some embodiments, R1is ethyl.

[0020] In some embodiments, in step 1), the methylenetransfer reagent is selected from a combination of one or more of trimethylsulfoxonium iodide, trimethylsulfoxonium bromide.

[0021] In some embodiments, in step 1), the base is selected from a combination of one or more of potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, potassium hydride, sodium hydride.

[0022] In some embodiments, in step 1), the molar ratio of the compound of formula I, the methylenetransfer reagent, and the base is 1:1.0-3.0:1.0-3.0.

[0023] In some embodiments, in step 2), the organic solvent is selected from a combination of one or more of isopropanol, propanol, ethanol, methanol, n-butanol, isobutanol, tert-butanol, tetrahydrofuran, dioxane, ethyl acetate, toluene.

[0024] In some embodiments, in step 2), the molar ratio of the compound of formula II to the alcohol amine compound is 1:1-3.0.

[0025] In some embodiments, in step 1), the ratio of the mass of the compound of formula II to the volume of the organic solvent is 1 g:1-20 mL.

[0026] In some embodiments, in step 2), the reaction is carried out under reflux.

[0027] In some embodiments, in step 2), after the reaction is completed, the compound of formula III is obtained by concentration under reduced pressure, beating, and filtration.

[0028] In some embodiments, in step 2), the compound of formula II is dissolved in the organic solvent, the alcohol amine compound is added to the organic solvent at one time, and the reaction is carried out by heating to reflux the system.

[0029] In some embodiments, in step 3), the solvent is selected from the group consisting of one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, and tetrahydrofuran.

[0030] In some embodiments, the base is selected from potassium tert-butoxide, sodium tert-butoxide, potassium hydride, or sodium hydride.

[0031] In some embodiments, the sulfonating agent is selected from p-toluenesulfonyl chloride, benzenesulfonyl chloride, or p-toluenesulfonylimidazole.

[0032] In some embodiments, in step 3), the base is potassium tert-butoxide, and the sulfonating agent is p-toluenesulfonyl chloride.

[0033] In some embodiments, in step 3), the base is sodium hydride, and the sulfonating agent is p-toluenesulfonylimidazole.

[0034] In some embodiments, when the base is sodium hydride and the sulfonating agent is p-toluenesulfonylimidazole, sodium hydride is added to the reaction system in 1-10 portions, and p-toluenesulfonylimidazole is added to the reaction system in 1-10 portions.

[0035] In some embodiments, when the base is sodium hydride and the sulfonating agent is p-toluenesulfonylimidazole, sodium hydride is added to the reaction system in 4-6 portions, and p-toluenesulfonylimidazole is added to the reaction system in 2-5 portions.

[0036] In some embodiments, in step 3), the molar ratio of the compound of formula III to the base and the sulfonating agent is 1:1-3:1-3.

[0037] In some embodiments, in step 3), the temperature of the cyclization reaction is -20 to 80°C.

[0038] In some embodiments, in step 3), the compound of formula III is dissolved in a solvent, the temperature is lowered to -20 to 10°C, the base and the sulfonating agent are added, and the cyclization reaction is carried out by heating to 15-80°C.

[0039] In some embodiments, in step 3), after the cyclization reaction is completed, hydrogen chloride is added to the reaction system for reaction, and filtration is performed to obtain a hydrochloride salt of the compound of formula IV, wherein the molar amount of the hydrogen chloride is 1-2 times the molar amount of the compound of formula III; the hydrochloride salt of the compound of formula IV is added to a mixture of an organic solvent and an aqueous sodium bicarbonate solution for reaction, and the organic phase is separated and collected to obtain the compound of formula IV. That is, the salt is first formed, and then the acid form is obtained after separation and acidification. By using this separation and purification method, column chromatography can be avoided. Moreover, this separation and purification method is easier to industrialize.

[0040] Further, the hydrogen chloride can be in the form of a hydrogen chloride-ethyl acetate solution.

[0041] Further, the organic solvent can be dichloromethane or the like.

[0042] Further, after the organic phase is collected, drying, filtration, concentration, and the like can be performed.

[0043] In some embodiments, in step 4), the catalyst is selected from one or more of a combination of palladium-carbon, palladium hydroxide-carbon, palladium hydroxide, and palladium black.

[0044] In some embodiments, in step 4), the reducing agent is selected from hydrogen.

[0045] In some embodiments, in step 4), the solvent is selected from one or more of a combination of ethanol, methanol, isopropanol, isobutanol, ethyl acetate, and acetic acid.

[0046] In some embodiments, in step 4), the molar ratio of the compound of formula IV to the catalyst is 1:0.001-0.5.

[0047] In some embodiments, in step 4), the mass-to-volume ratio of the compound of formula IV to the solvent is 1 g:1.0-50 mL.

[0048] In some embodiments, in step 4), the temperature of the reaction (which is a reduction reaction) is 0-50°C.

[0049] In some embodiments, in step 4), the time of the reaction (which is a reduction reaction) is 1-48 h.

[0050] In some embodiments, in step 4), the hydrogen chloride is generated in situ by reacting 1,1,2-trichloroethane with hydrogen in the reaction system. In this way, problems such as equipment corrosion caused by direct introduction of hydrogen chloride can be avoided.

[0051] In some embodiments, the preparation method further comprises a step of reacting the hydrochloride salt of the compound of formula V with a base to generate the compound of formula V.

[0052] The application also provides a compound of formula II as an intermediate for synthesizing a compound of formula V , wherein R1 is selected from C1-C6 alkyl. The compound of formula II as a synthetic intermediate is a brand new synthetic route which is significantly different from the prior art.

[0053] The application also provides a compound of formula III as an intermediate for synthesizing a compound of formula V , wherein R1 is selected from C1-C6 alkyl. The compound of formula III as a synthetic intermediate can make the reaction of the target product have good repeatability, the target product is easy to separate, and is easy to industrialize.

[0054] Compared with the prior art, the application has the following technical advantages:

[0055] (1) The application uses a compound of formula I as a starting material, which is reacted with a methylene transfer reagent to obtain a compound of formula II containing an epoxy structure, then the epoxy group on the compound of formula II is used to perform an epoxy ring-opening reaction with N-benzyl ethanolamine to obtain a compound of formula III which introduces a hydroxyl group and an N-benzyl group at the same time, then the compound of formula III and a sulfonating agent are reacted in the presence of a base to perform a cyclization reaction to obtain a compound of formula IV , which, after deprotection, can obtain the target product, a compound of formula V.

[0056] (2) The synthetic route of the application uses a compound of formula I as an initial material, and does not use expensive reagents, so the cost is relatively low. The application can obtain the final target product through 4 reaction steps, and the number of synthesis steps is significantly less than that of the prior art.

[0057] (3) The application introduces intermediates of the compound of formula II and the compound of formula III, which can make the reactions of steps 2) and 3) have good repeatability, and in particular, the cyclization reaction of step 3) has good repeatability, so that the target product can be easily scaled up and industrialized while ensuring the yield of the target product.

[0058] (4) In the synthetic route of the application, the product of each step is easy to separate, for example, the crude product of the compound of formula II does not need to be purified before proceeding to the next step, the compound of formula III can be purified by beating and filtering, the compound of formula IV can be purified by salification and acidification, and the final target product, the compound of formula V, can be purified by filtering, all without the column chromatography separation method which is difficult to industrialize in the prior art, which is beneficial to the industrial production of the target product. BRIEF DESCRIPTION OF DRAWINGS

[0059] Figure 1 Compound 13 in Example 1 1 H NMR spectrum;

[0060] Figure 2 The LCMS chromatogram of compound 14 in Example 1;

[0061] Figure 3 Compound 14 in Example 1 1 H NMR spectrum;

[0062] Figure 4 The LCMS chromatogram of compound 15 in Example 1;

[0063] Figure 5 Compound 15 in Example 1 1 H NMR spectrum;

[0064] Figure 6 The LCMS chromatogram of compound 7 in Example 1;

[0065] Figure 7 Compound 7 in Example 1 1 H NMR spectrum;

[0066] Figure 8 For compound 10 in Comparative Example 1 1 H NMR spectrum. Detailed Implementation

[0067] In existing technologies, such as patent CN115785019 A, compound 3 is used. Using compound 10 as the starting material, the hydrochloride salt of target compound 7 is synthesized through a four-step reaction. However, starting compound 3 is usually prepared from compound 1 through a two-step reaction. Therefore, from compound 1 to the final target product, a six-step reaction is required. Furthermore, the reaction reproducibility of compound 11 from compound 10 is poor, and a large amount of byproducts of formula 12 are easily generated. At the same time, the compound of formula 8 used in this reaction route is expensive, making the entire reaction route costly. Moreover, the post-processing purification of multiple steps all require column chromatography separation. However, column chromatography is difficult to industrialize due to the large amount of waste resin and waste mobile phase generated, making this reaction route difficult to mass-produce and industrialize.

[0068] The inventors of this application discovered through research that by innovatively introducing a compound of formula II containing an epoxy group into the synthetic route, and then reacting it with N-benzylethanolamine to undergo an epoxy ring-opening reaction, the desired benzylamine moiety can be introduced at the same time as the hydroxyl group, thus obtaining a compound of formula III. This compound can ensure the yield of the cyclization product, make the cyclization reaction highly reproducible, and make the product easy to separate, without the need for separation methods that are difficult to industrialize, such as column chromatography.

[0069] The present application innovatively uses N-benzyl ethanolamine to open the ring of the compound of formula II, and introduces an N-benzyl group, which can act as a protective group. The compound after ring opening can be cyclized under specific cyclization reaction conditions with high reaction repeatability and high yield. Then, through reduction, the target product can be obtained. The electron-withdrawing property of the N-benzyl group is significantly reduced compared to the N-Boc group in the prior art, which can eliminate a large amount of enyl amide by-products generated in the N-Boc group route.

[0070] The present application will be further described below in conjunction with examples. However, the present application is not limited to the following examples. The implementation conditions used in the examples can be further adjusted according to different specific requirements. The implementation conditions not specified are conventional conditions in the industry. The technical features involved in each embodiment of the present application can be combined with each other as long as there is no conflict.

[0071] The present application will be further described below in conjunction with specific examples.

[0072] Example 1: The reaction formula of this embodiment is shown below, and the target compound 7 is synthesized:

[0073]

[0074] (1) Synthesis of compound 13: At room temperature, dry tetrahydrofuran (1.9 L) and potassium tert-butoxide (95 g, 846.01 mmol) were added to a reactor, and stirring was started. Trimethylsulfoxonium iodide (194 g, 881.26 mmol) was added at once, and after the addition was completed, the reaction mixture was heated to reflux temperature and kept stirring at reflux for 2 hours. The reaction system was cooled to room temperature, and the raw material ethyl cyclohexanone formate (100 g, 587.51 mmol) was dissolved in 100 mL of tetrahydrofuran and added dropwise to the above reaction system, keeping the internal temperature below 20°C. After the dropwise addition was completed, the reaction system was heated to reflux and kept stirring at reflux for 3 hours. TLC point plate showed that the reaction was complete. The reaction system was cooled to room temperature, filtered, the filter cake was washed with 200 mL of ethyl acetate, and the filtrate was combined and concentrated to obtain a crude product. The crude product was diluted with 300 mL of ethyl acetate, washed with cold saturated ammonium chloride solution, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to obtain a yellow liquid crude product with a yield of 87% (molar ratio of cis-trans isomers 1:4.6). The crude product was directly used in the next reaction.

[0075] The crude product was dissolved in 300 mL of tetrahydrofuran, and 3-bromopropionyl chloride (100 g, 587.51 mmol) was added dropwise at room temperature. After the dropwise addition was completed, the reaction system was heated to reflux and kept stirring at reflux for 3 hours. TLC point plate showed that the reaction was complete. The reaction system was cooled to room temperature, filtered, and the filter cake was washed with 200 mL of ethyl acetate. The filtrate was combined and concentrated to obtain a crude product. The crude product was diluted with 300 mL of ethyl acetate, washed with cold saturated ammonium chloride solution, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to obtain a yellow liquid crude product with a yield of 87% (molar ratio of cis-trans isomers 1:4.6). The crude product was directly used in the next reaction. 1 H NMR(400 MHz, CDCl3) as Figure 1as shown, in particular: 4.175-4.122 (m, 2H), 2.653-2.618 (m, 2H), 2.435-2.350 (m, 1H), 1.993-1.750 (s, 6H), 1.529-1.387 (s, 2H), 1.265 (t, J = 7.20 Hz, 3H)。

[0076] (2) Synthesis of compound 14: Compound 13 crude product (80 g, 434.22 mmol) was dissolved in isopropyl alcohol (800 mL) at room temperature, and stirring was started. N-benzyl ethanolamine (65 g, 434.22 mmol) was added in one portion, and after the addition was completed, the reaction system was brought to reflux and reflux stirring was maintained for 20 hours. TLC point plate showed that the starting material was basically gone. After the reaction was completed, it was cooled to room temperature, and concentrated under reduced pressure to obtain a yellow oily crude product. The oily product was slurried with ethyl acetate-n-hexane, filtered, and the filter cake was washed with n-hexane. The filter cake was collected to obtain a white solid, with a yield of 77%.

[0077] LCMS: 336.35 [M+1] + , the molecular ion peak is shown in Figure 2 .

[0078] 1 H NMR (400 MHz, CDCl3) is 7.338-7.327 (m, 4H), 7.284-7.250 (m, 1H), 4.116 (q, J = 7.20 Hz, 2H), 3.770-3.757 (m, 2H), 3.622 (t, J = 5.20 Hz, 2H), 2.726 (t, J = 5.20 Hz, 2H), 2.677-2.582 (m, 2H), 2.218-2.140 (m, 1H), 1.850-1.723 (s, 6H), 1.259-1.264 (m, 5H) as shown in Figure 3 . It should be noted that the H in the two hydroxyl groups in the molecular structure is too active and does not peak, so the total number of H peaks is 27. Figure 3 The peak at 7.284-7.250 in the H NMR spectrum has a certain degree of overlap with the solvent peak (7.28), so its H integral number is slightly larger.

[0079] (3) Synthesis of compound 15: Compound 14 (70 g, 208.68 mmol) was added to N,N- dimethylformamide DMF (350 mL), replaced nitrogen three times, cooled to -2 °C in ice-salt bath, added p-toluenesulfonyl chloride TsCl (39.8 g, 208.68 mmol) and potassium tert-butoxide (46.8 g, 418 mmol), warmed to 45 °C and stirred for 2 h.

[0080] TLC spot plate detection to compound 14 reaction was complete. The reaction was quenched with cooled saturated aqueous ammonium chloride solution (600 ml), extracted with ethyl acetate three times (300 ml x 3), combined organic phase, washed with 10% brine twice (300 ml x 2), washed with saturated brine (300 ml) once, dried over anhydrous sodium sulfate, concentrated under reduced pressure to get the crude product, the crude product was dissolved in heptane / ethyl acetate (300 ml, 4: 1 V / V), slowly added hydrogen chloride-ethyl acetate solution (2.0 M, 200 ml) under ice bath and stirred for 1 h, filtered to get solid hydrochloride salt. The solid hydrochloride salt was added to a mixture of dichloromethane and saturated sodium bicarbonate solution (300 ml-500 ml) at room temperature, stirred for 1 h, separated and collected the organic phase, dried over anhydrous sodium sulfate, filtered and concentrated to get colorless oil, yield 50%.

[0081] LCMS: 318.15 [M+1] + , molecular ion peak, as shown in Figure 4 .

[0082] 1 H NMR (400 MHz, CDCl3) is 7.320-7.232 (m, 5H), 4.142-4.088 (m, 2H), 3.754-3.694 (m, 2H), 3.449-3.424 (m, 2H), 2.420-2.396 (m, 2H), 2.288-2.258 (m, 5H), 1.889-1.718 (m, 4H), 1.244 (t, J = 7.20 Hz, 3H), 1.160-1.081 (m, 2H). As shown in Figure 5 .

[0083] (4) Synthesis of compound 7 (hydrochloride salt): Compound 15 (35 g, 110.26 mmol) was added to 350 mL of ethanol, and stirring was started. 1,1,2-trichloroethane (29.1 g, 110.26 mmol) (which was hydrogenated with hydrogen gas in situ to produce hydrogen chloride gas, avoiding the use of hydrogen chloride gas directly, which can corrode equipment) and palladium hydroxide / carbon (7.65 g, with a palladium hydroxide content of 10%) were added in one portion each, and hydrogen gas was replaced three times after addition. Stirring was performed at room temperature (25 °C) for 16 hours. TLC spot tracking showed that the reaction was complete. After the reaction was completed, the mixture was filtered through 20 g of diatomite, and the filter cake was washed with 50 mL of ethanol. The organic phases were combined and concentrated under reduced pressure (45 °C) to a constant weight to obtain an oil.

[0084] At room temperature (25 °C), 30 g of the above crude product was dissolved in 30 mL of ethanol and stirred. Methyl tert-butyl ether was added dropwise while heating to reflux until a solid precipitated from the solution. The solution was slowly cooled to room temperature, filtered, and the filter cake was washed with 50 mL of methyl tert-butyl ether. The solid was collected and dried to obtain a white solid, with a yield of 99%.

[0085] LCMS: 228.05 [M+1] + , the free molecular ion peak after removal of the hydrochloride salt, and the molecular ion peak of the hydrochloride salt form does not appear in the mass spectrum. Figure 6

[0086] 1 H NMR (400 MHz, DMSO- d 6): 9.476 (s, 2H), 4.079-4.018 (m, 2H), 3.766-3.719 (m, 2H), 2.977-2.963 (m, 2H), 2.952-2.874 (m, 2H), 2.325-2.245 (m, 1H),2.090-2.056 (m, 2H), 1.793-1.492 (m, 4H), 1.339-1.262 (m, 2H), 1.169 (t, J =6.8 Hz, 3H). As shown in Figure 7 , the H in the hydrochloride moiety and the H on NH are collectively located at 9.476 ppm, and the peak is relatively wide.

[0087] Example 2: The procedure was basically the same as in Example 1, except that the amount of all raw materials and reagents was increased by 100 times for a pilot experiment. The yield of step (1) was 86%; the yield of step (2) was 71%; the yield of step (3) was 49%; and the yield of step (4) was 97%.

[0088] ​Example 3: The same as example 1, the only difference is that step (3) is different, as follows:

[0089] Compound 14 (70 g, 208.68 mmol) was added to 1.75 L of dry THF, replaced with nitrogen three times, and cooled to -2°C in an ice-salt bath. Sodium hydride (20.8 g, 521.70 mmol) was added in five batches to the system, and after the addition was complete, the temperature was raised to 20°C, and stirred for 1 hour.

[0090] The reaction system was cooled in an ice-salt bath, and p-toluenesulfonylimidazole solid (46.4 g, 208.68 mmol) was added in three batches, and after the addition was complete, the temperature was slowly raised to 20°C, and stirred for 16 hours at this temperature. TLC spot plate showed that the starting material was completely converted. The post-treatment was the same as example 1, and a colorless oil was obtained in a yield of 65%.

[0091] Example 4: The same as example 3, the only difference is that the amount of all raw materials and reagents is scaled up by 100 times for a pilot experiment. The results are as follows: step (1) yield 86%; step (2) yield 71%; step (3) yield 69%; step (4) yield 97%.

[0092] Example 5: The same as example 1, the only difference is that the reaction solvent in step (3) is replaced by tetrahydrofuran THF instead of N,N-dimethylformamide DMF. The yield of step (3) is 47%.

[0093] Comparative Example 1: The reaction formula of this comparative example is shown below, and the target compound 7 is synthesized:

[0094]

[0095] (1) Synthesis of compound 11:

[0096] Compound 10 (14.0, 40.6 mmol) was dissolved in tetrahydrofuran THF (140 mL), and p-toluenesulfonyl chloride TsCl (7.7 g, 40.6 mmol) and potassium tert-butoxide (7.0 g, 40.6 mmol) were added in turn. The reaction system was stirred at 50°C for 0.5 hours. After the disappearance of the starting material was monitored by TLC spot plate, water (60 mL) was added to quench the reaction, and extracted with ethyl acetate (140 mL x 2), and the organic phase was washed with saturated brine (140 mL), and dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate EA: petroleum ether PE = 1:4 V / V) to obtain yellow solid compound 11 in a yield of 33%. In addition, there was also a byproduct compound 12 , which was obtained in a yield of 31.8%.

[0097] Compound 11 1 H NMR (400 MHz, CDC13) was 4.151-4.098 (m, 2H), 3.684-3.620 (m, 2H), 3.416-3.402 (m, 2H), 3.348 (s, 0.53H, cis), 3.197 (s, 1.5H, trans), 2.425-2.398 (m, 0.2H, cis), 2.298-2.238 (m, 0.74H, trans), 2.002-1.770 (m, 6H), 1.458 (s, 9H), 1.269-1.184 (m, 5H).

[0098] Compound 12 1 H NMR (400 MHz, CDC13) was 6.934-6.873 (dd, 1H), 4.417-4.392 (m, 1H), 4.253-4.210 (m, 1H), 4.142 (q, J = 7.20 Hz, 2H), 3.373 (s, 2H), 2.375-2.298 (m, 1H), 2.093-1.093 (m, 6H), 1.642-1.552 (m, 2H), 1.259 (t, J = 7.00 Hz, 3H).

[0099] (2) Synthesis of compound 7:

[0100] Compound 11 (4.4 g, 13.45 mmol) was dissolved in ethyl acetate (17.6 mL), 4M HCl / EA (17.6 mL) was added dropwise, and stirred at room temperature (10 degrees) for 16 h. TLC spot plate monitoring showed that the reaction was complete. The reaction liquid was concentrated under reduced pressure (40 degrees) to obtain compound (cis / trans mixture: cis / trans = 1:4 (molar ratio)), with a yield of 99%.

[0101] Compound 10 was synthesized by the following method:

[0102]

[0103] The specific steps are as follows:

[0104] (1) Synthesis of compound 9:

[0105] Compound 13 (5 g, 27.14 mmol) was dissolved in ethanol (50 mL), and ethanolamine (2.4 g, 40.71 mmol) was added with stirring. The mixture was heated to 70°C and stirred continuously for 16 h. TLC monitoring showed that the reaction was essentially complete. The reaction system was cooled to room temperature and concentrated under reduced pressure to obtain crude compound 9, which could be directly used in the next reaction step.

[0106] (2) Synthesis of compound 10:

[0107] The crude compound 9 (6.6 g, 22.43 mmol) was dissolved in THF (38.5 mL) and water (38.5 mL). Stirring was started, and sodium bicarbonate (4.56 g, 54.28 mmol) and Boc anhydride ditert-butyl dicarbonate (11.86 g, 44.86 mmol) were added sequentially. The mixture was stirred at room temperature for 16 h, and TLC was used to monitor the reaction until complete. Extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel column chromatography (100-200 mesh) using petroleum ether:ethyl acetate as the eluent, initially 1:1 (V / V), later adjusted to 1:3, to obtain a yellow liquid (pure compound 10). The combined yield of the two steps was 70%.

[0108] 1 H NMR (400 MHz, CDCl3): 4.149-4.096 (t, J = 7.20 Hz, 2H), 3.908-3.841 (m, 2H), 3.508-3.451 (m, 2H), 3.381-3.273 (m, 2H), 2.448-2.182 (m, 1H), 1.907-1.717 (m, 6H), 1.463 (s, 9H), 1.330-1.303 (m, 2H), 1.280-1.231 (m, 3H). NMR spectrum as shown. Figure 8 As shown. It should be noted that the H atoms in the two hydroxyl groups in the molecular structure are too reactive and do not produce peaks; therefore, the total number of H atoms emitting peaks is 29.

[0109] This invention first uses compound 1, which is low-cost and readily available, as the initial raw material, and innovatively prepares compound 13 intermediate through reaction. Then, compound 13 undergoes epoxide ring-opening while introducing the desired benzylamine moiety. After that, a cyclization reaction is carried out, and finally the benzylamine moiety is reduced to obtain the target product.

[0110] The inventors found that the yield of the cyclization reaction step in the prior art could not be repeated when the Boc group protection strategy was used. When compound 10 was cyclized to compound 11 according to the prior art, the yield was actually significantly lower than the yield of the prior art. At the same time, the cyclization step also produced a large amount of enylamide byproduct compound 12, which resulted in the step and the corresponding synthetic route being unable to be used for industrial production. In addition, when the Boc group protection was used, the product 11 after cyclization could not be separated and purified by simple post-treatment such as salting and acidification in step (3) of Example 1, but could only be separated by column chromatography which is complex and difficult to industrialize.

[0111] The inventors also found that when the reaction route of Comparative Example 1 was used, the cyclization reaction of compound 10 to prepare compound 11 required very strict control of the temperature, and the reaction repeatability was poor. The larger the amount of the feedstock, the lower the yield of the cyclization reaction, and thus the reaction could not be used for industrial production.

[0112] The inventors innovatively used N-benzyl ethanolamine to open the epoxide ring of compound 13, and at the same time introduced an N-benzyl group. The N-benzyl group can be used as a protecting group, so that the compound after the epoxide ring opening can be cyclized under specific cyclization reaction conditions with high reaction repeatability and high yield, and then the target product can be obtained by deprotection. The mechanism is that in Comparative Example 1, the hydroxyethyl group connected to N in the Boc-protected compound 10 is converted into a p-toluenesulfonate intermediate by p-toluenesulfonyl chloride. Due to the strong electron-withdrawing ability of the Boc group, the intermediate easily loses one molecule of methanesulfonyl group to form a stable acylated enamine structure. At the same time, the tertiary alcohol in compound 10 forms an oxygen anion under the action of a strong base, thereby undergoing an intramolecular ester exchange reaction with the Boc group to form a more stable oxazolidinone structure (byproduct compound 12). In the examples, the protecting group is changed to benzyl, which has significantly less electron-withdrawing ability than the Boc group, so that the enylamide byproduct compound can be eliminated, and the cyclization product of the present application can be separated by simple salting and acidification. In addition, the two-step reaction of epoxide ring opening and upper protecting group in Comparative Example 1 can be saved as one-step reaction.

[0113] In addition, in Examples 1 and 3, the yield of the cyclization step in step (3) is higher than that of Comparative Example 1.

[0114] Comparative Example 2: basically the same as Example 1, the only difference is that step (3) is different, specifically as follows:

[0115] Compound 14 (400 mg, 1.13mmol) was dissolved in THF (10 mL), cooled to 0 °C, added triphenylphosphine (781 mg, 2.98mmol), replaced nitrogen three times, slowly added diisopropyl azodicarboxylate DIAD (603 mg, 2.98mmol), kept the internal temperature below 5 °C. After dropwise, 0 °C stirring for 1 h, gradually increased to room temperature, stirring for 16 h, the Mitsunobu reaction was carried out. TLC point plate showed that after the raw material reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by 300-400 mesh silica gel column chromatography (elution solvent was petroleum ether: ethyl acetate = 30:1 (V / V), then transition to 20:1 (V / V), and finally to 10:1 (V / V)) to obtain a colorless oil, with a yield of 30%. Since the reaction was relatively messy, the purification method of Example 1 could not be used, and column chromatography had to be used.

[0116] The above examples are only for illustrating the technical concept and characteristics of the present application, the purpose is to enable those skilled in the art to understand the content of the present application and to implement it, and cannot limit the protection scope of the present application. Any equivalent changes or modifications made in accordance with the spirit and essence of the present application should be covered within the protection scope of the present application.

[0117] The endpoints of the ranges and any values disclosed herein are not limited to the precise values recited as the exact dimensions are not considered critical for the present application. The endpoints of the ranges and any values are only approximate, and they are understood to encompass values approximately the same as the stated values. For ranges, the endpoints are included within the range unless otherwise indicated. For ranges of numerical values, the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are included within the range, and the endpoints of each range are

Claims

1. A method for preparing an azaspirocyclic carboxylic acid ester compound, characterized in that, The preparation method includes the following steps: 1) preparing compound I The compound reacts with a methylene transfer reagent in the presence of a base to give compound II. ;2) Replacing compound II with an alcoholamine compound The reaction is carried out in an organic solvent to give compound of formula III. 3) Compound III and a sulfonating agent are subjected to a cyclization reaction in a solvent in the presence of a base to obtain compound IV. ;4) The compound of formula IV is reacted with a reducing agent and hydrogen chloride in a solvent in the presence of a catalyst to obtain the compound of formula V. The hydrochloride salt; wherein, in each formula, R1 is selected from C1-C6 alkyl groups.

2. The method for preparing azaspirocyclic carboxylic acid ester compound according to claim 1, characterized in that, R1 is selected from methyl, ethyl, propyl, n-butyl, or tert-butyl.

3. The method for preparing azaspirocyclic carboxylic acid ester compound according to claim 1, characterized in that, In step 1), the methylene transfer reagent is selected from one or more combinations of trimethyl sulfoxide and trimethyl sulfoxide; and / or, in step 1), the base is selected from one or more combinations of potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, potassium hydride, and sodium hydride; and / or, in step 1), the molar ratio of the compound of formula I, the methylene transfer reagent, and the base is 1:1.0-3.0:1.0-3.

0.

4. The method for preparing azaspirocyclic carboxylic acid ester compound according to claim 1, characterized in that, In step 2), the organic solvent is selected from one or more combinations of isopropanol, propanol, ethanol, methanol, n-butanol, isobutanol, tert-butanol, tetrahydrofuran, dioxane, ethyl acetate, and toluene; and / or, in step 2), the molar ratio of the compound of formula II to the alkanolamine compound is 1:1-3.0; and / or, in step 1), the mass ratio of the compound of formula II to the volume ratio of the organic solvent is 1g:1-20mL.

5. The method for preparing azaspirocyclic carboxylic acid ester compound according to claim 1, characterized in that, In step 2), the reaction is carried out under reflux; and / or, in step 2), after the reaction is completed, the compound of formula III is obtained by vacuum concentration, pulping, and filtration; and / or, in step 2), the compound of formula II is dissolved in the organic solvent, the alkanolamine compound is added to the organic solvent in one go, the system is heated to reflux, and the reaction is carried out.

6. The method for preparing azaspirocyclic carboxylic acid ester compound according to claim 1, characterized in that, In step 3), the solvent is selected from one or more combinations of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, and tetrahydrofuran; and / or, the base is selected from potassium tert-butoxide, sodium tert-butoxide, potassium hydride, or sodium hydride; and / or, the sulfonating agent is selected from p-toluenesulfonyl chloride, benzenesulfonyl chloride, or p-toluenesulfonylimidazole benzenesulfonylimidazole.

7. The method for preparing azaspirocyclic carboxylic acid ester compound according to claim 1, characterized in that, In step 3), the base is potassium tert-butoxide and the sulfonating agent is p-toluenesulfonyl chloride; or, in step 3), the base is sodium hydride and the sulfonating agent is p-toluenesulfonylimidazole.

8. The method for preparing azaspirocyclic carboxylic acid ester compound according to claim 7, characterized in that, When the base is sodium hydride and the sulfonating agent is p-toluenesulfonylimidazole, sodium hydride is added to the reaction system in 1-10 portions, followed by p-toluenesulfonylimidazole in 1-10 portions.

9. The method for preparing azaspirocyclic carboxylic acid ester compound according to claim 1, characterized in that, In step 3), the molar ratio of the compound of formula III to the base and the sulfonating agent is 1:1-3:1-3; and / or, in step 3), the temperature of the cyclization reaction is -20 to 80°C; and / or, in step 3), the compound of formula III is dissolved in a solvent, cooled to -20 to 10°C, the base and the sulfonating agent are added, and the temperature is raised to 15-80°C to carry out the cyclization reaction.

10. The method for preparing azaspirocyclic carboxylic acid ester compound according to claim 1, characterized in that, In step 3), after the cyclization reaction is completed, hydrogen chloride is added to the reaction system to carry out the reaction, and the mixture is filtered to obtain the hydrochloride salt of compound IV. The molar amount of hydrogen chloride is 1-2 times that of compound III. The hydrochloride salt of compound IV is added to a mixture of organic solvent and sodium bicarbonate aqueous solution to carry out the reaction, and the organic phase is separated and collected to obtain compound IV.

11. The method for preparing azaspirocyclic carboxylic acid ester compound according to claim 1, characterized in that, In step 4), the catalyst is selected from one or more combinations of palladium-carbon, palladium hydroxide-carbon, palladium hydroxide, and palladium black; and / or, in step 4), the reducing agent is selected from hydrogen; and / or, in step 4), the solvent is selected from one or more combinations of ethanol, methanol, isopropanol, isobutanol, ethyl acetate, and acetic acid; and / or, in step 4), the hydrogen chloride is generated in situ by reacting 1,1,2-trichloroethane with hydrogen in the reaction system.

12. The method for preparing azaspirocyclic carboxylic acid ester compound according to claim 1, characterized in that, The preparation method further includes the step of reacting the hydrochloride salt of the compound of formula V with a base to generate the compound of formula V.

13. Compounds of Formula II As a synthetic V compound The uses of intermediates, among which, R1 is selected from C1-C6 alkyl groups.

14. Compounds of Formula III As a synthetic V compound The uses of intermediates, among which, R1 is selected from C1-C6 alkyl groups.

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