Preparation method of ethyl-1-oxo-4-azaspiro [5.5] undecane-9-carboxylic acid ethyl ester and homologues of ethyl-1-oxo-4-azaspiro [5.5] undecane-9-carboxylic acid ethyl ester

Abstract

The invention discloses a preparation method of ethyl-1-oxo-4-azaspiro [5.5] undecane-9-carboxylic acid ethyl ester and a homologue of the ethyl-1-oxo-4-azaspiro [5.5] undecane-9-carboxylic acid ethyl ester. According to the method, a compound 1 which is relatively low in cost and easy to obtain is taken as an initial raw material and is subjected to a reaction to prepare an intermediate of a compound 13, then the compound 13 is subjected to epoxy ring opening, meanwhile, a required benzylamine part is introduced, then a cyclization reaction is performed, and finally, the benzylamine part is reduced, so that a target product is obtained. According to the preparation method, the cost is low, the synthesis steps are simple, the reaction repeatability is good, the target product in each step is easy to separate, industrial production can be realized, and the yield of the target product is high.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing ethyl-1-oxo-4-azaspirocyclic [5.5]undecane-9-carboxylic acid ethyl ester and its homologues. Background Technology

[0002] The compound ethyl-1-oxo-4-azaspirocyclic [5.5]undecane-9-carboxylic acid ethyl ester has wide applications in the fields of chemical pharmaceuticals and organic synthesis, especially in radiopharmaceuticals in recent years. For example, patent WO2023030434A1 discloses the use of this compound to prepare an inhibitor of prostate-specific membrane antigen, and Example 9 specifically discloses this compound (compound V-1). Synthesize target drug compound V The synthetic route and steps are described. Patents CN118576737A and CN118576738A also disclose the same synthetic route.

[0003] Currently, there are few reported methods for synthesizing ethyl-1-oxo-4-azaspirocyclic [5.5]undecane-9-carboxylic acid ethyl ester, and no suitable large-scale synthesis method exists. Patent CN111662245A discloses a method for synthesizing ethyl-3-oxoylide-1-oxa-4-azaspiro[5.5]undecane-9-carboxylic acid ester (compound of formula 6). However, the yield of compound of formula 5 to compound 6 via a ring-closing reaction is only 17%. It uses compound of formula 3 as a starting material to obtain compound of formula 4, compound 4 undergoes halogen exchange to obtain compound 5, and compound 5 undergoes a ring-closing reaction to obtain compound 6. In the prior art, compound of formula 3 is usually prepared from compound of formula 1 through a two-step reaction, and compound 6 undergoes a reduction reaction to obtain the target product of this application, ethyl-1-oxo-4-azaspirocyclic [5.5]undecane-9-carboxylic acid ethyl ester (compound of formula 7), as shown in the following reaction formula:

[0004]

[0005]

[0006]

[0007] In this synthetic route, the yield of compound 5 to compound 6 is only 17%, and the yield of compound 6 to compound 7 is usually only about 1%-5%. Moreover, the reduction reaction has poor reproducibility and cannot be used for scale-up, making it unsuitable for industrial production.

[0008] Patent CN115785019 A discloses another synthetic method for ethyl-1-oxo-4-azaspirocyclic [5.5]undecane-9-carboxylic acid ethyl ester. The method involves reductive amination of compound 3 or its salt (e.g., hydrochloride) with compound 8 to obtain compound 9. Compound 9 is then reacted directly with a base and di-tert-butyl dicarbonate to obtain compound 10. Compound 10 is cyclized by treatment with p-toluenesulfonyl chloride and potassium tert-butoxide to obtain compound 11. Compound 11 is then deactivated under acidic conditions by removing the Boc group to obtain the hydrochloride salt of compound 7, i.e., ethyl-1-oxo-4-azaspirocyclic [5.5]undecane-9-carboxylic acid ethyl ester. The synthetic method is shown in the following formula:

[0009]

[0010]

[0011] The aforementioned compound of formula 3 is typically prepared from compound of formula 1 through a two-step reaction. However, this synthetic route involves numerous steps and a lengthy reaction process. Furthermore, the post-processing purification of each step requires column chromatography, which generates large amounts of waste silica gel and waste mobile phase organic solvents, making this reaction route difficult to mass-produce and industrialize. Secondly, the high cost of compound of formula 8 contributes to the overall high cost of the reaction route. Finally, the preparation of compound of formula 11 from compound of formula 10 exhibits poor reproducibility and easily generates a large amount of byproducts of formula 12. .

[0012] The challenge in synthesizing this compound lies in achieving a simple synthesis process with good reaction reproducibility, easy separation of the target product at each step, and industrial-scale production at a low cost. Summary of the Invention

[0013] The purpose of this invention is to address the shortcomings and deficiencies of the prior art by providing an improved method for preparing ethyl-1-oxo-4-azaspirocyclic [5.5]undecane-9-carboxylic acid ethyl ester. This method achieves lower cost, simpler synthesis steps, better reaction reproducibility, easy separation of the target product in each step, industrial-scale production capability, and higher yield of the target product.

[0014] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0015] A method for preparing an azaspirocyclic carboxylic acid ester compound, the method comprising the following steps: 1) preparing a compound of formula 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.

[0016] When R1 is ethyl, compound V is ethyl-1-oxo-4-azaspirocyclic [5.5]undecane-9-carboxylic acid ethyl ester (i.e., compound 7 or V-1 in the background art, which can be used to prepare inhibitors of prostate-specific membrane antigens). When R1 is other C1-C6 alkyl groups, it can also achieve the same use as compound 7 (because when preparing the corresponding drug in subsequent applications, the ester group will be hydrolyzed to a carboxyl group before the reaction).

[0017] In some embodiments, R1 is selected from methyl, ethyl, propyl, n-butyl, or tert-butyl.

[0018] In some embodiments, R1 is selected from methyl, ethyl, or butyl.

[0019] In some embodiments, R1 is ethyl.

[0020] In some embodiments, in step 1), the methylene transfer reagent is selected from one or more combinations of trimethyl sulfoxide and trimethyl sulfoxide.

[0021] In some embodiments, 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.

[0022] In some embodiments, 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.

[0023] In some embodiments, 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.

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

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

[0026] In some implementations, step 2) 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 vacuum concentration, pulping, and filtration.

[0028] In some embodiments, 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 step, and the system is heated to reflux to carry out the reaction.

[0029] In some embodiments, in step 3), the solvent is selected from one or more combinations 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, followed by p-toluenesulfonylimidazole 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 then 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 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, cooled to -20 to 10°C, the base and sulfonating agent are added, and the temperature is raised to 15-80°C to carry out a cyclization reaction.

[0039] In some embodiments, in step 3), after the cyclization reaction is completed, hydrogen chloride is added to the reaction system for further reaction, followed by filtration to obtain the hydrochloride salt of compound IV, wherein the molar amount of hydrogen chloride is 1-2 times that of compound III. The hydrochloride salt of compound IV is then added to a mixture of organic solvent and sodium bicarbonate aqueous solution for further reaction, and the organic phase is separated and collected to obtain compound IV. That is, the salt is first formed, separated, and then acidified to the acidic form. This separation and purification method eliminates the need for column chromatography and is more easily industrialized.

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

[0041] Furthermore, the organic solvent can be dichloromethane, etc.

[0042] Furthermore, after collecting the organic phase, it can be dried, filtered, concentrated, etc.

[0043] In some embodiments, in step 4), the catalyst is selected from one or more combinations 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 combinations 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 ratio of the compound of formula IV to the volume ratio of the solvent is 1 g: 1.0-50 mL.

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

[0049] In some implementations, in step 4), the reaction (a reduction reaction) takes 1-48 hours.

[0050] In some embodiments, in step 4), the hydrogen chloride is generated in situ by reacting 1,1,2-trichloroethane with hydrogen in a reaction system. This avoids problems such as equipment corrosion caused by directly introducing hydrogen chloride.

[0051] In some embodiments, 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.

[0052] The present invention also provides a compound of formula II. As a synthetic V compound The use of intermediates, wherein R1 is selected from C1-C6 alkyl groups. Using compounds of formula II as synthetic intermediates represents a novel synthetic route that differs significantly from existing techniques.

[0053] The present invention also provides a compound of formula III. As a synthetic V compound The use of intermediates, wherein R1 is selected from C1-C6 alkyl groups. Using compounds of formula III as synthetic intermediates can improve the reproducibility of the target product reaction, facilitate the separation of the target product, and make it easier to industrialize.

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

[0055] (1) The present invention uses a low-cost compound of formula I. Using it as a starting material, it is first reacted with a methylene transfer reagent to obtain a compound of formula II containing an epoxy structure. Then, utilizing the epoxy group on the compound of formula II, it undergoes an epoxy ring-opening reaction with N-benzylethanolamine to obtain compound of formula III, which simultaneously introduces hydroxyl and N-benzyl groups. Then, the compound of formula III and the sulfonating agent are subjected to a cyclization reaction in the presence of a base to obtain the compound of formula IV. After deprotection, the target product compound V can be obtained.

[0056] (2) The synthetic route of the present invention uses the compound of formula I as the starting material and does not use expensive reagents, thus the cost is relatively low. The present invention can obtain the final target product through 4 reaction steps, which is significantly fewer than the prior art.

[0057] (3) By introducing compounds of formula II and formula III as intermediates, the present invention can make the reaction of steps 2) and 3) reproducible, especially the cyclization reaction of step 3) reproducible, and can make the target product easy to scale up and industrialize while ensuring the yield of the target product.

[0058] (4) In the synthetic route of the present invention, the products of each step are easy to separate. For example, the crude product of compound II does not need to be purified before proceeding to the next reaction. Compound III can be purified by pulping and filtration. Compound IV can be purified by salt formation and acidification. The final target product, compound V, can be purified by filtration. All of these do not require column chromatography separation methods that are difficult to industrialize in the prior art, which is conducive to the industrial production of the target product. Attached Figure Description

[0059] Figure 1 Compound 13 in Example 1 1 H NMR spectrum; Figure 2 The LCMS chromatogram of compound 14 in Example 1; Figure 3 Compound 14 in Example 1 1 H NMR spectrum; Figure 4 The LCMS chromatogram of compound 15 in Example 1; Figure 5 Compound 15 in Example 1 1 H NMR spectrum; Figure 6 The LCMS chromatogram of compound 7 in Example 1; Figure 7 Compound 7 in Example 1 1 H NMR spectrum; Figure 8 For compound 10 in Comparative Example 1 1 H NMR spectrum. Detailed Implementation

[0060] 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.

[0061] 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.

[0062] This invention innovatively employs N-benzylethanolamine to perform epoxide ring-opening on the compound of formula II, while simultaneously introducing an N-benzyl group. This N-benzyl group can act as a protecting group, enabling the epoxide-opened compound to undergo cyclization reactions with high reproducibility and high yield under specific cyclization reaction conditions. The target product can then be obtained through reduction. Compared to the N-Boc group in existing technologies, the N-benzyl group has significantly reduced electron-withdrawing properties, thus eliminating the large amount of alkenyl amide byproducts generated during the N-Boc group route.

[0063] The present invention will be further described below with reference to embodiments. However, the present invention is not limited to the following embodiments. The implementation conditions used in the embodiments can be further adjusted according to different requirements of specific applications, and the implementation conditions not specified are conventional conditions in the industry. The technical features involved in the various embodiments of the present invention can be combined with each other as long as they do not conflict with each other.

[0064] The present invention will be further described in detail below with reference to specific embodiments.

[0065] Example 1: The reaction formula for this example is shown below, synthesizing target compound 7:

[0066]

[0067] (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 the reactor, and stirring was started. Trimethyl sulfoxide (194 g, 881.26 mmol) was added all at once. After the addition was complete, the reaction mixture was heated to reflux temperature and stirred under reflux for 2 hours. The reaction system was cooled to room temperature, and ethyl p-cyclohexanone carboxylate (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 addition was complete, the reaction system was heated to reflux and stirred under reflux for 3 hours. TLC 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 filtrates were combined and concentrated to obtain the 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 again with ethyl acetate. The combined organic phases were 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 in 87% yield (cis-trans isomer molar ratio 1:4.6). This crude product was used directly in the next reaction step.

[0068] coarse products 1 H NMR (400 MHz, CDCl3) such as Figure 1As shown, specifically: 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).

[0069] (2) Synthesis of Compound 14: At room temperature, crude Compound 13 (80 g, 434.22 mmol) was dissolved in isopropanol (800 mL) and stirred. N-Benzylethanolamine (65 g, 434.22 mmol) was added all at once. After the addition was complete, the reaction system was brought to reflux and stirred under reflux for 20 hours. TLC showed that the starting material had basically disappeared. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude yellow oil. The oil 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%.

[0070] LCMS: 336.35 [M+1] + Molecular ion peak, such as Figure 2 As shown.

[0071] 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). For example... Figure 3 As shown. It should be noted that the H atoms in the two hydroxyl groups in the molecular structure are too reactive to produce peaks, so the total number of H atoms emitting peaks is 27. Figure 3 The peak at 7.284-7.250 overlaps to some extent with the solvent peak (7.28), so its H integral number is slightly larger.

[0072] (3) Synthesis of compound 15: Compound 14 (70 g, 208.68 mmol) was added to N,N-dimethylformamide DMF (350 mL), nitrogen was purged three times, the temperature was lowered to -2 °C in an ice-salt bath, p-toluenesulfonyl chloride TsCl (39.8 g, 208.68 mmol) and potassium tert-butoxide (46.8 g, 418 mmol) were added, and the temperature was raised to 45 °C and stirred for 2 h.

[0073] TLC detection continued until compound 14 was fully reacted. The reaction was quenched with cooled saturated ammonium chloride aqueous solution (600 ml), extracted three times with ethyl acetate (300 ml x 3), the organic phases were combined, washed twice with 10% brine (300 ml x 2), washed once with saturated brine (300 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was dissolved in heptane / ethyl acetate (300 ml, 4:1 v / v), and a hydrogen chloride-ethyl acetate solution (2.0 M, 200 ml) was slowly added under ice bath while stirring for 1 hour. The mixture was filtered to obtain a solid hydrochloride. The obtained solid hydrochloride was added to a mixture of dichloromethane and saturated sodium bicarbonate solution (300 ml-500 ml) at room temperature and stirred for 1 hour. The organic phase was separated and collected, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a colorless oily substance with a yield of 50%.

[0074] LCMS: 318.15 [M+1] + Molecular ion peak, such as Figure 4 As shown.

[0075] 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). For example... Figure 5 As shown.

[0076] (4) Synthesis of Compound 7 (hydrochloride): 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 reacts with hydrogen on-site to produce hydrogen chloride gas in situ, avoiding the direct use of hydrogen chloride gas, which can easily corrode equipment) and palladium hydroxide / carbon (7.65 g, of which palladium hydroxide content is 10%) were added separately. After the addition, the hydrogen gas was purged three times. The mixture was stirred at room temperature (25 °C) for 16 hours until TLC showed complete reaction. After the reaction, the mixture was filtered through 20 g of diatomaceous earth, and the filter cake was washed with 50 mL of ethanol. The organic phases were combined and concentrated under reduced pressure (45 °C) to constant weight to obtain a crude oily product.

[0077] At room temperature (25℃), 30g of the above crude product was dissolved in 30mL of ethanol and stirred. Methyl tert-butyl ether was added dropwise while the temperature was raised to reflux until solid precipitated in the solution. The temperature was then slowly lowered to room temperature, filtered, and the filter cake was washed with 50mL of methyl tert-butyl ether. The solid was collected, dried, and a white solid was obtained with a yield of 99%.

[0078] LCMS: 228.05 [M+1] + The peak of the free molecular ion after the removal of hydrochloride is observed; molecules in hydrochloride form do not exhibit any mass spectrum peaks. For example... Figure 6 As shown.

[0079] 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). For example... Figure 7 As shown in the figure, the H in the hydrochloric acid fraction and the H on the NH4+ fraction are both located at 9.476 ppm, and the peaks are relatively broad.

[0080] Example 2: Basically the same as Example 1, except that the amount of all raw materials and reagents was increased by 100 times for pilot-scale experiment. Results: 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%.

[0081] Example 3: Basically the same as Example 1, except that step (3) is different, as follows:

[0082] Compound 14 (70 g, 208.68 mmol) was added to 1.75 L of dry THF, and nitrogen was purged three times. The mixture was then cooled to -2 °C in an ice-salt bath. Sodium hydride (20.8 g, 521.70 mmol, with each addition being approximately equal) was added to the system in five batches. After the addition was complete, the mixture was heated to an internal temperature of 20 °C and stirred for 1 hour.

[0083] Under ice-salt bath cooling, solid p-toluenesulfonyl imidazole (46.4 g, 208.68 mmol, each batch approximately equal in amount) was added to the above reaction system in three batches. After the addition was complete, the temperature was slowly raised to 20°C and maintained at this temperature with stirring for 16 hours. TLC showed complete conversion of the starting material. Post-treatment was the same as in Example 1, yielding a colorless oily substance with a yield of 65%.

[0084] Example 4: Basically the same as Example 3, except that the amount of all raw materials and reagents was increased by 100 times for pilot-scale testing. Results: The yield of step (1) was 86%; the yield of step (2) was 71%; the yield of step (3) was 69%; and the yield of step (4) was 97%.

[0085] Example 5: Basically the same as Example 1, except that the reaction solvent in step (3) was replaced with tetrahydrofuran (THF) instead of N,N-dimethylformamide (DMF). The yield of step (3) was 47%.

[0086] Comparative Example 1: The reaction formula for this comparative example is shown below. Target compound 7 was synthesized as follows:

[0087]

[0088] (1) Synthesis of compound 11:

[0089] Compound 10 (pure product, 14.0 g, 40.6 mmol) was dissolved in tetrahydrofuran (THF), 140 mL, followed by the sequential addition of p-toluenesulfonyl chloride (TsCl), 7.7 g, 40.6 mmol, and potassium tert-butoxide, 7.0 g, 40.6 mmol. The reaction mixture was stirred at 50 °C for 0.5 h. After the reaction was complete, water (60 mL) was added to quench the reaction mixture, which was then extracted with ethyl acetate (140 mL × 2). The organic phase was washed with saturated brine (140 mL), dried over 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 give compound 11 as a yellow solid, in 33% yield. Additionally, an alkenylamide byproduct, compound 12, was also obtained. Its yield was 31.8%.

[0090] Compound 11 1 H NMR (400 MHz, CDCl3) is 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).

[0091] Byproduct compound 12 1 H NMR (400 MHz, CDCl3) is 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).

[0092] (2) Synthesis of compound 7:

[0093] Compound 11 (4.4 g, 13.45 mmol) was dissolved in ethyl acetate (17.6 mL), and 4 M HCl / EA (17.6 mL) was added dropwise. The mixture was stirred at room temperature (10 °C) for 16 h. The reaction was monitored by TLC to ensure complete reaction. The reaction solution was concentrated under reduced pressure (40 °C) to give the compound (cis / trans mixture: cis / trans = 1:4 (molar ratio)) in 99% yield.

[0094] Compound 10, in its pure form, was synthesized via the following method:

[0095]

[0096] The specific steps are as follows:

[0097] (1) Synthesis of compound 9:

[0098] 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.

[0099] (2) Synthesis of compound 10:

[0100] 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%.

[0101] 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.

[0102] 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.

[0103] During actual research and development, the inventors initially referred to the existing technology's Boc group protection strategy in the cyclization reaction step. However, they found that the yield of the existing cyclization reaction step could not be replicated. That is, when compound 10 was synthesized into compound 11 using the existing cyclization method, the yield was actually significantly lower than that of the existing technology. At the same time, this cyclization step also generated a large amount of alkenylamide byproduct compound 12, making this step and the corresponding synthetic route unsuitable for industrial production. Furthermore, when using Boc group protection, the cyclized product 11 could not be separated and purified by simple post-treatment methods such as salt formation and acidification in step (3) of Example 1. It could only be separated by column chromatography, which is a complex process and difficult to industrialize.

[0104] Furthermore, the inventors discovered that when using the reaction route of Comparative Example 1, the reaction of compound 10 to prepare compound 11 via cyclization requires very strict temperature control, the reproducibility of the reaction is very poor, and the yield of cyclization reaction is lower when the amount of feed is larger, thus making industrial production impossible.

[0105] This invention innovatively employs N-benzylethanolamine to perform epoxide ring-opening on compound 13, while simultaneously introducing an N-benzyl group. This N-benzyl group can act as a protecting group, allowing the epoxide-opened compound to undergo cyclization reactions with high reproducibility and high yield under specific cyclization reaction conditions. Subsequently, deprotection yields the target product. The underlying mechanism is as follows: In compound 10 protected by Boc in Comparative Example 1, the N-linked hydroxyethyl group is converted to a p-toluenesulfonate intermediate by p-toluenesulfonyl chloride. Due to the strong electron-withdrawing ability of the Boc group, under strong base conditions, this intermediate readily loses a molecule of methanesulfonyl group, forming a stable acylated enamine structure. Simultaneously, the tertiary alcohol in compound 10 forms an oxonium under strong base conditions, thereby undergoing an intramolecular transesterification reaction with the Boc group to form a more stable oxazolidinone structure (byproduct compound 12). In the embodiments, the protecting group is changed to benzyl, which has a significantly lower electron-withdrawing property than the Boc group. Therefore, the alkenyl amide by-product compound can be eliminated, and the cyclization product of the present invention can be separated by simple salt formation and acidification. Furthermore, the two-step reaction of epoxy ring opening and the addition of the protecting group in Comparative Example 1 can be reduced to a single step.

[0106] Furthermore, in Examples 1 and 3, the yield of the cyclization step (3) is higher than that of Comparative Example 1.

[0107] Comparative Example 2: Basically the same as Example 1, except that step (3) is different, as follows:

[0108] Compound 14 (400 mg, 1.13 mmol) was dissolved in THF (10 mL), cooled to 0°C, and triphenylphosphine (781 mg, 2.98 mmol) was added. Nitrogen gas was purged three times, and diisopropyl azodicarbonate (DIAD) (603 mg, 2.98 mmol) was slowly added dropwise, maintaining the internal temperature below 5°C. After the addition was complete, the mixture was stirred at 0°C for 1 h, gradually increased to room temperature, and stirred for 16 h to carry out the Mitsunobu reaction. TLC showed complete reaction of the starting material. The reaction solution was concentrated under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (300-400 mesh) using petroleum ether:ethyl acetate = 30:1 (V / V), then transitioned to 20:1 (V / V), and finally to 10:1 (V / V) to obtain a colorless oily substance with a yield of 30%. Due to the relatively disordered reaction, the purification method of Example 1 could not be used for this comparative example; only column chromatography could be employed.

[0109] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

[0110] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

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.

Images