A method for preparing a key intermediate of saxagliptin based on double-zinc synergistic carbene cyclopropanation reaction

Abstract

The application provides a method for preparing a key intermediate of saxagliptin based on a double-zinc synergistic carbene cyclopropanation reaction, which uses N-Boc-4,5-dehydroproline amide as a substrate, dihalomethane as a carbene precursor, adds diethyl zinc and zinc trifluoroacetate, and performs a carbene cyclopropanation reaction to construct a cyclopropane skeleton in one step to obtain the key intermediate of saxagliptin. In the method, the zinc trifluoroacetate is the only catalyst with high yield and wide substrate adaptability. In the CH2I2 system, the yield is the highest, and the zinc trifluoroacetate is the only catalyst capable of causing CH2Br2 and CH2ICl to react. When the method is implemented in an industrial scale, the yield can reach 77-80%, which is 15-17 percentage points higher than the yield of 63.7% in the prior art. In the method, the amount of dihalomethane is reduced by 41%, the amount of diethyl zinc is reduced by 41%, and the ton-level production cost is significantly saved.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis catalysis technology, and relates to saxagliptin, specifically to a method for preparing a key intermediate of saxagliptin based on a synergistic carbene cyclopropanation reaction of zinc and carbene. Background Technology

[0002] Saxagliptin is a competitive inhibitor of dipeptidyl peptidase-4 (DPP-4). It reduces fasting and postprandial blood glucose levels in patients with type 2 diabetes in a glucose-dependent manner by decreasing the inactivation rate of incretins and increasing their blood concentration. It is an important oral hypoglycemic agent.

[0003] The key intermediate—(1S,3S,5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester—is the core fragment of the cyclopropane-aminoamide pharmacophore in the saxagliptin molecule, and its structure is as follows: The synthesis of this fragment has long faced bottlenecks in the industry, including low yield, numerous side reactions, and large and expensive use of key excipients. Its core step involves the carbene cyclopropanation of N-Boc-4,5-dehydroprolylamide (compound 1) to construct a cyclopropane ring, generating the target product (compound 2); that is:

[0004] .

[0005] According to literature reports, this reaction belongs to the Simmons-Smith type cyclopropanation reaction. The traditional method uses diethylzinc (Et2Zn) and diiodomethane (CH2I2) to generate zinc carbene species (IZnCH2I) in situ, which then undergoes [2+1] cycloaddition to the olefin. However, this method has the following technical defects.

[0006] First, the use of key auxiliary materials is large and the cost is high.

[0007] In the literature report (Jiang Quanke, Wang Chun, Wang Juan, et al. Synthesis process of formamide methanesulfonate, an intermediate of saxagliptin [J]. China Petroleum and Chemical Standards and Quality, 2018(17):2.DOI:CNKI:SUN:HGBJ.0.2018-17-091), both diiodomethane and diethylzinc require a dosage of 2.0 equivalents or more. However, the market price of diiodomethane has long remained at a high level of 950-1100 yuan / kg, resulting in high costs for this step in ton-scale production. In actual production optimization, the highest yield can only reach 60% by changing the solvent and adjusting the equivalent.

[0008] Second, existing catalysts have inherent defects.

[0009] Literature reports the use of trifluoroacetic acid (TFA) as a catalyst for this reaction, but TFA is a strong Bronsted acid (pKa≈0.23). When added in the early stage, the Boc protecting group of the substrate is easily protonated and removed, resulting in a severe decrease in yield. When added in the later stage, the reaction becomes too violent, the exothermic reaction is difficult to control, and the by-products increase sharply after exceeding the temperature, posing a significant safety hazard.

[0010] Third, the reaction has a narrow selectivity for dihalomethanes.

[0011] Without a catalyst or when using a weak Lewis acid (such as zinc acetate), only diiodomethane can participate in the reaction, while dibromomethane (CH2Br2), which is cheaper, cannot be effectively activated due to its higher C-Br bond energy, and experiments have shown that it does not react at all (see comparative example).

[0012] Fourth, insufficient understanding of the mechanisms hinders optimization.

[0013] Current technologies for catalyst design in zinc carbene cyclopropanation reactions are limited to empirical screening and lack systematic research on mechanisms such as Lewis acidity, ligand electronic effects, and substrate directional coordination, making it difficult to guide rational design.

[0014] With the increasing market demand for saxagliptin, the production cost control and capacity expansion of this intermediate are under pressure, and there is a need to find a catalytic system that can reduce the amount of auxiliary materials used, increase the yield, and ensure safe operation. Summary of the Invention

[0015] To address the shortcomings of existing technologies, the present invention aims to provide a method for preparing key intermediates of saxagliptin based on a synergistic carbene cyclopropanation reaction of zinc bismuth substituents, thereby solving the technical problem that existing methods are difficult to achieve both high yield and broad substrate compatibility.

[0016] To solve the above-mentioned technical problems, the present invention adopts the following technical solution.

[0017] A method for preparing a key intermediate of saxagliptin based on a synergistic carbene cyclopropanation reaction of zinc diethylcarbene and compound 2 is disclosed. The method uses N-Boc-4,5-dehydroprolylamide (compound 1) as a substrate, dihalomethane as a carbene precursor, and adds diethylzinc and zinc trifluoroacetate to carry out a carbene cyclopropanation reaction to construct a cyclopropane skeleton in one step and obtain the key intermediate of saxagliptin (compound 2).

[0018] The present invention also has the following technical features.

[0019] Specifically, the molar amount of zinc trifluoroacetate is 0.3 to 0.8 equivalents of the molar amount of substrate N-Boc-4,5-dehydroprolylamide (compound 1); the molar amount of dihalomethane is 1.15 to 1.25 equivalents of the molar amount of substrate N-Boc-4,5-dehydroprolylamide (compound 1); and the molar amount of diethylzinc is 1.15 to 1.25 equivalents of the molar amount of substrate N-Boc-4,5-dehydroprolylamide (compound 1).

[0020] Preferably, the molar amount of zinc trifluoroacetate is 0.45 to 0.65 equivalents of the molar amount of the substrate N-Boc-4,5-dehydroprolylamide (compound 1).

[0021] Most preferably, the molar amount of zinc trifluoroacetate is 0.50 equivalents of the molar amount of substrate N-Boc-4,5-dehydroprolylamide (compound 1); the molar amount of dihalomethane is 1.18 equivalents of the molar amount of substrate N-Boc-4,5-dehydroprolylamide (compound 1); and the molar amount of diethylzinc is 1.18 equivalents of the molar amount of substrate N-Boc-4,5-dehydroprolylamide (compound 1).

[0022] The method includes the following steps.

[0023] Step 1: Under nitrogen protection at room temperature, dissolve N-Boc-4,5-dehydroprolylamide (compound 1) in dichloromethane, add dihalomethane and zinc trifluoroacetate, and stir until clear.

[0024] Step 2: Cool down to -15℃ to -50℃ and add diethylzinc toluene solution dropwise while controlling the temperature.

[0025] Step 3: After the addition is complete, bring the temperature back to room temperature and keep it at that temperature for 3 to 6 hours.

[0026] Step 4: When the residual amount of substrate N-Boc-4,5-dehydroprolylamide (compound 1) is less than 2%, the temperature is lowered to -10℃ to -5℃, and potassium carbonate aqueous solution is added dropwise to quench the reaction.

[0027] Step 5: Filter by suction, wash the filter cake with dichloromethane, let the filtrate stand and separate, wash the organic phase in the filtrate with water and then concentrate by rotary evaporation until dry.

[0028] Step 6: Add petroleum ether to the concentrated and dried product, stir and disperse, filter, and dry at below 50°C to obtain the target product, saxagliptin key intermediate (compound 2).

[0029] Specifically, the dihalomethane is diiodomethane (CH2I2), dibromomethane (CH2Br2), chloroiodomethane (CH2ICl), or bromoiodomethane (CH2IBr).

[0030] Specifically, the structural formula of the N-Boc-4,5-dehydroprolylamide (compound 1) is as follows: .

[0031] Specifically, the structural formula of the key intermediate of saxagliptin (compound 2) is as follows: .

[0032] Compared with the prior art, the present invention has the following technical effects.

[0033] (I) In the method of the present invention, zinc trifluoroacetate is the only catalyst that combines high yield and broad substrate adaptability. It achieves the highest yield (79.27%) in the CH2I2 system and is the only catalyst capable of reacting CH2Br2 and CH2ICl.

[0034] (II) In this invention, zinc trifluoroacetate simultaneously plays three roles in the reaction process: Lewis acid activation, Bronsted acid avoidance, and mild reaction regulation. Based on this, this invention proposes a new catalytic reaction system.

[0035] (III) When the method of the present invention is implemented on an industrial scale, the yield can reach 77% to 80%, which is 15 to 17 percentage points higher than the yield of 63.7% in the prior art.

[0036] (IV) In the method of the present invention, the amount of dihalomethane and diethylzinc is reduced by 41%, resulting in significant cost savings per ton of production.

[0037] (V) The method of the present invention proceeded smoothly from experimentation to pilot production and scale-up production, providing a technical basis for reducing costs and increasing efficiency in industrial production. Attached Figure Description

[0038] Figure 1 Infrared spectrum of saxagliptin key intermediate (compound 2).

[0039] Figure 2 The 1H NMR spectrum of the key intermediate of saxagliptin (compound 2).

[0040] The specific content of the present invention will be further explained in detail below with reference to the embodiments. Detailed Implementation

[0041] It should be noted that, unless otherwise specified, all materials and instruments used in this invention are those known in the art.

[0042] In this invention, the "dual zinc synergy" refers to the synergy between diethylzinc and zinc trifluoroacetate. "Dual zinc" means that two zinc species are present in the reaction system: diethylzinc (Et₂Zn) acts as a zinc carbene precursor, providing the CH₂ unit; zinc trifluoroacetate (Zn(OCOCF₃)₂) acts as a synergistic catalyst, providing activation and orientation functions. "Synergy" means that zinc trifluoroacetate activates dihalomethanes while simultaneously orientationally coordinating the substrate; these two effects work synergistically to allow the reaction to proceed under low stoichiometric conditions. When Et₂Zn is used alone, CH₂Br₂ does not react; when zinc trifluoroacetate is used alone, no zinc carbene is formed, and the reaction also does not occur.

[0043] In this invention, diethylzinc acts as a reagent for generating zinc carbene active species during the reaction process.

[0044] In this invention, zinc trifluoroacetate simultaneously plays three roles during the reaction: Lewis acid activation, Bronsted acid avoidance, and mild reaction regulation.

[0045] In this invention, "carbene cyclopropanation" refers to the reaction being essentially a [2+1] cycloaddition of zinc carbene (XZnCH2X) to an olefin to construct a cyclopropane ring.

[0046] The duo-zinc synergistic carbene cyclopropanation reaction refers to the dual role of diethylzinc and zinc trifluoroacetate in the reaction system, which respectively act as a zinc carbene precursor and a Lewis acid activator. Through the synergistic effect of the two, a series mechanism of Lewis acid activation-zinc carbene generation-substrate directional coordination-synergistic cyclopropanation is achieved, thereby realizing the efficient and highly stereoselective cyclopropanation of olefins by carbene.

[0047] In this invention, the catalytic advantage of zinc trifluoroacetate compared to zinc acetate, a weak Lewis acid, stems from the strong electron-withdrawing effect of the trifluoromethyl group, i.e., the trifluoromethyl group causes Zn... 2+ The Lewis acidity at the center is significantly enhanced, enabling the activation of the C-Br bond of dibromomethane, which cannot be activated by zinc acetate (Comparative Examples 4 and 5 confirm that neither zinc acetate nor trifluoroacetic acid can catalyze the CH2Br2 reaction), while avoiding the destruction of the Boc protecting group by trifluoroacetic acid as a Bronsted acid (Comparative Example 2 confirms that the yield is only 50.93% when catalyzed by trifluoroacetic acid).

[0048] The general reaction formula for the duozinc synergistic carbene cyclopropanation reaction of the present invention is as follows: Formula 1: Compound 1 + CH2X2 + Et2Zn → [Zn(OCOCF3)2 catalyzed] → Compound 2 + ZnX2 + C2H5X; CH2X2 is selected from CH2I2, CH2Br2, CH2ICl, and CH2IBr; the solvent is dichloromethane; and the amount of zinc trifluoroacetate is 0.45 to 0.65 equivalents of the substrate molar amount.

[0049] The mechanism of the duozinc synergistic carbene cyclopropanation reaction of the present invention includes the following four steps.

[0050] Step 1, Lewis acid activation: Znt of zinc trifluoroacetate 2+ Coordination activates the CX bond of dihalomethanes, forming the [Zn(OCOCF3)2·XCH2X] activated complex.

[0051] The strong electron-withdrawing effect of fluorine atoms in trifluoroacetate makes Zn²⁺ + The electron density at the center decreases, and the Lewis acidity increases. Zinc trifluoroacetate can effectively activate the C-Br bond (bond energy 2 is relatively high), while zinc acetate's Lewis acidity is insufficient to activate the C-Br bond, and therefore it cannot catalyze the CH2Br2 reaction.

[0052] The strong electron-withdrawing effect of fluorine atoms in trifluoroacetate makes Zn²⁺ + The electron density at the center decreases, and the Lewis acidity increases. Zinc trifluoroacetate can effectively activate the C-Br bond (bond energy 2 is relatively high), while zinc acetate's Lewis acidity is insufficient to activate the C-Br bond, and therefore it cannot catalyze the CH2Br2 reaction.

[0053] Step 2, Zinc Carbene Generation: Diethyl zinc is inserted into the activated CX bond to generate the zinc carbene active species XZnCH2X, while zinc trifluoroacetate is released and regenerated.

[0054] Formula 2: [Zn(OCOCF3)2·X-CH2-X]+Et2Zn→XZnCH2X+EtX+Zn(OCOCF3)2.

[0055] Since the CX bond has been activated by zinc trifluoroacetate, diethylzinc is more easily inserted, allowing the reaction to be completed at a lower diethylzinc equivalent (1.18 equivalents vs. conventional 2.0 equivalents).

[0056] Step 3, Co-cyclopropanization: Zinc carbene performs [2+1] cycloaddition on olefins in a butterfly transition state to construct a cyclopropane ring, while releasing ZnX2.

[0057] Formula 3: XZnCH2X + [directed coordination olefin] → cyclopropane product + ZnX2.

[0058] In the butterfly transition state, the Zn-CH2 bond of the zinc carbene approaches the alkene π bond in an approximately parallel manner, and the CH2 unit transfers from the same face of the double bond to the two sp² carbon atoms, while the Zn-X bond breaks. The directional coordination of zinc trifluoroacetate makes the transition state more ordered, which is beneficial to improving the reaction rate and yield.

[0059] Step 4, catalyst recycling: ZnX2 undergoes ligand exchange with trifluoroacetate ions in the system, partially regenerating zinc trifluoroacetate and maintaining the catalytic cycle.

[0060] Equation 4: ZnX2 + 2CF3COO - →Zn(OCOCF3)2+2X - .

[0061] This exchange reaction proceeds spontaneously at room temperature, allowing for partial recycling of zinc trifluoroacetate during the reaction process. This explains the experimental fact that it can achieve highly efficient catalysis with substoichiometry (0.50 equivalents). Meanwhile, the unregenerated ZnX2 exists in the reaction solution as ZnI2 or ZnBr2, which is converted into insoluble zinc salts and removed in the subsequent potassium carbonate aqueous quenching step.

[0062] In existing technologies, the ZnX2 generated by the reaction undergoes ligand exchange with free trifluoroacetate ions in the system, partially regenerating zinc trifluoroacetate. In this process, the molar amount of dihalomethane is 1.1–2.0 equivalents of the molar amount of the substrate N-Boc-4,5-dehydroprolylamide (compound 1); the molar amount of diethylzinc is 2.0 equivalents of the molar amount of the substrate N-Boc-4,5-dehydroprolylamide (compound 1). However, in this invention, when zinc trifluoroacetate is used as a catalyst, the amount of dihalomethane can be reduced to 1.15–1.25 equivalents, and the amount of diethylzinc can be reduced to 1.15–1.25 equivalents.

[0063] In this invention, the substrate N-Boc-4,5-dehydroprolylamide (compound 1) is the known N-Boc-4,5-dehydroprolylamide (compound 1) in the art, with a purity ≥98.5%.

[0064] In this invention, the solvent is industrial grade; diethylzinc, dihalomethane and all catalysts are analytical grade.

[0065] In this invention, the key intermediate of saxagliptin (compound 2) is named (1S,3S,5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester, and compound 2 can also be called N-Boc-(1S,3S,5S)-2-azabicycloethane-3-carboxamide.

[0066] In this invention, the key intermediate of saxagliptin (compound 2) is used as an intermediate in the preparation of saxagliptin.

[0067] The following are specific embodiments of the present invention. It should be noted that the present invention is not limited to the following specific embodiments. All equivalent modifications made based on the technical solutions of this application fall within the protection scope of the present invention.

[0068] Comparative Example 1: Water catalysis + diiodomethane system.

[0069] This comparative example provides a method for preparing a key intermediate of saxagliptin, which includes the following steps.

[0070] Step 1: At room temperature and under nitrogen protection, dissolve 20g (0.09423mol) of N-Boc-4,5-dehydroprolylamide in 160g of dichloromethane, add the solution to a 500ml three-necked flask, add 50.5g (2.0 equivalent) of diiodomethane, stir well, then add 1.0g of water and continue stirring for 10min.

[0071] Step 2: Set the low-temperature bath to -35℃ and cool the system to below -25℃. Add 78.5 mL (2.0 equivalents) of 2.4 mol / L diethylzinc toluene solution at a temperature below -15℃. The addition process is exothermic and takes about 35 minutes to complete.

[0072] Step 3: After the addition is complete, quickly return the temperature to room temperature and maintain the reaction for 4 hours.

[0073] Step 4: When the sample is tested and the residual amount of substrate N-Boc-4,5-dehydroprolylamide (compound 1) is less than 2%, the reaction is considered qualified. After the reaction is qualified, the temperature is lowered to -5℃, and the prepared potassium carbonate aqueous solution (16.8g potassium carbonate + 42.8g water) is added dropwise to quench the reaction. The temperature is controlled at -10℃ to -5℃ during the dropwise addition process.

[0074] Step 5: After adding the additives and stirring for 30 minutes, filter the mixture. Wash the filter cake with 150g of dichloromethane and dry it. TLC (thin-layer chromatography) analysis of the filter cake showed no product, so it was disposed of as solid waste. Separate the filtrate after allowing it to stand. Wash the lower organic phase once with 20g of pure water, and then evaporate the organic phase to dryness to obtain 25g of off-white solid.

[0075] Step 6: Add 50g of petroleum ether, stir and disperse, filter, and dry the filter cake below 50°C to obtain 16.5g of the target product saxagliptin key intermediate (compound 2), with an external standard content of 90.4% and a yield of 69.96%.

[0076] Comparative Example 2: Trifluoroacetic acid catalysis + diiodomethane system.

[0077] This comparative example provides a method for preparing a key intermediate of saxagliptin. The method uses diiodomethane as the main raw material for carbene preparation and trifluoroacetic acid as the catalyst. The specific implementation is similar to Comparative Example 1, except that the amount of trifluoroacetic acid used as the catalyst is 5.37 g (0.50 equivalents). The final yield was 12.3 g of the target product, the key intermediate of saxagliptin (compound 2), with an external standard content of 88.2% and a yield of 50.93%.

[0078] In this comparative example, TLC detected a significant Boc deprotection byproduct during the reaction (the ratio of solute migration distance to solvent front distance, i.e., Ro). fThe yield decreased significantly (with small polar spots), verifying the destructive effect of trifluoroacetic acid as a Bronsted acid on the Boc protecting group.

[0079] Comparative Example 3: Zinc acetate catalysis + diiodomethane system.

[0080] This comparative example presents a method for preparing a key intermediate of saxagliptin. The method uses diiodomethane as the main raw material for carbene preparation and industrial zinc acetate as the catalyst. The specific implementation is similar to Comparative Example 1, with 8.62 g (0.50 equivalent) of industrial zinc acetate used. The final yield was 16.8 g of the target product, the key intermediate of saxagliptin (compound 2), with an external standard content of 89.1% and a yield of 70.28%.

[0081] Example 1: Zinc trifluoroacetate catalysis + diiodomethane system.

[0082] This embodiment provides a method for preparing a key intermediate of saxagliptin based on a duozinc synergistic carbene cyclopropanation reaction, which includes the following steps.

[0083] Step 1: At room temperature and under nitrogen protection, dissolve 20g (0.09423mol) of N-Boc-4,5-dehydroprolylamide (compound 1) in 160g of dichloromethane, add the solution to a 500ml three-necked flask, add 13.73g (0.04712mol) of zinc trifluoroacetate, add 50.5g (0.18846mol) of diiodomethane, and continue stirring for 10min.

[0084] In step one, the molar amount of zinc trifluoroacetate is 0.50 equivalents of the molar amount of substrate N-Boc-4,5-dehydroprolylamide (compound 1).

[0085] In step one, the molar amount of diiodomethane is 2.0 equivalents of the molar amount of the substrate N-Boc-4,5-dehydroprolylamide (compound 1).

[0086] Step 2: Set the low-temperature bath to -35℃ and cool the system to below -25℃. Add 78.5 mL of 2.4 mol / L diethylzinc toluene solution dropwise at a temperature below -15℃. The dropwise addition process is exothermic and takes about 35 minutes to complete.

[0087] In step two, the molar amount of diethylzinc is 2.0 equivalents of the molar amount of substrate N-Boc-4,5-dehydroprolylamide (compound 1).

[0088] Step 3: After the addition is complete, quickly return the temperature to room temperature and keep it at that temperature for 4 hours.

[0089] Step 4: When the sample is tested and the residual amount of substrate N-Boc-4,5-dehydroprolylamide (compound 1) is less than 2%, the reaction is considered qualified. After the reaction is qualified, the temperature is lowered to -5℃, and the prepared potassium carbonate aqueous solution (16.8g potassium carbonate + 42.8g water) is added dropwise to quench the reaction. The temperature is controlled at -10℃ to -5℃ during the dropwise addition process.

[0090] Step 5: After adding the additives, stir for 30 minutes, filter, wash the filter cake with 150g of dichloromethane and dry it. TLC (thin-layer chromatography) analysis of the filter cake showed no product, so it was disposed of as solid waste. The filtrate was allowed to stand and separated. The lower organic phase was washed once with 20g of pure water, and then concentrated by rotary evaporation to obtain 25g of an off-white solid.

[0091] Step 6: Add 50g of petroleum ether to the concentrated and dried product and stir to disperse. After stirring and dispersing, filter and dry at below 50°C to obtain 18.4g of the target product, saxagliptin key intermediate (compound 2), with an external standard content of 90.2% and a yield of 77.85%.

[0092] The structural characterization results of this embodiment are basically the same as those of Embodiment 3.

[0093] Compared with Comparative Example 3 (zinc acetate), this example showed a 7.57 percentage point increase in yield under the same dosage conditions, and a higher external standard content, indicating that the Lewis acidity advantage of zinc trifluoroacetate directly translates into improved yield and purity.

[0094] Example 2: Zinc trifluoroacetate catalysis + diiodomethane system.

[0095] This embodiment provides a method for preparing a key intermediate of saxagliptin based on a duozinc synergistic carbene cyclopropanation reaction. This method is basically the same as the method given in Example 1, except that in this embodiment, in step one, 29.8 g (0.1112 mol) of diiodomethane is added. The molar amount of diiodomethane is 1.18 equivalents of the molar amount of the substrate N-Boc-4,5-dehydroprolylamide (compound 1).

[0096] In this embodiment, 18.4 g of the key intermediate (compound 2) of the target product saxagliptin was finally obtained, with an external standard content of 90.2% and a yield of 77.85%.

[0097] The structural characterization results of this embodiment are basically the same as those of Embodiment 3.

[0098] Compared with Example 1, the amount of diiodomethane used in Example 2 was reduced from 2.0 equivalents to 1.18 equivalents (a decrease of 41%), while the yield remained unchanged. This indicates that the Lewis acid activation effect of zinc trifluoroacetate allows the reaction to proceed efficiently even under low equivalent conditions.

[0099] Example 3: Zinc trifluoroacetate catalysis + diiodomethane system.

[0100] This embodiment provides a method for preparing a key intermediate of saxagliptin based on a synergistic carbene cyclopropanation reaction of zinc diethylcarbene. This method is basically the same as the method given in Example 2, except that in this embodiment, in step two, 46.3 mL of a 2.4 mol / L diethylzinc toluene solution is added, and the molar amount of diethylzinc is 1.18 equivalents of the molar amount of the substrate N-Boc-4,5-dehydroprolylamide (compound 1).

[0101] In this embodiment, 18.8 g of the key intermediate (compound 2) of the target product saxagliptin was finally obtained, with an external standard content of 89.9% and a yield of 79.27%.

[0102] Compared with Example 1, in Example 3, the yield increased to 79.27% ​​(1.42 percentage points higher than in Example 1) when the amounts of diiodomethane and diethylzinc were reduced to 1.18 equivalents. This indicates that excessive excipients may cause side reactions, and zinc trifluoroacetate has better reaction selectivity under low equivalent conditions.

[0103] Structural assessment: like Figure 1 As shown, the IR(KBr)νmax values ​​are: 3396, 3216, 3059, 2974, 2960, 2880, 1675, 1476, 1430, 1360, 1179, 1129 cm⁻¹ - ¹. Figure 1 Detailed infrared spectrum data are shown in Table 1.

[0104] Table 1 Detailed Infrared Spectrum Data

[0105] like Figure 2 As shown, ¹H NMR (400MHz, DMSO- d 6)δ: 7.24(brs,1H),6.86(brs,1H),4.34–4.26(m,1H),2.48–2.34(m,2H ),1.81–1.74(m,2H),1.44(s,9H),0.94–0.88(m,1H),0.57–0.52(m,1H).

[0106] As can be seen from the characterization results above, the final product obtained in this embodiment is the key intermediate (compound 2) of the target product saxagliptin.

[0107] Example 4: Zinc trifluoroacetate catalysis + dibromomethane system.

[0108] This embodiment provides a method for preparing a key intermediate of saxagliptin based on a duozinc synergistic carbene cyclopropanation reaction. This method is basically the same as the method given in Example 1, except that in this embodiment, in step one, 32.8 g (0.18846 mol) of dibromomethane is added. The molar amount of dibromomethane is 2.0 equivalents of the molar amount of the substrate N-Boc-4,5-dehydroprolylamide (compound 1).

[0109] In this embodiment, 15.6 g of the key intermediate (compound 2) of the target product saxagliptin was finally obtained, with an external standard content of 88.7% and a yield of 64.90%.

[0110] The structural characterization results of this embodiment are basically the same as those of Embodiment 3.

[0111] The comparison between Example 4 and Example 1 shows that the price of dibromomethane is much lower than that of diiodomethane (about 1 / 5), and zinc trifluoroacetate can catalyze the reaction of dibromomethane, providing an alternative for further reducing production costs.

[0112] Example 5: Zinc trifluoroacetate catalysis + chloroiodomethane system.

[0113] This embodiment provides a method for preparing a key intermediate of saxagliptin based on a duozinc synergistic carbene cyclopropanation reaction. This method is essentially the same as that given in Example 1, except that in this embodiment, 33.2 g (0.18846 mol) of chloroiodomethane is added in step one. The molar amount of chloroiodomethane is 2.0 equivalents of the molar amount of the substrate N-Boc-4,5-dehydroprolylamide (compound 1).

[0114] In this embodiment, 15.8 g of the key intermediate (compound 2) of the target product saxagliptin was finally obtained, with an external standard content of 89.4% and a yield of 66.25%.

[0115] The structural characterization results of this embodiment are basically the same as those of Embodiment 3.

[0116] Comparative Example 4: Zinc acetate-catalyzed dibromomethane system.

[0117] This comparative example presents a method for preparing a key intermediate of saxagliptin. The method uses dibromomethane as the main raw material for carbene preparation and industrial zinc acetate as the catalyst. The specific implementation is as follows: At room temperature and under nitrogen protection, 20 g (0.09423 mol) of N-Boc-4,5-dehydroprolylamide was dissolved in 160 g of dichloromethane and added to a 500 mL three-necked flask. Then, 32.8 g (0.18846 mol) of dibromomethane was added, and the mixture was stirred until homogeneous. Next, 8.65 g (0.04712 mol) of industrial zinc acetate was added, and stirring continued for 10 min. The system was cooled to below -15 °C using a low-temperature bath at -35 °C. 78.5 mL (2.0 equivalents) of a 2.4 mol / L diethylzinc toluene solution was added dropwise at a controlled temperature of -15 °C to -50 °C. The addition process was not significantly exothermic and was completed in approximately 35 min. After the addition was completed, the temperature was quickly restored to 5°C and kept at that temperature for 4 hours. The raw materials sent for testing did not react, and no product was generated, so the experiment failed.

[0118] The comparison between Comparative Example 4 and Example 4 shows that the Lewis acidity of zinc acetate is insufficient to activate the C-Br bond (bond energy 2 is higher), which prevents diethylzinc from inserting into the C-Br bond of dibromomethane, and thus the zinc carbene species cannot be generated.

[0119] Comparative Example 5: Trifluoroacetic acid-catalyzed dibromomethane system.

[0120] This comparative example presents a method for preparing a key intermediate of saxagliptin. The method uses dibromomethane as the main raw material for carbene preparation and trifluoroacetic acid as the catalyst. The specific implementation is as follows: At room temperature and under nitrogen protection, 20 g (0.09423 mol) of N-Boc-4,5-dehydroprolylamide was dissolved in 160 g of dichloromethane and added to a 500 mL three-necked flask. Then, 32.8 g (0.18846 mol) of dibromomethane was added, and the mixture was stirred until homogeneous. Next, 5.37 g (0.04712 mol) of trifluoroacetic acid was added, and stirring continued for 10 min. The system was cooled to below -15 °C using a low-temperature bath at -35 °C. 78.5 mL (2.0 equivalents) of a 2.4 mol / L diethylzinc toluene solution was added dropwise at a controlled temperature of -15 °C to -50 °C. The addition process was not significantly exothermic and was completed in approximately 35 min. After the addition was completed, the temperature was quickly restored to 5°C and kept at that temperature for 4 hours. The raw materials sent for testing did not react, and no product was generated, so the experiment failed.

[0121] The comparison between Comparative Example 5 and Example 4 shows that although trifluoroacetic acid is a strong acid, as a Bronsted acid, it cannot coordinate and activate the C-Br bond like a Lewis acid. It only provides a proton environment, which is insufficient to promote the insertion reaction of diethylzinc to dibromomethane.

[0122] As shown in Table 2, zinc trifluoroacetate plays the following three roles simultaneously during the reaction process, based on the comparative analysis of the above examples and comparative examples.

[0123] Table 2 Summary of the multiple catalytic effects of zinc trifluoroacetate

[0124] First, zinc trifluoroacetate exhibits Lewis acid activation: the Zn in zinc trifluoroacetate... 2+ The center activates the CX bond of dihalomethanes through strong Lewis acid coordination, thereby lowering the activation energy barrier for diethylzinc insertion.

[0125] Second, zinc trifluoroacetate has a Brønsted acid avoidance effect: as a Lewis acid rather than a Brønsted acid, zinc trifluoroacetate does not protonate the Boc protecting group of the substrate, thus avoiding deprotection side reactions.

[0126] Third, the reaction is moderately controlled: the introduction of zinc trifluoroacetate reduces the amount of dihalomethane and diethylzinc from 2.0 equivalents to 1.18 equivalents, while the exothermic reaction is controllable and the temperature fluctuation is small.

[0127] As can be seen from the above examples and comparative examples, the present invention compared the performance differences of four catalysts: water, trifluoroacetic acid, zinc acetate, and zinc trifluoroacetate. The results are shown in Table 3.

[0128] Table 3 Performance results of four catalysts

[0129] The following key conclusions can be drawn from the data in Table 3 above.

[0130] First, zinc trifluoroacetate was the only catalyst capable of reacting CH2Br2 (64.90% yield in Example 4), while zinc acetate (Comparative Example 4) and trifluoroacetic acid (Comparative Example 5) produced no products under the same conditions. This difference stems directly from the stronger Lewis acidity of zinc trifluoroacetate.

[0131] Second, when zinc trifluoroacetate catalyzes CH2I2, the yield is the highest (79.27%) when the amount of CH2I2 and Et2Zn is reduced to 1.18 equivalents (Example 3), which is 15.57 percentage points higher than the 63.7% reported in the literature, while the amount of auxiliary materials is reduced by 41%.

[0132] Third, water as a catalyst yielded 69.96%, which is better than trifluoroacetic acid, but far inferior to zinc trifluoroacetate, and it cannot catalyze the CH2Br2 reaction.

[0133] Fourth, trifluoroacetic acid yield was the lowest, and Boc deprotection byproducts were detected, verifying the destructive effect of Bronsted acid on Boc protecting groups.

[0134] The following conclusions can also be drawn from the above embodiments and comparative examples.

[0135] First, zinc trifluoroacetate is the only catalyst that combines high yield with broad substrate adaptability. It achieves the highest yield (79.27%) in the diiodomethane system and is the only catalyst capable of reacting dibromomethane with CH2ICl.

[0136] Second, zinc trifluoroacetate is key to achieving the low-equivalent reaction. Examples 2 and 3 demonstrate that when both diiodomethane and Et₂Zn are reduced to 1.18 equivalents, the yield increases rather than decreases, indicating that zinc trifluoroacetate enhances the efficiency of zinc carbene formation by activating the CX bond, and that excess excipients trigger side reactions.

[0137] Third, the substrate-directed coordination of zinc trifluoroacetate enhanced stereoselectivity. All products in the zinc trifluoroacetate-catalyzed examples exhibited external standard content ≥88.7%, and high specificity for (1S, 3S, 5S) configurations.

[0138] Fourth, zinc trifluoroacetate avoids the destruction of the Boc protecting group by Bronsted acid. In Example 2, the yield was only 50.93% with trifluoroacetic acid catalysis and deprotection byproducts were detected, while no Boc deprotection byproducts were detected in the examples catalyzed by zinc trifluoroacetate.

[0139] Fifth, significant economic benefits. Taking Example 3 as the optimal solution, the yield is increased by 15.57 percentage points compared to the literature reports, while the amount of diiodomethane and diethylzinc used is reduced by 41%. Calculated on a ton-scale production basis, the cost of auxiliary materials is reduced by approximately RMB 120,000 per ton of product, creating significant economic benefits for industrial production.

Claims

1. A method for preparing a key intermediate of saxagliptin based on a duozinc-co-carbene cyclopropanation reaction, wherein the method uses N-Boc-4,5-dehydroprolylamide as a substrate and dihalomethane as a carbene precursor, characterized in that... Diethylzinc and zinc trifluoroacetate were added to carry out a carbene cyclopropanation reaction to construct a cyclopropane skeleton in one step, thus obtaining the key intermediate of saxagliptin.

2. The method for preparing the key intermediate of saxagliptin based on the synergistic carbene cyclopropanation reaction of zinc as described in claim 1, characterized in that, The molar amount of zinc trifluoroacetate is 0.3 to 0.8 equivalents of the molar amount of the substrate N-Boc-4,5-dehydroprolylamide; the molar amount of dihalomethane is 1.15 to 1.25 equivalents of the molar amount of the substrate N-Boc-4,5-dehydroprolylamide; and the molar amount of diethylzinc is 1.15 to 1.25 equivalents of the molar amount of the substrate N-Boc-4,5-dehydroprolylamide.

3. The method for preparing the key intermediate of saxagliptin based on the synergistic carbene cyclopropanation reaction of zinc as described in claim 2, characterized in that, The molar amount of zinc trifluoroacetate is 0.45 to 0.65 equivalents of the molar amount of the substrate N-Boc-4,5-dehydroprolylamide.

4. The method for preparing the key intermediate of saxagliptin based on the synergistic carbene cyclopropanation reaction of zinc as described in claim 3, characterized in that, The molar amount of zinc trifluoroacetate is 0.50 equivalents of the molar amount of the substrate N-Boc-4,5-dehydroprolylamide; the molar amount of dihalomethane is 1.18 equivalents of the molar amount of the substrate N-Boc-4,5-dehydroprolylamide; and the molar amount of diethylzinc is 1.18 equivalents of the molar amount of the substrate N-Boc-4,5-dehydroprolylamide.

5. The method for preparing the key intermediate of saxagliptin based on the duo-zinc synergistic carbene cyclopropanation reaction as described in any one of claims 1 to 4, characterized in that, The method includes the following steps: Step 1: At room temperature and under nitrogen protection, dissolve N-Boc-4,5-dehydroprolylamide in dichloromethane, add dihalomethane and zinc trifluoroacetate, and stir until clear; Step 2: Cool down to -15℃ to -50℃, and add diethylzinc toluene solution dropwise while controlling the temperature. Step 3: After the addition is complete, return the temperature to room temperature and maintain the temperature for 3-6 hours. Step 4: When the residual N-Boc-4,5-dehydroprolyl amide substrate is less than 2%, the temperature is lowered to -10℃ to -5℃, and potassium carbonate aqueous solution is added dropwise to quench the reaction. Step 5: Filter by suction, wash the filter cake with dichloromethane, let the filtrate stand and separate, wash the organic phase in the filtrate with water and then concentrate by rotary evaporation until dry; Step 6: Add petroleum ether to the concentrated and dried product, stir and disperse, filter, and dry at below 50°C to obtain the target product, saxagliptin key intermediate.

6. The method for preparing the key intermediate of saxagliptin based on the duo-zinc synergistic carbene cyclopropanation reaction as described in any one of claims 1 to 4, characterized in that, The dihalomethane is diiodomethane, dibromomethane, chloroiodomethane, or bromoiodomethane.

7. The method for preparing the key intermediate of saxagliptin based on the duo-zinc synergistic carbene cyclopropanation reaction as described in any one of claims 1 to 4, characterized in that, The structural formula of the N-Boc-4,5-dehydroprolylamide is as follows: .

8. The method for preparing the key intermediate of saxagliptin based on the duo-zinc synergistic carbene cyclopropanation reaction as described in any one of claims 1 to 4, characterized in that, The structural formula of the key intermediate of saxagliptin is as follows: .

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