Preparation method of 6-azaspiro [2.5] octane-6-carboxylic acid-1, 1-dimethyl ethyl ester

Abstract

The invention relates to a preparation method of 6-azaspiro [2.5] octane-6-carboxylic acid-1, 1-dimethyl ethyl ester (a compound as shown in a formula I). And by adopting the electrochemical selective dehalogenation reaction, the reaction safety is greatly improved, the yield can be maintained while mass production can be realized, the production cost is reduced, the safety is improved, and the method is suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of synthesis of pharmaceutical intermediates, and particularly relates to a preparation method of 6-azaspiro[2.5]octane-6-carboxylic acid 1,1-dimethylethyl ester. Background Art

[0002] 6-azaspiro[2.5]octane-6-carboxylic acid 1,1-dimethylethyl ester (Compound of Formula I) is an important fragment in drug design, and its derivatives have high biological activities and are widely used in the fields of chemistry, chemical engineering, and medicine, such as chemokine receptor CCR2 modulators (CN101472904B), protease inhibitors (CN102417490A), anti-tumor target Raf inhibitors (WO2009028629A1), Lp-PLA2-mediated related diseases (CN114057740A), etc. In recent years, seeking some screening drugs with good activities by connecting 6-azaspiro[2.5]octane-6-carboxylic acid 1,1-dimethylethyl ester (Compound of Formula I) with specific structures has become one of the research hotspots in the drug discovery stage. Therefore, 6-azaspiro[2.5]octane-6-carboxylic acid 1,1-dimethylethyl ester (Compound of Formula I) is a very promising pharmaceutical intermediate.

[0003]

[0004] Currently, the disclosed 6-azaspiro[2.5]octane-6-carboxylic acid 1,1-dimethylethyl ester (Compound of Formula I) is an electrochemical selective dehalogenation reaction. The traditional reaction route is achieved through the Simmons-smiths reaction. Under the action of trifluoroacetic acid and Et 2 Zn, and diiodomethane at low temperature to generate the target product, and the reported yield is 45%. The reaction route is as follows:

[0005]

[0006] This route involves the use of a large amount of acids and active reagents, the overall process conditions are relatively harsh, and a large amount of waste liquid is generated during the reaction process, resulting in a relatively high route cost, difficult post-treatment, and difficult reaction scale-up, making it difficult to carry out industrial mass production. Development and Scale-Up of the Electrochemical Dehalogenation for the Synthesis of a Key Intermediate for NS5A Inhibitors (Org. Process Res. Dev. 2015, 19, 1428-1433) discloses a method for electrochemical dehalogenation, and the reaction route is as follows:

[0007]

[0008] When this method is applicable to this substrate, although a relatively high yield can be achieved (the reported yield in the literature can reach 98%), the reaction equipment needs to use a proton exchange membrane, which has a relatively high cost and is prone to swelling during use. Therefore, this method is not conducive to large-scale amplification and increases the complexity and cost of equipment design;

[0009] Therefore, it is of great significance to develop a simple, safe, easily scalable and low-cost synthetic process for 6-azaspiro[2.5]octane-6-carboxylic acid 1,1-dimethylethyl ester (Compound of Formula I). Summary of the Invention

[0010] Object of the Invention: The object of the present invention is to adopt a scheme of selective dehalogenation by an electrochemical method to replace the traditional route. Two bromines on the three-membered ring of Compound of Formula III are selectively removed electrochemically to generate the target product; this scheme solves the problems of a large amount of acids and active reagents involved in the traditional scheme. At room temperature, the conversion can be completed using a graphite electrode. The reaction yield can reach 67% and the purity is 94%. This method overcomes the problems of high cost, low safety, non-compliance with the concept of green chemistry and unsuitability for industrial production in the traditional route, provides an improved preparation method for 6-azaspiro[2.5]octane-6-carboxylic acid 1,1-dimethylethyl ester (Compound of Formula I), greatly reduces the reaction cost, improves and stabilizes the yield, reduces the amount of three wastes, reduces the production cost, and is suitable for industrial production.

[0011] The present invention provides a preparation method for a Compound of Formula I, comprising the following steps:

[0012]

[0013] In an electrochemical reaction kettle, Compound of Formula Ib reacts with an electrolyte, a basic reagent, an organic solvent and water under a constant current condition to undergo a selective dehalogenation reaction to generate Compound of Formula Ia;

[0014] wherein, X is selected from -CH 2 -,-O- or -N(Boc);

[0015] Y and Z are each independently selected from a halogen;

[0016] R 1 is selected from hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2-C 6 an alkynyl group, a cyano group, a nitro group or a carboxyl group;

[0017] Each n is independently selected from 1 or 2;

[0018] m is selected from 1 or 2;

[0019] k is selected from 0, 1 or 2.

[0020] Preferably, the present invention also provides a method for preparing a compound of formula I, which is characterized by comprising the following steps:

[0021]

[0022] In an electrochemical reaction kettle, the compound of formula III reacts with an electrolyte, a basic reagent, an organic solvent and water under a constant current condition to undergo a selective dehalogenation reaction to form the compound of formula I.

[0023] Preferably, the cathode electrode material of the electrode is selected from platinum, graphite, stainless steel, copper-tin-lead alloy, copper, tin or nickel;

[0024] More preferably, the cathode electrode material of the electrode is selected from graphite, CuSn7Pb15 or tin.

[0025] Preferably, the anode electrode material of the electrode is a graphite, glassy carbon or graphite felt electrode.

[0026] Preferably, the electrolyte is selected from one of ammonium tetrabutylborate, ammonium tetrabutylhexafluorophosphate or ammonium tetraethyl-p-toluenesulfonate, and the molar mass ratio of the compound of formula III to the electrolyte is 1:0.8 - 5.

[0027] Preferably, the basic reagent is selected from one or more of DIPEA, DBU, TBD, triethylamine, diisopropylamine, aniline or pyridine.

[0028] More preferably, the basic reagent is selected from one or more of DBU or TBD, and the molar mass ratio of the compound of formula III to the basic reagent is 1:1.2 - 8.

[0029] Preferably, the organic solvent is one or more of DMF, DMSO or DMAc, and the dosage is 30 - 80 times the volume of the compound of formula III.

[0030] Preferably, the molar mass ratio of the compound of formula III to water is 1:10 - 30.

[0031] Preferably, the DC power supply of the electrochemical reaction kettle is set to a constant current mode, the current I = 0.1 - 2 A; the voltage is V = 2.0 - 20.0 V.

[0032] Preferably, the reaction time of the reaction is 5 to 20 h.

[0033] Preferably, the reaction temperature of the reaction is 0 to 80 °C.

[0034] More preferably, the electrode - electrode is a graphite - graphite electrode or a graphite - copper - tin - lead alloy electrode; the electrolyte is tetrabutylammonium tetrafluoroborate, and the molar mass ratio of the compound of formula III to the electrolyte is 1:1 to 1.1; the basic reagent is selected from one or more of DBU or TBD, and the molar mass ratio of the compound of formula III to the basic reagent is 1:3 to 5; the organic solvent is DMF, and the dosage is 50 to 70 times the volume of the compound of formula III; the DC power supply of the electrochemical reaction kettle is set to a constant current mode, the current I = 0.2 to 0.6 A; the initial voltage is V = 3.0 to 7.0 V; the reaction time is 4 to 8 h; the reaction temperature is 0 to 80 °C.

[0035] Some reaction reagents involved in the present invention are abbreviated as follows:

[0036] DMF: Tetrahydrofuran

[0037] TBD: 1,5,7 - Triazabicyclo[4.4.0]dec - 5 - ene

[0038] DBU: 1,8 - Diazabicyclo[5.4.0]undec - 7 - ene

[0039] DIPEA: N,N - Diisopropylethylamine

[0040] MeOH: Methanol

[0041] DMAc: Dimethylacetamide

[0042] Beneficial effects

[0043] A preparation method of 1,1 - dimethylethyl 6 - azaspiro[2.5]octane - 6 - carboxylate (compound of formula I) provided by the present invention uses tert - butyl 1,1 - dibromo - 6 - azaspiro[2.5]octane - 6 - carboxylate (compound of formula III) as a raw material. Under alkaline conditions and in the presence of an electrolyte, the compound of formula I is generated through an electrochemical reaction. Compared with the traditional process, the new process uses electrochemistry for selective dehalogenation reaction, and the reaction is safe, stable and controllable, solving the problems of limited production capacity, high danger and a large amount of three wastes in the original synthesis route process, which lead to the inability to be scaled up on a large scale and the difficulty in reducing production costs. It can maintain a high yield and improve safety during large - scale industrial production. In summary, the technical solution provided by the present invention has good economic effects, reduces production costs and is suitable for industrial production. Brief description of the drawings

[0044] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of the present invention.

[0045] Figure 1 For the end product of Example 1 of the present invention 1 1H NMR spectrum (400 MHz, CDCl 3 3). Detailed implementation manners

[0046] The following will further clarify the present invention in combination with specific embodiments. These embodiments are implemented on the premise of the technical solutions of the present invention. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention.

[0047] Example 1

[0048]

[0049] First, add the compound of formula III (6.10 g, 0.0165 mol, 1.00 eq.) and tetrabutylammonium tetrafluoroborate (5.88 g, 0.0179 mol, 1.08 eq.) to an electrochemical reactor (500 mL), and then add DMF (360.0 mL, 60 V), and stir to dissolve the solid. Then add DBU (10.94 g, 0.0716 mol, 4.30 eq.) and H 2 2O (7.90 g, 0.437 mol, 26.00 eq.), and stir to make the solution homogeneous and clear. After all the solids are dissolved, power can be supplied. The reaction uses double graphite electrodes, and the DC power supply is set in the constant current mode with a current of 0.6 A and a corresponding initial voltage of V = 7.0 V. Monitor the reaction. When GC shows that the raw materials have completely reacted and the product purity > 85%, the reaction can be stopped. Add 2M HCl to the reaction solution to adjust the pH of the reaction solution to 6, and then add 800 mL of water to the system. A solid precipitates, and 2.35 g of white solid is obtained, and the separation yield is 67%.

[0050] 1 1H NMR (400 MHz, CDCl 3 3): 3.43 (t, J = 5.7 Hz, 4H), 1.47 (d, J = 1.4 Hz, 9H), 1.32 (t, J = 5.7 Hz, 4H), 0.32 (d, J = 1.3 Hz, 4H). The NMR spectrum is as shown in the appendix Figure 1 as follows.

[0051] Comparative Example 1

[0052]

[0053] Take MTES([Et 3 NMe]O 3 SOMe)(0.30 g, 1.3 mmol), add acetonitrile (4 mL) and methanol (2 mL), stir evenly to prepare Solution A as the anodic reaction solution for standby; take the compound of Formula III (0.32 g, 1.3 mmol, 1.0 eq.), add MTES (0.36 g, 1.6 mmol), and acetonitrile (6 mL), stir evenly to prepare Solution B as the cathodic reaction solution for standby; 1.2 mL flow electrochemical reactor: the anode is a graphite electrode (specification: 25 mm * 6 mm), the cathode is a CuSn7Pb15 electrode (specification: 25 mm * 6 mm), and a Nafion 424 proton exchange membrane is placed in the middle; prepare the above equipment for standby; turn on the feed pump, set the feed flow rate to V = 0.3 mL / min, and the theoretical retention time is 4 min; set the DC power supply in constant current mode with current = 0.35 A; feed Solution A and Solution B simultaneously, and end the reaction after 25 min; recover the cathodic reaction solution, and monitor the reaction solution by GC. The quantitative yield of the product is 47.5%, and the purity is 75.10%.

[0054] The above reaction route is a repeated experiment according to the synthesis method of 1,1 - dimethylethyl 6 - azaspiro[2.5]octane - 6 - carboxylate (compound of Formula I) disclosed in the prior art in relevant literature, verifying that the new process developed in this application can obtain a higher yield (about 67%) and can reduce production costs at the same time, having great commercial value.

[0055] Comparative Example 2

[0056] The following is the exploration process for optimizing the experimental conditions, and the results are shown in the data in the table.

[0057] Unless otherwise stated, the left side of " / " is the anode and the right side is the cathode.

[0058] Table 1 Screening of cathode electrode materials

[0059]

[0060]

[0061] Table 2 Screening of anode electrode materials

[0062]

[0063] Through the screening of electrodes, the conclusion is drawn that graphite electrodes, copper-tin-lead alloy electrodes, and tin electrodes show good reactivity towards the reaction, can be used for subsequent production optimization, and have a better reaction effect than platinum electrodes (QNMR = 0.69%, AY = 52.17%), and the cost is lower than that of platinum electrodes. In addition, when attempting to change the anode material to a glassy carbon electrode, the overall analysis yield is much lower than before. Considering the comprehensive cost factors, graphite / graphite electrodes are selected for the reaction subsequently.

[0064] Table 3 Screening and Optimization of the Type and Dosage of Bases

[0065]

[0066]

[0067] Through the screening of the TBD equivalent, it is found that the reaction effect is the best in the presence of 4.0 equivalents of TBD. In addition, according to the reaction results, it is found that DBU may be able to replace TBD to complete the reaction; at the same time, it is also found during the reaction process that different bases have a certain influence on the selectivity of the reaction: when TBD and DBU participate in the reaction as basic reagents, they tend to generate the product of formula I compounds; while when DIPEA, triethylamine, and pyridine participate in the reaction as basic reagents, they tend to generate the product BP-1 with monobromine removed (as shown in the figure below). And when using triethylamine and DIPEA for the reaction and further prolonging the reaction time, the product with monobromine removed will transform into the compound of formula I.

[0068]

[0069] Table 4 Test on the Influence of the Dosages of Naphthalene and Water on the Experimental Results

[0070]

[0071] The above experimental data show that under alkaline conditions, when adding more than 20 equivalents of water, the conversion of the substrate to remove dibromine can be completed, and there is no need to add naphthalene to promote the reaction.

[0072] Table 5 Test on the Influence of Replacing Organic Solvents on the Experimental Results

[0073]

[0074] Based on a series of screenings of the reaction system, the optimal dosages of the reaction reagents and the selection of the electrode material in the electrochemical reaction are determined.

[0075] Although the specific implementation manners of the present invention are described above, they are not limitations on the protection scope of the present invention. For those of ordinary skill in the art in this technical field, without departing from the principle of the present invention, several improvements and retouches can still be made, and these improvements and retouches should also be regarded as within the protection scope of the present invention.

Claims

1. A method for preparing a compound of formula Ia, characterized in that it comprises the following steps: In an electrochemical reaction kettle, the compound of formula Ib reacts with an electrolyte, a basic reagent, an organic solvent and water under a constant current condition to undergo a selective dehalogenation reaction to form the compound of formula Ia; wherein X is selected from -CH 2 -, -O-, -NH- or -N(Boc)-; Y and Z are each independently selected from halogen; R 1 selected from hydrogen, C 1 -C 6 alkyl, halo-C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cyano, nitro or carboxyl; Each n is independently selected from 1 or 2; m is selected from 1 or 2; k is selected from 0, 1 or 2.

2. A method for preparing a compound of formula I, characterized in that it comprises the following steps: In an electrochemical reaction kettle, the compound of formula III reacts with an electrolyte, a basic reagent, an organic solvent and water under a constant current condition to undergo a selective dehalogenation reaction to form the compound of formula I.

3. The preparation method according to claim 2, characterized in that: The cathode electrode material of the electrode is selected from platinum, graphite, stainless steel, copper-tin-lead alloy, copper, tin or nickel.

4. The preparation method according to claim 2, characterized in that: The cathode electrode material of the electrode is selected from graphite, CuSn7Pb15 or tin.

5. The preparation method according to claim 2, characterized in that: The anode electrode material of the electrode is graphite, glassy carbon or graphite felt.

6. The preparation method according to claim 2, characterized in that: The electrolyte is selected from one of ammonium tetrabutylborate, ammonium tetrabutylhexafluorophosphate, tetraethylammonium chloride, tetraethylammonium iodide or tetraethylammonium p-toluenesulfonate, and the molar mass ratio of the compound of formula III to the electrolyte is 1:0.8 - 5.

7. The preparation method according to claim 2, characterized in that: The basic reagent is selected from one or more of DIPEA, DBU, TBD, triethylamine, diisopropylamine, aniline or pyridine.

8. The preparation method according to claim 2, characterized in that: The basic reagent is selected from one or more of DBU or TBD, and the molar mass ratio of the compound of formula III to the basic reagent is 1:1.2 - 8.

9. The preparation method according to claim 2, characterized in that: The organic solvent is one or more of DMF, DMSO or DMAc, and the dosage is 30 - 80 times the volume of the compound of formula III.

10. The preparation method according to claim 2, characterized in that: The molar mass ratio of the compound of formula III to water is 1:10 - 30.

11. The preparation method according to claim 2, characterized in that: The power supply in the electrochemical reaction kettle is a DC power supply, and the DC power supply is set in a constant current mode, with the current I = 0.1 - 2A; the voltage is V = 2 - 20V.

12. The preparation method according to claim 2, characterized in that: The reaction time of the reaction is 5 - 20h.

13. The preparation method according to claim 2, characterized in that: The reaction temperature of the reaction is 0 - 80°C.

14. The preparation method according to claim 2, characterized in that: The electrode - electrode is a graphite - graphite electrode or a graphite - copper - tin - lead alloy electrode; the electrolyte is tetrabutylammonium tetrafluoroborate, and the molar mass ratio of the compound of formula III to the electrolyte is 1:1 to 1.1; the basic reagent is selected from one or more of DBU or TBD, and the molar mass ratio of the compound of formula III to the basic reagent is 1:3 to 5; the organic solvent is DMF, and the dosage is 50 to 70 times the volume of the compound of formula III; the DC power supply of the electrochemical reaction kettle is set in a constant - current mode, the current I = 0.2 to 0.6 A; the starting voltage is V = 3.0 to 7.0 V; the reaction time is 4 to 8 h; the reaction temperature is 0 to 80 °C.

Images