Preparation and analysis method of 1-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-boronic acid pinacol ester

Abstract

The invention discloses a preparation method and an analysis method of 1-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-boronic acid pinacol ester, and belongs to the technical field of medical intermediates. The preparation method comprises the following steps: by taking 1-tert-butyloxycarbonyl-4-hydroxypyrrole-2-carboxylic acid as a raw material, generating 1-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole-2-carboxylic acid under the action of tris (pentafluorophenyl) boron; the preparation method comprises the following steps: carrying out addition reaction with bromine to generate 1-tert-butyloxycarbonyl-3, 4-dibromo pyrrole-2-carboxylic acid; the preparation method comprises the following steps of: generating 3-bromine-1-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole under the action of DBU (Dibutyl Unit) and a copper catalyst; the preparation method comprises the following steps: reacting 1-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-boronic acid with tetrahydroxy diboron through a nickel catalyst, and then reacting with pinacol to obtain 1-tert-butyloxycarbonyl-2, 5-dihydro-1H-pyrrole-3-boronic acid pinacol ester. The whole route is simple and efficient, the alkenyl bromide is obtained with high selectivity through key debromination and decarboxylation steps, and meanwhile, an analysis method of an effective product is also developed.

Description

Technical Field

[0001] The invention relates to a preparation and analysis method of 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boric acid pinacol ester, belonging to the technical field of pharmaceutical intermediates. Background Art

[0002] 1-tert-Butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester, CAS: 212127-83-8, is an important boric acid ester innovative drug intermediate containing 2,5-dihydropyrrole structural unit. This compound is mainly used in chemical synthesis to prepare dihydropyrrole derivatives, and the chemical transformation activity of its boric acid ester unit is used to achieve the construction of complex structures.

[0003] Pharmaceutical chemical intermediates: 2,5-Dihydropyrrole units are often used as important intermediates in drug synthesis and can generate a variety of target drug molecules, such as renin inhibitors, vasodilators, arylpyrrolidine alkaloids, etc.

[0004] Catalyst: The nitrogen atom in the molecular structure of 2,5-dihydropyrrole is reactive and can be used in combination with other catalysts to promote chemical reactions.

[0005] Scientific research and industrial production: 1-tert-Butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester can introduce the pyrrole ring structure into the field of pesticides and materials through transition metal-catalyzed cross-coupling reactions.

[0006] The synthesis method of 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester, representative routes include: Patents [US2010204265; WO2021247841; WO2015100617; CN109956931; WO201665236; EP20163042907; WO201548662] use 1-tert-butyloxycarbonyl-3-pyrrolidone as a raw material, through a two-step reaction, to obtain the target product, the chemical reaction equation is as follows:

[0007]

[0008] Literature [European Journal of Organic Chemistry, 2021, 2021, 6551; Journal of the American Chemical Society, 1998, 120, 7995] generates the target product through a cyclization reaction. The chemical reaction equation is as follows:

[0009]

[0010] In view of the defects of the above technical route, it is necessary to conduct in-depth research on the synthesis route of 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boric acid pinacol ester to meet the growing market demand. Summary of the invention

[0011] In order to overcome the above technical defects, the present invention provides a preparation and analysis method of 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boric acid pinacol ester. Using 1-tert-butoxycarbonyl-4-hydroxypyrrole-2-carboxylic acid as a raw material, under the action of tri(pentafluorophenyl)boron, 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-2-carboxylic acid is generated; 1-tert-butoxycarbonyl-3,4-dibromopyrrole-2-carboxylic acid is generated by addition with bromine; 3-bromo-1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole is generated under DBU and copper catalyst; nickel catalyst reacts with tetrahydroxydiboron, and then reacts with pinacol to obtain 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boric acid pinacol ester. The overall route of the present invention is brief and efficient. After the key debromination and decarboxylation steps, the alkenyl bromide is obtained with high selectivity, and an analysis method for effective products is also developed.

[0012] The preparation method of 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boric acid pinacol ester of the present invention is represented by the following reaction equation:

[0013]

[0014] The steps include:

[0015] A. reacting 1-tert-butoxycarbonyl-4-hydroxypyrrole-2-carboxylic acid in the presence of tri(pentafluorophenyl)boron to obtain 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-2-carboxylic acid;

[0016] B. subjecting 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-2-carboxylic acid to an addition reaction with bromine to obtain 1-tert-butoxycarbonyl-3,4-dibromopyrrole-2-carboxylic acid;

[0017] C. reacting 1-tert-butoxycarbonyl-3,4-dibromopyrrole-2-carboxylic acid in the presence of DBU and copper salt to obtain 3-bromo-1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole;

[0018] D. 3-bromo-1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole and tetrahydroxydiboron are reacted in the presence of a nickel catalyst, triphenylphosphine and an organic base, and then pinacol is added to obtain 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boric acid pinacol ester.

[0019] Furthermore, in the above technical solution, the reaction in step A is carried out in toluene.

[0020] Furthermore, in the above technical solution, the molar ratio of 1-tert-butyloxycarbonyl-4-hydroxypyrrole-2-carboxylic acid to tri(pentafluorophenyl)borane in step A is 1:0.03-0.06.

[0021] Furthermore, in the above technical solution, the reaction in step B is carried out in dichloromethane or 1,2-dichloroethane.

[0022] Furthermore, in the above technical solution, in step B, the molar ratio of 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-2-carboxylic acid to bromine is 1:1-1.2.

[0023] Furthermore, in the above technical solution, the reaction in step C is carried out in cyclohexanol or sulfolane.

[0024] Furthermore, in the above technical solution, the copper catalyst in step C is cuprous chloride; the molar ratio of 1-tert-butyloxycarbonyl-3,4-dibromopyrrole-2-carboxylic acid, DBU and copper catalyst is 1:2.5-3.5:0.03-0.07.

[0025] Furthermore, in the above technical scheme, the nickel catalyst in step D is 1,3-bis(diphenylphosphinopropane)nickel dichloride; the organic base is selected from triethylamine or diisopropylamine; the reaction is carried out in a mixed solvent of ethanol and ethylene glycol or glycerol. When only ethanol solvent is used, 1.5-2.0eq of tetrahydroxydiboron is required, and a small amount of olefin reduction byproduct is generated.

[0026] Furthermore, in the above technical scheme, the molar ratio of 3-bromo-1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole, tetrahydroxydiboron, nickel catalyst, triphenylphosphine, organic base and pinacol in step D is 1:1-1.5:0.01-0.03:0.02-0.06:2-3:2.5-3.5.

[0027] The present invention further provides an analysis method for 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester. The purity of the product is measured using DB-530m×250μm×0.25μm; the temperature is first maintained at 80°C for 2 minutes, then the temperature is increased at a rate of 20°C / min until it is maintained at 290°C for 10 minutes, and gas phase analysis is performed.

[0028] The present invention has the following beneficial effects:

[0029] 1. 1-tert-Butyloxycarbonyl-3,4-dibromopyrrole-2-carboxylic acid is used in the presence of DBU and copper catalyst to carry out debromination and decarboxylation in one step, which retains the positional selectivity of olefin bromine, is simple to operate, and has a novel route.

[0030] 2. Use 3-bromo-1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole and tetrahydroxydiboron in the presence of a nickel catalyst, triphenylphosphine and a base to generate boric acid, which is then reacted with pinacol to prepare boric esters. The route has a high yield.

[0031] 3. This process starts from the cheap and readily available 1-tert-butyloxycarbonyl-4-hydroxypyrrole-2-carboxylic acid raw material. After four steps of reaction, all intermediates can be purified. The process is simple, safe and stable, and is suitable for industrial scale expansion. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 The GC spectrum of 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester was obtained for Example 6;

[0033] Figure 2 The HNMR spectrum of 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester was obtained for Example 6. Specific embodiments

[0034] The present invention is further described below by specific examples. These embodiments should be understood to be only used to illustrate the present invention and not to limit the scope of protection of the present invention. After reading the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

[0035] Example 1

[0036]

[0037] Under nitrogen protection, 23.1 g (0.1 mol) of 1-tert-butoxycarbonyl-4-hydroxypyrrole-2-carboxylic acid and 2.6 g (0.005 mol) of tris(pentafluorophenyl)boron were mixed in 120 mL of toluene, and dehydrated for 3 hours under reflux conditions. The mixture was cooled to room temperature and concentrated. The crude product was slurried with ethyl acetate / petroleum ether (v / v=1 / 10) and filtered to obtain 19.6 g of 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-2-carboxylic acid with a yield of 92% and a GC of 99.0%. 1 HNMR (400MHz, CDCl3): 10.9 (s, 1H), 5.93-6.05 (m, 1H), 5.72-5.88 (m, 1H), 5.03-5.12 (m, 1H), 4.08-4.30 (m, 2H), 1.46 (s, 9H).

[0038] Example 2

[0039]

[0040] Under nitrogen protection, 8.8g (0.055mol) of bromine was mixed in 100mL of dichloromethane, the temperature was lowered to 0-5°C, 10.7g (0.05mol) of 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-2-carboxylic acid and 100mL of dichloromethane solution were slowly added dropwise, and the reaction was carried out at room temperature for 2 hours, and 10% sodium bisulfite aqueous solution was added to quench, and the dichloromethane extraction was carried out, and the layers were washed with saturated brine, and the organic layer was concentrated. The crude product was slurried with ethyl acetate / petroleum ether (v / v=1 / 4), and filtered to obtain 17.7g of 1-tert-butyloxycarbonyl-3,4-dibromopyrrole-2-carboxylic acid, with a yield of 95%, and GC 98.5%. HPLC-MS [M+H] + =374.

[0041] Example 3

[0042]

[0043] Under nitrogen protection, 8.3 g (0.052 mol) of bromine was mixed in 100 mL of 1,2-dichloroethane, the temperature was lowered by 0-5 ° C, 10.7 g (0.05 mol) of 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-2-carboxylic acid and 100 mL of 1,2-dichloroethane solution were slowly added dropwise, and the reaction was carried out at room temperature for 2 hours. A 10% aqueous sodium bisulfite solution was added to quench, and the mixture was extracted with 1,2-dichloroethane and the layers were separated. The mixture was washed with saturated brine, and the organic layer was concentrated. The crude product was slurried with ethyl acetate / petroleum ether (v / v=1 / 4) and filtered to obtain 17.9 g of 1-tert-butoxycarbonyl-3,4-dibromopyrrole-2-carboxylic acid with a yield of 96% and a GC of 98.8%.

[0044] Example 4

[0045]

[0046] Under nitrogen protection, 1-tert-butyloxycarbonyl-3,4-dibromopyrrole-2-carboxylic acid 18.7g (0.05mol), DBU 22.8g (0.15mol) and cuprous chloride 0.25g (2.5mmol) were mixed in 200mL cyclohexanol, reacted at 100-105°C for 5 hours, cooled to room temperature, and hydrochloric acid (10%) was added to adjust the pH to 5-6, then separated, the organic layer was concentrated, and the crude product was slurried with ethyl acetate / petroleum ether (v / v=1 / 12) to generate 3-bromo-1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole, 10.5g, yield 85%, GC 98.6%. HPLC-MS [M+H]+ =249.1.

[0047] Example 5

[0048]

[0049] Under nitrogen protection, 18.7 g (0.05 mol) of 1-tert-butoxycarbonyl-3,4-dibromopyrrole-2-carboxylic acid and 22.8 g (0.15 mol) of DBU were mixed in 200 mL of cyclohexanol, reacted under reflux conditions for 16 hours, cooled to room temperature, and hydrochloric acid (10%) was added to adjust the pH to 5-6. The layers were then separated, and the organic layer was concentrated. The crude product was slurried with ethyl acetate / petroleum ether (v / v=1 / 12) to generate 9.1 g of 3-bromo-1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole with a yield of 73% and a GC of 97.9%.

[0050] Example 6

[0051]

[0052] Under nitrogen protection, 12.4 g (0.05 mol) of 3-bromo-1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole, 5.4 g (0.06 mol) of tetrahydroxydiboron, 0.41 g (0.75 mmol) of 1,3-bis(diphenylphosphinopropane)nickel dichloride, 0.4 g (1.5 mmol) of triphenylphosphine and 12.6 g (0.125 mol) of triethylamine were mixed in 100 mL of ethanol and 10 mL of ethylene glycol, and the mixture was heated to 40-45 ° C and reacted for 4 hours. The mixture was cooled to room temperature, and then 17.7 g (0.15 mol) of pinacol was added. The mixture was stirred at room temperature for 3 hours. 100 mL of deionized water was added, and then extracted three times with 100 mL of ethyl acetate. The organic layer was concentrated, and the crude product was slurried with ethyl acetate / petroleum ether (v / v=1 / 15) and filtered to obtain 12.1 g of 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boric acid pinacol ester with a yield of 82% and a GC of 98.0%. 1 HNMR (400MHz, CDCl3): 6.47 (m, 1H), 4.21 (m, 4H), 1.47 (s, 9H), 1.28 (s, 12H).

[0053] Example 7

[0054] The product analysis method of 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester was optimized and the following conditions were used:

[0055] Instrument: Agilent 7820

[0056] Injection volume:2μL

[0057] Inlet temp.:275℃

[0058] Split ratio:1:90

[0059] Carrier gas: N2 (1mL / min)

[0060] Agilent DB-5 30m×250μm×0.25μm

[0061] Gradient:80℃(2mins).20℃ / min-290℃(10mins)

[0062] Run time: 25 minutes

[0063] Detector:FID

[0064] Temperature:300℃

[0065] Make-up gas (N2) flow: 25mL / min

[0066] Hydrogen flow: 30mL / min

[0067] Air flow: 400mL / min.

[0068] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boric acid pinacol ester, characterized in that: The steps include: A. reacting 1-tert-butoxycarbonyl-4-hydroxypyrrole-2-carboxylic acid in the presence of tri(pentafluorophenyl)boron to obtain 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-2-carboxylic acid; B. subjecting 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-2-carboxylic acid to an addition reaction with bromine to obtain 1-tert-butoxycarbonyl-3,4-dibromopyrrole-2-carboxylic acid; C. reacting 1-tert-butoxycarbonyl-3,4-dibromopyrrole-2-carboxylic acid in the presence of DBU and copper salt to obtain 3-bromo-1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole; D. 3-bromo-1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole and tetrahydroxydiboron are reacted in the presence of a nickel catalyst, triphenylphosphine and an organic base, and then pinacol is added to obtain 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boric acid pinacol ester.

2. The method for preparing 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boric acid pinacol ester according to claim 1, characterized in that: In step A, the reaction is carried out in toluene.

3. The method for preparing 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boric acid pinacol ester according to claim 1, characterized in that: In step A, the molar ratio of 1-tert-butyloxycarbonyl-4-hydroxypyrrole-2-carboxylic acid to tri(pentafluorophenyl)borane is 1:0.03-0.

06.

4. The method for preparing 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boric acid pinacol ester according to claim 1, characterized in that: In step B, the reaction is carried out in dichloromethane or 1,2-dichloroethane.

5. The method for preparing 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester according to claim 1, characterized in that: In step B, the molar ratio of 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-2-carboxylic acid to bromine is 1:1-1.

2.

6. The method for preparing 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boric acid pinacol ester according to claim 1, characterized in that: In step C, the reaction is carried out in sulfolane or cyclohexanol.

7. The method for preparing 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester according to claim 1, characterized in that: In step C, the copper catalyst is cuprous chloride; the molar ratio of 1-tert-butyloxycarbonyl-3,4-dibromopyrrole-2-carboxylic acid, DBU and copper catalyst is 1:2.5-3.5:0.03-0.

07.

8. The method for preparing 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester according to claim 1, characterized in that: In step D, the nickel catalyst is 1,3-bis(diphenylphosphinopropane)nickel dichloride; the organic base is selected from triethylamine or diisopropylamine; and the reaction is carried out in a mixed solvent of ethanol and ethylene glycol or glycerol.

9. The method for preparing 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester according to claim 1, characterized in that: In step D, the molar ratio of 3-bromo-1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole, tetrahydroxydiboron, nickel catalyst, triphenylphosphine, organic base and pinacol is 1:1-1.5:0.01-0.03:0.02-0.06:2-3:2.5-3.

5.

10. The method for preparing 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester according to claim 1, characterized in that: The purity of 1-tert-butyloxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester was determined using DB-530m×250μm×0.25μm; the temperature was first maintained at 80°C for 2 minutes, then the temperature was increased at a rate of 20°C / min until it was maintained at 290°C for 10 minutes, and gas phase analysis was performed.

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