Preparation method, intermediate and application of menochromone
By adopting a simplified synthetic route, 4-bromopyrrole-2-carboxylic acid is reacted with propargylamine, pinacolborane and 2-(tert-butoxycarbonylamino)-5-iodo-1H-imidazol to generate membranous lecithin, which solves the problem of the lengthy and complex synthetic routes in the prior art and realizes high-yield industrial production.
Patent Information
- Application Number
- CN202510737161.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-04
- Publication Date
- 2025-11-07
AI Technical Summary
Existing methods for preparing hymenoplasmin have lengthy synthetic routes and complex operations, making them unsuitable for industrial production.
A novel synthetic route was adopted, which involved reacting 4-bromopyrrole-2-carboxylic acid with propargylamine to generate 4-bromo-N-propynylpyrrole-2-carboxamide, followed by reaction with pinacol borane and Schwarz reagent to generate a mixture, then reaction with 2-(tert-butoxycarbonylamino)-5-iodo-1H-imidazol, and finally reacting with dioxane hydrochloride solution to generate membranous cystin.
A high product yield and simple preparation process for membranous lecithin were achieved, making it suitable for industrial production.
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Figure CN120904170A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of organic synthesis, in particular to a preparation method of hymenidin, an intermediate and application thereof. BACKGROUND
[0002] Hymenidin, with an English name of Hymenidin and a CAS number of 107019-95-4, is an alkaloid isolated from Hymeniacidon perleche, which has potential biological activity and is concerned in the researches of nerve signal regulation, gene and metabolic intervention.
[0003] However, the preparation methods of hymenidin reported in the current literature are not only limited in number, but also have problems such as long synthetic route, complicated operation process and unsuitability for industrial production.
[0004] Therefore, it is necessary to develop a method for synthesizing hymenidin with a short synthetic route, simple operation and high yield. SUMMARY
[0005] In view of the deficiencies of the prior art, the present application provides a preparation method of hymenidin, an intermediate and application thereof, which has a short synthetic route, simple operation, high product yield and is suitable for industrial production.
[0006] To achieve the above-mentioned purposes, the embodiments of the present application adopt the following technical solutions:
[0007] A preparation method of hymenidin, raw materials including a compound shown in formula (1) and a compound shown in formula (5):
[0008]
[0009] A preparation method of hymenidin, the preparation method including the following synthetic route:
[0010]
[0011] According to an aspect of the present application, step S1 includes: dissolving the compound shown in formula (1) in tetrahydrofuran, adding DIEA and HATU respectively, stirring uniformly, and then adding propargylamine to react to generate a compound shown in formula (2).
[0012] According to an aspect of the present application, the molar ratio of the 4-bromopyrrole-2-carboxylic acid shown in formula (1), propargylamine, DIEA and HATU is 1:1-1.5:1.8-2.2:0.9-1.2. Preferably, the molar ratio of the 4-bromopyrrole-2-carboxylic acid shown in formula (1), propargylamine, DIEA and HATU is 1:1.2:2:1.1.
[0013] According to an aspect of the present application, the temperature of the reaction is 18-22°C, and the time of the reaction is 11-13h. Preferably, the temperature of the reaction is 20°C. The time of the reaction is 12h.
[0014] According to an aspect of the present application, the reaction is followed by purification. Specifically, the purification comprises the following steps: after the reaction is completed, petroleum ether is added to the reaction solution under stirring, solid is precipitated, the reaction solution is filtered, the filter cake is washed with petroleum ether, and then collected and rotary evaporated to remove excess solvent.
[0015] According to an aspect of the present application, step S2 comprises: mixing the compound shown in formula (2) with pinacol borane under inert gas protection, and then adding Schwartz reagent and triethylamine to react to form a mixture of compounds shown in formula (3) and formula (4).
[0016] According to an aspect of the present application, the molar ratio of the compound shown in formula (2), pinacol borane, Schwartz reagent and triethylamine is 1:1.3-1.7:0.1-0.2:0.1-0.2. Preferably, the molar ratio of the compound shown in formula (2), pinacol borane, Schwartz reagent and triethylamine is 1:1.5:0.1:0.1.
[0017] According to an aspect of the present application, the temperature of the reaction is 62-68°C. Preferably, the temperature of the reaction is 65°C.
[0018] According to an aspect of the present application, the inert gas is selected from any one of nitrogen, helium and argon. Preferably, the inert gas is selected from nitrogen.
[0019] According to an aspect of the present application, the reaction is followed by purification. Specifically, the purification comprises the following steps: the reaction mixture is cooled to room temperature. The reaction mixture is diluted with ethyl acetate. The organic phase is washed with saturated aqueous sodium bicarbonate solution and brine, the organic phase is collected, dried with sodium sulfate, and filtered. The organic phase is concentrated by rotary evaporation, purified using a reverse phase column, and the eluent is concentrated.
[0020] According to an aspect of the present application, step S3 comprises: mixing the mixture, the compound shown in formula (5), a palladium catalyst, potassium carbonate, dioxane and water under inert gas protection to react to form the compound shown in formula (6).
[0021] According to an aspect of the present application, the temperature of the reaction is 76-84°C. Preferably, the temperature of the reaction is 80°C.
[0022] According to an aspect of the present application, the reaction further comprises a purification. Specifically, the purification comprises the following steps: diluting the reaction mixture with ethyl acetate, washing the organic matter with pure water and brine, collecting the organic phase, drying the organic phase with sodium sulfate, and concentrating the eluent.
[0023] According to an aspect of the present application, the step S4 comprises: reacting the compound shown in formula (6) with a hydrochloric acid dioxane solution to generate the filmorin shown in formula (7).
[0024] According to an aspect of the present application, the reaction is performed at a temperature of 18-22°C. Preferably, the reaction is performed at a temperature of 20°C.
[0025] According to an aspect of the present application, the method for preparing the compound shown in formula (5) comprises the following steps:
[0026] reacting the imidazo[1,2-a]pyrimidine with NIS to generate 3-iodoimidazo[1,2-A]pyrimidine;
[0027] reacting the 3-iodoimidazo[1,2-A]pyrimidine with hydrazine hydrate to generate 5-iodo-1H-imidazole-2-amine;
[0028] reacting the 5-iodo-1H-imidazole-2-amine with (Boc)2O to generate the 2-(tert-butoxycarbonylamino)-5-iodo-1H-imidazole shown in formula (5);
[0029] The synthesis route is as follows:
[0030]
[0031] According to an aspect of the present application, the molar ratio of the imidazo[1,2-A]pyrimidine and NIS is 1:1.0-2.0. Preferably, the molar ratio of the imidazo[1,2-A]pyrimidine and NIS is 1:1.6. The reaction of the imidazo[1,2-A]pyrimidine with NIS comprises dissolving the imidazo[1,2-A]pyrimidine in acetonitrile, then adding NIS to the reaction solution, and stirring at 50°C for 12 hours.
[0032] According to an aspect of the present application, the molar ratio of the 3-iodoimidazo[1,2-A]pyrimidine and hydrazine hydrate is 1.0-2.0:1. Preferably, the molar ratio of the 3-iodoimidazo[1,2-A]pyrimidine and hydrazine hydrate is 2.0:1.
[0033] According to an aspect of the present application, the reaction temperature of the reaction of the 3-iodoimidazo[1,2-A]pyrimidine with hydrazine hydrate is 20-30°C, and the reaction time is 11-13 hours.
[0034] According to one aspect of the present application, the molar ratio of 5-iodo-1H-imidazol-2-amine to (Boc)2O is 1:3.7-4.2. Preferably, the molar ratio of 5-iodo-1H-imidazol-2-amine to (Boc)2O is 1:4.0.
[0035] According to one aspect of the present application, the reaction of 5-iodo-1H-imidazol-2-amine with (Boc)2O to form 2-(tert-butoxycarbonylamino)-5-iodo-1H-imidazole comprises: dissolving 5-iodo-1H-imidazol-2-amine in tetrahydrofuran, and then adding (Boc)2O and triethylamine into the reaction solution to react at 15-25℃ for 11-13 hours.
[0036] According to one aspect of the present application, an intermediate of halofuginone is a mixture of compounds of formula (3) and formula (4):
[0037]
[0038] The synthesis method of the above intermediate comprises the following steps:
[0039] The synthesis method of the above intermediate comprises the following steps:
[0040]
[0041] According to one aspect of the present application, an intermediate of halofuginone is a compound of formula (6):
[0042]
[0043] The synthesis method of the above intermediate comprises the following steps:
[0044] The synthesis method of the above intermediate comprises the following steps:
[0045]
[0046] The embodiment of the present application has the advantages that the present application discloses a preparation method of film worm, which comprises the following steps: reacting 4-bromopyrrole-2-carboxylic acid shown in formula (1) with propargylamine to generate 4-bromo-N-propargylpyrrole-2-carboxamide shown in formula (2); reacting 4-bromo-N-propargylpyrrole-2-carboxamide shown in formula (2) with pinacol borane to generate a mixture composed of formula (3) and formula (4); reacting the mixture with 2-(tert-butoxycarbonylamino)-5-iodo-1H-imidazole shown in formula (5) to generate tert-butyl (E)-(5-(3-(4-bromo-1H-pyrrol-2-carboxamido)prop-1-en-1-yl)-1H-imidazol-2-yl)carbamate shown in formula (6); and reacting tert-butyl (E)-(5-(3-(4-bromo-1H-pyrrol-2-carboxamido)prop-1-en-1-yl)-1H-imidazol-2-yl)carbamate shown in formula (6) with a dioxane solution of hydrochloric acid to generate film worm. The present application provides a preparation method of film worm, which has the advantages of short synthesis route, simple operation, high product yield and suitability for industrial production. BRIEF DESCRIPTION OF DRAWINGS
[0047] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings needed in the embodiments will be briefly introduced as follows. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can be obtained by those skilled in the art without any creative effort.
[0048] Figure 1 The synthesis route map of the preparation method of film worm according to the present application;
[0049] Figure 2 The nuclear magnetic resonance hydrogen spectrum of film worm in embodiment 7 of the present application. DETAILED DESCRIPTION
[0050] The present application will be described in detail through specific embodiments, so that the technical solutions of the present application are more easily understood and mastered. However, the present application is not limited to the embodiments described, and the described embodiments are only some embodiments of the present application, but not all the embodiments.
[0051] The endpoints of the ranges and any values disclosed herein are not limited to the precise values recited as the exact dimensions are not considered critical for the purposes of the application. The ranges, endpoints, and individual points disclosed herein can be combined with one or more of the disclosed ranges, endpoints, and individual points to form new ranges, endpoints, and individual points, which are also considered to be disclosed herein. The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Numerical ranges are inclusive of the recited endpoints and fractions thereof.
[0052] All other embodiments obtained by those of ordinary skill in the art based on the embodiments disclosed herein without creative work shall fall within the scope of protection of the present application.
[0053] The raw materials and instruments used in the embodiments are not specifically limited in source, and can be purchased on the market or prepared according to conventional methods well known to those skilled in the art.
[0054] In the following examples and comparative examples, the English abbreviations involved and the Chinese interpretations thereof are shown in Table 1 below:
[0055] Table 1 Abbreviation and full name
[0056]
[0057] A preparation method of a tape wormin, as shown in the following reaction scheme: Figure 1 Specifically, the preparation method comprises: reacting 4-bromopyrrole-2-carboxylic acid shown in formula (1) with propargylamine to generate 4-bromo-N-propargylpyrrole-2-carboxamide shown in formula (2); reacting 4-bromo-N-propargylpyrrole-2-carboxamide shown in formula (2) with pinacolborane to generate a mixture consisting of formula (3) and formula (4); reacting the mixture with 2-(tert-butoxycarbonylamino)-5-iodo-1H-imidazole shown in formula (5) to generate tert-butyl (E)-(5-(3-(4-bromo-1H-pyrrole-2-carboxamido)prop-1-en-1-yl)-1H-imidazol-2-yl)carbamate shown in formula (6); and reacting tert-butyl (E)-(5-(3-(4-bromo-1H-pyrrole-2-carboxamido)prop-1-en-1-yl)-1H-imidazol-2-yl)carbamate shown in formula (6) with a hydrochloric acid dioxane solution to generate the tape wormin shown in formula (7).
[0058] Example 1:
[0059] Imidazo[1,2-A]pyrimidine (3.00 g, 25.2 mmol, 1.00 eq) was dissolved in 20.0 mL of acetonitrile, and then NIS (9.60 g, 40.4 mmol, 1.60 eq) was added to the reaction solution, which was stirred at 50 °C for 12 hours. After spotting showed that imidazo[1,2-A]pyrimidine was completely consumed and a product was detected, the reaction solution was cooled and filtered, and the filtrate was collected and spin-dried to obtain a crude product. The crude product after spin-drying was dissolved in ethyl acetate and washed with pure water. The organic phase was washed with brine and dried over anhydrous sodium sulfate, filtered and spin-dried to obtain a brownish solid compound (5.80 g, yield 89.1%, purity 80%).
[0060] The specific equation of the chemical reaction is as follows:
[0061]
[0062] After identification by nuclear magnetic resonance and mass spectrometry, the brownish solid crude product was 3-iodoimidazo[1,2-A]pyrimidine. Specifically:
[0063] LCMS (3-iodoimidazo[1,2-A]pyrimidine): (M-1) - = 245.9; Rt = 0.661 min;
[0064] 1H NMR: 3-iodoimidazo[1,2-A]pyrimidine (400 MHz, DMSO-d6) δ 8.78 (dd, J = 6.8, 1.9 Hz, 1H), 8.55 (dd, J = 4.1, 1.9 Hz, 1H), 7.91 (s, 1H), 7.19 (dd, J = 6.8, 4.1 Hz, 1H).
[0065] Example 2:
[0066] 3-iodoimidazo[1,2-A]pyrimidine (200 mg, 0.82 mmol, 1.00 eq) was dissolved in ethanol (2.00 mL), and then hydrazine hydrate (25 mg, 0.42 mmol, 0.5 eq, 85% purity) was added to the reaction solution, which was stirred at 20 °C for 12 hours. After mass spectrometry showed that the reaction was complete, the reaction solution was poured into a stirring mixture of ice water and ethyl acetate, and the liquid was separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate and spin-dried to obtain an intermediate 5-iodo-1H-imidazole-2-amine (120 mg, yield 70%, purity 90%).
[0067] The specific equation of the chemical reaction is as follows:
[0068]
[0069] Among them:
[0070] LCMS (5-iodo-1H-imidazol-2-amine): (M-1) - = 210.0; Rt = 0.171 min.
[0071] 1H NMR: 5-iodo-1H-imidazol-2-amine (400 MHz, DMSO-d6) δ 8.07 (s, 1H).
[0072] Example 3:
[0073] 5-iodo-1H-imidazol-2-amine (0.50 g, 2.39 mmol, 1.00 eq) was dissolved in tetrahydrofuran (5.0 mL), (Boc)20 (2.09 g, 9.57 mmol, 4.00 eq), triethylamine (0.97 g, 9.57 mmol, 4.00 eq) were added to the reaction solution, then the reaction solution was stirred at 20 °C for 12 hours. Mass spectrum showed that the reaction of 5-iodo-1H-imidazol-2-amine was completely consumed, and a main peak with a correct MS value was detected. The reaction solution was poured into a stirring mixture of ice water and ethyl acetate, separated, the aqueous phase was extracted with ethyl acetate, the combined organic phase was washed with brine, dried over anhydrous sodium sulfate and rotary evaporated to give a crude product, which was purified by column to give a brownish solid product 2-(tert-butoxycarbonylamino)-5-iodo-1H-imidazole (250 mg, purity 90%, yield 85%).
[0074] The chemical reaction specific equation is as follows:
[0075]
[0076] 1H NMR: 2-(tert-butoxycarbonylamino)-5-iodo-1H-imidazole (400 MHz, DMSO-d6) δ ppm 1.53 (s, 9H) 7.00 (s, 1H).
[0077] Example 4:
[0078] Dissolve 4-bromopyrrole-2-carboxylic acid (10 g, 52.5 mmol, 1.00 eq) in tetrahydrofuran (500 mL), add DIEA (13.5 g, 105.5 mmol, 2.00 eq) and stir at room temperature for 10 minutes, then add HATU (22 g, 58 mmol, 1.10 eq) to the reaction solution and continue to stir at room temperature for 20 minutes, then add propargylamine (3.5 g, 63 mmol, 1.20 eq), then the reaction solution is stirred at 20 °C for 12 hours. Mass spectrometry shows that the 4-bromopyrrole-2-carboxylic acid reaction is completely consumed, and a main peak with a correct MS value is detected. After the reaction is completed, petroleum ether is added to the reaction solution under stirring, and the solid is precipitated. The reaction solution is filtered, the filter cake is washed with petroleum ether, then collected and rotary evaporated to remove excess solvent to obtain yellow solid product 4-bromo-N-propargylpyrrole-2-carboxamide (8.50 g, 92% purity, 71.1 yield).
[0079] The chemical reaction specific equation is as follows:
[0080]
[0081] Wherein:
[0082] LCMS (4-bromo-N-propargylpyrrole-2-carboxamide): (M+1) + : 226.9.
[0083] Example 5:
[0084] The reaction mixture was stirred at 65 °C under N2protection. The progress of the reaction was monitored in real time by TLC. When TLC showed that the 4-bromo-N-propynylpyrrole-2-carboxamide was completely consumed, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with ethyl acetate and the organic was washed with saturated aqueous sodium bicarbonate solution and brine. The organic phase was collected, dried over sodium sulfate and filtered. The organic phase was concentrated by rotary evaporation and purified using reverse phase column. After the eluent was concentrated, a mixture of 4-bromo-N-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)prop-l-enyl]-lH-pyrrole-2- carboxamide and (4-bromo-lH-pyrrol-2-yl)(2-hydroxy-2,5-dihydro-lH-l,2-azaborin-l- yl)methanone as shown in formula (3) and (4) (320 mg, mixture) was obtained.
[0085] The chemical reaction specific equation is as follows:
[0086]
[0087] LCMS (4-bromo-N-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)prop-l-enyl]-lH- pyrrole-2-carboxamide): (M+1) + : 254.9;
[0088] LCMS ((4-bromo-lH-pyrrol-2-yl)(2-hydroxy-2,5-dihydro-lH-l,2-azaborin-l- yl)methanone): (M+23) + : 276.9.
[0089] Example 6:
[0090] The mixture of above formula (3) and formula (4) (200 mg, mixture), 2-(tert- butyloxycarbonylamino)-5-iodo-1H-imidazole (242 mg, 0.7 mmol, 1.0 eq), Pd(pph3)4 (91 mg, 0.07 mmol, 0.10 eq), potassium carbonate (163 mg, 1.18 mmol, 1.50 eq), dioxane (3 ml) and water (0.3 ml) were mixed and stirred at 80 °C for 12 hours under nitrogen protection. The reaction was monitored by mass spectrometry and product was detected. The reaction mixture was diluted with ethyl acetate and the organic phase was washed with pure water and brine. The organic phase was collected and dried over sodium sulfate. The eluent was concentrated to obtain the crude product. The crude product was purified by column to obtain the compound of formula (6) (E)-(5-(3-(4-bromo-1H-pyrrole-2-carboxamido)prop-1-en-1-yl)-1H- imidazol-2-yl)carbamic acid tert-butyl ester (120 mg, 83% purity) as light yellow solid.
[0091] The chemical reaction specific equation is as follows:
[0092]
[0093] LCMS: ((E)-(5-(3-(4-bromo-1H-pyrrole-2-carboxamido)prop-1-en-1-yl)-1H- imidazol-2-yl)carbamic acid tert-butyl ester): (M+1) + = 410.0.
[0094] Example 7:
[0095] The compound of formula (6) (200 mg, 83% purity) was dissolved in hydrochloric acid dioxane solution and stirred at 20 °C overnight. The reaction was monitored by mass spectrometry and the starting material disappeared and the product was detected. The reaction solution was concentrated under reduced pressure and then purified by reverse phase column to obtain the pure final product. The final product, membranacin (75 mg, 98% purity, 82.7% yield), was detected by mass spectrometry and nuclear magnetic resonance hydrogen spectrum as shown in Figure 2 .
[0096] The chemical reaction specific equation is as follows:
[0097]
[0098] LCMS (membranacin): (M-1) - = 312.0; Rt = 0.853 min.
[0099] Comparative Example 1
[0100] The difference between Comparative Example 1 and Example 2 is that the reaction solution in Comparative Example 1 was stirred at 40 °C, as follows:
[0101] The 3-iodoimidazo[1,2-A]pyrimidine (200 mg, 0.82 mmol, 1.00 eq) was dissolved in ethanol (2.00 mL), then hydrazine hydrate (25 mg, 0.42 mmol, 0.5 eq, 85% purity) was added to the reaction solution, and then the reaction solution was stirred at 40 °C for 12 hours. After the reaction was completed by mass spectrometry detection, the reaction solution was poured into a stirring mixture of ice water and ethyl acetate, and the liquid was separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and rotary evaporated to obtain the intermediate 5-iodo-1H-imidazol-2-amine (30 mg, yield 19.8%, purity 70%).
[0102] Comparative Example 2:
[0103] Comparative Example 2 differs from Example 2 in that the molar ratio of 3-iodoimidazo[1,2-A]pyrimidine to hydrazine hydrate in Comparative Example 2 is 1:2, and the reaction solution is stirred at 40 °C, as follows:
[0104] The 3-iodoimidazo[1,2-A]pyrimidine (200 mg, 0.82 mmol, 1.00 eq) was dissolved in ethanol (2.00 mL), then hydrazine hydrate (25 mg, 0.42 mmol, 0.5 eq, 85% purity) was added to the reaction solution, and then the reaction solution was stirred at 40 °C for 12 hours. After the reaction was completed by mass spectrometry detection, the reaction solution was poured into a stirring mixture of ice water and ethyl acetate, and the liquid was separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and rotary evaporated to obtain the intermediate 5-iodo-1H-imidazol-2-amine (30 mg, yield 19.8%, purity 70%).
[0105] Comparative Example 3:
[0106] Comparative Example 1 differs from Example 3 in that the molar ratio of 5-iodo-1H-imidazol-2-amine to (Boc)2O in Comparative Example 1 is 1:1.5, as follows:
[0107] To a solution of 5-iodo-lH-imidazole-2-amine (0.50 g, 2.39 mmol, 1.00 eq) in tetrahydrofuran (5.0 mL) was added (Boc)20 (0.78 g, 3.59 mmol, 1.50 eq), triethylamine (0.97 g, 9.57 mmol, 4.00 eq) and the reaction was stirred at 20 °C for 12 h. Mass spectrum showed that the reaction of 5-iodo-lH-imidazole-2-amine was complete and a major peak with the correct MS value was detected. The reaction was poured into stirring ice water and ethyl acetate mixture, the aqueous phase was extracted with ethyl acetate and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by column to give the product 2-(tert-butoxycarbonylamino)-5-iodo-lH-imidazole as a tan solid (0.12 g, 85% purity, 40.5% yield).
[0108] Comparative Example 4:
[0109] To a solution of 4-bromopyrrole-2-carboxylic acid (0.20 g, 1.05 mmol, 1.00 eq), propargylamine (0.07 g, 1.26 mmol, 1.20 eq) in tetrahydrofuran (5.0 mL) was added DIEA (0.27 g, 2.11 mmol, 2.00 eq), HATU (0.44 g, 1.16 mmol, 1.10 eq) and the reaction was stirred at 20 °C for 12 h. Mass spectrum showed that the reaction of 4-bromopyrrole-2-carboxylic acid was complete and a major peak with the correct MS value was detected. The reaction was poured into stirring water and ethyl acetate mixture, the aqueous phase was extracted with ethyl acetate and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by column to give the product 4-bromo-N-propargylpyrrole-2-carboxamide as a yellow solid (50 mg, 85% purity, 20.9% yield).
[0110] Comparative Example 5:
[0111] The flask was purged with N2and then pinacolborane (0.844 g, 6.6 mmol, 3.0 eq) was added followed by 4-bromo-N-propynylpyrrole-2-carboxamide (0.50 g, 2.20 mmol, 1.0 eq). To the mixture was added Schwartz reagent (56 mg, 0.22 mmol, 0.10 eq) followed by triethylamine (44 mg, 0.44 mmol, 0.20 eq) to give a reaction mixture. The reaction mixture was stirred at 50 °C for 12 h under N2protection. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with ethyl acetate. The organic was washed with saturated aqueous sodium bicarbonate and brine, the organic phase was collected, dried over sodium sulfate, and the organic was filtered. The organic phase was concentrated by rotary evaporation and purified using reverse phase column to give a mixture of 4-bromo-N-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)prop-l-enyl]-lH-pyrrole-2- carboxamide of formula (3) and (4-(bromo-lH-pyrrol-2-yl)(2-hydroxy-2,5-dihydro- lH-l,2-azaborin-l-yl)methanone of formula (4) (40 mg, mixture).
[0112] Comparative Example 6:
[0113] Comparative Example 6 differs from Example 6 in that Pd(dppf)Cl2was used instead of Pd(pph3)4in Comparative Example 6 as follows:
[0114] The mixture of formula (3) and formula (4) (200 mg, mixture), 2-(tert- butyloxycarbonylamino)-5-iodo-lH-imidazole (242 mg, 0.7 mmol, 1.0 eq), Pd(dppf)Cl2(57 mg, 0.07 mmol, 0.10 eq), potassium carbonate (163 mg, 1.18 mmol, 1.50 eq), dioxane (3 ml), and water (0.3 ml) were mixed and reacted at 80 °C for 12 h under nitrogen protection. The reaction was monitored by mass spectrometry and product was detected. The reaction mixture was diluted with ethyl acetate and the organic was washed with pure water and brine, the organic phase was collected, dried over sodium sulfate, and the eluent was concentrated to give a crude product. The crude product was purified by column to give (E)-(5-(3-(4-bromo-lH-pyrrole-2-carboxamido)prop-l-en-l-yl)-lH- imidazol-2-yl)carbamic acid tert-butyl ester of formula (6) as a light yellow solid (40 mg, 83% purity).
[0115] Comparative Example 7:
[0116] Comparative Example 7 differs from Example 7 in that hydrochloric acid in methanol was used instead of hydrochloric acid in dioxane in Comparative Example 7 as follows:
[0117] The compound shown in formula (6) (200 mg, 83% purity) was dissolved in a methanolic hydrochloric acid solution and stirred at 20°C overnight. Mass spectrometry detected that the reaction was complete, the starting material was gone, and the product was generated. The reaction solution was concentrated under reduced pressure and then purified by reverse phase column to obtain pure end product. Mass spectrometry and nuclear magnetic detection showed that the end product, membranilysin (25 mg, 98% purity, 27.6% yield) was obtained.
[0118] Advantages of the embodiment of the present application: The present application discloses a preparation method of membranilysin, which comprises the following steps: reacting 4-bromopyrrole-2-carboxylic acid shown in formula (1) with propargylamine to generate 4-bromo-N-propargylpyrrole-2-carboxamide shown in formula (2); reacting 4-bromo-N-propargylpyrrole-2-carboxamide shown in formula (2) with pinacol borane to generate a mixture consisting of formula (3) and formula (4); reacting the mixture with 2-(tert-butoxycarbonylamino)-5-iodo-1H-imidazole shown in formula (5) to generate tert-butyl (E)-(5-(3-(4-bromo-1H-pyrrole-2-carboxamido)prop-1-en-1-yl)-1H-imidazol-2-yl)carbamate shown in formula (6); and reacting tert-butyl (E)-(5-(3-(4-bromo-1H-pyrrole-2-carboxamido)prop-1-en-1-yl)-1H-imidazol-2-yl)carbamate shown in formula (6) with a dioxane solution of hydrochloric acid to generate membranilysin. The present application provides a preparation method of membranilysin, which has a short synthesis route, is easy to operate, has high product yield, and is suitable for industrial production.
[0119] The above merely provides a specific embodiment of the present application, but the protection scope of the present application is not limited thereto, any changes or replacements within the technical scope disclosed by the present application can be easily thought by those skilled in the art, which should be covered within the protection scope of the present application. Therefore, the protection scope of the present application should be subject to the protection scope of the claims.
Claims
1. A method for preparing a filmixine, characterized by, The raw materials include a compound shown in formula (1) and a compound shown in formula (5):
2. The production method according to claim 1, characterized by, The synthesis route comprises the following steps:
3. The preparation method according to claim 2, characterized in that: Step S1 comprises: dissolving the compound shown in formula (1) in tetrahydrofuran, adding DIEA and HATU respectively, stirring uniformly, and then adding propargylamine to react to generate the compound shown in formula (2); Step S2 comprises: mixing the compound shown in formula (2) with pinacol borane under inert gas protection, and then adding Schwartz reagent and triethylamine to react to generate a mixture of formula (3) and formula (4); Step S3 comprises: mixing the mixture, the compound shown in formula (5), a palladium catalyst, potassium carbonate, dioxane and water under inert gas protection to react to generate the compound shown in formula (6); Step S4 comprises: reacting the compound shown in formula (6) with a hydrochloric acid dioxane solution to generate the compound shown in formula (7).
4. The production method according to claim 2, characterized by, The preparation method of the compound shown in formula (5) comprises the following steps: reacting imidazo[1,2-a]pyrimidine with NIS to generate 3-iodoimidazo[1,2-A]pyrimidine; reacting 3-iodoimidazo[1,2-A]pyrimidine with hydrazine hydrate to generate 5-iodo-1H-imidazole-2-amine; reacting 5-iodo-1H-imidazole-2-amine with (Boc)2O to generate 2-(tert-butoxycarbonylamino)-5-iodo-1H-imidazole shown in formula (5); The synthesis route is as follows:
5. The preparation method according to claim 3, characterized in that, The molar ratio of the compound shown in formula (2) to pinacol borane is 1:1.
5.
6. An intermediate of a kinetin, characterized by, The intermediate is a mixture of formula (3) and formula (4):
7. The method of synthesis of intermediates as claimed in claim 6, wherein, The synthesis route comprises the following steps: reacting the compound shown in formula (2) with pinacol borane under inert gas protection, and then adding Schwartz reagent and triethylamine to react to generate a mixture of formula (3) and formula (4); 8. An intermediate of a tape wormin, characterized in that, The intermediate is a compound shown in formula (6):
9. The method of synthesis of intermediates as claimed in claim 8, wherein, The synthesis route comprises the following steps: mixing the compounds shown in formula (3), formula (4) and formula (5), a palladium catalyst, potassium carbonate, dioxane and water under inert gas protection to react to generate the compound shown in formula (6); 10. Use of the preparation method according to any one of claims 1-5 or the intermediate according to any one of claims 6 and 8 or the synthesis method according to any one of claims 7 and 9 in the preparation of a compound shown in formula (7).