Synthesis method of 7H-pyrrolo [2, 3-d] pyrimidine-4-amine

Abstract

The invention relates to a synthesis method of 7H-pyrrolo [2, 3-d] pyrimidine-4-amine, and belongs to the technical field of synthesis of drug intermediates. In order to solve the problems of easy generation of metal residues and low yield in the prior art, the invention provides a synthetic method of 7H-pyrrolo [2, 3-d] pyrimidine-4-amine, which comprises the following steps: in the presence of alkali, reacting aziridine with malononitrile to obtain a compound shown as a formula III; under the action of organic alkali and trichloroisocyanuric acid, the compound shown in the formula III is subjected to oxidative dehydrogenation reaction to be converted into 2-amino-3-cyano-1H-pyrrole; the 2-amino-3-cyano-1H-pyrrole and formamidine acetate are subjected to a reaction, and the 7H-pyrrolo [2, 3-d] pyrimidine-4-amine is obtained. According to the method, the problem of metal residues caused by the adoption of a noble metal catalyst can be effectively avoided, the product yield is better guaranteed, the high-purity quality effect is achieved, and the purity of an intermediate product in each step can reach 99% or above.

Description

Technical Field

[0001] The invention relates to a method for synthesizing 7H-pyrrolo[2,3-d]pyrimidine-4-amine, and belongs to the technical field of drug intermediate synthesis. Background Art

[0002] 7H-pyrrolo[2,3-d]pyrimidine-4-amine (I) is a key intermediate in the synthesis of tofacitinib and has broad application prospects. The structural formula of the key intermediate is shown below:

[0003]

[0004] In the existing literature, the synthesis of the above key intermediates is mainly carried out by alkylation reaction of bromoacetaldehyde diethyl acetal with malononitrile, and then reacting with thiourea to form a pyrimidine ring, and then neutralizing the potassium salt of the thiol with hydrochloric acid aqueous solution, and then cyclizing under alkaline conditions to obtain a thiol compound, and finally reducing the thiol by Raney nickel catalysis to obtain 7H-pyrrolo[2,3-d]pyrimidin-4-amine, with a total yield of 25%. The reaction equation is as follows:

[0005]

[0006] This synthetic route has the problem of low product yield, and the reaction uses precious metal catalysts such as Raney nickel, which easily causes metal residues and affects the purity and quality of the product.

[0007] There is also a method of using diaminopyrimidine hemisulfate hydrate as a raw material, sequentially undergoing iodination reaction, cross-coupling and cyclization reaction to generate 7H-pyrrolo[2,3-d]pyrimidin-4-amine (I), with a total yield of 31%. The reaction equation is as follows:

[0008]

[0009] This synthetic route also uses a metal palladium catalyst to promote the coupling reaction, but it also has problems such as high cost and easy to cause metal residues. Summary of the invention

[0010] In view of the defects in the above prior art, the present invention provides a method for synthesizing 7H-pyrrolo[2,3-d]pyrimidin-4-amine, which solves the problem of how to avoid metal residue and improve the purity and quality of the product.

[0011] The object of the present invention is achieved by the following technical scheme: a method for synthesizing 7H-pyrrolo[2,3-d]pyrimidin-4-amine, the method comprising the following steps:

[0012] A. reacting the compound of formula II, aziridine, and malononitrile in the presence of a base to obtain a compound of formula III;

[0013]

[0014] B. Under the action of an organic base and trichloroisocyanuric acid, the compound of formula III is subjected to an oxidative dehydrogenation reaction in an inert organic solvent to be converted into the compound of formula IV, 2-amino-3-cyano-1H-pyrrole;

[0015]

[0016] C. The compound of formula IV, 2-amino-3-cyano-1H-pyrrole, is subjected to a cyclization reaction with formamidine acetate to obtain the compound of formula I, 7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0017]

[0018] By improving the synthesis route, the compound of formula II, aziridine, is used as a starting material to react with malononitrile to first obtain the compound of formula III, and the intermediate is further reacted downward. More importantly, since the intermediate compound of formula III synthesized from the compound of formula II, aziridine, as a starting material contains two amino structures, how to avoid the two amino positions from participating in the reaction and generating impurities and affecting the product yield during the oxidative dehydrogenation process, in order to achieve a synthesis process without the need for protection and subsequent deprotection of the two amino groups, a simple operation and a synthetic route, and avoid problems such as metal residues, the present invention adopts an organic base and trichloroisocyanuric acid as a synergistic catalyst system, which can highly selectively remove the corresponding hydrogen on the pyrrole ring to form an unsaturated bond. Due to the use of the catalyst system of trichloroisocyanuric acid and an organic base, the problem of metal residues caused by the use of precious metal catalysis is also effectively avoided, and the product yield is better guaranteed while having the effect of high product purity quality. The purity of the intermediate product in each step can reach more than 99%. At the same time, it can avoid the amino group from participating in the reaction and forming a side reaction, thereby achieving the step of not needing to pre-protect the two amino groups, and can also avoid the subsequent process of removing the protecting group, thereby better simplifying the operation, avoiding too many intermediate processes, and better reducing the generation of unnecessary impurities, which is beneficial to improving the yield and purity quality of the product, and the purity reaches more than 99%.

[0019] In the above-mentioned synthesis method of 7H-pyrrolo[2,3-d]pyrimidine-4-amine, as a preference, the organic base in step B is selected from one or more of 1,8-diazabicycloundec-7-ene, 1,5-diazabicyclo[4.3.0]-5-nonene, triethylamine, diisopropylethylamine and pyridine. By adopting the above-mentioned organic base, it is possible to better form a synergistic effect with trichloroisocyanuric acid, promote the reaction, and achieve the effect of oxidative dehydrogenation; at the same time, the presence of the organic base can also neutralize the small molecule acid formed during the reaction, which is beneficial to the reaction to proceed in the forward direction and improve the efficiency of the reaction. As a further preference, the organic base is preferably 1,8-diazabicycloundec-7-ene or 1,5-diazabicyclo[4.3.0]-5-nonene. The combined system of 1,8-diazabicycloundec-7-ene or 1,5-diazabicyclo[4.3.0]-5-nonene and trichloroisocyanuric acid is used to catalyze the reaction, so that the reaction can be carried out under milder conditions with high reaction efficiency. At the same time, since trichloroisocyanuric acid can be used as a chlorinated product in addition to oxidation and dehydrogenation, the combined system has a high oxidation and dehydrogenation yield, and no chlorinated impurities can be detected, which is more conducive to reducing unnecessary impurities and ensuring the purity and quality of the product.

[0020] In the above-mentioned synthesis method of 7H-pyrrolo[2,3-d]pyrimidin-4-amine, preferably, the molar ratio of the compound of formula III: trichloroisocyanuric acid: organic base in step B is 1: 0.1-0.3: 1.0-3.0. By making the dosage of the three more reasonably adjusted and controlled, it can be more conducive to the full reaction, promote oxidative dehydrogenation, and effectively avoid the reaction of the two amino positions to produce by-products, with the advantages of high product yield and purity quality, and at the same time, it can reduce unnecessary waste of raw materials and is conducive to cost control.

[0021] In the above-mentioned synthesis method of 7H-pyrrolo[2,3-d]pyrimidine-4-amine, the reactions in the field of general organic synthesis are carried out in a solvent, which can make the reaction proceed evenly. Here, the selection of organic solvent 1 is usually to use an inert organic solvent first, that is, a solvent that does not participate in the reaction. In order to adopt a better solvent selection, as a preference, the inert organic solvent in step B is selected from one or more of ether solvents, ester solvents, nitrile solvents and ketone solvents; the ether solvent is selected from one or more of tetrahydrofuran, methyl tert-butyl ether, ethyl tert-butyl ether, butyl ether and isopropyl ether; the nitrile solvent is selected from one or more of acetonitrile, propionitrile and butyronitrile; the ketone solvent is selected from acetone and / or isopropyl ketone; the ester solvent is selected from one or more of ethyl acetate, methyl acetate and ethyl propionate. The trichloroisocyanuric acid used has the characteristics of high solubility in the above-mentioned solvents, so that it can have a higher probability of contacting with the substrate during the reaction, so that the reaction can be more efficiently promoted and carried out gently. The amount of the inert organic solvent can be based on the general amount in the chemical field. It is best to make the volume ratio of the inert organic solvent to the mass ratio of the compound of formula III 8 to 12:1, that is, 8 to 12 mL of the inert organic solvent is added for every 1 g of the compound of formula III.

[0022] In the above-mentioned synthesis method of 7H-pyrrolo[2,3-d]pyrimidin-4-amine, preferably, the temperature of the oxidative dehydrogenation reaction in step B is -30°C to 40°C. Due to the use of an organic base and trichloroisocyanuric acid catalytic system, the oxidative dehydrogenation reaction can be achieved under mild conditions, without the need to promote the reaction under high temperature conditions. As a further preference, the temperature of the oxidative dehydrogenation reaction is -15°C to 25°C.

[0023] In the above-mentioned synthesis method of 7H-pyrrolo[2,3-d]pyrimidine-4-amine, preferably, the base in step A is selected from one or more of alkali metal alkoxides, alkali metal hydrides and alkali metal hydroxides; the alkali metal alkoxide is selected from one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium ethoxide; the alkali metal hydroxide is selected from one or more of sodium hydroxide, potassium hydroxide and potassium hydroxide, and the alkali metal hydride is selected from sodium hydride, lithium hydride, potassium hydride, etc. The combination formed with trichloroisocyanuric acid can better promote the oxidative dehydrogenation reaction and improve the conversion efficiency of the reaction.

[0024] In the above-mentioned synthesis method of 7H-pyrrolo[2,3-d]pyrimidine-4-amine, the reaction in step A is carried out in an organic solvent, preferably an ether solvent, an amide solvent, an alkane solvent, etc. Preferably, the reaction in step A is carried out in an organic solvent, and the organic solvent is selected from one or more of tetrahydrofuran, DMF, DMSO and 1,2-dimethoxyethane; the reaction temperature is 10°C to 50°C. By adding a solvent and controlling the temperature, the reaction can be carried out more uniformly and stably, which is conducive to ensuring the quality of the product. As a further preference, the reaction temperature is 20°C to 35°C.

[0025] In the above-mentioned synthesis method of 7H-pyrrolo[2,3-d]pyrimidine-4-amine, preferably, the molar ratio of the compound of formula II, aziridine: malononitrile: base in step A is 1:1.1-2.5:1.1-2.0, which can more efficiently improve the utilization rate of raw materials.

[0026] In the above-mentioned synthesis method of 7H-pyrrolo[2,3-d]pyrimidine-4-amine, preferably, the compound of formula II aziridine in step A is obtained by the following method:

[0027] Under the action of an inorganic base, 2-chloroethylamine or its acid salt is reacted in a water-based solvent system to obtain the compound of formula II, aziridine. The above-mentioned 2-chloroethylamine acid salt can be hydrochloride, sulfate, etc., and 2-chloroethylamine hydrochloride is preferably used.

[0028] The chemical equation for the synthesis of the above-mentioned compound of formula II, aziridine, is shown below (taking 2-chloroethylamine hydrochloride as an example):

[0029]

[0030] In the above-mentioned synthesis method of 7H-pyrrolo[2,3-d]pyrimidin-4-amine, preferably, the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide. Preferably, the molar ratio of the 2-chloroethylamine or its acid salt: the inorganic base is 1:2.0-3.0.

[0031] In the above-mentioned method for synthesizing 7H-pyrrolo[2,3-d]pyrimidin-4-amine, it is preferred that the reaction temperature of 2-chloroethylamine or its acid salt is controlled at 40°C to 60°C.

[0032] In the above-mentioned synthesis method of 7H-pyrrolo[2,3-d]pyrimidin-4-amine, preferably, the cyclization reaction in step C is carried out in an alcohol solvent, and the temperature of the cyclization reaction is 45°C to reflux temperature. The alcohol solvent here can be one or more of methanol, ethanol, propanol and isopropanol. It is further preferred that the cyclization reaction is preferably carried out under reflux conditions.

[0033] In the above-mentioned method for synthesizing 7H-pyrrolo[2,3-d]pyrimidin-4-amine, preferably, in step C, the molar ratio of the compound of formula IV, 2-amino-3-cyano-1H-pyrrole, to formamidine acetate is 1:1.1-2.2.

[0034] The chemical reaction equation of the synthesis method of the above-mentioned 7H-pyrrolo[2,3-d]pyrimidin-4-amine of the present invention is as follows:

[0035]

[0036] In summary, compared with the prior art, the present invention has the following advantages:

[0037] 1. The organic base and trichloroisocyanuric acid are used as a synergistic catalytic system, which can selectively remove the corresponding hydrogen on the pyrrole ring to form an unsaturated bond, effectively avoiding the metal residue problem caused by the use of precious metal catalysts, better ensuring the product yield while achieving high purity quality, and the purity of the intermediate product in each step can reach more than 99%.

[0038] 2. It can avoid the amino group from participating in the reaction and forming a side reaction, thus realizing the step of not needing to pre-protect the two amino groups and avoiding the subsequent process of removing the protecting agent, thus better simplifying the synthesis operation and being conducive to improving the yield of the product. DETAILED DESCRIPTION

[0039] The technical solution of the present invention is further specifically described below through specific embodiments, but the present invention is not limited to these embodiments.

[0040] Example 1

[0041] Synthesis of Aziridine (Ⅱ)

[0042]

[0043] Add an aqueous solution of sodium hydroxide (44.0 g (1.1 mol) + 200 mL of water) into a clean four-necked flask containing 58.0 g (0.5 mol) of 2-chloroethylamine hydrochloride, start heating to 50°C and control the temperature to stir and react for 2 hours, then perform reduced pressure distillation to collect the crude aziridine, take the upper layer, add potassium hydroxide, dry overnight, and filter to obtain 16.3 g of colorless oily aziridine with a yield of 76% and a purity of 99.2%.

[0044] Example 2

[0045] Synthesis of 2-amino-3-cyano-4,5-dihydro-1H-pyrrole (Ⅲ)

[0046]

[0047] Take a 500mL clean four-necked bottle, add 18.4g 60% NaH (0.46mol), 53.2g (0.76mol) malononitrile and 150mL tetrahydrofuran, stir for 0.5h, then add aziridine tetrahydrofuran solution (aziridine 16.3g (0.38mol) + 150mL tetrahydrofuran), then control the temperature at 30℃ ~ 35℃ to keep warm for 4h. After the reaction is completed, recover THF by rotary evaporation, pour the residue into ice water and stir to precipitate a large amount of solid, filter, and separate. Wash with ice water and petroleum ether, collect the filter cake, and add ethyl acetate-petroleum ether (volume ratio 2:1) solvent system to obtain crude 2-amino-3-cyano-4,5-dihydro-1H-pyrrole (III), heat to 75℃~80℃ to dissolve, then slowly cool to room temperature for recrystallization until solid is fully precipitated, filter, dry the obtained wet product, and obtain 32.7g of light yellow solid dry product 2-amino-3-cyano-4,5-dihydro-1H-pyrrole, with a yield of 79% and a purity of 99.4%. The obtained 2-amino-3-cyano-4,5-dihydro-1H-pyrrole was analyzed:

[0048] Mp: 143℃~145℃.

[0049] 1 H-NMR (400MHz, DMSO-d6) δ: 11.57 (s, 1H), 6.08 (s, 2H), 4.01-3.73 (m, 2H), 3.65-2.51 (m, 2H).

[0050] 13 C-NMR (100MHz, DMSO-d6) δ: 168.8, 118.1, 62.2, 35.3, 34.5.

[0051] MS (ESI): m / z = 110.1 [M+H] + .

[0052] Example 3

[0053] Synthesis of 2-amino-3-cyano-1H-pyrrole (Ⅳ)

[0054]

[0055] In a 500mL clean four-necked bottle, add 32.7g (0.30mol) of 2-amino-3-cyano-4,5-dihydro-1H-pyrrole, 68.4g (0.45mol) of 1,8-diazabicycloundec-7-ene and 250mL of methyl tert-butyl ether, cool to -5°C, and add 20.9g (0.09mol) of trichloroisocyanuric acid in methyl tert-butyl ether (100mL) solution dropwise under stirring. After the dropwise addition, continue the reaction. 2h, after the reaction is completed, water is added to the reaction solution for washing twice, each time with 300 mL of water, and the mixture is allowed to stand for stratification. The collected organic phase is dried with 6 g of anhydrous sodium sulfate for 1 hour, filtered, and the collected filtrate is concentrated to remove the solvent to obtain a crude product. The crude product is recrystallized with ethyl acetate-petroleum ether (volume ratio 3:2) system to obtain 29.5 g of yellow solid, which is 2-amino-3-cyano-1H-pyrrole (IV), with a yield of 92% and a purity of 99.3%.

[0056] The obtained 2-amino-3-cyano-1H-pyrrole (IV) was analyzed.

[0057] Mp: 112℃~113℃.

[0058] 1 H-NMR (400MHz, DMSO-d6) δ: 11.32 (s, 1H), 6.54 (d, J = 4.0Hz, 1H), 6.26 (d, J = 4.0Hz, 1H), 5.74 (brs, 2H).

[0059] 13 C-NMR (100MHz, DMSO-d6) δ: 142.8, 117.1, 116.0, 108.9, 80.2.

[0060] MS (ESI): m / z = 108.1 [M+H] + .

[0061] Example 4

[0062] Synthesis of 7H-pyrrolo[2,3-d]pyrimidin-4-amine (Ⅰ)

[0063]

[0064] Take a 500mL four-necked bottle, add 29.5g (0.27mol) of 2-amino-3-cyano-1H-pyrrole, 56.2g (0.54mol) of formamidine acetate and 300mL of ethanol, heat and reflux for 1h. After the end, slowly cool to room temperature to precipitate a large amount of solid, filter, and use ethanol as a solvent to dissolve the crude product 7H-pyrrolo[2,3-d]pyrimidin-4-amine. Then slowly cool to room temperature for recrystallization, collect the filter cake by filtration, and dry to obtain a dry yellow solid 7H-pyrrolo[2,3-d]pyrimidin-4-amine 31.8g, with a yield of 88% and a purity of 99.6%.

[0065] Mp: 255℃~257℃.

[0066] 1 H-NMR (400MHz, DMSO-d6) δ: 11.42 (s, 1H), 8.01 (s, 1H), 7.04 (d, J = 3.2 Hz, 1H), 6.84 (s, 2H), 6.58 (d, J = 3.2 Hz, 1H).

[0067] 13 C-NMR (DMSO-d6, 100MHz): δ156.8, 150.4, 159.7, 120.4, 102.0, 97.8.

[0068] MS (ESI): m / z = 135.1 [M+H] + .

[0069] Example 5

[0070] Synthesis of 2-amino-3-cyano-1H-pyrrole (Ⅳ)

[0071]

[0072] In a 500mL clean four-necked bottle, add 32.7g (0.30mol) of 2-amino-3-cyano-4,5-dihydro-1H-pyrrole, 91.2g (0.6mol) of 1,8-diazabicycloundec-7-ene and 300mL of ethyl tert-butyl ether, cool to -10℃~-5℃, and add 13.9g (0.06mol) of trichloroisocyanuric acid in ethyl tert-butyl ether (100mL) solution dropwise under stirring. After the dropwise addition, continue to control the temperature at - The reaction was carried out at 10°C to -5°C for 2.5 hours. After the reaction was completed, water was added to the reaction solution for washing twice (300 mL of water each time), and the reaction mixture was allowed to stand for stratification. The collected organic phase was dried over 6 g of anhydrous sodium sulfate for 1 hour and filtered. The collected filtrate was concentrated to remove the solvent to obtain a crude product. The crude product was recrystallized from ethyl acetate-petroleum ether to obtain 29.3 g of a yellow solid, which was 2-amino-3-cyano-1H-pyrrole (IV) with a yield of 91.2% and a purity of 99.2%.

[0073] Example 6

[0074] Synthesis of 7H-pyrrolo[2,3-d]pyrimidin-4-amine (Ⅰ)

[0075]

[0076] Take a 500mL four-necked bottle, add 21.4g (0.2mol) 2-amino-3-cyano-1H-pyrrole, 31.2g (0.3mol) of formamidine acetate and 300mL of anhydrous propanol, heat and reflux for 1.5h. After the end, slowly cool to room temperature and stir thoroughly to precipitate a large amount of solid, filter, and use ethanol as a solvent to dissolve the crude 7H-pyrrolo[2,3-d]pyrimidin-4-amine, then slowly cool to room temperature for recrystallization, collect the filter cake by filtration, and dry to obtain a dry yellow solid 7H-pyrrolo[2,3-d]pyrimidin-4-amine 31.5g, with a yield of 87.2% and a purity of 99.4%.

[0077] Example 7

[0078] Synthesis of 7H-pyrrolo[2,3-d]pyrimidin-4-amine (Ⅰ)

[0079]

[0080] In a 500mL clean four-necked bottle, 32.7g (0.30mol) of 2-amino-3-cyano-4,5-dihydro-1H-pyrrole, 77.4g (0.6mol) of diisopropylethylamine and 300mL of ethyl acetate were added, cooled to -5℃~0℃, and a solution of 13.9g (0.06mol) of trichloroisocyanuric acid in ethyl acetate (100mL) was added dropwise with stirring. After the addition, the temperature was continued to be controlled at -5℃~0℃ for 2h. After the reaction was completed, water was added to the reaction solution for washing twice (each time with 300mL of water), and the reaction solution was allowed to stand for stratification. The collected organic phase was dried with 6g of anhydrous sodium sulfate for 1 hour and filtered. The collected filtrate was concentrated to remove the solvent to obtain a crude product, which was recrystallized with ethyl acetate-petroleum ether system to obtain 29.7g of yellow solid, which was 2-amino-3-cyano-1H-pyrrole (IV) with a yield of 92.5% and a purity of 99.1%.

[0081] Take a 500mL four-necked bottle, add the above-obtained 29.7g (0.28mol) 2-amino-3-cyano-1H-pyrrole, 45.8g (0.44mol) of formamidine acetate and 300mL of anhydrous ethanol, heat and reflux for 1.5h. After the end, slowly cool to room temperature and stir thoroughly to precipitate a large amount of solid, filter, and use ethanol as a solvent to obtain the crude product 7H-pyrrolo[2,3-d]pyrimidin-4-amine. After heating and dissolving, slowly cool to room temperature for recrystallization, collect the filter cake by filtration, and dry it to obtain a dry yellow solid 7H-pyrrolo[2,3-d]pyrimidin-4-amine 31.3g, with a yield of 86.7% and a purity of 99.2%.

[0082] Example 8

[0083] Synthesis of 2-amino-3-cyano-4,5-dihydro-1H-pyrrole (Ⅲ)

[0084]

[0085] Take a 500mL clean four-necked bottle, add 31.2g sodium ethoxide (0.46mol), 29.7g (0.45mol) malononitrile and 150mL DMSO, stir for 0.5h, then add aziridine DMSO solution (aziridine 12.9g (0.3mol) + DMSO 150mL), then control the temperature at 20℃~25℃ to keep warm for 5h. After the reaction is completed, perform rotary evaporation to recover DMSO, pour the residue into ice water and stir to precipitate a large amount of solid, filter, collect the filter cake, and obtain the crude product of 2-amino-3-cyano-4,5-dihydro-1H-pyrrole (III) , washed with ice water and petroleum ether respectively, and dried; then the dried 2-amino-3-cyano-4,5-dihydro-1H-pyrrole (III) was added to an ethyl acetate-petroleum ether solvent system and heated to 70°C to 80°C to dissolve, then slowly cooled to room temperature for recrystallization until solid was fully precipitated, filtered, and the obtained wet product was dried to obtain 33.5 g of light yellow solid dry product 2-amino-3-cyano-4,5-dihydro-1H-pyrrole, with a yield of 81% and a purity of 99.2%.

[0086] Example 9

[0087] Synthesis of 2-amino-3-cyano-1H-pyrrole (Ⅳ)

[0088]

[0089] In a 500mL clean four-necked bottle, 32.7g (0.30mol) of 2-amino-3-cyano-4,5-dihydro-1H-pyrrole, 76.8g (0.8mol) of sodium tert-butoxide and 330mL of acetonitrile were added, cooled to 0℃~5℃, and a solution of 16.3g (0.07mol) of trichloroisocyanuric acid in acetonitrile (100mL) was added dropwise under stirring. After the addition, the temperature was continued to be controlled at 0℃~5℃ for 1.5h. After the reaction was completed, 300mL of methyl tert-butyl ether and 100mL of water were added to the reaction solution, stirred for 15min, and allowed to stand for stratification. The collected organic phase was dried with 6g of anhydrous sodium sulfate for 1 hour and filtered. The collected filtrate was concentrated to remove the solvent to obtain a crude product, which was recrystallized with ethyl acetate-petroleum ether system to obtain 29g of yellow solid, which was 2-amino-3-cyano-1H-pyrrole (IV) with a yield of 90.5% and a purity of 99.1%.

[0090] Example 10

[0091] Synthesis of Aziridine (Ⅱ)

[0092]

[0093] Add an aqueous solution of potassium hydroxide (55.2 g (1.2 mol) + 200 mL of water) into a clean four-necked flask containing 58.0 g (0.5 mol) of 2-chloroethylamine hydrochloride, start heating to 60°C and control the temperature to stir and react for 2 hours, then perform reduced pressure distillation to collect the crude aziridine, take the upper layer, add potassium hydroxide, dry overnight, and filter to obtain 16.8 g of colorless oily substance, which is aziridine, with a yield of 78.2% and a purity of 99.3%.

[0094] The specific embodiments described in the present invention are merely examples of the spirit of the present invention. Those skilled in the art may make various modifications or additions to the specific embodiments described or replace them in similar ways, but they will not deviate from the spirit of the present invention or exceed the scope defined by the attached claims.

[0095] Although the present invention has been described in detail and some specific embodiments have been cited, it is obvious to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the present invention.

Claims

1. A method for synthesizing 7H-pyrrolo[2,3-d]pyrimidin-4-amine, characterized in that: The method comprises the following steps: A. reacting the compound of formula II, aziridine, and malononitrile in the presence of a base to obtain a compound of formula III; B. Under the action of an organic base and trichloroisocyanuric acid, the compound of formula III is subjected to an oxidative dehydrogenation reaction in an inert organic solvent to be converted into the compound of formula IV, 2-amino-3-cyano-1H-pyrrole; C. The compound of formula IV, 2-amino-3-cyano-1H-pyrrole, undergoes a cyclization reaction with methyl imidazole acetate to obtain the compound of formula I, 7H-pyrrolo[2,3-d]pyrimidin-4-amine; 2. The method for synthesizing 7H-pyrrolo[2,3-d]pyrimidin-4-amine according to claim 1, characterized in that: The organic base in step B is selected from one or more of 1,8-diazabicycloundec-7-ene, 1,5-diazabicyclo[4.3.0]-5-nonene, triethylamine, diisopropylethylamine and pyridine.

3. The method for synthesizing 7H-pyrrolo[2,3-d]pyrimidin-4-amine according to claim 1, characterized in that: In step B, the molar ratio of the compound of formula III: trichloroisocyanuric acid: organic base is 1: 0.1-0.3: 1.0-3.

0.

4. The method for synthesizing 7H-pyrrolo[2,3-d]pyrimidin-4-amine according to claim 1, 2 or 3, characterized in that: The inert organic solvent in step B is selected from one or more of ether solvents, ester solvents, nitrile solvents and ketone solvents; the ether solvent is selected from one or more of tetrahydrofuran, methyl tert-butyl ether, ethyl tert-butyl ether, butyl ether and isopropyl ether; the nitrile solvent is selected from one or more of acetonitrile, propionitrile and butyronitrile; the ketone solvent is selected from one or more of acetone and / or isopropyl ketone; the ester solvent is selected from one or more of ethyl acetate, methyl acetate and ethyl propionate.

5. The method for synthesizing 7H-pyrrolo[2,3-d]pyrimidin-4-amine according to claim 4, characterized in that: The temperature of the oxidative dehydrogenation reaction in step B is -30°C to 40°C.

6. The method for synthesizing 7H-pyrrolo[2,3-d]pyrimidin-4-amine according to claim 1, 2 or 3, characterized in that: In step A, the base is selected from one or more of alkali metal alkoxides, alkali metal hydrides and alkali metal hydroxides; the alkali metal alkoxide is selected from one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium ethoxide; the alkali metal hydroxide is selected from one or more of sodium hydroxide, potassium hydroxide and potassium hydroxide; the alkali metal hydride is selected from one or more of sodium hydride, lithium hydride and potassium hydride.

7. The method for synthesizing 7H-pyrrolo[2,3-d]pyrimidin-4-amine according to claim 6, characterized in that: The reaction in step A is carried out in an organic solvent at a temperature of 10° C. to 50° C.; the organic solvent is selected from one or more of tetrahydrofuran, DMF, DMSO and 1,2-dimethoxyethane.

8. The method for synthesizing 7H-pyrrolo[2,3-d]pyrimidin-4-amine according to claim 7, characterized in that: In step A, the molar ratio of the compound of formula II, aziridine: malononitrile: base is 1:1.1-2.5:1.1-2.

0.

9. The method for synthesizing 7H-pyrrolo[2,3-d]pyrimidin-4-amine according to claim 1, 2 or 3, characterized in that: The compound of formula II described in step A, aziridine, is obtained by the following method: Under the action of an inorganic base, 2-chloroethylamine or its acid salt is reacted in a system with water as a solvent to obtain the compound of formula II, aziridine.

10. The method for synthesizing 7H-pyrrolo[2,3-d]pyrimidin-4-amine according to claim 9, characterized in that: The cyclization reaction in step C is carried out in an alcohol solvent, and the temperature of the cyclization reaction is 45° C. to reflux temperature.

Images