CN112500417B - Preparation method of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine - Google Patents
Preparation method of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine Download PDFInfo
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Abstract
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine. The method comprises the following steps: s1, stirring and mixing triethyl orthoformate and glacial acetic acid in a reaction kettle, and then introducing ammonia gas for pressure maintaining reaction; s2; after the triethyl orthoformate reacts with ammonia gas, the temperature is reduced, 1-aminopyrrole-2-formonitrile hydrochloride is added to continue to be introduced with ammonia for heating reaction, the solvent is concentrated after the reaction is finished, deionized water is added to stir, the temperature is reduced and crystallization is carried out, the 4-aminopyrrole [2,1-f ] [1,2,4] triazine crude product is obtained through centrifugation, and the 4-aminopyrrole [2,1-f ] [1,2,4] triazine fine product is obtained through refining. The method has the advantages of simple synthetic route, less raw and auxiliary materials, low cost, less three wastes, environmental protection and high product purity, and is more suitable for industrial mass production.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine.
Background
4-aminopyrrolo [2,1-f ] [1,2,4] triazine is an important intermediate of antiviral drug Reidesciclovir, and the structural formula is as follows:
reidcivir is a nucleoside analog with antiviral activity developed by Gilidard scientific, USA. The drug was initially found to have anti-ebola virus activity and was used in clinical trials for treating ebola infected patients. However, subsequent studies have shown that the drug may also be effective in diseases caused by coronaviruses including SARS (SARS), Middle East Respiratory Syndrome (MERS), etc. Research shows that the Redexilvir has certain curative effect on the cure of the new corona, and the earlier the Redexilvir is used, the better the Redexilvir is used. On 22 days 10/2020, FDA approved redciclovir for hospitalized new coronary pneumonia patients also became the first drug approved for new coronary patients in the united states.
Patent CN110092787A discloses the preparation and application of a compound or its pharmaceutical salt or composition, wherein 4-aminopyrrolo [2,1-f ] is involved][1,2,4]The synthesis method of triazine comprises the following specific steps: 1-amino-1H-pyrrole-2-carbonitrile hydrochloride (50g), formamidine acetate (109g, 1.05mol), K were added to a 2-L round-bottomed flask3PO4(222g, 1.05mol) and EtOH (800mL) were heated to reflux for 16 h. After the reaction was complete, filtration was carried out and the filter residue was washed with EtOH. The filtrate was concentrated, the residue was dissolved in EtOAc and the organic phase was washed with saturated NaCl solution and anhydrous Na2SO4Drying, filtering and concentrating to obtain red solid. The obtained solid is dispersed in CH2Cl2Filtering, and adding CH to the filter residue2Cl2Washing to obtain 35g of light yellow solid; the molar yield was 74.6%. In the method, under the alkaline condition provided by solid alkali, formamidine acetate and 1-aminopyrrole-2-formonitrile hydrochloride react in ethanol to generate a target product. The method has the following defects: the raw material formamidine acetate is expensive in market price, so the production cost is high; the method has low yield; and the solid with 6.62 times of the weight of the added substrate in the reaction causes the system to become very viscous, even if 16 times of the solvent amount of the added substrate is added, the dispersion of reactants is not facilitated, the reaction is incomplete, the yield and the yield are low, and the production cost is further increased.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine. The method has the advantages of simple synthetic route, less raw and auxiliary material feeding, low cost, less three wastes, environmental protection and high product purity, and is more suitable for industrial mass production.
The invention is realized by the following technical scheme:
a preparation method of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine comprises the following steps:
s1, stirring and mixing triethyl orthoformate and glacial acetic acid in a reaction kettle, and then introducing ammonia gas for pressure maintaining reaction;
s2; after the triethyl orthoformate and ammonia react, cooling, adding 1-aminopyrrole-2-formonitrile hydrochloride to continue to introduce ammonia for heating reaction, concentrating the solvent after the reaction is finished, adding deionized water, stirring, cooling, crystallizing, centrifuging to obtain a crude product of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, and refining to obtain a refined product of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine.
The reaction equation of the preparation method is as follows:
in the above method for preparing 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, the mass ratio of triethyl orthoformate to glacial acetic acid is 2.0-5.0:1, preferably 2.5-3.0: 1.
In the above method for producing 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, the temperature in step S1 is 45 to 90 ℃, preferably 60 to 90 ℃.
In the above method for producing 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, the mass ratio of triethyl orthoformate to ammonia gas is 1.5-5.0:1, preferably 2.0-4.0: 1.
In the above method for preparing 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, the mass ratio of the 1-aminopyrrole-2-carbonitrile hydrochloride to triethyl orthoformate is 1:2.0-8.0, preferably 1: 2.6-5.0.
In the above method for preparing 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, the reaction temperature in the step S2 is 30 to 80 ℃, preferably 60 to 70 ℃.
In the above-mentioned process for producing 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, the reaction is carried out under a pressure of 0.01 to 0.3MPa, preferably 0.02 to 0.1MPa, while maintaining the pressure.
In the above-mentioned process for producing 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, the solvent for purification is one or more selected from methanol, ethanol and isopropanol, and the weight of the solvent is 5 to 20 times, preferably 7 to 15 times the weight of 1-aminopyrrole-2-carbonitrile hydrochloride.
Preferably, the preparation method of the 4-aminopyrrolo [2,1-f ] [1,2,4] triazine comprises the following steps: stirring and mixing triethyl orthoformate and glacial acetic acid in a reaction kettle, inserting a vent pipe below the liquid level, heating to 30 ℃, introducing ammonia gas under a protective pressure, heating to 60-90 ℃ for reaction, adding 1-aminopyrrole-2-formonitrile hydrochloride after the reaction is finished and cooling, heating to 60-65 ℃, introducing ammonia gas for heat preservation reaction, concentrating under reduced pressure after the reaction is finished until no solvent is evaporated out, adding deionized water for pulping to obtain a crude wet product, dissolving the wet product with methanol, cooling and crystallizing after concentration, and centrifuging to obtain the 4-aminopyrrolo [2,1-f ] [1,2,4] triazine refined product.
More preferably, the preparation method of the 4-aminopyrrolo [2,1-f ] [1,2,4] triazine comprises the following detailed steps:
adding 720kg of triethyl orthoformate and 266kg of glacial acetic acid into a reaction kettle, stirring and heating to 30-35 ℃, vacuumizing the reaction kettle, introducing ammonia below the liquid level, keeping the temperature for 2h at 80-90 ℃ until the raw materials disappear, introducing 208kg of ammonia, cooling to below 50 ℃, adding 265kg of 1-aminopyrrole-2-formonitrile hydrochloride, sealing the reaction kettle, heating to 60-65 ℃ for ammonia-introducing heat-preserving reaction, after the reaction is finished, concentrating under reduced pressure until no solvent is evaporated, adding 1590kg of deionized water, pulping for 30min, centrifuging to obtain a crude product of 4-aminopyrrole [2,1-f ] [1,2,4] triazine, putting the crude product into 1877kg of methanol, heating to 50-55 ℃, stirring until the solid is completely dissolved, concentrating under reduced pressure to obtain a viscous feed liquid, cooling, crystallizing and centrifuging, the wet product was dried to obtain 212.9kg of a 4-aminopyrrolo [2,1-f ] [1,2,4] triazine competitive product.
The preparation method of the 7-iodopyrrolo [2,1-F ] [1,2,4] triazine-4-amine comprises the following steps:
(1) preparation of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine
Stirring and mixing triethyl orthoformate and glacial acetic acid in a reaction kettle, inserting a vent pipe below the liquid level, heating to 30 ℃, introducing ammonia gas under a protective pressure, heating to 60-90 ℃ for reaction, adding 1-aminopyrrole-2-formonitrile hydrochloride after the reaction is finished and cooling, heating to 60-65 ℃, introducing ammonia gas for heat preservation reaction, concentrating under reduced pressure after the reaction is finished until no solvent is evaporated out, adding deionized water for pulping to obtain a crude wet product, dissolving the wet product with methanol, cooling and crystallizing after concentration, and centrifuging to obtain the 4-aminopyrrolo [2,1-f ] [1,2,4] triazine refined product.
(2) Preparation of 7-iodopyrrolo [2,1-F ] [1,2,4] triazin-4-amine
Reacting 4-aminopyrrolo [2,1-f ] [1,2,4] triazine and iodine in DMF at the temperature of below-5 ℃ for 1h, controlling the temperature to be between 10 ℃ below zero and 0 ℃, and adding a solution of N-iodosuccinimide and DMF; after the addition, the reaction is continued for 1.5 h; then adding aqueous solution of sodium sulfite and sodium hydroxide, stirring, crystallizing completely, centrifuging, and drying wet product to obtain 7-iodopyrrolo [2,1-F ] [1,2,4] triazine-4-amine.
In the preparation method of the 7-iodopyrrolo [2,1-F ] [1,2,4] triazine-4-amine, the mass ratio of the 4-aminopyrrolo [2,1-F ] [1,2,4] triazine to iodine is 20: 5.6. In the solution of N-iodosuccinimide and DMF, the mass ratio of the N-iodosuccinimide to the DMF is 32: 150. in the aqueous solution of sodium sulfite and sodium hydroxide, the mass ratio of water of the sodium sulfite to the water of the sodium hydroxide is 3: 2:100.
The invention has the beneficial effects that:
1. according to the preparation method of the 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, the excessive ammonia gas in the step of preparing the formamidine acetate can provide alkaline conditions for the next reaction, and the ammonia gas is used for replacing solid alkali for reaction, so that the cost of raw materials is lower. Meanwhile, the phenomenon of solution viscosity caused by a large amount of solid materials is avoided.
2. According to the preparation method of the 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, the ethanol generated in the first step of reaction provides a solvent for the next step of cyclization reaction, so that the solvent is not required to be added in the reaction, the raw material cost is greatly reduced, the discharge of waste liquid is reduced, and the preparation method is green and environment-friendly; the problem of complicated operation is also solved.
3. The reported synthetic method needs to add formamidine acetate with the mass ratio of 3-5 times of 1-aminopyrrole-2-formonitrile hydrochloride into the system and add solid base with the mass ratio of 5-8 times of formamidine acetate into the system, so that the reaction system is very viscous and the stirring paddle of the reaction kettle is easy to be stopped. According to the preparation method of the 4-aminopyrrole [2,1-f ] [1,2,4] triazine, only one solid of 1-aminopyrrole-2-formonitrile hydrochloride reacts in the formamidine acetate ethanol solution, the reaction system is uniform, the equipment is more friendly, and the production cost of the product is reduced.
4. According to the preparation method of the 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, the formamidine acetate ethanol solution obtained in the first step is directly subjected to the next step of reaction after 1-aminopyrrole-2-carbonitrile hydrochloride is added without crystallization and purification, so that the production period is shortened; more importantly, the operation steps are reduced, and the production cost is reduced.
5. According to the preparation method of the 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, the methanol recovered in the refining step can be applied to the production of the next batch, and the industrial popularization is very facilitated.
6. According to the preparation method of the 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, the liquid phase purity is far higher than 98% reported in the current literature by 99.75%; and a foundation is laid for producing high-quality iodides or bromides in the next step, and the purity of the liquid phase of the 7-iodopyrrolo [2,1-F ] [1,2,4] triazine-4-amine produced in the next step in the embodiment reaches over 99.2% without purification, so that the quality requirement that the purity of the liquid phase of the subsequent reaction step of the Reidcisvir is more than 99% is met.
Detailed Description
The present invention will be further described with reference to specific examples so that those skilled in the art may better understand the present invention, but the present invention is not limited thereto.
Example 1:
adding 200kg of triethyl orthoformate and 74kg of glacial acetic acid into a reaction kettle, stirring and heating to 30-35 ℃, vacuumizing the reaction kettle, introducing ammonia below the liquid level, keeping the pressure under airtight condition and 0.08-0.1MPa for reaction until the system does not heat up any more, keeping the temperature at 60-70 ℃ for 2h until the raw materials disappear, introducing 55kg of ammonia gas, cooling to below 50 ℃, adding 74kg of 1-aminopyrrole-2-formonitrile hydrochloride, sealing the reaction kettle, heating to 40-50 ℃, introducing ammonia gas for temperature-keeping reaction, after the reaction is finished, concentrating under reduced pressure until no solvent is evaporated, adding 444kg of deionized water, pulping for 30min, centrifuging to obtain a crude product of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, putting the crude product into 521kg of methanol, heating to 50-55 ℃, stirring until the solid is completely dissolved, concentrating under reduced pressure until the feed liquid is viscous, cooling, crystallizing, centrifuging, and drying the wet product to obtain 52.6kg of refined 4-aminopyrrolo [2,1-f ] [1,2,4] triazine product with liquid phase purity of 99.83% and molar yield of 76.1%.
Example 2:
adding 720kg of triethyl orthoformate and 266kg of glacial acetic acid into a reaction kettle, stirring and heating to 30-35 ℃, vacuumizing the reaction kettle, introducing ammonia below the liquid level, keeping the pressure under 0.01-0.05MPa for reaction until the system is not heated any more, keeping the temperature at 80-90 ℃ for 2h until the raw materials disappear, introducing 208kg of ammonia, cooling to below 50 ℃, adding 265kg of 1-aminopyrrole-2-formonitrile hydrochloride, sealing the reaction kettle, heating to 60-65 ℃, introducing ammonia for heat preservation reaction, after the reaction is finished, concentrating under reduced pressure until no solvent is evaporated, adding 1590kg of deionized water, pulping for 30min, centrifuging to obtain a crude product of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, putting the crude product into 1877kg of methanol, heating to 50-55 ℃, stirring until the solid is completely dissolved, concentrating under reduced pressure until the feed liquid is viscous, cooling, crystallizing, centrifuging, and drying the wet product to obtain 212.9kg of refined 4-aminopyrrolo [2,1-f ] [1,2,4] triazine product with liquid phase purity of 99.75% and molar yield of 85.5%.
1539kg of recovered refined methanol is used in the next batch production.
Example 3:
adding 480kg of triethyl orthoformate and 178kg of glacial acetic acid into a reaction kettle, stirring and heating to 30-35 ℃, vacuumizing the reaction kettle, introducing ammonia below the liquid level, keeping the pressure for 0.05-0.08MPa for reaction in a gas-tight manner until the temperature of the system does not rise any more, keeping the temperature at 70-80 ℃ for 2h until the raw materials disappear, introducing 140kg of ammonia gas at the moment, cooling to below 50 ℃, adding 177kg of 1-aminopyrrole-2-formonitrile hydrochloride, sealing the reaction kettle, heating to 50-60 ℃, introducing ammonia gas for temperature-keeping reaction, after the reaction is finished, concentrating under reduced pressure until no solvent is evaporated, adding 1062kg of deionized water for pulping for 30min, centrifuging to obtain crude 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, putting the crude product into 1251kg of methanol recovered in example 2, heating to 50-55 ℃, stirring until the solid is completely dissolved, concentrating under reduced pressure until the material liquid is viscous, cooling, crystallizing, centrifuging, and drying wet product to obtain 132.5kg of refined 4-aminopyrrolo [2,1-f ] [1,2,4] triazine product with liquid phase purity of 99.89% and molar yield of 79.8%.
Example 47 preparation of iodopyrrolo [2,1-F ] [1,2,4] triazin-4-amine:
1. the reaction equation is as follows:
2. reaction operation:
adding 100kg of DMF into a clean and dry reaction kettle, adding 20kg of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine prepared in the embodiment under stirring, and cooling to below-10 ℃; 5.6kg of iodine was added and reacted at-5 ℃ for 1 hour. Controlling the temperature to be-10-0 ℃, and adding a solution of 32 kgN-iodosuccinimide and 150 kgDMF; after the addition, the reaction was continued for 1.5 h. Adding 400kg of aqueous solution of 12kg of sodium sulfite and 10kg of sodium hydroxide, stirring for crystallization, centrifuging after complete crystallization, and drying a wet product to obtain 33.7kg of off-white 7-iodopyrrolo [2,1-F ] [1,2,4] triazin-4-amine with the yield of 86.9%; the purity of the liquid phase is 99.23%.
Claims (12)
1. A preparation method of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine comprises the following steps:
s1, stirring and mixing triethyl orthoformate and glacial acetic acid in a reaction kettle, and then introducing ammonia gas for pressure maintaining reaction;
s2; after the triethyl orthoformate and ammonia react, cooling, adding 1-aminopyrrole-2-formonitrile hydrochloride to continue to introduce ammonia for heating reaction, concentrating the solvent after the reaction is finished, adding deionized water, stirring, cooling and crystallizing, centrifuging to obtain a crude product of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine, and refining to obtain a refined product of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine;
the reaction temperature in the step S1 is 60-90 ℃;
the mass ratio of the triethyl orthoformate to the ammonia gas is 1.5-5.0: 1;
the reaction pressure is 0.01-0.3 MPa.
2. The method for preparing 4-aminopyrrolo [2,1-f ] [1,2,4] triazine according to claim 1, wherein the mass ratio of triethyl orthoformate to glacial acetic acid is 2.0-5.0: 1.
3. The method for preparing 4-aminopyrrolo [2,1-f ] [1,2,4] triazine according to claim 2, wherein the mass ratio of triethyl orthoformate to glacial acetic acid is 2.5-3.0: 1.
4. The method for producing 4-aminopyrrolo [2,1-f ] [1,2,4] triazine according to claim 1, wherein the mass ratio of the triethyl orthoformate to the ammonia gas is 2.0-4.0: 1.
5. The method for preparing 4-aminopyrrolo [2,1-f ] [1,2,4] triazine according to claim 1, wherein the mass ratio of the 1-aminopyrrole-2-carbonitrile hydrochloride to triethyl orthoformate is 1: 2.0-8.0.
6. The method for preparing 4-aminopyrrolo [2,1-f ] [1,2,4] triazine according to claim 5, wherein the mass ratio of the 1-aminopyrrole-2-carbonitrile hydrochloride to triethyl orthoformate is 1: 2.6-5.0.
7. The process for preparing 4-aminopyrrolo [2,1-f ] [1,2,4] triazine according to claim 1, wherein the reaction temperature of step S2 is 30-80 ℃.
8. The process for preparing 4-aminopyrrolo [2,1-f ] [1,2,4] triazine according to claim 7, wherein the reaction temperature of step S2 is 60-70 ℃.
9. The process for the preparation of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine according to claim 1, wherein the reaction pressure is 0.02-0.1 MPa.
10. The process for producing 4-aminopyrrolo [2,1-f ] [1,2,4] triazine according to claim 1, wherein the purification solvent is one or more selected from methanol, ethanol and isopropanol, and the amount of the purification solvent is 5 to 20 times the mass of 1-aminopyrrole-2-carbonitrile hydrochloride.
11. The process according to claim 10, wherein the purification solvent is one or more selected from methanol, ethanol and isopropanol, and the amount of the purification solvent is 7 to 15 times the mass of 1-aminopyrrole-2-carbonitrile hydrochloride.
12. A process for the preparation of 4-aminopyrrolo [2,1-f ] [1,2,4] triazine according to claim 1, comprising the steps of:
stirring and mixing triethyl orthoformate and glacial acetic acid in a reaction kettle, inserting a vent pipe below the liquid level, heating to 30 ℃, introducing ammonia gas under a protective pressure, heating to 60-90 ℃ for reaction, cooling after the reaction is finished, adding 1-aminopyrrole-2-formonitrile hydrochloride, heating to 60-65 ℃, introducing ammonia gas, preserving heat for reaction, concentrating under reduced pressure until no solvent is evaporated out after the reaction is finished, adding deionized water for pulping once to obtain a crude wet product, dissolving the wet product with methanol, cooling for crystallization after concentration, and centrifuging to obtain the 4-aminopyrrolo [2,1-f ] [1,2,4] triazine refined product.
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| CN202111310962.3A CN113880846B (en) | 2020-12-31 | 2020-12-31 | Preparation method of 7-iodopyrrolo [2,1-F ] [1,2,4] triazin-4-amine |
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| JP2005126332A (en) * | 2003-10-21 | 2005-05-19 | Nippo Kagaku Kk | Method for producing formamidine acetate |
| CN111909153A (en) * | 2020-04-16 | 2020-11-10 | 山东鲁西药业有限公司 | Synthesis process of 7-iodopyrrolo [2,1-F ] [1,2,4] triazin-4-amine |
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| DE4001160A1 (en) * | 1990-01-17 | 1991-07-18 | Huels Chemische Werke Ag | Amidine carboxylic acid salts prodn. - by reacting tri:methyl ortho-carboxylate in presence of higher alcohol with ammonia or prim. amine and carboxylic acid or salt |
| CN101717351B (en) * | 2009-12-02 | 2013-01-09 | 淄博万昌科技股份有限公司 | Method for preparing formamidine acetate |
| UA119050C2 (en) * | 2013-11-11 | 2019-04-25 | Ґілеад Саєнсиз, Інк. | Pyrrolo [1,2,f] [1,2,4] triazines useful for treating respiratory syncitial virus infections |
| CN110092787B (en) * | 2018-01-31 | 2021-10-15 | 深圳铂立健医药有限公司 | Preparation and application of compound or medicinal salt or composition thereof |
| CN111423443A (en) * | 2020-04-03 | 2020-07-17 | 广州科锐特生物科技有限公司 | Preparation method of 4-amino-7-iodopyrrolo [2,1-f ] [1,2,4] triazine |
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| JP2005126332A (en) * | 2003-10-21 | 2005-05-19 | Nippo Kagaku Kk | Method for producing formamidine acetate |
| CN111909153A (en) * | 2020-04-16 | 2020-11-10 | 山东鲁西药业有限公司 | Synthesis process of 7-iodopyrrolo [2,1-F ] [1,2,4] triazin-4-amine |
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