CN112979577A - Preparation method of oxadiazole derivative - Google Patents
Preparation method of oxadiazole derivative Download PDFInfo
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- CN112979577A CN112979577A CN202011482203.0A CN202011482203A CN112979577A CN 112979577 A CN112979577 A CN 112979577A CN 202011482203 A CN202011482203 A CN 202011482203A CN 112979577 A CN112979577 A CN 112979577A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
Abstract
The invention discloses a preparation method of an oxadiazole ring compound, which comprises the following steps: taking a compound I as a raw material, reacting with a compound II under an alkaline condition to obtain a compound III, deprotecting the compound III under an acidic condition to generate a compound IV, reacting the compound IV with N, N-di-tert-butoxycarbonyl-1H-formamidine to generate a compound V, and deprotecting the compound V under an acidic condition to generate an oxadiazole ring target compound. The method has the advantages of low impurity content, simple operation, mild conditions, low cost, high yield and the like, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of an oxadiazole derivative.
Background
Scientists have long desired to use the patient's own strong immune system to fight cancer, and recent success of cancer immunotherapy with CTLA-4 antibodies, PD-1/PD-L1 antibodies, and recently approved CARs-T has also demonstrated the feasibility of this approach. Cancer immunotherapy has also been the first of ten years of scientific breakthroughs in the journal of Science in 2013. The IDO inhibitor appears in the wave tide, and data prove that the IDO inhibitor can obviously improve the curative effect of PD-1/PD-L1, and the development heat of the IDO inhibitor reaches the climax due to the good performance of the PD-1/PD-L1 antibody in the aspect of immunotherapy.
Indoleamine 2, 3-dioxygenase (IDO) is an iron-containing heme monomeric protease which is secreted mainly by placental trophoblasts and peripheral blood mononuclear/macrophages, is widely distributed in tissues other than liver, such as lung, small and large intestine, rectum, spleen and kidney, stomach and brain, etc., of humans and other mammals, and is the only rate-limiting enzyme other than liver which catalyzes the catabolism of tryptophan along the canine uric acid pathway [ Hayaishi O.et al, Proceedings of the ten FEBS meetings, 1975,131-144 ]. In one aspect, IDO converts L-tryptophan to N-formylkynurenine, degrading tryptophan levels to create a local L-tryptophan deficiency, thereby inhibiting T cell proliferation, resulting in tumorigenesis. Studies have demonstrated a significant enhancement of IDO expression in tumor tissues of various solid tumors such as lung, liver, breast, colon, etc. [ Nat Med, 2003, 9 (10): 1269-1274]. On the other hand, the kynurenine pathway can lead to increase of the excitotoxin quinolinic acid, induce T cell apoptosis, and also lead to a plurality of serious human diseases such as nervous system diseases such as Alzheimer [ Guillemia G.J.et al, Neurophathol. and appl. Neurobiol.2005,31,395-404 ]. IDO inhibitors may be useful in the treatment of diseases with pathological features of IDO-mediated tryptophan metabolic pathways, such as cancer, alzheimer's disease, mood disorders [1, CN 103070868; 2 Dan Yu et al, Journal of Alzheimer's Disease,2015,291-302], has received increasing attention as an important drug.
In 2009, Incyte firstly obtained a series of N-hydroxyamidine derivatives (structural formula shown below) through High Throughput Screening (HTS), which can competitively inhibit the metabolic process of IDO catalytic tryptophan. In the middle position, the meta-substituted and 3, 4-disubstituted compounds on the benzene ring have higher activity. The oxygen atom on the hydroxyamidine can bind to the heme ferrous of IDO1, while the amino substituent on the oxadiazole ring can form a hydrogen bond with the propionic acid group of the heme ring. Therefore, the compound with the structure has wide application prospect in treating diseases with IDO mediated tryptophan metabolic pathway. Incyte modified the 4-amino group on the oxadiazole ring and issued a related patent in the United states (US8450351B 2). In 2010, Incyte further extended the length of the side chain, thereby obtaining an inhibitor that showed excellent IDO inhibitory effect in the nanomolar range, which includes epacadostat. The Epacadostat binds in a similar manner to the unmodified compound, except that the side chain extending from the oxadiazole ring forms a hydrophobic interaction with Pocket B. U.S. patent application to Incyte has been filed and granted (US8088803B 2). In addition, there are also many patents relating to IDO inhibitors, such as WO2006122150, WO2007075598, WO2012142237, WO2016041489 and WO20161555545, but these published IDO inhibitors do not relate to their specific preparation process routes.
Therefore, the invention discloses a specific preparation process route of the IDO inhibitor.
The invention content is as follows:
the invention aims to overcome the defects of the prior art and provides a preparation method of an oxadiazole derivative. The structural formula of the oxadiazole derivative is shown as follows:
the preparation method specifically comprises the following steps:
(1) and I and II react under the alkaline condition by heating to generate III:
wherein the alkali used in the step (1) is selected from NaOH, KOH, LiOH and C2H5ONa, lithium diisopropylamide, hexamethylphosphoric triamide and Na2CO3、K2CO3One or more of N, N-isopropyl ethylamine, ethylenediamine, triethylamine, ethanolamine and alkali formed by tert-butyl, isopropyl, isobutyl and sodium or potassium; preferably tBuOK, tBuONa, iBuOK, iBuONa, iPrOK, iPrONa, C2H5One or more of ONa, lithium diisopropylamide and hexamethylphosphoric triamide; tBuOK, tBuONa, iBuOK, iBuONa, iPrOK and iPrONa are preferred.
The solvent used in the step (1) is one or more of DMF, THF, acetonitrile, dichloromethane, chloroform, ethyl acetate, dioxane, methanol, ethanol, isopropanol, isobutanol, sec-butanol, tert-butanol and n-butanol; two mixed solvents of ethanol, isopropanol, isobutanol, sec-butanol, tert-butanol and THF are preferred. Preferably, the solvent used is a mixed solvent of isopropanol, isobutanol, sec-butanol or tert-butanol and THF.
The reaction temperature in the step (1) is more than 30 ℃; preferably, the reaction temperature in the step (1) is 40-the reflux temperature of the solvent; further, the temperature is preferably 60 ℃ or higher.
(2) And deprotecting III under acidic condition to obtain IV.
Specifically, the solvent used in step (2) is one or more of DMF, DMSO, acetonitrile, THF, dichloromethane, chloroform, ethyl acetate, dioxane, methanol, ethanol, isopropanol, isobutanol, sec-butanol, tert-butanol, and n-butanol, preferably dichloromethane and chloroform.
The acid used in the step (2) is one or more of hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid, and preferably at least one of trifluoroacetic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid.
(3) IV reacts with N, N' -di-tert-butoxycarbonyl-1H-pyrazole-1-formamidine to obtain V:
the alkali used in the step (3) is NaOH, KOH, LiOH, tBuOK, C2H5ONa、LDA、HMPA、Na2CO3、K2CO3One or more of DIPEA, ethylenediamine, triethylamine and ethanolamine; preferably at least one of LDA, HMPA and DIPEA.
The solvent used in the step (3) is one or more of DMF, DMSO, acetonitrile, THF, dichloromethane, chloroform, ethyl acetate, dioxane, methanol, ethanol, isopropanol, isobutanol, sec-butanol, tert-butanol and n-butanol.
(4) Deprotection of V under acidic conditions gives oxadiazole derivatives, i.e. vi:
the solvent and acid used in step (4) are the same as in step (2).
The reactants of the present invention are used in amounts similar to the ratio of the amounts of the materials in the reaction equation, in some cases, the amount of material II is greater than or equal to that of material I; IV is used in an amount greater than or equal to that of N, N' -di-tert-butoxycarbonyl-1H-pyrazole-1-carboxamidine; the dosage of the alkali in the step (1) is 0.01-1 time (the dosage of the substance is multiple) of that of the I; the dosage of the acid in the step (2) is 0.01-1 time (the dosage of the substance is multiple) of the dosage of the I; the dosage of the alkali in the step (3) is 0.01-1 time (the dosage of the substance is multiple) of that of the I; the dosage of the acid in the step (4) is 0.01-1 time (the dosage of the substance is multiple) of that of the I; the total volume of the solvent used is conventional. Wherein, in the mixed solution with THF, the amount of THF is 5-50% of the total solvent volume. The reaction temperature, not specified, is room temperature.
The prior art generally adopts
Reacting with N- (tert-butyloxycarbonyl) ethanolamine, deprotecting, and ring-opening reaction to obtain targetAnd (3) an intermediate. The method has the advantages of more steps, low total yield, high byproduct, and difficult removal of some byproducts, such as byproducts with 1,2, 4-oxadiazole, in subsequent reactions. HPLC detection results show that the preparation method disclosed by the invention can effectively avoid the ring opening of the intermediate product 1,2, 5-oxadiazole or/and the generation of the new 1,2, 4-oxadiazole, such as avoiding the generation
The preparation method of the intermediate IV disclosed by the invention has higher yield, the corresponding yield in the prior art is generally not more than 40 percent and generally not more than 30 percent, and the yield obtained by the technical scheme is more than 70 percent.
The preparation method of VI disclosed by the invention has the advantages of short time, high efficiency, simple operation, mild conditions, low cost and the like, and is suitable for industrial production.
Detailed Description
The advantageous effects of the present invention will now be further described by the following examples, which should be understood as being for illustrative purposes only and not limiting the scope of the present invention, and that changes and modifications apparent to those of ordinary skill in the art in light of the present invention are also included within the scope of the present invention.
Example 1
Weighing 12.6g of compound I, 15.1g of compound II and 5.8g of KOH in sequence, adding the mixture into a three-neck flask, weighing 200ml of ethanol and 20ml of THF, adding the mixture into the system, starting stirring to heat the system to 62 ℃, enabling the solution to be gradually transparent, continuing stirring for reaction for 1h, removing the solvent by rotary evaporation, adding 30ml of water and 30ml of ethyl acetate into the system, standing for liquid separation, extracting the water phase with ethyl acetate once again, combining the organic phases, washing the organic phases with saturated salt water once, separating, adding a proper amount of anhydrous Na into the organic phases2SO4And (5) drying. The organic phase was concentrated under reduced pressure to give a brownish red viscous material.
Dissolving the brown red viscous substance with 200ml dichloromethane, adding 52ml TFA into the system, stirring at room temperature, detecting by TLC until the material point disappears, stopping reaction, and adding saturated NaHCO3Quenching the solution, and adding the systemExtracting with ethyl acetate, washing the organic phase with saturated saline once, adding appropriate amount of Na2SO4And (5) drying. The organic phase was concentrated under reduced pressure and purified by column chromatography to give a coffee-colored solid product IV of 10.1g with a yield of 71%.
Example 2
Weighing 12.6g of compound I, 15.1g of compound II and 8.8g of EtOK in sequence, adding the compound I, the compound II and the compound II into a three-neck flask, weighing 220mL of ethanol, adding the ethanol into the system, starting stirring to heat the system to 76 ℃, keeping the temperature, stirring for 1 hour, stopping reaction, concentrating under reduced pressure, evaporating to remove the solvent, adding 30mL of water and 40mL of ethyl acetate into the system, fully mixing, standing, separating, extracting the water phase with ethyl acetate once, combining the organic phases, washing with saturated salt water once, adding a proper amount of anhydrous Na into the organic phases2SO4And (5) drying. Concentrating the organic phase under reduced pressure to obtain brownish red viscous substance.
Dissolving the brown red viscous substance with 200ml dichloromethane, adding 52ml TFA into the system, stirring at room temperature, detecting by TLC until the material point disappears, stopping reaction, and adding saturated NaHCO3Quenching the solution, extracting the system with ethyl acetate, washing the organic phase with saturated salt solution, adding Na, and filtering to obtain filtrate2SO4And (5) drying. The organic phase was concentrated under reduced pressure and purified by column chromatography to give a coffee-colored solid product IV of 10.3g in a yield of 72%.
Example 3
Weighing 12.6g of compound I, 15.1g of compound II and 7.1g of EtONa in sequence, adding the compound I, the compound II and the compound II into a three-neck flask, weighing a mixed solution of 120mL of ethanol and 100mL of isopropanol, adding the mixed solution into the system, starting stirring to heat the system to 60 ℃, keeping the temperature and stirring for 1h, stopping reaction, concentrating under reduced pressure, evaporating to remove the solvent, adding 30mL of water and 40mL of ethyl acetate into the system, fully mixing, standing for liquid separation, extracting the water phase with ethyl acetate once again, combining the organic phases, washing with saturated salt water once, adding a proper amount of anhydrous Na into the organic phase, and adding a proper amount of anhydrous Na into2SO4And (5) drying. Concentrating the organic phase under reduced pressure to obtain brownish red viscous substance.
The brownish red dope obtained in the above step was dissolved in 200ml of dichloromethane, and the mixture was poured into a systemAdding 52ml TFA, stirring at room temperature, detecting by TLC until the material point disappears, stopping reaction, and adding saturated NaHCO3Quenching the solution, extracting the system with ethyl acetate, washing the organic phase with saturated salt solution, adding Na, and filtering to obtain filtrate2SO4And (5) drying. The organic phase was concentrated under reduced pressure and purified by column chromatography to give a coffee-colored solid product IV of 10.1g in a yield of 70.5%.
Example 4
Weighing 12.6g of compound I, 15.1g of compound II and 10.2g of potassium isopropoxide in sequence, adding the compound I, the compound II and the potassium isopropoxide into a three-neck flask, weighing 220mL of isopropanol, adding the isopropanol into the system, starting stirring to heat the system to 70 ℃, keeping the system pasty, continuously stirring for reacting for 40 minutes, stopping reaction, concentrating under reduced pressure, evaporating to remove a solvent, adding 30mL of water and 40mL of ethyl acetate into the system, fully and uniformly mixing, standing, separating, extracting the water phase with ethyl acetate once again, combining the organic phases, washing with saturated salt water once, adding a proper amount of anhydrous Na into the organic phases2SO4And (5) drying. The organic phase was concentrated under reduced pressure to give a brownish red viscous material.
Dissolving the brown red viscous substance with 200ml dichloromethane, adding 52ml TFA into the system, stirring at room temperature, detecting by TLC until the material point disappears, stopping reaction, and adding saturated NaHCO3Quenching the solution, extracting the system with ethyl acetate, washing the organic phase with saturated salt solution, adding Na, and filtering to obtain filtrate2SO4And (5) drying. The organic phase was concentrated under reduced pressure and purified by column chromatography to give a coffee-colored solid product IV of 10.3g in a yield of 72%.
Example 5
Weighing 12.6g of compound I, 15.1g of compound II and 8.5g of potassium isopropoxide in sequence, adding the compound I, the compound II and the potassium isopropoxide into a three-neck flask, weighing 220mL of isopropanol, adding the isopropanol into the system, starting stirring to heat the system to 62 ℃, keeping the system pasty, continuously stirring for reaction for 0.5h, stopping reaction, reducing pressure, concentrating, evaporating to remove the solvent, adding 30mL of water and 40mL of ethyl acetate into the system, fully and uniformly mixing, standing, separating, extracting the water phase once again with ethyl acetate, combining the organic phases, washing with saturated salt water, adding a proper amount of anhydrous Na into the organic phase2SO4And (5) drying. The organic phase was concentrated under reduced pressure to give a brownish red viscous material.
Dissolving the brown red viscous substance with 200ml dichloromethane, adding 52ml TFA into the system, stirring at room temperature, detecting by TLC until the material point disappears, stopping reaction, and adding saturated NaHCO3Quenching the solution, extracting the system with ethyl acetate, washing the organic phase with saturated salt solution, adding Na, and filtering to obtain filtrate2SO4And (5) drying. The organic phase was concentrated under reduced pressure and purified by column chromatography to give a solid product IV of coffee color 10.5g with a yield of 73%.
Example 6
Weighing 12.6g of compound I, 15.12g of compound II and 10.0g of sodium isobutanolate in sequence, adding the mixture into a three-neck flask, weighing 220ml of isobutanol, adding the isobutanol into the system, starting stirring to heat the system to reflux, keeping the system pasty, continuously stirring for reacting for 40 minutes, removing the solvent by rotary evaporation, adding 30ml of water and 30ml of ethyl acetate into the system, standing for liquid separation, extracting the water phase with ethyl acetate once again, combining the organic phases, washing the organic phases with saturated salt water once, separating, and adding a proper amount of anhydrous Na into the organic phases2SO4And (5) drying. The organic phase was concentrated under reduced pressure to give a brownish red viscous material.
Dissolving the brown red viscous substance with 200ml dichloromethane, adding 52ml TFA into the system, stirring at room temperature, detecting by TLC until the material point disappears, stopping reaction, and adding saturated NaHCO3Quenching the solution, extracting the system with ethyl acetate, washing the organic phase with saturated salt solution, adding Na, and filtering to obtain filtrate2SO4And (5) drying. The organic phase was concentrated under reduced pressure and purified by column chromatography to give a coffee-colored solid product IV of 10.3g in a yield of 72%.
Example 7
Weighing 12.6g of compound I, 15.12g of compound II and 12.1g of potassium isobutyl alcohol in sequence, adding the compound I, 15.12g of compound II and 12.1g of potassium isobutyl alcohol into a three-neck flask, weighing 220ml of isobutyl alcohol, adding the isobutyl alcohol into the system, starting stirring to heat the system to reflux, keeping the system pasty, continuously stirring for reaction for 1.0h, removing the solvent by rotary evaporation, adding 30ml of water and 30ml of ethyl acetate into the system, standing for liquid separation, extracting the water phase once again by using ethyl acetate, combining the organic phases, washing the organic phases once by using saturated salt water, separating, and adding a proper amount of anhydrous Na into the2SO4And (5) drying. The organic phase was concentrated under reduced pressure to give a brownish red viscous material.
Dissolving the brown red viscous substance with 200ml dichloromethane, adding 52ml TFA into the system, stirring at room temperature, detecting by TLC until the material point disappears, stopping reaction, and adding saturated NaHCO3Quenching the solution, extracting the system with ethyl acetate, washing the organic phase with saturated salt solution, adding Na, and filtering to obtain filtrate2SO4And (5) drying. The organic phase was concentrated under reduced pressure and purified by column chromatography to give a solid product IV of coffee color 10.5g with a yield of 73%.
Example 8
Weighing 12.6g of compound I, 15.12g of compound II and 10.0g of sodium tert-butoxide in turn, adding the mixture into a three-neck flask, weighing 200ml of isobutanol and 20ml of THF, adding the isobutanol and the THF into the system, starting stirring to ensure that the system is heated to 50 ℃, enabling the solution to be gradually transparent, continuing stirring to react for 0.5h, removing the solvent by rotary evaporation, adding 30ml of water and 30ml of ethyl acetate into the system, standing for liquid separation, extracting the water phase once again by using ethyl acetate, combining the organic phases, washing the organic phases by using saturated salt water, separating, adding a proper amount of anhydrous Na into the organic phase2SO4And (5) drying. The organic phase was concentrated under reduced pressure to give a brownish red viscous material.
Dissolving the brown red viscous substance with 200ml dichloromethane, adding 52ml TFA into the system, stirring at room temperature, detecting by TLC until the material point disappears, stopping reaction, and adding saturated NaHCO3Quenching the solution, extracting the system with ethyl acetate, washing the organic phase with saturated salt solution, adding Na, and filtering to obtain filtrate2SO4And (5) drying. The organic phase was concentrated under reduced pressure and purified by column chromatography to give 11.0g of a coffee-colored solid product with a yield of 77%.
Example 9
Weighing 12.6g of compound I, 15.12g of compound II and 11.7g of potassium tert-butoxide in turn, adding the mixture into a three-neck flask, weighing 100ml of isobutanol, 100ml of tert-butanol and 20ml of THF, adding the mixture into the system, starting stirring to heat the system for refluxing, allowing the solution to be gradually transparent, continuing stirring for reaction for 0.5h, removing the solvent by rotary evaporation, adding 30ml of water and 30ml of ethyl acetate into the system, standing for liquid separation, and using ethyl acetate for the aqueous phaseExtracting again, mixing organic phases, washing with saturated salt water, separating, adding appropriate amount of anhydrous Na2SO4And (5) drying. The organic phase was concentrated under reduced pressure to give a brownish red viscous material.
Dissolving the brown red viscous substance with 200ml dichloromethane, adding 52ml TFA into the system, stirring at room temperature, detecting by TLC until the material point disappears, stopping reaction, and adding saturated NaHCO3Quenching the solution, extracting the system with ethyl acetate, washing the organic phase with saturated salt solution, adding Na, and filtering to obtain filtrate2SO4And (5) drying. The organic phase was concentrated under reduced pressure and purified by column chromatography to give 11.7g of a coffee-colored solid product with a yield of 82%.
Example 10
Weighing 12.6g of compound I, 15.12g of compound II and 12.1g of potassium iso-butoxide in turn, adding the compound I, 15.12g of compound II and 12.1g of potassium iso-butoxide into a three-neck flask, weighing 200ml of iso-butoxide and 20ml of THF, adding the mixture into the system, starting stirring to heat the system to reflux, gradually enabling the solution to be transparent, continuing stirring to react for 0.5h, removing the solvent by rotary evaporation, adding 30ml of water and 30ml of ethyl acetate into the system, standing for liquid separation, extracting the water phase once again by using ethyl acetate, combining the organic phases, washing the organic phases once by using saturated salt water, separating, adding a proper amount of2SO4And (5) drying. The organic phase was concentrated under reduced pressure to give a brownish red viscous material.
Dissolving the brown red viscous substance with 200ml dichloromethane, adding 52ml TFA into the system, stirring at room temperature, detecting by TLC until the material point disappears, stopping reaction, and adding saturated NaHCO3Quenching the solution, extracting the system with ethyl acetate, washing the organic phase with saturated salt solution, adding Na, and filtering to obtain filtrate2SO4And (5) drying. The organic phase was concentrated under reduced pressure and purified by column chromatography to give a coffee solid product IV of 10.7g in 75% yield.
Example 11 preparation of compound of formula v:
adding 11.2g of the compound IV, 31.3ml of dichloromethane and 15.6ml of THF into a three-necked flask in sequence, stirring at room temperature to dissolve the compound IV, the dichloromethane and the THF, weighing 9.7g N, N' -di-tert-butoxycarbonyl-1H-pyrazole-1-formamidine, dissolving the weighed compound IV in 31.3ml of dichloromethane to obtain a colorless transparent solution, and mixing the colorless transparent solution with the dichloromethane to obtain a solutionAdding the solution into the reaction system, adding 6.6g DIPEA into the system, stirring at room temperature for reaction, detecting by TLC that the raw material disappears, stopping the reaction, adjusting the system to neutral, adding appropriate amount of ethyl acetate, mixing, standing, separating, washing with organic phase saturated salt water, and adding appropriate amount of anhydrous Na2SO4Drying, and concentrating the organic phase under reduced pressure to obtain white solid 17.6g with yield 93.7%.
Preparation of the compound of example 12 formula vi:
stirring and dissolving 17.6g of the compound V by 180ml of dichloromethane at room temperature to obtain a wine red clear solution, adding 44ml of TFA into the system, deepening the color of the system, continuously stirring and reacting at room temperature, stopping the reaction after TLC detects that the compound V basically disappears, directly concentrating the system under reduced pressure, dissolving the concentrated solution by using a proper amount of toluene, and continuously concentrating the concentrated solution under reduced pressure to dry to obtain a white-like solid 10.9g with the yield of 93.2%.
Claims (10)
1. A method for preparing oxadiazole derivative shown as VI is characterized by comprising the following steps:
(1) and I and II react under the alkaline condition by heating to generate III:
wherein the alkali in the step (1) is selected from NaOH, KOH, LiOH and C2H5ONa, lithium diisopropylamide, hexamethylphosphoric triamide and Na2CO3、K2CO3One or more of N, N-isopropyl ethylamine, ethylenediamine, triethylamine, ethanolamine and alkali formed by tert-butyl, isopropyl, isobutyl and sodium or potassium;
the solvent used in the step (1) is one or more of DMF, THF, dichloromethane, chloroform, ethyl acetate, dioxane, methanol, ethanol, isopropanol, isobutanol, sec-butanol, tert-butanol and n-butanol;
the reaction temperature in the step (1) is more than 30 ℃;
(2) deprotection of III under acidic conditions gives IV:
the solvent used in the step (2) is one or more of DMF, DMSO, acetonitrile, THF, dichloromethane, chloroform, ethyl acetate, dioxane, methanol, ethanol, isopropanol, isobutanol, sec-butanol, tert-butanol and n-butanol;
the acid used in the step (2) is one or more of hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid;
(3) IV reacts with N, N' -di-tert-butoxycarbonyl-1H-pyrazole-1-formamidine to obtain V:
the alkali used in the step (3) is NaOH, KOH, LiOH, tBuOK, C2H5ONa、LDA、HMPA、Na2CO3、K2CO3One or more of DIPEA, ethylenediamine, triethylamine and ethanolamine; the solvent used in the step (3) is one or more of DMF, DMSO, acetonitrile, THF, dichloromethane, chloroform, ethyl acetate, dioxane, methanol, ethanol, tert-butanol and n-butanol;
(4) deprotection of V under acidic conditions gives vi:
the solvent and acid used in step (4) are the same as in step (2).
2. The method according to claim 1, wherein the base in the step (1) is selected from the group consisting of tBuOK, tBuONa, iBuOK, iBuONa, iPrOK, iPrONa, and C2H5One or more of ONa, LDA and HMPASeveral kinds of them.
3. The method according to claim 2, wherein the base in step (1) is one or more selected from tBuOK, tBuONa, iBuOK, iBuONa, iPrOK and iPrONa.
4. The process according to claim 3, wherein the solvent used in the step (1) is a mixed solvent of two selected from the group consisting of ethanol, isopropanol, isobutanol, sec-butanol, tert-butanol and THF.
5. The process according to claim 4, wherein the solvent used in step (1) is a mixed solvent of isopropanol, isobutanol, sec-butanol or tert-butanol with THF.
6. The method according to claim 5, wherein the reaction temperature in the step (1) is from 40 ℃ to the reflux temperature of the solvent.
7. The method of claim 6, wherein the base in step (3) is at least one of LDA, HMPA and DIPEA.
8. The process according to any one of claims 1 to 7, wherein the solvent used in step (2) is one or more selected from dichloromethane, chloroform and n-butanol.
9. The method according to claim 8, wherein the acid in the step (2) is at least one of trifluoroacetic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid.
10. The method according to claim 8, wherein the solvent in the step (4) is at least one selected from the group consisting of ethanol, t-butanol, n-butanol and THF.
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