CN110845502A - Preparation method of 7-bromopyrrolo [2,1-f ] [1,2,4] thiazine-4-amine - Google Patents
Preparation method of 7-bromopyrrolo [2,1-f ] [1,2,4] thiazine-4-amine 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 7-bromopyrrolo [2,1-f ] [1,2,4] thiazine-4-amine, which comprises the following steps: 1) taking tert-butyl carbazate and 2, 5-dimethoxy tetrahydrofuran as raw materials to synthesize an intermediate I, namely 1-Boc-1-aminopyrrole; 2) reacting the intermediate I with methanesulfonic acid isocyanate to synthesize an intermediate II, namely 1-Boc-1-amino- (9ci) -1H-pyrrole-2-carbonitrile; 3) deaminating the intermediate II under acidic conditions to obtain an intermediate III, namely 1-amino- (9ci) -1H-pyrrole-2-carbonitrile hydrochloride; 4) enabling the intermediate III and formamidine acetate to perform ring closure reaction to obtain an intermediate IV, namely 4-aminopyrrolo [2,1-f ] [1,2,4] triazine; 5) and (3) reacting the intermediate IV with a brominating reagent to obtain a final product, namely 7-bromopyrrolo [2,1-f ] [1,2,4] thiazin-4-amine. The preparation method has the advantages of cheap and easily-obtained raw materials, few reaction steps and high yield. The reaction condition is mild, and large-scale production can be realized.
Description
Technical Field
The invention relates to the technical field of chemical synthetic drugs, in particular to a preparation method of 7-bromopyrrolo [2,1-f ] [1,2,4] thiazine-4-amine.
Background
Feline Infectious Peritonitis (FIP) is one of the chronic viral infections of cats, and GS-441524 is a second targeted antiviral drug to treat FIP following GC 376. Experiments showed that GS-441524 was more potent than GC376 for naturally occurring FIP. GS-441524 is a nucleoside drug in the experimental stage, has the inhibiting effect on various RNA viruses, has the synthesis difficulty not lower than that of GC376, but has the dosage far lower than that of GC376, and is more surprising in that the compound can pass through the blood brain barrier, namely has the control effect on the case with neurological symptoms, 3C protease inhibitor, nucleoside and MS-02 (preventing viruses from adsorbing target cells) are simultaneously used in the future, and the FIP is certainly overcome when the compounds with different mechanisms are simultaneously used.
The existing preparation method of 7-bromopyrrolo [2,1-f ] [1,2,4] thiazine-4-amine is expensive in raw material, more in intermediate by-product, extremely high in finished product yield, relatively harsh in reaction condition and incapable of realizing large-scale production, so that the price of GS-441524 is expensive, and the FIP research process is severely restricted.
Disclosure of Invention
The invention aims to provide a method for preparing 7-bromopyrrolo [2,1-f ] [1,2,4] thiazin-4-amine with high yield, few intermediate byproducts and high efficiency on a large scale.
The invention provides a preparation method of 7-bromopyrrolo [2,1-f ] [1,2,4] thiazine-4-amine, which comprises the following specific synthetic route:
the specific synthetic route is as follows:
(1) taking tert-butyl carbazate and 2, 5-dimethoxy tetrahydrofuran as raw materials to synthesize an intermediate I, namely 1-Boc-1-aminopyrrole;
(2) reacting the intermediate I with methanesulfonic acid isocyanate to synthesize an intermediate II, namely 1-Boc-1-amino- (9ci) -1H-pyrrole-2-carbonitrile;
(3) deaminating the intermediate II under acidic conditions to obtain an intermediate III, namely 1-amino- (9ci) -1H-pyrrole-2-carbonitrile hydrochloride;
(4) enabling the intermediate III and formamidine acetate to perform ring closure reaction to obtain an intermediate IV, namely 4-aminopyrrolo [2,1-f ] [1,2,4] triazine;
(5) and (3) reacting the intermediate IV with a brominating reagent to obtain a final product, namely 7-bromopyrrolo [2,1-f ] [1,2,4] thiazin-4-amine.
Compared with the prior art, the invention has the following advantages and beneficial effects:
the invention provides a novel synthesis method of 7-bromopyrrolo [2,1-f ] [1,2,4] thiazine-4-amine, which is characterized in that synthesis raw materials used in the method are easy to obtain, and intermediate byproducts generated in the preparation method are few, so that the yield and purity of a finished product are extremely high, a complex purification process is not required subsequently, the reaction conditions in the preparation process are mild, complex and expensive synthesis equipment is not required, the method is suitable for industrial large-scale production, the synthesis cost of the 7-bromopyrrolo [2,1-f ] [1,2,4] thiazine-4-amine can be greatly reduced, the price of GS-441524 is reduced, and the development of FIP research is promoted.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto, and various substitutions and alterations can be made without departing from the technical idea of the present invention as described above, according to the common technical knowledge and the conventional means in the field.
The present invention will be described in further detail with reference to the following examples for the purpose of making clear the objects, process conditions and advantages of the present invention, which are given by way of illustration only and are not intended to be limiting of the present invention.
Example 1:
in the embodiment, tert-butyl carbazate and 2, 5-dimethoxy tetrahydrofuran are used as raw materials to synthesize an intermediate I, namely 1-Boc-1-aminopyrrole.
The specific synthetic route is as follows:
the specific synthesis method comprises the following steps:
1000g of tert-butyl carbazate (7.6mol, 1.0eq), 1100g of 2, 5-dimethoxytetrahydrofuran (8.3nol, 1.09eq) and 8L of solvent were put in a 20L three-necked flask, and after stirring uniformly, 100mL of 2N hydrochloric acid was slowly added, and the temperature was slowly raised to 90 ℃ to react for 10 hours. And (4) monitoring the reaction, stopping heating after the raw materials are reacted, cooling to 20 ℃, adding 16L of water, and stirring to separate out a solid. Suction filtering, washing the filter cake with water, and dissolving with dichloromethane; washing the dichloromethane phase with saturated salt water, performing suction filtration through a silica gel column, decompressing, concentrating and drying the filtrate, and pulping with petroleum ether to obtain 960g of colorless crystals, namely the intermediate I (1-Boc-1-aminopyrrole).
The purity of this intermediate I was 96% with a yield of 70%.
It is composed of1The H NMR data are as follows:
1H NMR(300MHz,DMSO-d6)δppm 10.27(br.s,1H),6.69(t,2H,J＝4.4Hz),5.96(t,2H,J＝4.4Hz),1.42(s,9H),UPLC/MS(3min)retention time 1.42min.LRMS:m/z 183(M+1).
the solvent used is one of N-methylpyrrolidone, N-dimethylformamide, 1, 4-dioxane and tetrahydrofuran, in this embodiment, 1, 4-dioxane is preferably used as the solvent, and the other solvents can be selected, and the specific amount of the solvent is the same as that of 1, 4-dioxane, which does not affect the generation of the reaction product.
The progress of the reaction was monitored by TLC using a mixture of polyethylene and ethyl acrylate as the developing solvent in a molar ratio of 3: 1.
Example 2:
this example reacted intermediate I, prepared in the above example, with methanesulfonic acid isocyanate to synthesize intermediate II, 1-Boc-1-amino- (9ci) -1H-pyrrole-2-carbonitrile.
The specific synthetic route is as follows:
the specific synthesis method comprises the following steps:
under the protection of inert gas, 1000g of intermediate I (5.49mol,1.0eq) and 10L of anhydrous acetonitrile are added into a 20L three-necked bottle, fully stirred and cooled to 0 ℃, 500 ml of chlorosulfonyl isocyanate (5.77mol,1.05eq) is slowly dropped, the internal temperature is kept lower than 5 ℃, and the generation of white suspension can be observed within about 20 min. After 30min, 1L of anhydrous DMF was added and the reaction solution became clear. The reaction was maintained at 0 ℃ for 30 min. After the reaction is finished, pouring the reaction liquid into a mixed liquid of ice water and ethyl acetate, and stirring and separating the liquid; the organic phase was washed with saturated sodium bicarbonate solution and brine in sequence, then dried over anhydrous sodium sulfate, separated and concentrated to obtain 980g of a white solid, i.e., intermediate II (1-Boc-1-amino- (9ci) -1H-pyrrole-2-carbonitrile).
The purity of this intermediate II was 97% and the yield was 87%.
It is composed of1The H NMR data are as follows:
1H NMR(CD3OD):δ7.01(dd,IH,J＝3.0,1.6Hz),6.82(dd,IH,J＝4.4,1.7Hz),6.19(dd,IH,/＝4.2,2.9Hz),4.88(s,IH,H2ONH-),1.50(br s,9H,HN-BOC)；MS:LC/MS(+esi),m/z＝207.9[M+H].
wherein, in the mixed liquid of ice water and ethyl acetate, the molar ratio of the ice water to the ethyl acetate is 1: 1; the inert gas used for protection is preferably nitrogen, and other inert gases can be selected, such as argon or helium. The progress of the reaction was monitored by TLC using a mixture of polyethylene and ethyl acrylate as the developing solvent in a molar ratio of 3: 1.
Example 3:
this example deaminated intermediate II prepared in the above example under acidic conditions to give intermediate III, 1-amino- (9ci) -1H-pyrrole-2-carbonitrile hydrochloride.
The specific reaction route is as follows:
the preparation method comprises the following steps:
adding 1000g of compound II (4.83mol,1.0eq) and 3L of anhydrous ethyl acetate into a 20L three-necked bottle, stirring for dissolving, and cooling to 0 ℃ to obtain a reaction solution for later use; 5L of ethyl acetate solution with the concentration of 1mol/L is prepared by taking acid as solute and ethyl acetate as solvent, and the ethyl acetate solution is completely added into the prepared reaction liquid. The reaction was maintained at 0 ℃ and a large amount of white solid was observed to be produced for 30 min. After TLC monitoring reaction, suction filtration, washing residue with anhydrous ethyl acetate, and vacuum drying to obtain 680g white solid, namely intermediate III (1-amino- (9ci) -1H-pyrrole-2-formonitrile hydrochloride).
The purity of this intermediate III was 99% and the yield 97%.
It is composed of1The H NMR data are as follows:
1H-NMR(CD3OD):87.05(dd,1H,J＝2.8,1.9Hz),6.75(dd,1H,J＝1.8,4.2Hz),6.13(d d,1H,J＝2.8,4.4Hz),5.08(s,3H,NH3 +)；MS:GC/MS,m/z＝108.2[M+H].
the reaction progress is monitored by TLC, the developing agent used for monitoring the reaction is a mixed solution of polyethylene and ethyl acrylate, and the molar ratio of the polyethylene to the ethyl acrylate is 3: 1. The acid in the ethyl acetate solution with the concentration of 1mol/l is gaseous hydrogen chloride, one of trifluoroacetic acid and hydrochloric acid, the preferred acid in this embodiment is gaseous hydrogen chloride, and the other acids can be selected, and the specific dosage is the same as that of the gaseous hydrogen chloride, so that the generation of the reaction product is not affected.
Example 4:
in this example, intermediate III prepared in the above example and formamidine acetate undergo a ring closure reaction to obtain intermediate IV, i.e., 4-aminopyrrolo [2,1-f ] [1,2,4] triazine.
The specific synthetic route is as follows:
the preparation method comprises the following steps:
1000g of intermediate III (6.97mol, 1.0eq), 3630g of formamidine acetate (34.84mol, 5.0eq) and 15L of solvent are added into a 20L three-necked bottle under the protection of inert gas, stirred uniformly, added with 1925g of anhydrous potassium carbonate (2.0eq) and heated to 78 ℃ for reaction for 15 h. Monitoring the reaction progress, cooling and filtering after the reaction is finished. The filtrate was concentrated in vacuo to give a solid residue, which was mixed with 20L of ice water, stirred, filtered, and the filter cake was washed with water to give 850g of a pale yellow solid, i.e., intermediate IV (4-aminopyrrolo [2,1-f ] [1,2,4] triazine).
The purity of this intermediate IV was 98% and the yield was 91%.
It is composed of1The H NMR data are as follows:
1H NMR(CD3OD):δ7.72(s,1H),7.52(dd,1H,J＝2.5,1.6Hz),6.85(dd,1H1J＝4.5,1.6Hz),6.64(dd,1H,J＝4.5,2.7Hz)LC/MS(+esi):m/z＝135.1[M+H].
the reaction progress is monitored by TLC, the developing agent used for monitoring the reaction is a mixed solution of polyethylene and ethyl acrylate, and the molar ratio of the polyethylene to the ethyl acrylate is 3: 1. The added solvent is one of absolute methanol, absolute ethanol, 1, 4-dioxane and N, N-dimethylformamide, absolute ethanol is preferably used in the embodiment, and other solvents can be selected and the specific dosage is the same as that of the absolute ethanol, so that the generation of a reaction product is not influenced; the molar ratio of the intermediate III to the formamidine acetate can be 1.0: 1.5-5.0; the inert gas used is preferably nitrogen, but may also be argon or helium.
Example 5:
this example reacted the intermediate IV prepared in the above example with a brominating reagent to give the final product, 7-bromopyrrolo [2,1-f ] [1,2,4] thiazin-4-amine.
The specific synthetic route is as follows:
the preparation method comprises the following steps:
adding 1000g of intermediate IV (7.45mol,1.0eq) into a 20L three-necked bottle, adding 10L of solvent, uniformly stirring, and cooling to-15 ℃ to obtain a reaction solution for later use; 1065.7g of the brominating reagent was dissolved in 2L of the solvent, and was slowly added dropwise to the reaction solution. Keeping the temperature in the three-mouth bottle below-10 ℃ and reacting for 45 min. After TLC monitoring reaction, 15L of sodium sulfite solution with the mass fraction of 25% is added, and solid is separated out. And (3) carrying out suction filtration, washing a filter cake with water, dissolving and separating with ethyl acetate and a 5% sodium carbonate solution in a molar ratio of 1:1, washing an organic phase with the sodium carbonate solution, drying after washing with salt water, separating, and concentrating to obtain 1450g of white solid, namely the final product (7-bromopyrrolo [2,1-f ] [1,2,4] thiazine-4-amine).
The final product was 97% pure and 91% yield, containing 1.2% dibrominated by-products.
It is composed of1The H NMR data are as follows:
1H NMR(CD3OD)：δ7.84(s，1h)，6.95(d，1h，j＝4.7h z)，6.71(d，1h，j＝4.7hz)，4.89(s，3h，-nh2+h2o)；ms:lc/ms(+esi)，m/z＝213.1[m+h]。
the reaction progress is monitored by TLC, the developing agent used for monitoring the reaction is a mixed solution of polyethylene and ethyl acrylate, and the molar ratio of the polyethylene to the ethyl acrylate is 3: 1.
The added brominating reagent is one of N-bromosuccinimide, dibromohydantoin and NBS, the dibromohydantoin is preferably used in the embodiment, and other brominating reagents can be selected without influencing the reaction product.
The added solvent is one of anhydrous DMF, dichloromethane and tetrahydrofuran; anhydrous DMF is preferably used in this example, and other brominating reagents can be selected without affecting the reaction product.
The molar ratio of the intermediate IV to the brominating reagent is 1.0: 0.5-1.5.
While embodiments of the invention have been shown and described, it will be understood by those of ordinary skill in the art that: various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.
Claims (10)
1. A preparation method of 7-bromopyrrolo [2,1-f ] [1,2,4] thiazin-4-amine is characterized by comprising the following steps:
(1) taking tert-butyl carbazate and 2, 5-dimethoxy tetrahydrofuran as raw materials to synthesize an intermediate I, namely 1-Boc-1-aminopyrrole;
(2) reacting the intermediate I with methanesulfonic acid isocyanate to synthesize an intermediate II, namely 1-Boc-1-amino- (9ci) -1H-pyrrole-2-carbonitrile;
(3) deaminating the intermediate II under acidic conditions to obtain an intermediate III, namely 1-amino- (9ci) -1H-pyrrole-2-carbonitrile hydrochloride;
(4) enabling the intermediate III and formamidine acetate to perform ring closure reaction to obtain an intermediate IV, namely 4-aminopyrrolo [2,1-f ] [1,2,4] triazine;
(5) and (3) reacting the intermediate IV with a brominating reagent to obtain a final product, namely 7-bromopyrrolo [2,1-f ] [1,2,4] thiazin-4-amine.
2. The preparation method of 7-bromopyrrolo [2,1-f ] [1,2,4] thiazin-4-amine according to claim 1, wherein the specific preparation process of the intermediate I in the step (1) is as follows:
adding tert-butyl carbazate, 2, 5-dimethoxy tetrahydrofuran and a solvent into a three-necked bottle in sequence, stirring uniformly, slowly adding hydrochloric acid with the equivalent concentration of 2N, slowly heating to 80 ℃, and reacting for 10 hours; monitoring the reaction progress by using TLC (thin layer chromatography), wherein a developing agent used for monitoring the reaction is a mixed solution of polyethylene and ethyl acrylate, and the molar ratio of the polyethylene to the ethyl acrylate is 3: 1; and after the raw materials are reacted, stopping heating, adding a saturated sodium bicarbonate solution when the raw materials are naturally cooled to 20 ℃, stirring for 20 minutes, filtering out solids, concentrating the filtrate under reduced pressure, dissolving solid residues by using dichloromethane, filtering by using a magnetic sol pad, concentrating and drying the filtrate under reduced pressure, and pulping by using petroleum ether to obtain colorless crystals, namely the intermediate I.
3. The method for preparing 7-bromopyrrolo [2,1-f ] [1,2,4] thiazin-4-amine according to claim 2, wherein the solvent used in the step (1) is one of N-methylpyrrolidone, N-dimethylformamide, 1, 4-dioxane and tetrahydrofuran.
4. The preparation method of 7-bromopyrrolo [2,1-f ] [1,2,4] thiazin-4-amine according to any one of claims 1 to 3, wherein the specific preparation process of the intermediate II in the step (2) is as follows:
under the protection of inert gas, adding the intermediate I and a solvent into a three-necked bottle, fully stirring, cooling to 0 ℃, slowly dropwise adding chlorosulfonyl isocyanate, keeping the temperature in the three-necked bottle not higher than 5 ℃, observing the generation of white suspension in about 20 minutes, adding the solvent after 30 minutes, and clarifying the reaction solution; keeping the temperature at 0 ℃ for reaction for 30 minutes; monitoring the reaction progress by using TLC (thin layer chromatography), wherein a developing agent used for monitoring the reaction is a mixed solution of polyethylene and ethyl acrylate, and the molar ratio of the polyethylene to the ethyl acrylate is 3: 1; after the reaction is finished, pouring the reaction liquid into a mixed liquid of ice water and ethyl acetate, and stirring and separating the liquid; and washing the organic phase with saturated sodium bicarbonate solution and salt water in sequence, then drying with anhydrous sodium sulfate, separating and concentrating to obtain a white solid, namely an intermediate II.
5. The preparation method of 7-bromopyrrolo [2,1-f ] [1,2,4] thiazin-4-amine according to claim 4, wherein the solvent used in the step (2) is one of anhydrous DMF, anhydrous acetonitrile and anhydrous dichloromethane, and the molar ratio of ice water to ethyl acetate in a mixed solution of ice water and ethyl acetate is 1: 1; the inert gas used is one of nitrogen, argon and helium.
6. The preparation method of 7-bromopyrrolo [2,1-f ] [1,2,4] thiazin-4-amine according to any one of claims 1 to 3, wherein the specific preparation process of the intermediate III in the step (3) is as follows:
adding the intermediate II and anhydrous ethyl acetate into a three-necked bottle, stirring for dissolving, and cooling to 0 ℃ to obtain a reaction solution for later use; preparing an ethyl acetate solution with the concentration of 1mol/l by using acid as a solute and ethyl acetate as a solvent, adding the ethyl acetate solution into the prepared reaction solution, keeping the temperature at 0 ℃ for reaction, and observing that a large amount of white solid is generated after 30 minutes; monitoring the reaction progress by using TLC (thin layer chromatography), wherein a developing agent used for monitoring the reaction is a mixed solution of polyethylene and ethyl acrylate, and the molar ratio of the polyethylene to the ethyl acrylate is 3: 1; after the reaction is finished, carrying out suction filtration, washing the residue with anhydrous ethyl acetate, and carrying out vacuum drying to obtain a white solid, namely the intermediate III.
7. The process according to claim 6, wherein the acid used in step (3) is one of gaseous hydrogen chloride, trifluoroacetic acid and hydrochloric acid.
8. The preparation method of 7-bromopyrrolo [2,1-f ] [1,2,4] thiazin-4-amine according to any one of claims 1 to 3, wherein the specific preparation process of the intermediate IV in the step (4) is as follows:
under the protection of inert gas, adding the intermediate III, formamidine acetate and a solvent into a three-necked bottle, uniformly stirring, adding anhydrous potassium carbonate, heating to 78 ℃, and reacting for 15 hours; monitoring the reaction progress by using TLC (thin layer chromatography), wherein a developing agent used for monitoring the reaction is a mixed solution of polyethylene and ethyl acrylate, and the molar ratio of the polyethylene to the ethyl acrylate is 3: 1; and after the reaction is finished, cooling and filtering, mixing and stirring the solid residue obtained by vacuum concentration of the filtrate and ice water, filtering, washing a filter cake with water, and treating to obtain a light yellow solid, namely the intermediate IV.
9. The method for preparing 7-bromopyrrolo [2,1-f ] [1,2,4] thiazin-4-amine according to claim 8, wherein the solvent added in the step (4) is one of absolute methanol, absolute ethanol, 1, 4-dioxane and N, N-dimethylformamide; the molar ratio of the intermediate III to the formamidine acetate can be 1.0: 1.5-5.0; the inert gas used is one of nitrogen, argon and helium.
10. The method for preparing 7-bromopyrrolo [2,1-f ] [1,2,4] thiazin-4-amine according to any one of claims 1 to 3, wherein the specific preparation process of the final product in the step (5) is as follows:
adding the intermediate IV into a three-necked bottle, adding a solvent, uniformly stirring, and cooling to-15 ℃ to obtain a reaction solution for later use; dissolving a brominating reagent in a solvent, slowly dripping the solution into the reaction solution, keeping the temperature in the three-necked bottle lower than-10 ℃, and reacting for 45 minutes; monitoring the reaction progress by using TLC (thin layer chromatography), wherein a developing agent used for monitoring the reaction is a mixed solution of polyethylene and ethyl acrylate, and the molar ratio of the polyethylene to the ethyl acrylate is 3: 1; after the reaction is finished, adding a sodium sulfite aqueous solution with the mass fraction of 25% to separate out solids; performing suction filtration, washing a filter cake with water, dissolving and separating with ethyl acetate and 5% of sodium carbonate solution according to the molar ratio of 1:1, washing an organic phase with the sodium carbonate solution, drying after washing with salt solution, separating, and concentrating to obtain a final product; the bromination reagent is one of N-bromosuccinimide, dibromohydantoin and NBS, and the solvent is one of anhydrous DMF, dichloromethane and tetrahydrofuran; wherein the molar ratio of the intermediate IV to the brominating reagent is 1.0: 0.5-1.5.
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