CN110204542B - Synthetic method of JAK1 inhibitor Filgotinib - Google Patents
Synthetic method of JAK1 inhibitor Filgotinib Download PDFInfo
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Abstract
The invention provides a preparation method of Filgotinib, which comprises the following steps: (1) reacting 2-amino-6-bromopyridine with a p-methylbenzene derivative to prepare a compound 1; (2) reacting the compound 1 with ethyl isothiocyanatecarboxylate to prepare a compound 2; (3) reacting the compound 2 with hydroxylamine hydrochloride and N, N-diisopropylethylamine to prepare a compound 3; (4) reacting the compound 3 with cyclopropane carbonyl chloride to obtain a compound 4; (5) reacting the compound 4, N-bromosuccinimide with azobisisobutyronitrile to obtain a compound 5; (6) the compound 5 reacts with thiomorpholine-1, 1-dioxide to obtain Filgotinib. The synthesis route of the Filgotinib is coupling first and then ring closing, the raw materials are cheap, the reaction operation is simple, the product is easy to purify, the yield is high, and the method is suitable for commercial large-scale production.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a synthesis method of a JAK1 inhibitor Filgotinib.
Background
Cartilage degeneration is a hallmark of many diseases, of which rheumatoid arthritis and osteoarthritis are the most prominent. Rheumatoid Arthritis (RA) is a chronic degenerative disease of the joints characterized by inflammation and destruction of the joint structure. When the disease is not inhibited, substantial disability and pain, and even premature death, result from loss of joint functionality. However, there is no effective drug for the correction of rheumatoid arthritis and osteoarthritis.
Janus kinases (JAKs) are cytoplasmic tyrosine kinases that transduce cytokine signals from membrane receptors to STAT transcription factors. Four JAK family members have been described in the prior art: JAK1, JAK2, JAK3 and TYK 2. When cytokines bind to their receptors, JAK family members are autophosphorylated and/or transphosphorylated to each other, followed by phosphorylation of STATs, which then migrate into the nucleus to regulate transcription. JAK-STAT intracellular signaling is applicable to interferons, most interleukins, and a variety of cytokines and endocrine factors, such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF, and PRL (Vainchenker w. et al (2008)). Vandeghinnste et al (WO 2005/124342) found that JAK1 could be a target, inhibition of which may be relevant for the treatment of several diseases, including OA.
WO 2010/149769(Menet and Smits,2010) discloses the compound cyclopropanecarboxylic acid {5- [4- (1, 1-dioxo-thiomorpholin-4-ylmethyl) -phenyl ] - [1,2,4] triazolo [1,5-a ] pyridin-2-yl } -amide (Filgotinib, CAS: 1206161-97-8), which has been shown to be a JAK inhibitor, more particularly a JAK1 inhibitor, and to be useful in the treatment of inflammatory disorders, autoimmune diseases, proliferative diseases, allergy, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 or interferons.
Therefore, the method for preparing Filgotinib, which is simple to operate, easy to purify and high in yield, has great application value.
Disclosure of Invention
The invention aims to provide a simple and efficient method for preparing Filgotinib serving as a JAK1 inhibitor.
The invention provides a preparation method of Filgotinib, which comprises the following steps:
(1) reacting 2-amino-6-bromopyridine with a p-methylbenzene derivative to prepare a compound 1;
(2) reacting the compound 1 with ethyl isothiocyanatecarboxylate to prepare a compound 2;
(3) reacting the compound 2 with hydroxylamine hydrochloride and N, N-diisopropylethylamine to prepare a compound 3;
(4) reacting the compound 3 with cyclopropane carbonyl chloride to obtain a compound 4;
(5) reacting the compound 4, N-bromosuccinimide with azobisisobutyronitrile to obtain a compound 5;
(6) reacting the compound 5 with thiomorpholine-1, 1-dioxide to obtain Filgotinib;
wherein the p-methylbenzene derivative is selected from p-methylbenzene boric acid and p-methylbenzene boric acid ester, and the structure of the compound 1 is
Compound 2 has the structure
Compound 3 has the structure
Compound 4 has the structure
Compound 5 has the structure
The Filgotinib has the structure of
Further, in the step (1), the reaction process comprises: dissolving 2-amino-6-bromopyridine and p-methylbenzene derivatives in a reaction solvent, heating and reacting in a nitrogen atmosphere in the presence of a catalyst, and purifying after the reaction is finished;
and/or, in the step (2), the reaction process comprises the following steps: dissolving the compound 1 in a reaction solvent, cooling, adding ethyl isothiocyanatecarboxylate, heating for reaction, and purifying after the reaction is finished;
and/or, in the step (3), the reaction process comprises the following steps: dissolving a compound 2, hydroxylamine hydrochloride and N, N-diisopropylethylamine in a reaction solvent, heating for reaction, and purifying after the reaction is finished;
and/or, in the step (4), the reaction process comprises the following steps: dissolving the compound 3 and a catalyst in a reaction solvent, then dropwise adding cyclopropane carbonyl chloride, heating for reaction, and purifying after the reaction is finished;
and/or, in the step (5), the reaction process comprises the following steps: the reaction process comprises the following steps: dissolving a compound 4, N-bromosuccinimide and azobisisobutyronitrile in a reaction solvent, heating for reaction, and purifying after the reaction is finished;
and/or, in the step (6), the reaction process comprises the following steps: dissolving the compound 5, thiomorpholine-1, 1-dioxide and a catalyst in a reaction solvent, heating for reaction, and purifying after the reaction is finished.
Further, in the step (1), the p-methylbenzene derivative is selected from p-methylbenzeneboronic acid.
Further, in the step (1), the molar ratio of the 2-amino-6-bromopyridine to the p-methylbenzene derivative is 1: (1.1-1.5); the mass-volume ratio of the 2-amino-6-bromopyridine to the reaction solvent is 1: (10-30) g/mL; the reaction solvent is selected from a mixed solvent of 1, 4-dioxane and water, and the volume ratio of the 1, 4-dioxane to the water is (2-4): 1; the catalyst for the reaction is potassium acetate and Pd (dppf) Cl2Potassium acetate and Pd (dppf) Cl2The molar ratio of (40-60): 1;
and/or, in the step (2), the molar ratio of the compound 1 to the ethyl isothiocyanatecarboxylate is 1: (1: 1.5); the mass-to-volume ratio of the compound 1 to the reaction solvent is 1: (5-10) g/mL; the reaction solvent is selected from organic solvents;
and/or in the step (3), the molar ratio of the compound 2, hydroxylamine hydrochloride and N, N-diisopropylethylamine is 1: (4-6): (2-4); the mass-to-volume ratio of the compound 2 to the reaction solvent is 1: (10-15) g/mL; the reaction solvent is selected from organic solvents;
and/or, in the step (4), the molar ratio of the compound 3, the catalyst and the cyclopropane carbonyl chloride is 1: (2-3): (1.2-2); the catalyst is selected from bases; the mass-to-volume ratio of the compound 3 to the reaction solvent is 1: (5-10) g/mL; the reaction solvent is selected from organic solvents;
and/or in the step (5), the molar ratio of the compound 4, the N-bromosuccinimide and the azobisisobutyronitrile is 1: (1.1-1.3): (0.11-0.13); the mass-to-volume ratio of the compound 4 to the reaction solvent is 1: (5-10) g/mL; the reaction solvent is selected from organic solvents;
and/or, in the step (6), the molar ratio of the compound 5, the thiomorpholine-1, 1-dioxide and the catalyst is 1: (1.1-1.2): (1.5-2.5); the catalyst is selected from bases; the mass-to-volume ratio of the compound 5 to the reaction solvent is 1: (5-10) g/mL; the reaction solvent is selected from organic solvents.
Further, in the step (1), the molar ratio of the 2-amino-6-bromopyridine to the p-methylbenzene derivative is 1: 1.2; the mass-volume ratio of the 2-amino-6-bromopyridine to the reaction solvent is 1: 20 g/mL; the reaction solvent is selected from a mixed solvent of 1, 4-dioxane and water, and the volume ratio of the 1, 4-dioxane to the water is 3: 1; the catalyst for the reaction is potassium acetate and Pd (dppf) Cl2Potassium acetate and Pd (dppf) Cl2In a molar ratio of 50: 1;
and/or, in the step (2), the molar ratio of the compound 1 to the ethyl isothiocyanatecarboxylate is 1: 1.1; the mass-to-volume ratio of the compound 1 to the reaction solvent is 1: 8 g/mL; the reaction solvent is selected from ethyl acetate;
and/or, in the step (3), the molar ratio of the compound 2, hydroxylamine hydrochloride and N, N-diisopropylethylamine is 1: 5: 3; the mass-to-volume ratio of the compound 2 to the reaction solvent is 1: 12.5 g/mL; the reaction solvent is selected from ethanol;
and/or, in the step (4), the molar ratio of the compound 3, the catalyst and the cyclopropane carbonyl chloride is 1: 2.5: 1.5; the catalyst is selected from potassium carbonate; the mass-to-volume ratio of the compound 3 to the reaction solvent is 1: 7.8 g/mL; the reaction solvent is selected from N, N-dimethylformamide;
and/or in the step (5), the molar ratio of the compound 4, the N-bromosuccinimide and the azobisisobutyronitrile is 1: 1.2: 0.12; the mass-to-volume ratio of the compound 4 to the reaction solvent is 1: 8.6 g/mL; the reaction solvent is selected from carbon tetrachloride;
and/or, in the step (6), the molar ratio of the compound 5, the thiomorpholine-1, 1-dioxide and the catalyst is 1: 1.125: 2; the catalyst is selected from potassium carbonate; the mass-to-volume ratio of the compound 5 to the reaction solvent is 1: 8.3 g/mL; the reaction solvent is selected from N, N-dimethylformamide.
Further, in the step (1), the heating temperature is reflux temperature, and the reaction time is 10-15 hours;
and/or in the step (2), the temperature reduction is-2 ℃, the heating temperature is 40-60 ℃, and the reaction time is 15-25 hours;
and/or, in the step (3), the reaction time is 3-8 hours;
and/or, in the step (4), the heating temperature is 60-100 ℃, and the reaction time is 2-6 hours;
and/or, in the step (5), the heating temperature is the reflux temperature, and the reaction time is 8-12 hours;
and/or, in the step (6), the heating temperature is 60-100 ℃, and the reaction time is 3-8 hours.
Further, in the step (1), the reaction time is 13 hours;
and/or, in the step (2), the temperature reduction is 0 ℃, the heating temperature is 50 ℃, and the reaction time is 20 hours;
and/or, in the step (3), the heating temperature is the reflux temperature, and the reaction time is 5 hours;
and/or, in the step (4), the heating temperature is 80 ℃, and the reaction time is 4 hours;
and/or, in the step (5), the reaction time is 10 hours;
and/or, in the step (6), the heating temperature is 80 ℃, and the reaction time is 5 hours.
Further, in the step (1), the purification process comprises: at room temperature, adjusting the system after the reaction to be acidic, separating out solid, filtering, taking the solid, dissolving the solid by using an alkaline solution, extracting by using ethyl acetate, taking an organic phase, and concentrating;
and/or, in the step (2), the purification process comprises the following steps: concentrating the system after the reaction is finished, adding n-hexane, filtering, washing the solid with n-hexane, and drying;
and/or in the step (3), the purification process comprises the following steps: adding n-hexane into the system after the reaction is finished at room temperature, filtering, washing the solid with methyl tert-butyl ether, and drying;
and/or, in the step (4), the purification process comprises the following steps: adding water into the system after the reaction is finished at room temperature, extracting with ethyl acetate, taking an organic layer, drying with anhydrous sodium sulfate, filtering, and concentrating;
and/or, in the step (5), the purification process comprises the following steps: filtering the system after the reaction is finished at room temperature, taking the filtrate, washing with water, drying and concentrating;
and/or, in the step (6), the purification process comprises the following steps: and pouring the reacted system into ice water at room temperature, stirring, filtering, washing the solid with methyl tert-butyl ether, and drying.
Further, in the step (1), in the purification process, adjusting the pH of the system after the reaction to be 3-6 by using 2mol/L hydrochloric acid, wherein the alkaline solution is 2mol/L sodium hydroxide aqueous solution;
and/or, in the step (2), in the purification process, the volume ratio of n-hexane added before filtration to the reaction solvent is 1: 1.6;
and/or, in the step (3), in the purification process, the volume ratio of the n-hexane to the reaction solvent is 1: 1.7;
and/or, in the step (4), the purification process comprises the following steps: the volume ratio of the water to the reaction solvent is 0.8-1.2;
and/or, in the step (6), in the purification process: the volume ratio of the ice water to the reaction solvent is 3: 1.
experiments prove that the method for preparing the JAK1 inhibitor Filgotinib adopts a route of coupling first and then ring closing, has cheap raw materials, simple reaction operation, easy purification of products and high yield, and is suitable for commercial large-scale production.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention is described in further detail below with reference to examples, but it should not be construed that the scope of the above subject matter is limited to the examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and reagents used in the invention are known products, and are obtained by purchasing commercial products.
Example 1 Synthesis of the Compound Filgotinib
Compound Filgotinib was prepared according to the following synthetic route:
1. synthesis of 6- (4-methylphenyl) -2-aminopyridine (Compound 1)
2-amino-6-bromopyridine (50g, 0.29mol), p-methylphenylboronic acid (47g, 0.35mol), 1, 4-dioxane (750ml) and water (250ml) were added to a reaction flask, followed by potassium acetate (85g, 0.87mol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (Pd (dppf) Cl212.7g, 0.0174 mol). Nitrogen was bubbled, heated to reflux for 13h, and TLC monitored the reaction to completion. Cooling to room temperature, adding 2N hydrochloric acid to pH>3, the solid was precipitated, filtered, the cake was dissolved in 2N aqueous sodium hydroxide solution, extracted with ethyl acetate (300ml X3), and the organic phase was concentrated to give 144.7g of the product 6- (4-methylphenyl) -2-aminopyridine (compound 1) with a yield of 83.6%.
2. Synthesis of ethyl [6- (4-methylphenyl) pyridin-2-ylthiocarbamoyl ] carbamate (Compound 2)
Compound 1(100g, 0.54mol) and ethyl acetate (800ml) were added to a reaction flask, the temperature was reduced to 0 ℃ and ethyl isothiocyanatecarboxylate (78g, 0.59mol) was added dropwise. After the completion of the dropwise addition, the reaction was heated to 50 ℃ for 20 hours, and the completion of the reaction was monitored by TLC. After concentration, n-hexane (500ml) was added for dilution, filtration was carried out, and the cake was washed twice with n-hexane (200ml X2), and dried to obtain 153.6g of ethyl [6- (4-methylphenyl) pyridin-2-ylthiocarbamoyl ] carbamate (Compound No. 2), yield 90.2%.
3. Synthesis of 5- (4-tolyl) - [1,2,4] trithiazolo [1,5-A ] pyridin-2-amine (Compound 3)
Compound 2(80g, 0.25mol), hydroxylamine hydrochloride (87g, 1.25mol), N-diisopropylethylamine (97g, 0.75mol) and ethanol (1000ml) were added to a reaction flask, and the reaction was heated under reflux for 5h, and the completion of the reaction was monitored by TLC. 600ml of n-hexane was added, the temperature was reduced to room temperature, filtration was carried out, the filter cake was washed with methyl t-butyl ether, and drying was carried out to give 47.9g of 5- (4-tolyl) - [1,2,4] dithiazolo [1,5-A ] pyridin-2-amine (Compound 3) in 85.4% yield.
4. Synthesis of N- [5- (4-tolyl) - [1,2,4] trithiazolo [1,5-A ] pyridin-2-yl ] cyclopropanecarboxamide (Compound 4) Compound 3(90g, 0.4mol), potassium carbonate (138g, 1mol) and N, N-dimethylformamide (700ml) were added to a reaction flask, cyclopropanecarbonyl chloride (52g, 0.5mol) was added dropwise thereto, and after completion of the addition, the mixture was heated to 80 ℃ for 4 hours and the reaction was monitored by TLC for completion of the reaction. After the temperature was reduced to room temperature, 800ml of water was added, followed by extraction with ethyl acetate, drying over anhydrous sodium sulfate, filtration and concentration to give 107.2g of N- [5- (4-tolyl) - [1,2,4] trithiazolo [1,5-A ] pyridin-2-yl ] cyclopropanecarboxamide (Compound No. 4), yield 91.7%.
5. Synthesis of N- [5 (4-bromomethylphenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) cyclobenzamide (Compound 5) Compound 4(105g, 0.36mol), N-bromosuccinimide (77g, 0.43mol), azobisisobutyronitrile (7.1g, 0.043mol) and carbon tetrachloride (900ml) were added to a reaction flask, and the reaction was refluxed for 10 hours and monitored by TLC for completion. Cooling to room temperature, filtering, washing the filtrate with water, drying, and concentrating to obtain solid. Washed with N-hexane (1000ml), and dried to obtain 115.2g of N- [5 (4-bromomethylphenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) cyclobenzamide (compound 5), with a yield of 86.2%.
6. Synthesis of N- (5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) cyclobenzamide (Filgotinib)
Compound 5(60g, 0.16mol), thiomorpholine-1, 1-dioxide (24g, 0.18mol), potassium carbonate (44.6g, 0.32mol) and N, N-dimethylformamide (500ml) were added to a reaction flask, heated to 80 ℃ for 5h and TLC monitored for completion of the reaction. The temperature is reduced to room temperature, the reaction solution is slowly poured into 1500ml of ice water, stirred for 20 minutes, filtered, the filter cake is washed by methyl tert-butyl ether and dried to obtain 56.7g of N- (5- (4- ((1, 1-dioxothiomorpholine) methyl) phenyl) - [1,2,4] triazolo [1,5-a ] pyridin-2-yl) cycloformamide (Filgotinib) with the yield of 82.5 percent.
Taking the final product obtained in step 6 of example 1, and utilizing nuclear magnetic hydrogen spectrum (1H-NMR) and liquid mass spectrometer (LCMS) as follows:
1H-NMR(400MHz,DMSO-d6):0.78-0.90(4H,m,2×CH2),2.02(1H,br,CH),2.92(4H,m,2×CH2),3.52(4H,m,2×CH2),4.05(2H,s,CH2),7.33(1H,dd,ArH),7.58(1H,dd,ArH),7.68(1H,dd,ArH),7.75(2H,m,ArH),8.13(2H,m,ArH),11.10(1H,br s,NH).
LCMS:m/z 426.0(M+H+).
according to the results, the final product obtained in example 1 of the present invention is the compound Filgotinib.
In conclusion, the synthesis method of the JAK1 inhibitor Filgotinib adopts a route of coupling first and then ring closing, has cheap raw materials, simple reaction operation, easy purification of products and high yield, and is suitable for commercial large-scale production.
Claims (8)
1. A preparation method of Filgotinib is characterized in that: the method comprises the following steps:
(1) reacting 2-amino-6-bromopyridine with a p-methylbenzene derivative to prepare a compound 1;
(2) reacting the compound 1 with ethyl isothiocyanatecarboxylate to prepare a compound 2;
(3) reacting the compound 2 with hydroxylamine hydrochloride and N, N-diisopropylethylamine to prepare a compound 3;
(4) reacting the compound 3 with cyclopropane carbonyl chloride to obtain a compound 4;
(5) reacting the compound 4, N-bromosuccinimide with azobisisobutyronitrile to obtain a compound 5;
(6) reacting the compound 5 with thiomorpholine-1, 1-dioxide to obtain Filgotinib;
wherein the p-methylbenzene derivative is p-methylbenzeneboronic acid, and the structure of the compound 1 is
Compound 2 has the structure
Compound 3 has the structure
Compound 4 has the structure
Compound 5 has the structure
The Filgotinib has the structure of
2. The method of claim 1, wherein: in the step (1), the reaction process comprises the following steps: dissolving 2-amino-6-bromopyridine and p-methylbenzene derivatives in a reaction solvent, heating and reacting in a nitrogen atmosphere in the presence of a catalyst, and purifying after the reaction is finished;
and/or, in the step (2), the reaction process comprises the following steps: dissolving the compound 1 in a reaction solvent, cooling, adding ethyl isothiocyanatecarboxylate, heating for reaction, and purifying after the reaction is finished;
and/or, in the step (3), the reaction process comprises the following steps: dissolving a compound 2, hydroxylamine hydrochloride and N, N-diisopropylethylamine in a reaction solvent, heating for reaction, and purifying after the reaction is finished;
and/or, in the step (4), the reaction process comprises the following steps: dissolving the compound 3 and a catalyst in a reaction solvent, then dropwise adding cyclopropane carbonyl chloride, heating for reaction, and purifying after the reaction is finished;
and/or, in the step (5), the reaction process comprises the following steps: the reaction process comprises the following steps: dissolving a compound 4, N-bromosuccinimide and azobisisobutyronitrile in a reaction solvent, heating for reaction, and purifying after the reaction is finished;
and/or, in the step (6), the reaction process comprises the following steps: dissolving the compound 5, thiomorpholine-1, 1-dioxide and a catalyst in a reaction solvent, heating for reaction, and purifying after the reaction is finished.
3. The method of claim 2, wherein: in the step (1), the molar ratio of the 2-amino-6-bromopyridine to the p-methylbenzene derivative is 1: (1.1-1.5); the mass-volume ratio of the 2-amino-6-bromopyridine to the reaction solvent is 1: (10-30) g/mL; the reaction solvent is selected from a mixed solvent of 1, 4-dioxane and water, and the volume ratio of the 1, 4-dioxane to the water is (2-4): 1; the catalyst for the reaction is potassium acetate and Pd (dppf) Cl2Potassium acetate and Pd (dppf) Cl2The molar ratio of (40-60): 1;
and/or, in the step (2), the molar ratio of the compound 1 to the ethyl isothiocyanatecarboxylate is 1: (1-1.5); the mass-to-volume ratio of the compound 1 to the reaction solvent is 1: (5-10) g/mL; the reaction solvent is selected from organic solvents;
and/or in the step (3), the molar ratio of the compound 2, hydroxylamine hydrochloride and N, N-diisopropylethylamine is 1: (4-6): (2-4); the mass-to-volume ratio of the compound 2 to the reaction solvent is 1: (10-15) g/mL; the reaction solvent is selected from organic solvents;
and/or, in the step (4), the molar ratio of the compound 3, the catalyst and the cyclopropane carbonyl chloride is 1: (2-3): (1.2-2); the catalyst is selected from bases; the mass-to-volume ratio of the compound 3 to the reaction solvent is 1: (5-10) g/mL; the reaction solvent is selected from organic solvents;
and/or in the step (5), the molar ratio of the compound 4, the N-bromosuccinimide and the azobisisobutyronitrile is 1: (1.1-1.3): (0.11-0.13); the mass-to-volume ratio of the compound 4 to the reaction solvent is 1: (5-10) g/mL; the reaction solvent is selected from organic solvents;
and/or, in the step (6), the molar ratio of the compound 5, the thiomorpholine-1, 1-dioxide and the catalyst is 1: (1.1-1.2): (1.5-2.5); the catalyst is selected from bases; the mass-to-volume ratio of the compound 5 to the reaction solvent is 1: (5-10) g/mL; the reaction solvent is selected from organic solvents.
4. The method of claim 3, wherein: in the step (1), the molar ratio of the 2-amino-6-bromopyridine to the p-methylbenzene derivative is 1: 1.2; the mass-volume ratio of the 2-amino-6-bromopyridine to the reaction solvent is 1: 20 g/mL; the reaction solvent is selected from a mixed solvent of 1, 4-dioxane and water, and the volume ratio of the 1, 4-dioxane to the water is 3: 1; the catalyst for the reaction is potassium acetate and Pd (dppf) Cl2Potassium acetate and Pd (dppf) Cl2In a molar ratio of 50: 1;
and/or, in the step (2), the molar ratio of the compound 1 to the ethyl isothiocyanatecarboxylate is 1: 1.1; the mass-to-volume ratio of the compound 1 to the reaction solvent is 1: 8 g/mL; the reaction solvent is selected from ethyl acetate;
and/or, in the step (3), the molar ratio of the compound 2, hydroxylamine hydrochloride and N, N-diisopropylethylamine is 1: 5: 3; the mass-to-volume ratio of the compound 2 to the reaction solvent is 1: 12.5 g/mL; the reaction solvent is selected from ethanol;
and/or, in the step (4), the molar ratio of the compound 3, the catalyst and the cyclopropane carbonyl chloride is 1: 2.5: 1.5; the catalyst is selected from potassium carbonate; the mass-to-volume ratio of the compound 3 to the reaction solvent is 1: 7.8 g/mL; the reaction solvent is selected from N, N-dimethylformamide;
and/or in the step (5), the molar ratio of the compound 4, the N-bromosuccinimide and the azobisisobutyronitrile is 1: 1.2: 0.12; the mass-to-volume ratio of the compound 4 to the reaction solvent is 1: 8.6 g/mL; the reaction solvent is selected from carbon tetrachloride;
and/or, in the step (6), the molar ratio of the compound 5, the thiomorpholine-1, 1-dioxide and the catalyst is 1: 1.125: 2; the catalyst is selected from potassium carbonate; the mass-to-volume ratio of the compound 5 to the reaction solvent is 1: 8.3 g/mL; the reaction solvent is selected from N, N-dimethylformamide.
5. The method of claim 2, wherein: in the step (1), the heating temperature is reflux temperature, and the reaction time is 10-15 hours;
and/or in the step (2), the temperature is reduced to-2 ℃, the heating temperature is 40-60 ℃, and the reaction time is 15-25 hours;
and/or, in the step (3), the reaction time is 3-8 hours;
and/or, in the step (4), the heating temperature is 60-100 ℃, and the reaction time is 2-6 hours;
and/or, in the step (5), the heating temperature is the reflux temperature, and the reaction time is 8-12 hours;
and/or, in the step (6), the heating temperature is 60-100 ℃, and the reaction time is 3-8 hours.
6. The method of claim 5, wherein: in the step (1), the reaction time is 13 hours;
and/or, in the step (2), the temperature reduction temperature is 0 ℃, the heating temperature is 50 ℃, and the reaction time is 20 hours;
and/or in the step (3), the heating temperature is the reflux temperature, and the reaction time is 5 hours;
and/or, in the step (4), the heating temperature is 80 ℃, and the reaction time is 4 hours;
and/or, in the step (5), the reaction time is 10 hours;
and/or, in the step (6), the heating temperature is 80 ℃, and the reaction time is 5 hours.
7. The method according to any one of claims 2-6, wherein: in the step (1), the purification process comprises the following steps: at room temperature, adjusting the system after the reaction to be acidic, separating out solid, filtering, taking the solid, dissolving the solid by using an alkaline solution, extracting by using ethyl acetate, taking an organic phase, and concentrating;
and/or, in the step (2), the purification process comprises the following steps: concentrating the system after the reaction is finished, adding n-hexane, filtering, washing the solid with n-hexane, and drying;
and/or, in the step (3), the purification process comprises the following steps: adding n-hexane into the system after the reaction is finished at room temperature, filtering, washing the solid with methyl tert-butyl ether, and drying;
and/or in the step (4), the purification process comprises the following steps: adding water into the system after the reaction is finished at room temperature, extracting with ethyl acetate, taking an organic layer, drying with anhydrous sodium sulfate, filtering, and concentrating;
and/or, in the step (5), the purification process comprises the following steps: filtering the system after the reaction is finished at room temperature, taking the filtrate, washing with water, drying and concentrating;
and/or, in the step (6), the purification process comprises the following steps: and pouring the reacted system into ice water at room temperature, stirring, filtering, washing the solid with methyl tert-butyl ether, and drying.
8. The method of claim 7, wherein: in the step (1), in the purification process, adjusting the pH value to acidity is to adjust the pH value of a system after the reaction to 3-6 by using 2mol/L hydrochloric acid, and the alkaline solution is 2mol/L sodium hydroxide aqueous solution;
and/or, in the step (2), in the purification process, the volume ratio of n-hexane added before filtration to the reaction solvent is 1: 1.6;
and/or, in the step (3), in the purification process, the volume ratio of the n-hexane to the reaction solvent is 1: 1.7;
and/or, in the step (4), in the purification process: the volume ratio of the water to the reaction solvent is 0.8-1.2;
and/or, in the step (6), in the purification process: the volume ratio of the ice water to the reaction solvent is 3: 1.
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