CN110204542A - A kind of synthetic method of JAK1 inhibitor Filgotinib - Google Patents
A kind of synthetic method of JAK1 inhibitor Filgotinib Download PDFInfo
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Abstract
The present invention provides the preparation methods of Filgotinib a kind of, comprising the following steps: (1) 2- amino -6- bromopyridine with to methylbenzene derivatives reaction, prepare compound 1；(2) compound 1 is reacted with different sulphur cyanato- Ethyl formate, prepare compound 2；(3) compound 2 is reacted with hydroxylamine hydrochloride, n,N-diisopropylethylamine, prepare compound 3；(4) compound 3 is reacted with cyclopropyl formyl chloride, obtains compound 4；(5) compound 4, N- bromo-succinimide are reacted with azodiisobutyronitrile, obtain compound 5；(6) compound 5 and thiomorpholine -1,1- dioxide react, and obtain Filgotinib.The route that the present invention synthesizes Filgotinib is first to be coupled closed loop again, and raw material is cheap, and operation is simple, product easy purification, high income, and commercial size metaplasia is suitble to produce.
Description
Technical field
The present invention relates to pharmaceutical synthesis field more particularly to a kind of synthetic methods of JAK1 inhibitor Filgotinib.
Background technique
Cartilage degeneration is the mark of many diseases, and wherein rheumatoid arthritis and osteoarthritis are most important.Class wind
Wet arthritis (RA) is chronic joint degenerative disease, it is characterised in that the inflammation and destruction of joint structure.When disease is not suppressed
When processed, since the forfeiture of function of joint leads to substantive disability and pain or even premature death.But do not have still at present
The drug of effective correction rheumatoid arthritis and osteoarthritis disorders.
Janus kinases (JAK) is transducer cell factor signal from membrane receptor to the cytoplasmic tyrosine of STAT transcription factor
Kinases.Four kinds of JAK family members: JAK1, JAK2, JAK3 and TYK2 have been described in the prior art.When cell factor and its by
When body combines, JAK family member autophosphorylation and/or turn phosphorylation each other, then subsequent STATs phosphorylation is migrated to cell
To adjust transcription in core.JAK-STAT intracellular signal transduction is suitable for interferon, most of interleukins and a variety of thin
Intracellular cytokine and endocrine factor, such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF and PRL (Vainchenker W. et al.
(2008)).Vandeghinste et al. (WO 2005/124342) discovery JAK1 can be used as target spot, to its inhibition for number
The treatment of kind disease (including OA) may have correlation.
WO 2010/149769 (Menet and Smits, 2010) discloses compound cyclopropane-carboxylic acid { 5- [4- (1,1- bis-
Oxo-thiomorpholin -4- ylmethyl)-phenyl]--2 base of [1,2,4] triazol [1,5-a] pyridine }-amide (Filgotinib,
CAS:1206161-97-8), studies have shown that Filgotinib is JAK inhibitor, more particularly JAK1 inhibitor, and can be used
In treatment inflammatory conditions, autoimmune disease, proliferative diseases, allergy, graft rejection, it is related to the impaired disease of cartilage update
Sick, congenital cartilage deformity and/or disease relevant to IL6 or interferon hypersecretion.
Therefore, developing one kind easy to operate, easy purification, the method for preparing Filgotinib of high income has very greatly
Application value.
Summary of the invention
The purpose of the present invention is to provide a kind of simple, efficient methods, to prepare JAK1 inhibitor Filgotinib.
The present invention provides the preparation methods of Filgotinib a kind of, comprising the following steps:
(1) 2- amino -6- bromopyridine with to methylbenzene derivatives reaction, prepare compound 1；
(2) compound 1 is reacted with different sulphur cyanato- Ethyl formate, prepare compound 2；
(3) compound 2 is reacted with hydroxylamine hydrochloride, n,N-diisopropylethylamine, prepare compound 3；
(4) compound 3 is reacted with cyclopropyl formyl chloride, obtains compound 4；
(5) compound 4, N- bromo-succinimide are reacted with azodiisobutyronitrile, obtain compound 5；
(6) compound 5 and thiomorpholine -1,1- dioxide react, and obtain Filgotinib；
Wherein, described that methyl benzene derivative is selected to methylphenylboronic acid, to methylphenylboronic acid ester, the structure of compound 1
ForThe structure of compound 2 isThe structure of compound 3 isThe structure of compound 4 isThe structure of compound 5 isThe structure of Filgotinib is
Further, in step (1), the technique of the reaction includes: by 2- amino -6- bromopyridine, to methyl benzenesulfonamide derivative
Object is dissolved in reaction dissolvent, in the presence of a catalyst, reaction is heated in nitrogen atmosphere, is purified after reaction；
And/or in step (2), the technique of the reaction includes: that compound 1 is dissolved in reaction dissolvent, cooling, then plus
Enter different sulphur cyanato- Ethyl formate, heating reaction purifies after reaction；
And/or in step (3), the technique of the reaction includes: by compound 2, hydroxylamine hydrochloride and N, N- diisopropyl second
Amine is dissolved in reaction dissolvent, and heating reaction purifies after reaction；
And/or in step (4), the technique of the reaction includes: that compound 3, catalyst are dissolved in reaction dissolvent, then
Cyclopropyl formyl chloride is added dropwise, heating reaction purifies after reaction；
And/or in step (5), the technique of the reaction includes: that the technique of the reaction includes: by compound 4, N- bromine
It is dissolved in reaction dissolvent for succimide, azodiisobutyronitrile, heating reaction purifies after reaction；
And/or in step (6), the technique of the reaction include: by compound 5, thiomorpholine -1,1- dioxide and
Catalyst is dissolved in reaction dissolvent, and heating reaction purifies after reaction.
Further, described that methyl benzene derivative is selected to methylphenylboronic acid in step (1).
Further, in step (1), 2- amino -6- bromopyridine is 1:(1.1- with the molar ratio to methyl benzene derivative
1.5)；The mass volume ratio of 2- amino -6- bromopyridine and reaction dissolvent is 1:(10-30) g/mL；Reaction dissolvent is selected from 1,4- bis-
The volume ratio of the mixed solvent of oxygen six rings and water, the Isosorbide-5-Nitrae-dioxane and water is (2-4): 1；The catalyst of reaction is acetic acid
Potassium and Pd (dppf) Cl2, potassium acetate and Pd (dppf) Cl2Molar ratio be (40-60): 1；
And/or in step (2), the molar ratio of the compound 1 and different sulphur cyanato- Ethyl formate is 1:(1:1.5)；Chemical combination
The mass volume ratio of object 1 and reaction dissolvent is 1:(5-10) g/mL；Reaction dissolvent is selected from organic solvent；
And/or in step (3), the molar ratio of the compound 2, hydroxylamine hydrochloride and n,N-diisopropylethylamine is 1:(4-
6): (2-4)；The mass volume ratio of compound 2 and reaction dissolvent is 1:(10-15) g/mL；Reaction dissolvent is selected from organic solvent；
And/or in step (4), the molar ratio of the compound 3, catalyst and cyclopropyl formyl chloride is 1:(2-3): (1.2-
2)；The catalyst is selected from alkali；The mass volume ratio of compound 3 and reaction dissolvent is 1:(5-10) g/mL；Reaction dissolvent is selected from
Organic solvent；
And/or in step (5), the molar ratio of the compound 4, N- bromo-succinimide and azodiisobutyronitrile is
1:(1.1-1.3): (0.11-0.13)；The mass volume ratio of compound 4 and reaction dissolvent is 1:(5-10) g/mL；Reaction dissolvent
Selected from organic solvent；
And/or in step (6), the molar ratio of the compound 5, thiomorpholine -1,1- dioxide and catalyst is 1:
(1.1-1.2): (1.5-2.5)；The catalyst is selected from alkali；The mass volume ratio of compound 5 and reaction dissolvent is 1:(5-10)
g/mL；Reaction dissolvent is selected from organic solvent.
Further, in step (1), the 2- amino -6- bromopyridine is 1 with the molar ratio to methyl benzene derivative:
1.2；The mass volume ratio of 2- amino -6- bromopyridine and reaction dissolvent is 1:20g/mL；Reaction dissolvent is selected from 1,4- dioxane
With the mixed solvent of water, the volume ratio of the Isosorbide-5-Nitrae-dioxane and water is 3:1；The catalyst of reaction is potassium acetate and Pd
(dppf)Cl2, potassium acetate and Pd (dppf) Cl2Molar ratio be 50:1；
And/or in step (2), the molar ratio of the compound 1 and different sulphur cyanato- Ethyl formate is 1:1.1；Compound 1
Mass volume ratio with reaction dissolvent is 1:8g/mL；Reaction dissolvent is selected from ethyl acetate；
And/or in step (3), the molar ratio of the compound 2, hydroxylamine hydrochloride and n,N-diisopropylethylamine is 1:5:
3；The mass volume ratio of compound 2 and reaction dissolvent is 1:12.5g/mL；Reaction dissolvent is selected from ethyl alcohol；
And/or in step (4), the molar ratio of the compound 3, catalyst and cyclopropyl formyl chloride is 1:2.5:1.5；Institute
It states catalyst and is selected from potassium carbonate；The mass volume ratio of compound 3 and reaction dissolvent is 1:7.8g/mL；Reaction dissolvent is selected from N, N-
Dimethylformamide；
And/or in step (5), the molar ratio of the compound 4, N- bromo-succinimide and azodiisobutyronitrile is
1:1.2:0.12；The mass volume ratio of compound 4 and reaction dissolvent is 1:8.6g/mL；Reaction dissolvent is selected from carbon tetrachloride；
And/or in step (6), the molar ratio of the compound 5, thiomorpholine -1,1- dioxide and catalyst is 1:
1.125:2；The catalyst is selected from potassium carbonate；The mass volume ratio of compound 5 and reaction dissolvent is 1:8.3g/mL；React molten
Agent is selected from N,N-dimethylformamide.
Further, in step (1), the heating temperature is reflux temperature, and the reaction time is 10-15 hours；
And/or in step (2), the cooling temperature is -2~2 DEG C, and heating temperature is 40-60 DEG C, reaction time 15-
25 hours；
And/or in step (3), the reaction time is 3-8 hours；
And/or in step (4), the heating temperature is 60-100 DEG C, and the reaction time is 2-6 hours；
And/or in step (5), the heating temperature is reflux temperature, and the reaction time is 8-12 hours；
And/or in step (6), the heating temperature is 60-100 DEG C, and the reaction time is 3-8 hours.
Further, in step (1), the reaction time is 13 hours；
And/or in step (2), the cooling temperature is 0 DEG C, and heating temperature is 50 DEG C, and the reaction time is 20 hours；
And/or in step (3), the heating temperature is reflux temperature, and the reaction time is 5 hours；
And/or in step (4), the heating temperature is 80 DEG C, and the reaction time is 4 hours；
And/or in step (5), the reaction time is 10 hours；
And/or in step (6), the heating temperature is 80 DEG C, and the reaction time is 5 hours.
Further, in step (1), the purifying technique are as follows: at room temperature, system after reaction is adjusted to acid
Property, solid is precipitated, filtering takes solid, dissolved with alkaline solution, is then extracted with ethyl acetate, takes organic phase, is concentrated；
And/or in step (2), the purifying technique are as follows: n-hexane, mistake will be added after system concentration after reaction
Filter, solid are washed with n-hexane, dry；
And/or in step (3), the purifying technique are as follows: be added at room temperature into system after reaction just oneself
Alkane, filtering, solid are washed with methyl tertiary butyl ether(MTBE), dry；
And/or in step (4), the purifying technique are as follows: water is added into system after reaction at room temperature, uses
Ethyl acetate extraction, takes organic layer to be dried, filtered with anhydrous sodium sulfate, is concentrated；
And/or in step (5), the purifying technique are as follows: at room temperature, system after reaction is filtered, filter is taken
Liquid is concentrated after washing, drying；
And/or in step (6), the purifying technique are as follows: at room temperature, system after reaction is poured into ice water,
Stirring, filtering, takes solid to be washed with methyl tertiary butyl ether(MTBE), dries.
Further, in step (1), in the purifying technique, being adjusted to acidity is to use 2mol/L hydrochloric acid will after reaction
The PH of system be adjusted to 3~6, the alkaline solution is 2mol/L sodium hydrate aqueous solution；
And/or in step (2), in the purifying technique, the volume ratio of the n-hexane and reaction dissolvent that are added before filtering is
1:1.6；
And/or in step (3), in the purifying technique, the volume ratio of the n-hexane and reaction dissolvent is 1:1.7；
And/or in step (4), in the purifying technique: the volume ratio of the water and reaction dissolvent is 0.8-1.2；
And/or in step (6), in the purifying technique: the volume ratio of the ice water and reaction dissolvent is 3:1.
It is experimentally confirmed, the method provided by the invention for preparing JAK1 inhibitor Filgotinib uses first to be coupled closes again
The route of ring, raw material is cheap, and operation is simple, product easy purification, high income, and commercial size metaplasia is suitble to produce.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
Above content of the invention is described in further detail by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below.All technologies realized based on above content of the present invention belong to this
The range of invention.
Specific embodiment
The raw materials used in the present invention and reagent are known product, as obtained by purchase commercial product.
The synthesis of embodiment 1, compound Filgotinib
According to following synthetic route, prepare compound Filgotinib:
1, the synthesis of 6- (4- aminomethyl phenyl) -2-aminopyridine (compound 1)
By 2- amino -6- bromopyridine (50g, 0.29mol), to methylphenylboronic acid (47g, 0.35mol), Isosorbide-5-Nitrae-dioxane
(750ml) and water (250ml) are added in reaction flask, add potassium acetate (85g, 0.87mol) and [1,1'- bis- (diphenylphosphines
Base) ferrocene] palladium chloride (Pd (dppf) Cl2, 12.7g, 0.0174mol).It is passed through nitrogen, is heated to back flow reaction 13h,
TLC monitors fully reacting.It is cooled to room temperature, 2N hydrochloric acid is added to PH > 3, solid, filtering, filter cake 2N sodium hydroxide water is precipitated
Solution dissolution, ethyl acetate (300mlX3) extraction, is concentrated organic phase, obtains product 6- (4- aminomethyl phenyl) -2-aminopyridine
(compound 1) 144.7g, yield 83.6%.
2, the synthesis of [6- (4- aminomethyl phenyl) pyridine -2- base thiocarbamoyl] urethanes (compound 2)
Compound 1 (100g, 0.54mol) and ethyl acetate (800ml) are added in reaction flask, are cooled to 0 DEG C, is added dropwise
Different sulphur cyanato- Ethyl formate (78g, 0.59mol).It is heated to 50 DEG C of reactions 20h, TLC after dripping off and monitors fully reacting.After concentration
N-hexane (500ml) dilution, filtering is added, filter cake is washed twice with n-hexane (200mlX2), is dried to obtain [6- (4- methylbenzene
Base) pyridine -2- base thiocarbamoyl] urethanes (compound 2) 153.6g, yield 90.2%.
3, the synthesis of-[1,2,4] three thiazole [1,5-A] pyridine -2- amine (compound 3) of 5- (4- tolyl)
By compound 2 (80g, 0.25mol), hydroxylamine hydrochloride (87g, 1.25mol), n,N-diisopropylethylamine (97g,
It 0.75mol) is added in reaction flask with ethyl alcohol (1000ml), heating reflux reaction 5h, TLC monitor fully reacting.600ml is added
N-hexane is cooled to room temperature, and filtering, filter cake is washed with methyl tertiary butyl ether(MTBE), obtains (4- tolyl)-[1,2,4] 5- after dry
Three thiazoles [1,5-A] pyridine -2- amine (compound 3) 47.9g, yield 85.4%.
4, N- [- [1,2,4] three thiazole [1,5-A] pyridine -2- base of 5- (4- tolyl)] cyclopropane carboxamide (compound 4)
Synthesis compound 3 (90g, 0.4mol), potassium carbonate (138g, 1mol) and n,N-Dimethylformamide (700ml) are added to
In reaction flask, then cyclopropyl formyl chloride (52g, 0.5mol) is added dropwise, 80 DEG C of reactions 4h, TLC are heated to after dripping off and monitor fully reacting.
It is cooled to room temperature, 800ml water is added, is extracted with ethyl acetate, anhydrous sodium sulfate dries, filters, and N- [5- (4- is obtained after concentration
Tolyl)-[1,2,4] three thiazole [1,5-A] pyridine -2- base] cyclopropane carboxamide (compound 4) 107.2g, yield 91.7%.
5, N- [5 (4- 2-bromomethylphenyl)-[1,2,4] triazoles simultaneously [1,5-a] pyridine -2- base) ring and formamide (chemical combination
Object 5) synthesis by compound 4 (105g, 0.36mol), N- bromo-succinimide (77g, 0.43mol), azodiisobutyronitrile
(7.1g, 0.043mol) and carbon tetrachloride (900ml) are added in reaction flask, and back flow reaction 10h, TLC monitor fully reacting.Drop
It warms to room temperature, filters, be concentrated after filtrate washing, drying, obtain solid.It is washed with n-hexane (1000ml), obtains N- after dry
[5 (4- 2-bromomethylphenyl)-[1,2,4] triazoles simultaneously [1,5-a] pyridine -2- base) ring and formamide (compound 5) 115.2g, are received
Rate 86.2%.
6, N- (5- (4- ((1,1- dioxothiomorpholin) methyl) phenyl)-[1,2,4] triazole simultaneously [1,5-a] pyridine-
2- yl) ring and formamide (Filgotinib) synthesis
By compound 5 (60g, 0.16mol), thiomorpholine -1,1- dioxide (24g, 0.18mol), potassium carbonate
(44.6g, 0.32mol) and n,N-Dimethylformamide (500ml) are added in reaction flask, are heated to 80 DEG C of reaction 5h, TLC prisons
Control fully reacting.It is cooled to room temperature, reaction solution is poured slowly into 1500ml ice water, is stirred 20 minutes, filtering, filter cake methyl
Tertbutyl ether washing, drying, obtaining N-, (- [1,2,4] triazole is simultaneously by 5- (4- ((1,1- dioxothiomorpholin) methyl) phenyl)
[1,5-a] pyridine -2- base) ring and formamide (Filgotinib) 56.7g, yield 82.5%.
1 step 6 gained final product of Example, using nucleus magnetic hydrogen spectrum (1H-NMR it) is examined with LC-MS mass spectrograph (LCMS)
It surveys, as a result 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+).
It is compound Filgotinib according to 1 gained final product of the result embodiment of the present invention.
To sum up, the present invention provides the synthetic method of JAK1 inhibitor Filgotinib a kind of, synthetic methods of the invention
Using the route for being first coupled again closed loop, raw material is cheap, and operation is simple, product easy purification, high income, is suitble to commercial size
Production.
Claims (9)
1. a kind of preparation method of Filgotinib, it is characterised in that: the following steps are included:
(1) 2- amino -6- bromopyridine with to methylbenzene derivatives reaction, prepare compound 1；
(2) compound 1 is reacted with different sulphur cyanato- Ethyl formate, prepare compound 2；
(3) compound 2 is reacted with hydroxylamine hydrochloride, n,N-diisopropylethylamine, prepare compound 3；
(4) compound 3 is reacted with cyclopropyl formyl chloride, obtains compound 4；
(5) compound 4, N- bromo-succinimide are reacted with azodiisobutyronitrile, obtain compound 5；
(6) compound 5 and thiomorpholine -1,1- dioxide react, and obtain Filgotinib；
Wherein, described to be selected from methyl benzene derivative to methylphenylboronic acid, to methylphenylboronic acid ester, the structure of compound 1 isThe structure of compound 2 isThe structure of compound 3 isThe structure of compound 4 isThe structure of compound 5 isThe structure of Filgotinib is
2. according to the method described in claim 1, it is characterized by: the technique of the reaction includes: by 2- ammonia in step (1)
Base -6- bromopyridine is dissolved in reaction dissolvent to methyl benzene derivative, in the presence of a catalyst, reaction is heated in nitrogen atmosphere, instead
It is purified after answering；
And/or in step (2), the technique of the reaction includes: that compound 1 is dissolved in reaction dissolvent, then cooling is added different
Sulphur cyanato- Ethyl formate, heating reaction, purifies after reaction；
And/or in step (3), the technique of the reaction includes: that compound 2, hydroxylamine hydrochloride and n,N-diisopropylethylamine is molten
In reaction dissolvent, heating reaction purifies after reaction；
And/or in step (4), the technique of the reaction includes: that compound 3, catalyst are dissolved in reaction dissolvent, is then added dropwise
Cyclopropyl formyl chloride, heating reaction, purifies after reaction；
And/or in step (5), the technique of the reaction includes: that the technique of the reaction includes: by compound 4, N- bromo fourth
Imidodicarbonic diamide, azodiisobutyronitrile are dissolved in reaction dissolvent, and heating reaction purifies after reaction；
And/or in step (6), the technique of the reaction includes: by compound 5, thiomorpholine -1,1- dioxide and catalysis
Agent is dissolved in reaction dissolvent, and heating reaction purifies after reaction.
3. described to be selected from methyl benzene derivative to first according to the method described in claim 2, it is characterized by: in step (1)
Base phenyl boric acid.
4. according to the method in claim 2 or 3, it is characterised in that: in step (1), 2- amino -6- bromopyridine with to methyl
The molar ratio of benzene derivative is 1:(1.1-1.5)；The mass volume ratio of 2- amino -6- bromopyridine and reaction dissolvent is 1:(10-
30)g/mL；Reaction dissolvent is selected from the mixed solvent of Isosorbide-5-Nitrae-dioxane and water, and the volume ratio of the Isosorbide-5-Nitrae-dioxane and water is
(2-4): 1；The catalyst of reaction is potassium acetate and Pd (dppf) Cl2, potassium acetate and Pd (dppf) Cl2Molar ratio be (40-
60): 1；
And/or in step (2), the molar ratio of the compound 1 and different sulphur cyanato- Ethyl formate is 1:(1:1.5)；Compound 1
Mass volume ratio with reaction dissolvent is 1:(5-10) g/mL；Reaction dissolvent is selected from organic solvent；
And/or in step (3), the molar ratio of the compound 2, hydroxylamine hydrochloride and n,N-diisopropylethylamine is 1:(4-6):
(2-4)；The mass volume ratio of compound 2 and reaction dissolvent is 1:(10-15) g/mL；Reaction dissolvent is selected from organic solvent；
And/or in step (4), the molar ratio of the compound 3, catalyst and cyclopropyl formyl chloride is 1:(2-3): (1.2-2)；
The catalyst is selected from alkali；The mass volume ratio of compound 3 and reaction dissolvent is 1:(5-10) g/mL；Reaction dissolvent is selected from organic
Solvent；
And/or in step (5), the molar ratio of the compound 4, N- bromo-succinimide and azodiisobutyronitrile is 1:
(1.1-1.3): (0.11-0.13)；The mass volume ratio of compound 4 and reaction dissolvent is 1:(5-10) g/mL；Reaction dissolvent choosing
From organic solvent；
And/or in step (6), the molar ratio of the compound 5, thiomorpholine -1,1- dioxide and catalyst is 1:
(1.1-1.2): (1.5-2.5)；The catalyst is selected from alkali；The mass volume ratio of compound 5 and reaction dissolvent is 1:(5-10)
g/mL；Reaction dissolvent is selected from organic solvent.
5. according to the method described in claim 4, it is characterized by: in step (1), the 2- amino -6- bromopyridine with to first
The molar ratio of base benzene derivative is 1:1.2；The mass volume ratio of 2- amino -6- bromopyridine and reaction dissolvent is 1:20g/mL；Instead
Solvent is answered to be selected from the mixed solvent of Isosorbide-5-Nitrae-dioxane and water, the volume ratio of the Isosorbide-5-Nitrae-dioxane and water is 3:1；Reaction
Catalyst is potassium acetate and Pd (dppf) Cl2, potassium acetate and Pd (dppf) Cl2Molar ratio be 50:1；
And/or in step (2), the molar ratio of the compound 1 and different sulphur cyanato- Ethyl formate is 1:1.1；Compound 1 and anti-
The mass volume ratio for answering solvent is 1:8g/mL；Reaction dissolvent is selected from ethyl acetate；
And/or in step (3), the molar ratio of the compound 2, hydroxylamine hydrochloride and n,N-diisopropylethylamine is 1:5:3；Change
The mass volume ratio for closing object 2 and reaction dissolvent is 1:12.5g/mL；Reaction dissolvent is selected from ethyl alcohol；
And/or in step (4), the molar ratio of the compound 3, catalyst and cyclopropyl formyl chloride is 1:2.5:1.5；It is described to urge
Agent is selected from potassium carbonate；The mass volume ratio of compound 3 and reaction dissolvent is 1:7.8g/mL；Reaction dissolvent is selected from N, N- diformazan
Base formamide；
And/or in step (5), the molar ratio of the compound 4, N- bromo-succinimide and azodiisobutyronitrile is 1:
1.2:0.12；The mass volume ratio of compound 4 and reaction dissolvent is 1:8.6g/mL；Reaction dissolvent is selected from carbon tetrachloride；
And/or in step (6), the molar ratio of the compound 5, thiomorpholine -1,1- dioxide and catalyst is 1:
1.125:2；The catalyst is selected from potassium carbonate；The mass volume ratio of compound 5 and reaction dissolvent is 1:8.3g/mL；React molten
Agent is selected from N,N-dimethylformamide.
6. according to the method in claim 2 or 3, it is characterised in that: in step (1), the heating temperature is reflux temperature,
Reaction time is 10-15 hours；
And/or in step (2), the cooling temperature is -2~2 DEG C, and heating temperature is 40-60 DEG C, and the reaction time is that 15-25 is small
When；
And/or in step (3), the reaction time is 3-8 hours；
And/or in step (4), the heating temperature is 60-100 DEG C, and the reaction time is 2-6 hours；
And/or in step (5), the heating temperature is reflux temperature, and the reaction time is 8-12 hours；
And/or in step (6), the heating temperature is 60-100 DEG C, and the reaction time is 3-8 hours.
7. according to the method described in claim 6, it is characterized by: the reaction time is 13 hours in step (1)；
And/or in step (2), the cooling temperature is 0 DEG C, and heating temperature is 50 DEG C, and the reaction time is 20 hours；
And/or in step (3), the heating temperature is reflux temperature, and the reaction time is 5 hours；
And/or in step (4), the heating temperature is 80 DEG C, and the reaction time is 4 hours；
And/or in step (5), the reaction time is 10 hours；
And/or in step (6), the heating temperature is 80 DEG C, and the reaction time is 5 hours.
8. the method according to claim 2, it is characterised in that: in step (1), the purifying technique are as follows: in
At room temperature, system after reaction is adjusted to acidity, solid is precipitated, filtering takes solid, dissolved with alkaline solution, then used
Ethyl acetate extraction, takes organic phase, is concentrated；
And/or in step (2), the purifying technique are as follows: n-hexane will be added after system concentration after reaction, filters, Gu
Body is washed with n-hexane, dry；
And/or in step (3), the purifying technique are as follows: n-hexane, mistake is added into system after reaction at room temperature
Filter, solid are washed with methyl tertiary butyl ether(MTBE), dry；
And/or in step (4), the purifying technique are as follows: water is added into system after reaction at room temperature, uses acetic acid
Ethyl ester extraction, takes organic layer to be dried, filtered with anhydrous sodium sulfate, is concentrated；
And/or in step (5), the purifying technique are as follows: at room temperature, system after reaction is filtered, filtrate, water are taken
Wash, dry after be concentrated；
And/or in step (6), the purifying technique are as follows: at room temperature, system after reaction is poured into ice water, is stirred
It mixes, filters, solid is taken to be washed with methyl tertiary butyl ether(MTBE), dry.
9. according to the method described in claim 8, it is characterized by: in the purifying technique, being adjusted to acidity is in step (1)
The PH of system after reaction is adjusted to 3~6 with 2mol/L hydrochloric acid, the alkaline solution is that 2mol/L sodium hydroxide is water-soluble
Liquid；
And/or in step (2), in the purifying technique, the volume ratio of the n-hexane and reaction dissolvent that are added before filtering is 1:
1.6；
And/or in step (3), in the purifying technique, the volume ratio of the n-hexane and reaction dissolvent is 1:1.7；
And/or in step (4), in the purifying technique: the volume ratio of the water and reaction dissolvent is 0.8-1.2；
And/or in step (6), in the purifying technique: the volume ratio of the ice water and reaction dissolvent is 3:1.
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