CN117285506A - Rayleigh Lu Geli intermediate and preparation method thereof - Google Patents

Rayleigh Lu Geli intermediate and preparation method thereof Download PDF

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Publication number
CN117285506A
CN117285506A CN202311218931.4A CN202311218931A CN117285506A CN 117285506 A CN117285506 A CN 117285506A CN 202311218931 A CN202311218931 A CN 202311218931A CN 117285506 A CN117285506 A CN 117285506A
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compound
structural formula
mmol
formula vii
reaction
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杨峰
朱高翔
黄伟平
周立勇
叶四明
冯玉杰
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JIANGXI SYNERGY PHARMACEUTICAL CO Ltd
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JIANGXI SYNERGY PHARMACEUTICAL CO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a Rayleigh Lu Geli intermediate and a preparation method thereof. The preparation method comprises the following steps: alkaline hydrolysis is carried out on the compound with the structural formula VII-2 to obtain a compound with the structural formula VII-a; activating a compound of a structural formula VII-a by using N, N' -carbonyl diimidazole, and then reacting with nitromethane in the presence of alkali to generate a compound of a structural formula VII-b; reacting a compound of the structural formula VII-b with N, N-dimethylformamide dimethyl acetal to prepare a compound of the structural formula VII-c; the compounds of formulas VII-c were reduced with a reducing agent in the presence of water to afford the intermediate of the Rayleigh Lu Geli. The invention has low production cost and simple preparation method, and is beneficial to large-scale industrialized production.

Description

Rayleigh Lu Geli intermediate and preparation method thereof
Technical Field
The invention belongs to the field of organic chemistry, and particularly relates to a Rayleigh Lu Geli intermediate and a preparation method thereof.
Background
Rayleigh Lu Geli (CAS: 737789-87-6), chemical name: n- [4- [1- [ (2, 6-difluorophenyl) methyl ] -5- [ (dimethylamino) methyl ] -1,2,3, 4-tetrahydro-3- (6-methoxy-3-pyridazinyl) -2, 4-dioxothieno [2,3-D ] pyrimidin-6-yl ] phenyl ] -N' -methoxyurea, developed by Wuta-further pharmaceutical and ASKA Pharmaceutical, is a small molecule GnRH receptor antagonist that reduces GnRH (luteinizing hormone and follicle stimulating hormone) release by binding to and blocking the GnRH receptor (GnRHR) in the anterior pituitary, thereby reducing estrogen and progesterone secretion in the female ovary and ultimately achieving an effective reduction of uterine fibroids. In addition to being used to treat uterine fibroids, rayleigh Lu Geli has also been approved for the treatment of advanced prostate cancer.
The molecular structure of the Rui Lu Geli is shown in formula I:
the synthetic method of the wuta pharmaceutical publication is shown below (CN 104703992): firstly, p-nitrophenylacetic acid (compound A) reacts with thionyl chloride to prepare acyl chloride B, and the acyl chloride B is directly used for the next reaction without separation; step two, the compound B is subjected to hydrolysis decarboxylation after condensation with malonate to obtain a compound C, and the compound C is directly used for the next reaction without separation; thirdly, condensing the compound C with elemental sulfur and ethyl cyanoacetate to form a ring to prepare a compound D, wherein the yield of the three steps is 80 percent; fourth, compound D is reacted with ethyl chloroformate to obtain compound F in 96% yield; fifthly, carrying out substitution reaction on the compound E and 2, 3-difluorobenzyl bromide in the presence of alkali to generate a compound F, wherein the yield is 95%; step six, bromine is added to the compound F by NBS through free radical reaction, and the compound G is obtained in 92 percent yield with the purity of 93 percent; seventhly, carrying out substitution reaction on the compound G and dimethylamine hydrochloride to prepare a compound H, wherein the yield is 89%; eighth step, compound F is hydrolyzed to obtain compound J with 90 percent of yield; ninth, the carboxyl of the compound J is activated firstly, and then the compound J is condensed with 3-amino-6-methoxypyridazine through amide to prepare the compound K, and the yield is 97%; tenth step, compound K is cyclized with a base to give compound L in 98% yield; eleventh, the compound of formula L is reduced to afford the compound of formula M in 84% yield; in the twelfth step, compound M is activated with CDI (N, N' -carbonyldiimidazole) and then reacted with methoxyamine to prepare the final compound I, i.e., r. Lu Geli.
The above route has a certain problem, firstly, thionyl chloride is used in the preparation of the compound B, so that the compound B has large odor and is toxic, and is not beneficial to environmental protection; secondly, a large amount of acid is used for preparing the compound C, and the waste liquid amount is large; finally, the free radical reaction used in the synthesis of compound G from compound F is poorly controlled, and impurities which are difficult to separate (compound G purity 93%) are formed. Therefore, developing a method for synthesizing the synthetic target Lu Geli which is easy to control, moderate in cost and environment-friendly is necessary for ensuring safe production and reducing the cost of mass administration.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a thiophene compound with a structural formula M, a preparation method thereof and application thereof in preparation of a Rayleigh Lu Geli and an intermediate VII thereof.
The synthesis of Guan Ruilu gol in the prior art requires the use of a large amount of acid, is strong in odor during synthesis, is not environment-friendly, and has free radical reaction, so that the impurity content is high and the removal is difficult. In the invention, the initial raw material for synthesizing the thiophene compound with the structural formula M is replaced by paranitrotoluene, the synthetic route is reduced from 4 steps to 3 steps, the cost price of the raw material is greatly reduced, and the use of toxic and malodorous SOCl is avoided 2 And a large amount of acid, which is beneficial to reducing the production cost and being beneficial to safe and environment-friendly production. In the prior art, methyl on the thiophene ring of the intermediate E is converted into bromomethyl through free radical reaction in the subsequent process, and then the bromomethyl is substituted with dimethylamine to generate-CH 2 NMe 2 The free radical reaction is used in the route, so that the reaction is not easy to control, impurities which are difficult to separate can be generated, and the whole process has two steps; intermediate M of the inventionIn the subsequent process, introducing-CH on thiophene ring by Mannich reaction 2 NMe 2 Free radical reaction is not used and only one step is used; in addition, the whole route for synthesizing the rake Lu Geli is reduced from the original 12 steps to 10 steps, so that the production cost and time are greatly reduced.
In order to achieve the above object, the present invention adopts the following technical scheme:
thiophene compounds of the following structural formula M:
wherein R is 1 Is OH, NH 2 Methoxy, ethoxy, propoxy, n-butoxy, n-pentoxy, n-hexoxy or benzyloxy, R 2 Is C 1 -C 6 Alkyl or benzyl.
The preparation method of the compound of the structural formula M comprises the following steps:
step A: the method comprises the steps of (1) carrying out condensation reaction on paranitrotoluene of a structural formula XI serving as a starting material and N, N-dimethylformamide dimethyl acetal to obtain a compound of a structural formula X;
and (B) step (B): compounds of formula X with elemental sulfur and cyano compounds NCCH 2 COR 1 Reacting in the presence of a base to obtain a compound of formula IX;
step C: the compound of formula IX is reacted with chloroformate to give the compound of formula M.
Preferably, the molar ratio of para-nitrotoluene of formula XI to N, N-dimethylformamide dimethyl acetal in step A is from 1:1 to 1:10, more preferably from 1:1 to 1:3.
Preferably, the reaction solvent in the step a is one of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, and toluene, and more preferably N, N-dimethylformamide.
Preferably, the reaction temperature of step A is 50-200deg.C, more preferably 80-160deg.C.
Preferably, the molar ratio of the compound of formula X to elemental sulfur in step B is from 1:1 to 1:2, more preferably from 1:1 to 1:1.2.
Preferably, the compound of formula X in step B is combined with a cyano compound NCCH 2 COR 1 The molar ratio of (2) is 1:1 to 1:2, more preferably 1:1 to 1:1.2.
Preferably, the base in the step B is one of morpholine, piperidine and pyrrolidine, and more preferably morpholine.
Preferably, the molar ratio of the compound of formula X to the base in step B is from 1:0.5 to 1:5, more preferably from 1:0.5 to 1:3.
Preferably, the reaction solvent in the step B is one of methanol, ethanol, isopropanol, tert-butanol, dichloromethane, ethyl acetate, acetone and tetrahydrofuran, and more preferably methanol or ethanol.
Preferably, the cyano compound NCCH in step B 2 COR 1 One of cyanoacetic acid, cyanoacetamide, methyl cyanoacetate, ethyl cyanoacetate, n-propyl cyanoacetate, isopropyl cyanoacetate, n-butyl cyanoacetate, n-pentyl cyanoacetate, n-hexyl cyanoacetate and benzyl cyanoacetate. More preferably one of cyanoacetic acid, cyanoacetamide, methyl cyanoacetate, and ethyl cyanoacetate.
Preferably, the reaction temperature of step B is from 30 to 100deg.C, more preferably from 50 to 80deg.C.
Preferably, the molar ratio of the compound of formula IX to chloroformate in step C is from 1:1 to 1:10, more preferably from 1:1 to 1:3.
Preferably, the reaction solvent in the step C is one of toluene, N-dimethylformamide and dimethyl sulfoxide, and more preferably toluene.
Preferably, the reaction temperature of step C is 50-150deg.C, more preferably 100-130deg.C.
The invention also provides a revascularization Lu Geli intermediate of structural formula VII:
wherein R is 3 Is methoxy, ethoxy, propoxy, n-butoxy, n-pentoxy, n-hexoxy or benzyloxy, R 2 Is C 1 -C 6 Alkyl or benzyl.
The preparation of the intermediate of formula VII, r Lu Geli, is as follows:
wherein R is 3 Is methoxy, ethoxy, propoxy, n-butoxy, n-pentoxy, n-hexoxy or benzyloxy, R 2 Is C 1 -C 6 Alkyl or benzyl.
And step A, carrying out substitution reaction on the compound of the structural formula VIII and 2, 6-difluorobenzyl chloride in the presence of alkali to generate the compound of the structural formula VII.
Preferably, the molar ratio of the compound of formula VIII to 2, 6-difluorobenzyl chloride in step A is from 1:1 to 1.5:1, more preferably from 1:1 to 1.2:1.
Preferably, the base in the step a is one of potassium carbonate, sodium carbonate, potassium hydroxide, sodium methoxide, sodium ethoxide and potassium tert-butoxide, and more preferably is potassium carbonate or sodium carbonate.
Preferably, the molar ratio of the compound of formula VIII to the base in step A is from 1:0.5 to 1:2, more preferably from 1:0.8 to 1:1.5.
Preferably, the reaction solvent in the step a is one of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, acetonitrile and tetrahydrofuran, and more preferably N, N-dimethylformamide.
Preferably, the reaction temperature of step A is from 30 to 120℃and more preferably from 50 to 100 ℃.
Another object of the present invention is to provide a process for preparing rayl Lu Geli from a rayl Lu Geli intermediate of formula VII, comprising the steps of:
wherein R is 3 Is methoxy, ethoxy, propoxy, n-butoxy, n-pentoxy, n-hexoxy or benzyloxy, R 2 Is C 1 -C 6 Alkyl or benzyl.
Step 1, reducing a compound with a structural formula VII by a catalyst to obtain a compound with a structural formula VI;
step 2, reacting a compound of a structural formula VI with a condensing agent in the presence of alkali with methoxyamine hydrochloride to prepare a compound of a structural formula V;
step 3, carrying out alkaline hydrolysis on the compound with the structural formula V to obtain a compound with the structural formula IV;
step 4, performing a Mannich reaction on the compound of the structural formula IV, dimethylamine and formaldehyde in an acid solvent to generate a compound of the structural formula III;
step 5, reacting a compound of the structural formula III with 3-amino-6-methoxypyridazine in the presence of an activating reagent and a base to generate a compound of the structural formula II;
and 6, cyclizing the compound of the structural formula II under alkaline conditions to obtain the compound of the structural formula I.
Preferably, the catalyst in the step 1 is one of palladium carbon, platinum carbon and Raney nickel, and more preferably palladium carbon.
Preferably, the mass ratio of catalyst to compound of formula VII in step 1 is from 0.05:1 to 0.5:1, more preferably from 0.1:1 to 0.3:1.
Preferably, the reducing agent in the step 1 is one of ammonium formate, formic acid and hydrogen, and more preferably ammonium formate.
Preferably, the reaction solvent in the step 1 is one or a combination of several of dichloromethane, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, N-dimethylformamide and dimethyl sulfoxide.
Preferably, the reaction temperature in step 1 is 20 to 100 ℃, more preferably 40 to 80 ℃.
Preferably, the molar ratio of condensing agent to compound of formula VI in step 2 is from 1:1 to 4:1, more preferably from 1.1:1 to 2.5:1. The condensing agent is N, N '-carbonyl diimidazole or N, N' -dicyclohexyl carbodiimide.
Preferably, the molar ratio of methoxyamine hydrochloride of step 2 to the compound of formula VI is from 1:1 to 4:1, more preferably from 1.1:1 to 2.5:1.
Preferably, the base in the step 2 is one of triethylamine, N-methylmorpholine, N-methylpyrrolidine, pyridine and triethylenediamine, and more preferably triethylamine.
Preferably, the molar ratio of base to compound of formula VI in step 2 is from 1:1 to 4:1, more preferably from 1.1:1 to 2.5:1.
Preferably, the reaction solvent in the step 2 is one of dichloromethane, tetrahydrofuran, ethyl acetate, acetone, methanol, ethanol, isopropanol, acetonitrile and toluene, and more preferably dichloromethane.
Preferably, the reaction temperature of step 2 is 10-80 ℃, more preferably 20-50 ℃.
Preferably, the alkali in the step 3 is sodium hydroxide or potassium hydroxide.
Preferably, the molar ratio of the compound of formula V to the base in step 3 is from 1:1 to 3:1, more preferably from 1.1:1 to 2:1.
Preferably, the reaction temperature in step 3 is 20 to 100 ℃, more preferably 40 to 70 ℃.
Preferably, the molar ratio of the compound of formula IV to formaldehyde in step 4 is from 1:1 to 1:100, more preferably from 1:2 to 1:30.
Preferably, the molar ratio of the compound of formula IV to dimethylamine in step 4 is from 1:1 to 1:100, more preferably from 1:2 to 1:30.
Preferably, the acidic solvent in the step 4 is one of acetic acid, formic acid, hydrochloric acid and sulfuric acid, and more preferably acetic acid.
Preferably, the reaction temperature in step 4 is 20 to 80 ℃, more preferably 30 to 60 ℃.
Preferably, the activator of the step 5 is one of 1-propyl phosphoric acid cyclic anhydride, triphosgene and N, N' -carbonyl diimidazole, and more preferably 1-propyl phosphoric acid cyclic anhydride.
Preferably, the molar ratio of the activator of step 5 to the compound of formula III is from 0.4:1 to 5:1, more preferably from 0.4:1 to 3:1.
Preferably, the base in the step 5 is one of triethylamine, N-methylmorpholine, N-methylpyrrolidine, pyridine and triethylenediamine, and more preferably triethylamine.
Preferably, the molar ratio of the base to compound III in step 5 is from 1:1 to 3:1, more preferably from 1:1 to 2:1.
Preferably, the molar ratio of 3-amino-6-methoxypyridazine of step 5 to the compound of formula III is 1:1 to 3:1, more preferably 1:1 to 2:1.
Preferably, the reaction solvent in the step 5 is one of tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, acetonitrile, N-dimethylformamide and dimethyl sulfoxide, and more preferably tetrahydrofuran.
Preferably, the reaction temperature of step 5 is 20 to 100 ℃, more preferably 40 to 80 ℃.
Preferably, the alkali in the step 6 is one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide and sodium hydride, and more preferably sodium methoxide.
Preferably, the molar ratio of base to compound of formula II in step 6 is from 0.1:1 to 1.2:1, more preferably from 0.2:1 to 0.8:1.
Preferably, the reaction solvent in the step 6 is one of methanol, ethanol and isopropanol, and more preferably methanol.
Preferably, the reaction temperature of step 6 is 30-100deg.C, more preferably 40-80deg.C.
The invention also provides a novel synthesis method for preparing the intermediate J of Lu Geli in the background technology by using the VII-2 compound, which comprises the following steps:
step S1, carrying out alkaline hydrolysis on a compound with a structural formula VII-2 to obtain a compound with a structural formula VII-a;
s2, activating a compound with a structural formula VII-a through N, N' -carbonyl diimidazole, and reacting with nitromethane in the presence of alkali to generate a compound with a structural formula VII-b;
s3, reacting the compound with the structural formula VII-b with N, N-dimethylformamide dimethyl acetal to prepare a compound with the structural formula VII-c;
in step S4, the compound of formula VII-c is reduced by a reducing agent in the presence of water to provide the intermediate of formula J, namely, rayleigh Lu Geli.
Preferably, the alkali in the step S1 is sodium hydroxide or potassium hydroxide.
Preferably, the molar ratio of base to compound of formula VII-2 of step S1 is from 1:1 to 3:1, more preferably from 1.1:1 to 2:1.
Preferably, the reaction temperature of step S1 is 10-100deg.C, more preferably 40-80deg.C.
Preferably, the molar ratio of N, N' -carbonyldiimidazole to the compound of formula VII-a in step S2 is 1:1-3:1, more preferably 1.1:1-2:1.
Preferably, the base of step S2 is selected from potassium tert-butoxide or 1, 8-diazabicyclo undec-7-ene.
Preferably, the molar ratio of base to compound of formula VII-a of step S2 is from 1:1 to 10:1, more preferably from 1.1:1 to 5:1.
Preferably, the molar ratio of nitromethane to the compound of formula VII-a of step S2 is from 1:1 to 10:1, more preferably from 1.1:1 to 5:1.
Preferably, the reaction solvent of step S2 is selected from tetrahydrofuran or acetonitrile.
Preferably, the reaction temperature of step S2 is 0-80 ℃, more preferably 10-40 ℃.
Preferably, the molar ratio of the compound of formula VII-b to N, N-dimethylformamide dimethyl acetal in step S3 is from 1:1 to 1:5, more preferably from 1:1 to 1:2.
Preferably, the reaction solvent of step S3 is selected from tetrahydrofuran or acetonitrile.
Preferably, the reaction temperature of step S3 is 20-80 ℃, more preferably 30-60 ℃.
Preferably, the reducing agent in the step S4 is sodium borohydride or potassium borohydride.
Preferably, the molar ratio of the compound of formula VII-c to the reducing agent in step S4 is from 1:0.3 to 1:3, more preferably from 1:0.3 to 1:1.5.
Preferably, the reaction solvent in the step S4 is ethanol.
Preferably, the reaction temperature of step S4 is 0-80℃and more preferably 0-50 ℃.
Compared with the prior art, the invention has the following beneficial effects:
1. the initial raw materials of paranitrotoluene and N, N-dimethylformamide dimethyl acetal are very cheap and easy to obtain, the synthetic route is reduced from 4 steps to 3 steps, the cost price of the raw materials is greatly reduced, and the use of toxic and malodorous SOCl is avoided 2 And a large amount of acid, which is beneficial to reducing the production cost and being beneficial to safe and environment-friendly production;
2. the free radical reaction from the compound of formula E to the compound of formula G is avoided in this route, so that no impurities which are difficult to isolate are formed, the intermediate VIII of the invention is introduced into the thiophene ring by the Mannich reaction in the subsequent process 2 NMe 2 Free radical reaction is not used and only one step is used;
3. the route for synthesizing the praise Lu Geli is only ten steps, and compared with twelve steps in the prior art, the method greatly reduces the production time and the cost.
Detailed Description
The invention is described below with reference to specific examples. It will be appreciated by those skilled in the art that these examples are for illustration of the invention only and are not intended to limit the scope of the invention in any way.
The experimental methods in the following examples are conventional methods unless otherwise specified. The raw materials, reagent materials and the like used in the examples described below are commercially available products unless otherwise specified.
Example 1
The preparation method of the compound of the structural formula X comprises the following steps:
to the flask were added 30.0g (0.21 mol) of paranitrotoluene of formula XI, 28.7g (0.24 mol) of N, N-dimethylformamide dimethyl acetal and 100mL of N, N-dimethylformamide, and the mixture was heated to 120℃to react for 9 hours; additional 5.2g (43.6 mmol) of N, N-dimethylformamide dimethyl acetal was added and the reaction was continued for 5h at 120 ℃; then, 5.2g (43.6 mmol) of N, N-dimethylformamide dimethyl acetal was added again, and the reaction was carried out at 120℃for 5 hours; cooling to room temperature, pouring the reaction solution into 600mL of ice water, stirring for 30min, and filtering; sequentially washing with 200mL of water and 200mL of n-hexane, and drying to obtain 36.1g of brownish red solid of structural formula X, with 86% yield and 98% purity, 1 H-NMR(400M，DMSO-d 6 )：7.95(2H，d)，7.50(1H，d)，7.27(2H，d)，5.19(1H，d)，2.92(6H，s)。
example 2
The preparation method of the compound of the structural formula X comprises the following steps:
the preparation was identical to example 1, except that the N, N-dimethylformamide used in example 1 was replaced by dimethyl sulfoxide, giving 37.0g of a reddish brown solid of the formula X in 88% yield and 98% purity, and the nuclear magnetic data were identical to those of example 1.
Example 3
The preparation method of the compound of the structural formula X comprises the following steps:
to the flask were added 30.0g (0.22 mol) of paranitrotoluene of formula XI, 28.7g (0.24 mol) of N, N-dimethylformamide dimethyl acetal and 100mL of N, N-dimethylformamide, and the mixture was heated to 140℃to react for 7 hours; 7.2g (60.0 mmol) of N, N-dimethylformamide dimethyl acetal was added thereto, and the reaction was continued at 140℃for 3 hours; then 7.2g (60.0 mmol) of N, N-dimethylformamide dimethyl acetal was added again, and the reaction was carried out at 140℃for 3 hours; cooling to room temperature, pouring the reaction solution into 600mL of ice water, stirring for 30min, and filtering; washing with 200mL of water and 200mL of n-hexane in this order, and drying gave 39.1g of a reddish brown solid of formula X in 93% yield, 98% purity and nuclear magnetic data consistent with example 1.
Example 4
The preparation method of the compound of the structural formula M-1 comprises the following steps:
step 1, preparation of a compound of formula IX-1:
14.3g (74.4 mmol) of the compound of formula X, 7.45g (75.2 mmol) of methyl cyanoacetate, 2.4g (74.8 mmol) of elemental sulfur, 150mL of methanol and 15.0mL (173 mmol) of morpholine are introduced into a flask, and the mixture is heated to 80℃and reacted for 3 hours; distilling under reduced pressure until 70mL of methanol remains, pouring the reaction solution into 500mL of ice water, stirring for 30min, and precipitating a large amount of reddish brown solid; filtering, washing once with 50mL of water, drying to obtain 19.7g of red solid IX-1, yield 95% and purity 99%, 1 H-NMR(400M,CDCl 3 )：8.16(2H，d)，7.51(2H，d)，7.49(1H，s)，6.27(2H，s)，3.86(3H，s)。
step 2, preparation of a compound of the structural formula M-1:
10.0g (35.9 mmol) of the compound of formula IX-1 are introduced into a bottle and crushed into powder, 35mL of toluene and 4.1g (43.1 mmol) of methyl chloroformate are further added, and the mixture is heated to 120℃and reacted for 3 hours; 1.4g (14.7 mmol) of methyl chloroformate was additionally added thereto and reacted at 120℃for 2 hours; finally, 1.4g (14.7 mmol) of methyl chloroformate is added and reacted at 120 ℃ for 2 hours; cooling to 55 ℃, and dropwise adding 100mL of methanol; cooling to 5 ℃ after the addition, and stirring for 60min; filtering, washing with 20mL of methanol, drying to obtain 11.7g of yellow solid compound M-1, with 97% yield and 99% purity, 1 H-NMR(400M,CDCl 3 )：10.26(1H，s)，8.21(2H，d)，7.66(2H，d)，7.55(1H，s)，3.91(6H，s)。
example 5
The preparation method of the compound of the structural formula M-2 comprises the following steps:
step 1, preparation of a compound of formula IX-2:
14.3g (74.4 mmol) of the compound of formula X, 9.1g (80 mmol) of ethyl cyanoacetate, 2.6g (80 mmol) of elemental sulfur, 150mL of ethanol and 17.3mL (200 mmol) of morpholine are added to the flask, and the mixture is heated to 70℃for reaction for 5h; distilling under reduced pressure until 70mL of ethanol remains, pouring the reaction solution into 500mL of ice water, stirring for 30min, and precipitating a large amount of brownish red solid; filtering, washing once with 50mL of water, drying to obtain 20.4g of red solid IX-2, yield 94% and purity 99%, 1 H-NMR(400M,CDCl 3 )：8.18(2H，d)，7.52(2H，d)，7.49(1H，s)，6.28(2H，s)，4.32(2H，q)，1.38(3H，t)。
step 2, preparation of a compound of the structural formula M-2:
10.5g (35.9 mmol) of the compound of formula IX-2 are introduced into a bottle and crushed into powder, 35mL of toluene and 4.7g (43.1 mmol) of ethyl chloroformate are further added, and the mixture is heated to 110℃and reacted for 4 hours; 2.2g (20.0 mmol) of ethyl chloroformate was additionally added, and the mixture was reacted at 110℃for 2 hours; finally, 2.2g (20.0 mmol) of ethyl chloroformate is added for reaction for 2 hours at 110 ℃; cooling to 55 ℃, and dripping 100mL of ethanol; cooling to 5 ℃ after the addition, and stirring for 60min; filtering, washing with 20mL of ethanol, drying to obtain 12.6g of yellow solid compound M-2, with 96% yield and 99% purity, 1 H-NMR(400M,CDCl 3 )：10.29(1H，s)，8.21(2H，d)，7.66(2H，d)，7.56(1H，s)，4.33-4.38(4H，m)，1.37-1.40(6H，m)。
example 6
The preparation method of the compound of the structural formula M-3 comprises the following steps:
step 1, preparation of a compound of formula IX-3:
14.3g (74.4 mmol) of the compound of formula X, 13.2g (75 mmol) of benzyl cyanoacetate, 2.4g (75 mmol) of elemental sulfur, 150mL of t-butanol and 15.0mL (173 mmol) of morpholine are introduced into a bottle and reacted for 4 hours at 75℃temperature; distilling under reduced pressure until 70mL of tertiary butanol remains, pouring the reaction solution into 500mL of ice water, stirring for 30min, and precipitating a large amount of red solid; passing throughFiltering, washing once with 50mL of water, and drying to obtain 23.5g of red solid IX-3, with 89% yield and 97% purity, 1 H-NMR(400M,CDCl 3 )：8.19(2H，d)，7.53-7.55(4H，m)，7.52(1H，s)，7.48(2H，dd)，7.41(1H，t)，6.30(2H，s)，5.41(2H，s)；
step 2, preparation of a compound of the structural formula M-3:
to the flask was added 12.7g (35.9 mmol) of the compound of formula IX-3 and crushed into a powder, and 35mL of toluene and 7.4g (43.1 mmol) of benzyl chloroformate were added and the mixture was heated to 115℃to react for 3 hours; 2.7g (16.0 mmol) of benzyl chloroformate was additionally added, and the mixture was reacted at 115℃for 2 hours; finally, 2.7g (16.0 mmol) of benzyl chloroformate was added thereto and reacted at 115℃for 2 hours; cooling to 5 ℃, and dropwise adding 100mL of methanol; after the addition, keeping the temperature of 5 ℃ and stirring for 3 hours; filtering, washing with 20mL of methanol, drying to obtain 15.9g of yellow solid compound M-3, with 91% yield and 97% purity, 1 H-NMR(400M,CDCl 3 )：10.35(1H，s)，8.29(2H，d)，7.69(2H，d)，7.60(1H，s)，7.55-7.40(10H，m)，5.41(4H，s)。
example 7
The preparation method of the compound of the structural formula VIII-4 comprises the following steps:
step 1, preparation of a compound of formula IX-4:
14.3g (74.4 mmol) of the compound of formula X, 6.8g (80 mmol) of cyanoacetic acid, 2.6g (80 mmol) of elemental sulfur, 150mL of ethanol and 15.0mL (173 mmol) of morpholine are added to the flask, and the mixture is heated to 80℃for reaction for 8h; spin-drying, recrystallizing the obtained solid isopropyl ether to obtain 16.5g of red solid IX-4 with yield of 84% and purity of 99%, 1 H-NMR(400M,CDCl 3 )：11.45(1H，br)，8.11(2H，d)，7.49(2H，d)，7.40(1H，s)，6.18(2H，s)；
step 2, preparation of a compound of the structural formula M-4:
9.5g (35.9 mmol) of the compound of formula IX-4 are introduced into a bottle and crushed into powder, 35mL of toluene and 4.1g (43.1 mmol) of methyl chloroformate are further added, and the mixture is heated to 90℃and reacted for 3 hoursThe method comprises the steps of carrying out a first treatment on the surface of the 1.4g (14.7 mmol) of methyl chloroformate was additionally added thereto and reacted at 90℃for 2 hours; finally, 1.4g (14.7 mmol) of methyl chloroformate is added and reacted at 90 ℃ for 2 hours; cooling to 55 ℃, and dropwise adding 100mL of methanol; cooling to 5 ℃ after the addition, and stirring for 60min; filtering, washing with 20mL of methanol, drying to obtain 9.8g of yellow solid compound M-4, with yield of 85% and purity of 99%, 1 H-NMR(400M,CDCl 3 )：12.25(1H，br)，10.20(1H，s)，8.20(2H，d)，7.64(2H，d)，7.53(1H，s)，3.87(3H，s)。
example 8
The preparation method of the compound of the structural formula M-5 comprises the following steps:
step 1, preparation of a compound of formula IX-5:
14.3g (74.4 mmol) of the compound of formula X, 6.8g (80.4 mmol) of cyanoacetamide, 2.6g (80 mmol) of elemental sulfur, 150mL of methanol and 15.0mL (173 mmol) of morpholine are added to a bottle, and the mixture is heated to 70℃for reaction for 6h; spin-drying and recrystallization of the resulting solid from isopropyl ether gave 16.8g of red solid IX-5 in 86% yield and 99% purity. 1 H-NMR(400M,CDCl 3 )：10.05(2H，br)，8.13(2H，d)，7.50(2H，d)，7.41(1H，s)，6.20(2H，s)；
Step 2, preparation of a compound of the structural formula M-5:
9.45g (35.9 mmol) of the compound of formula IX-5 are introduced into a bottle and crushed into powder, 35mL of toluene and 4.1g (43.1 mmol) of methyl chloroformate are further added, and the mixture is heated to 110℃and reacted for 3 hours; 1.4g (14.7 mmol) of methyl chloroformate was additionally added thereto and reacted at 110℃for 2 hours; finally, 1.4g (14.7 mmol) of methyl chloroformate is added and reacted at 110 ℃ for 2 hours; cooling to 55 ℃, and dropwise adding 100mL of methanol; cooling to 5 ℃ after the addition, and stirring for 60min; filtering, washing with 20mL of methanol, drying to obtain 9.6g of yellow solid compound M-5, yield 83% and purity 99%, 1 H-NMR(400M,CDCl 3 )：10.22-10.15(3H，br)，8.23(2H，d)，7.65(2H，d)，7.54(1H，s)，3.89(3H，s)。
example 9
A process for the preparation of a compound of formula VII-1 comprising the steps of:
to the flask were added 11.5g (34.25 mmol) of the compound of formula VIII-1, 5.20g (37.7 mmol) of potassium carbonate powder, 50mL of N, N-dimethylformamide and 6.1g (37.7 mmol) of 2, 6-difluorobenzyl chloride, and the mixture was heated to 85℃for reaction for 4 hours; the reaction solution was poured into 150mL of ice water and extracted with ethyl acetate (80 mL each time, three times); the organic phases were combined and spin distilled to a volume of about 40mL; cooling to 5 ℃, gradually adding 160mL of heptane, and stirring for 60min after the addition is finished; filtering and drying to obtain 15.4g yellow solid compound VII-1 with yield of 96% and purity of 99%, 1 H-NMR(400M,CDCl 3 )：8.22(2H，d)，7.68(1H，s)，7.63(2H，d)，7.25(1H，dd)，6.84(2H，t)，5.04(2H，s)，3.83(3H，s)，3.73(3H，s)。
example 10
A process for the preparation of a compound of formula VII-2 comprising the steps of:
to the flask were added 12.5g (34.25 mmol) of the compound of formula VIII-2, 5.8g (42.0 mmol) of potassium carbonate powder, 50mL of N, N-dimethylformamide and 6.8g (42.0 mmol) of 2, 6-difluorobenzyl chloride, and the mixture was heated to 85℃to react for 4 hours; the reaction solution was poured into 150mL of ice water and extracted with ethyl acetate (80 mL each time, three times); the organic phases were combined and spin distilled to a volume of about 40mL; cooling to 5 ℃, gradually adding 160mL of heptane, and stirring for 60min after the addition is finished; filtering and drying to obtain 16.3g yellow solid compound VII-2 with 97 percent yield and 99 percent purity, 1 H-NMR(400M，CDCl 3 )：8.22(2H，d)，7.68(1H，s)，7.63(2H，d)，7.25(1H，dd)，6.84(2H，t)，5.04(2H，s)，4.30-4.35(4H，m)，1.35-1.39(6H，m)。
example 11
A process for the preparation of a compound of formula VII-3 comprising the steps of:
to the flask were added 16.7g (34.25 mmol) of the compound of formula VIII-3, 5.8g (42.0 mmol) of potassium carbonate powder, 50mL of N, N-dimethylformamide and 6.7g (41.2 mmol) of 2, 6-difluorobenzyl chloride, and the mixture was heated to 75℃for reaction for 6 hours; the reaction solution was poured into 150mL of ice water and extracted with ethyl acetate (80 mL each time, three times); the organic phases were combined and spin distilled to a volume of about 40mL; cooling to 5 ℃, gradually adding 160mL of heptane, and stirring for 60min after the addition is finished; filtering and drying to obtain 20.0g yellow solid compound VII-3 with yield of 95% and purity of 99%, 1 H-NMR(400M，CDCl 3 )：8.30(2H，d)，7.70(1H，s)，7.65(2H，d)，7.55-7.41(10H，m)，7.25(2H，dd)，6.86(1H，m)，5.41(2H，s)，5.37(2H，s)，5.04(2H，s)。
example 12
The preparation method of the compound of the structural formula I comprises the following steps:
step 1-3, preparation of a compound of formula IV-1:
to the flask were added 10.0g (21.63 mmol) of the compound of formula VII-1, 50mL of methylene chloride, 50mL of methanol, 1.5g of palladium on carbon (10% content, 50% aqueous), and the mixture was warmed to 30℃and 5.45g (86.52 mmol) of ammonium formate was added in portions, and after the addition was completed, the mixture was allowed to react at 30℃for 5 hours; cooling to 10deg.C, adding 50mL of dichloromethane, stirring for 30min, filtering, and spin-drying to obtain compound of formula VI-1, which can be directly used in the next step without separation; 100mL of dichloromethane, 7.0g (43.26 mmol) of N, N' -carbonyldiimidazole and 2.63g (26.0 mmol) of triethylamine are added into another reaction bottle, the temperature is reduced to 10 ℃, 4.0g (47.6 mmol) of methoxyamine hydrochloride is added in batches, the temperature is raised to 30 ℃ after the addition is finished, the reaction is carried out for 30min, the compound with the structural formula VI-1 is added, the reaction is carried out for 6h at the temperature of 40 ℃ after the addition is finished, and the compound with the structural formula V-1 is obtained after spin drying, and is directly used in the next step without separation; in the compound V-1 thus obtained70mL of methanol, 30mL of water and 1.8g (32.45 mmol) of potassium hydroxide are added, the temperature is raised to 60 ℃ for reaction for 5 hours, heating is stopped, 70mL of ice water is added, the pH is adjusted to 2 by hydrochloric acid, the aqueous phase is extracted by ethyl acetate (three times, 70mL each) after methanol is removed by reduced pressure distillation, the organic phases are combined, dried by anhydrous sodium sulfate, filtered, distilled to about the remaining 40mL of ethyl acetate, cooled to 5 ℃, 60mL of heptane is added dropwise, stirring is carried out for 2 hours after the addition, the filtration and drying are carried out, 9.0g of white solid compound with the structural formula IV-1 is obtained, the yield is 85 percent, the purity is 99 percent, 1 H-NMR(400M，CDCl 3 )：8.53(1H，br)，7.59(1H，br)，7.52-7.41(5H，m)，7.22(1H，m)，6.82(2H，t)，6.77(1H，br)，5.05(2H，br)，3.84(3H，s)，3.74(3H，s)；
step 4, preparation of a compound of structural formula III-1:
to the flask were added 8.0g (16.28 mmol) of the compound of formula IV-1, 80mL of glacial acetic acid, 6.6g of formalin (81.4 mmol of formaldehyde, 37% content), 7.3g of aqueous dimethylamine solution (81.4 mmol,50% content), and the mixture was heated to 50℃for reaction for 4 hours; the reaction solution was poured into 120mL of water, extracted with ethyl acetate (three times, 100mL each time), the organic phases were combined, washed with water (two times, 50mL each time), the organic phases were spin-dried, and the obtained solid was recrystallized from toluene to give 7.86g of a white solid compound of the structural formula III-1 in 88% yield and 99% purity, 1 H-NMR(400M，CDCl 3 )：8.05(1H，br)，7.58(1H，br)，7.46-7.40(4H，m)，7.22(1H，m)，6.82(2H，t)，6.75(1H，br)，5.03(2H，br)，3.83(3H，s)，3.72(3H，s)，3.65(2H，s)，2.09(6H，s)；
step 5-6, preparation of a compound of structural formula I:
6.0g (10.94 mmol) of the compound of formula III-1, 2.05g (16.41 mmol) of 3-amino-6-methoxypyridazine, 1.66g (16.41 mmol) of triethylamine and 30mL of tetrahydrofuran are added into a bottle, the temperature is raised to 55 ℃ under the protection of nitrogen, 10.4g (16.41 mmol,50% content) of ethyl acetate solution of 1-propylphosphoric acid cyclic anhydride is dropwise added, after the dropwise addition is completed, the reaction is carried out for 3 hours at 55 ℃, 100mL of ice water is added, the pH is adjusted to 9 by potassium carbonate, the stirring is carried out for 2 hours at 5 ℃, the filtration and the drying are carried out, so that a white solid compound II-1 is obtained, and can be directly used for the next step; 50mL of methanol was added to Compound II-10.3g (5.5 mmol) of sodium methoxide, heating to 55 ℃ for reaction for 6 hours, stopping heating, adding 100mL of ice water, adjusting pH to 8 with hydrochloric acid, keeping stirring at 5 ℃ for 2 hours, filtering, drying to obtain 6.4g of off-white solid compound I, namely, lu Geli, 94% yield and 99% purity, 1 H-NMR(400M，CDCl 3 )：7.64-7.12(8H，m)，6.91(2H，t)，6.80(1H，br)，5.33(2H，br)，4.17(3H，s)，3.81(3H，s)，3.69(2H，s)，2.13(6H，s)。
example 13
The preparation method of the compound of the structural formula I comprises the following steps:
step 1-3, preparation of a compound of formula IV-2:
to the flask were added 10.6g (21.63 mmol) of the compound of formula VII-2, 50mL of methylene chloride, 50mL of methanol, 2.0g of palladium on carbon (10% content, 50% aqueous), and the mixture was warmed to 30℃and 6.3g (100 mmol) of ammonium formate was added in portions, and after the addition was completed, the mixture was allowed to react at 40℃for 3 hours; cooling to 10deg.C, adding 50mL of dichloromethane, stirring for 30min, filtering, and spin-drying to obtain compound of formula VI-2, which can be directly used in the next step without separation; 100mL of dichloromethane, 8.1g (50 mmol) of N, N' -carbonyldiimidazole and 3.0g (30 mmol) of triethylamine are added into another reaction bottle, the temperature is reduced to 10 ℃, 4.2g (50 mmol) of methoxyamine hydrochloride is added in batches, the temperature is raised to 30 ℃ after the addition is finished, the reaction is carried out for 30min, then the compound of the structural formula VI-2 is added, the reaction is carried out for 4h at 50 ℃ after the addition is finished, and the compound of the structural formula V-2 is obtained by spin drying and is directly used for the next step without separation; 70mL of methanol, 30mL of water and 1.94g (35 mmol) of potassium hydroxide are added to the obtained compound V-2, the temperature is raised to 50 ℃ for reaction for 7 hours, heating is stopped, 70mL of ice water is added, the pH is adjusted to 2 by hydrochloric acid, the aqueous phase is extracted by ethyl acetate (three times each time of 70 mL) after methanol is removed by reduced pressure distillation, the organic phases are combined, dried by anhydrous sodium sulfate, filtered, distilled to about 40mL of ethyl acetate left, cooled to 5 ℃, 60mL of heptane is dropwise added, stirring is carried out for 2 hours after the addition, filtering and drying are carried out, 9.2g of white solid compound of the structural formula IV-2 is obtained, the yield is 84%, the purity is 99%, 1 H-NMR(400M，CDCl 3 )：8.52(1H，br)，7.58(1H，br)，7.52-7.41(5H，m)，7.21(1H，m)，6.82(2H，t)，6.76(1H，br)，5.04(2H，br)，3.84(3H，s)，4.15(2H，q)，1.36(3H，t)；
step 4, preparation of a compound of structural formula III-2:
to the flask were added 8.23g (16.28 mmol) of the compound of formula IV-2, 80mL of glacial acetic acid, 8.1g of formalin (100 mmol of formaldehyde, 37% content), 9.0g of aqueous dimethylamine solution (100 mmol,50% content), and the mixture was heated to 40℃for reaction for 6 hours; the reaction solution was poured into 120mL of water, extracted with ethyl acetate (three times, 100mL each time), the organic phases were combined, washed with water (two times, 50mL each time), the organic phases were spin-dried, and the obtained solid was recrystallized from toluene to give 8.15g of a white solid compound of the structural formula III-2 in 89% yield and 99% purity, 1 H-NMR(400M，CDCl 3 )：8.01(1H，br)，7.57(1H，br)，7.46-7.40(4H，m)，7.21(1H，m)，6.81(2H，t)，6.75(1H，br)，5.01(2H，br)，4.15(2H，q)，3.83(3H，s)，3.65(2H，s)，2.09(6H，s)，1.36(3H，t)；
step 5-6, preparation of a compound of structural formula I:
6.15g (10.94 mmol) of the compound of formula III-2, 2.5g (20 mmol) of 3-amino-6-methoxypyridazine, 2.02g (20 mmol) of triethylamine and 30mL of tetrahydrofuran are added into a bottle, the temperature is raised to 55 ℃ under the protection of nitrogen, 12.7g (20 mmol,50% content) of ethyl acetate solution of 1-propylphosphoric acid cyclic anhydride is dropwise added, after the dropwise addition is completed, the reaction is carried out for about 60min at 55 ℃, 100mL of ice water is added, the pH is regulated to 9 by potassium carbonate, the stirring is carried out for 2h at 5 ℃, the filtration and the drying are carried out, so that a white solid compound II-2 is obtained, and can be directly used for the next step; 50mL of ethanol and 0.41g (6.0 mmol) of sodium ethoxide were added to the compound II-2, the reaction was stopped by heating to 55℃for 6 hours, 100mL of ice water was added, the pH was adjusted to 8 with hydrochloric acid, and the mixture was kept at 5℃and stirred for 2 hours, and the mixture was filtered and dried to obtain 6.48g of an off-white solid compound I, namely, rayleigh Lu Geli, in a yield of 95% and a purity of 99%. The nuclear magnetic data is consistent with example 12.
Example 14
The preparation method of the compound of the structural formula I comprises the following steps:
step 1-3, preparation of a compound of formula IV-3:
13.3g (21.63 mmol) of the compound of formula VII-3, 50mL of methylene chloride, 50mL of methanol and 1.8g of palladium on carbon (10% content, 50% water) were added to the flask, the temperature was raised to 30℃and 5.45g (86.52 mmol) of ammonium formate was added in portions, and after the addition was completed, the reaction was carried out at 35℃for 4 hours; cooling to 10deg.C, adding 50mL of dichloromethane, stirring for 30min, filtering, and spin-drying to obtain compound of formula VI-3, which can be directly used in the next step without separation; 100mL of dichloromethane, 7.0g (43.26 mmol) of N, N' -carbonyldiimidazole and 2.63g (26.0 mmol) of triethylamine are added into another reaction bottle, the temperature is reduced to 10 ℃, 4.2g (50 mmol) of methoxyamine hydrochloride is added in batches, the temperature is raised to 30 ℃ after the addition is finished, the reaction is carried out for 30min, the compound with the structural formula VI-3 is added, the reaction is carried out for 8h at 35 ℃ after the addition is finished, and the compound with the structural formula V-3 is obtained by spin drying and is directly used for the next step without separation; 70mL of methanol, 30mL of water and 1.46g (26 mmol) of potassium hydroxide are added to the obtained compound V-3, the temperature is raised to 55 ℃ for reaction for 2 hours, heating is stopped, 70mL of ice water is added, the pH is adjusted to 2 by hydrochloric acid, the aqueous phase is extracted by ethyl acetate after methanol is removed by reduced pressure distillation (three times, 70mL each time), the organic phases are combined, dried by anhydrous sodium sulfate, filtered, distilled to about 30mL of ethyl acetate which remains, cooled to 5 ℃, 60mL of heptane is added dropwise, stirring is carried out for 2 hours after the addition, filtering and drying are carried out, 10.6g of white solid compound of the structural formula IV-3 is obtained, the yield is 86%, the purity is 99%, 1 H-NMR(400M，CDCl 3 )：8.67(1H，br)，7.60(1H，br)，7.55-7.41(10H，m)，7.25(1H，m)，6.83(2H，t)，6.75(1H，br)，5.41(2H，s)，5.09(2H，br)，3.85(3H，s)；
step 4, preparation of a compound of structural formula III-3:
9.24g (16.28 mmol) of the compound of formula IV-3, 80mL of glacial acetic acid, 6.6g of formalin (formaldehyde 81.4mmol,37% content), 9.0g of aqueous dimethylamine solution (100 mmol,50% content) are added to the flask, and the mixture is heated to 45℃and reacted for 5 hours; the reaction solution was poured into 120mL of water and extracted with ethyl acetate (three times each 100 mL)The organic phases were combined, washed with water (twice, 50mL each), the organic phases were spin-dried, and the resulting solid was recrystallized from toluene to give 8.44g of a white solid compound of the formula III-3 in 83% yield and 98% purity, 1 H-NMR(400M，CDCl 3 )：8.19(1H，br)，7.59(1H，br)，7.56-7.41(9H，m)，7.27(1H，m)，6.86(2H，t)，6.79(1H，br)，5.41(2H，s)，5.11(2H，br)，3.83(3H，s)，3.69(2H，s)，2.12(6H，s)；
step 5-6, preparation of a compound of structural formula I:
6.83g (10.94 mmol) of the compound of formula III-3, 2.25g (18.0 mmol) of 3-amino-6-methoxypyridazine, 1.66g (16.41 mmol) of triethylamine and 30mL of tetrahydrofuran are added into a bottle, the temperature is raised to 55 ℃ under the protection of nitrogen, 10.4g (16.41 mmol,50% content) of ethyl acetate solution of 1-propylphosphoric acid cyclic anhydride is dropwise added, after the dropwise addition is completed, the reaction is carried out for 3 hours at 55 ℃, 100mL of ice water is added, the pH is adjusted to 10 by potassium carbonate, the stirring is carried out for 2 hours at 5 ℃, the filtration and the drying are carried out, so that a white solid compound II-3 is obtained, and can be directly used for the next step; 50mL of methanol and 0.3g (5.5 mmol) of sodium methoxide were added to the compound II-3, the reaction was continued for 3 hours at 55℃while stopping the heating, 100mL of ice water was added, the pH was adjusted to 9 with hydrochloric acid, and the mixture was kept under stirring at 5℃for 2 hours, and the mixture was filtered and dried to give 6.34g of an off-white solid compound I, namely, rayleigh Lu Geli, 93% yield, 99% purity and nuclear magnetic data were consistent with those of example 12.
Example 15
A process for the preparation of a compound of formula J comprising the steps of:
step 1, preparation of a compound of formula VII-a:
31.0g (63.0 mmol) of the compound of formula VII-2, 140mL of ethanol, 60mL of water, and 5.3g (94.5 mmol) of potassium hydroxide were added to the flask; heating to 60 ℃ for reaction for 4 hours, distilling under reduced pressure to remove ethanol, adding 40mL of ice water, and adjusting pH to 5 with hydrochloric acid; stirring at 15deg.C for 60min, filtering, and oven drying; the resulting solid was recrystallized from isopropyl ether to give 24.2g of yellow solid compound VII-a in yield83%, purity 99%, 1 H-NMR(400M,CDCl 3 )：9.64(1H，br)，8.22(2H，d)，7.68(1H，s)，7.63(2H，d)，7.25(1H，dd)，6.84(2H，t)，5.04(2H，s)，4.29(2H，q)，3.83(3H，s)，1.39(3H，t)：
step 2-4, preparation of a compound of formula J:
to the flask were added 10.0g (21.63 mmol) of the compound of formula VII-a, 100mL of tetrahydrofuran, 5.2g (32.0 mmol) of N, N-carbonyldiimidazole, and the reaction was stirred at room temperature for 2 hours; 4.0g (64.86 mmol) nitromethane and 4.85g (43.24 mmol) potassium tert-butoxide were added and the reaction was continued at room temperature for 3h; 5.15g (43.24 mmol) of N, N-dimethylformamide dimethyl acetal was added, and the temperature was raised to 40℃for reaction for 10 hours; then 5mL of water is added, and the temperature is kept at 40 ℃ for reaction for 4 hours; spin-drying, adding 100mL of ethanol, cooling to 5 ℃, adding 0.82g (21.63 mmol) of sodium borohydride in batches, and heating to 30 ℃ for reaction for 1h after the addition; ethanol was distilled off under reduced pressure, 100mL of ice water was added, the pH was adjusted to 6 with hydrochloric acid, and extraction was performed with ethyl acetate (three times, 70mL each); the organic phases are combined, distilled to about 30mL of solvent, cooled to 5 ℃, 70mL of heptane is added dropwise, and the mixture is stirred for 2h at 5 ℃ after the addition; filtering, washing with 20mL isopropyl ether, drying to obtain 10.34g yellow solid with structure J, yield 92%, purity 99%, 1 H-NMR(400M，CDCl 3 )：8.85(1H，br)，8.30(2H，d)，7.45(2H，d)，7.24(1H，dd)，6.85(2H，t)，5.09(2H，s)，4.12(2H，br)，3.80(2H，s)，2.41(6H，s)，1.32(3H，t)。
example 16
A process for the preparation of a compound of formula J comprising the steps of:
step 1, preparation of a compound of formula VIII-a: exactly the same as in example 15;
step 2-4, preparation of a compound of formula J:
to the flask were added 10.0g (21.63 mmol) of the compound of formula VIII-a, 100mL of acetonitrile and 7.0g (43.26 mmol) of N, N' -carbonyldiimidazole, and the reaction was stirred at room temperature for 2 hours; 6.6g (108.2 mmol) of nitromethane and 7.28g (64.86 mmol) of potassium tert-butoxide were added and the reaction was continued at room temperature for 5h; 7.73g (64.86 mmol) of N, N-dimethylformamide dimethyl acetal was added, and the temperature was raised to 50℃for reaction for 70 hours; then 5mL of water is added, and the temperature is kept at 50 ℃ for 2 hours of reaction; spin-drying, adding 100mL of ethanol, cooling to 5 ℃, adding 1.75g (32.45 mmol) of potassium borohydride in batches, and heating to 30 ℃ for reaction for 1h after the addition; ethanol was distilled off under reduced pressure, 100mL of ice water was added, the pH was adjusted to 6 with hydrochloric acid, and extraction was performed with ethyl acetate (three times, 70mL each); the organic phases are combined, distilled to about 30mL of solvent, cooled to 5 ℃, 70mL of heptane is added dropwise, and the mixture is stirred for 2h at 5 ℃ after the addition; filtration, washing with 20mL isopropyl ether and drying gave 9.77g of a yellow solid of formula J in 87% yield and 98% purity and nuclear magnetic data consistent with those of example 15.

Claims (2)

1. A process for the preparation of intermediate J of revascular Lu Geli comprising the steps of:
step S1, carrying out alkaline hydrolysis on a compound with a structural formula VII-2 to obtain a compound with a structural formula VII-a; s2, activating a compound with a structural formula VII-a through N, N' -carbonyl diimidazole, and reacting with nitromethane in the presence of alkali to generate a compound with a structural formula VII-b; s3, reacting the compound with the structural formula VII-b with N, N-dimethylformamide dimethyl acetal to prepare a compound with the structural formula VII-c; in step S4, the compound of formula VII-c is reduced by a reducing agent in the presence of water to provide the intermediate of formula J, namely, rayleigh Lu Geli.
2. The process for preparing intermediate J of claim 1, wherein: the alkali in the step S1 is sodium hydroxide or potassium hydroxide; the molar ratio of the alkali in the step S1 to the compound of the structural formula VII-2 is 1:1-3:1; the reaction temperature in the step S1 is 10-100 ℃; the molar ratio of the N, N' -carbonyldiimidazole to the compound of the structural formula VIII-a in the step S2 is 1:1-3:1; the base of the step S2 is selected from potassium tert-butoxide or 1, 8-diazabicyclo undec-7-ene; the molar ratio of the alkali in the step S2 to the compound of the structural formula VII-a is 1:1-10:1; the molar ratio of nitromethane to the compound of the structural formula VII-a in the step S2 is 1:1-10:1; the reaction solvent in the step S2 is selected from tetrahydrofuran or acetonitrile; the reaction temperature of the step 2 is 0-80 ℃; the molar ratio of the compound with the structural formula VII-b to the N, N-dimethylformamide dimethyl acetal in the step 3 is 1:1-1:5; the reaction solvent in the step 3 is selected from tetrahydrofuran or acetonitrile; the reaction temperature of the step 3 is 20-80 ℃; the reducing agent in the step 4 is sodium borohydride or potassium borohydride; the molar ratio of the compound of the structural formula VII-c to the reducing agent in the step 4 is 1:0.3-1:3; the reaction solvent in the step 4 is ethanol; the reaction temperature of the step 4 is 0-80 ℃.
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