Synthesis method of 6-hydroxy-2-azaspiro [3.3] heptane compound

Abstract

The invention discloses an efficient synthesis method of a 6-hydroxy-2-azaspiro [3.3] heptane compound and a preparation method of the 6-hydroxy-2-azaspiro [3.3] heptane compound. The method is simple to operate, low in raw material cost, few in three wastes, low in cost, high in yield and easy for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of preparation of pharmaceutical intermediates, and particularly to a method for synthesizing 6-hydroxy-2-azaspiro[3.3]heptane compounds. Background Art

[0002] Compounds of 6-hydroxy-2-azaspiro[3.3]heptane and their related derivatives are widely used in pharmaceuticals and organic synthesis.

[0003]

[0004] Currently, there are several reported synthetic routes for tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate in the literature, but all are for laboratory preparation and there is no report on industrial production.

[0005] The literature [Org. Lett., 2009, 11, 3523] reported a method for preparing tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate starting from 1-Boc-3-azetidinone, through Wittig reaction, [2+2] cycloaddition reaction and dechlorination reaction. This route has short steps but the overall yield of the three steps is only 20%, and the cost is very high.

[0006] Patent CN102442934 disclosed a route for synthesizing tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate starting from isopropyl 3,3-dimethoxycyclopropane-1,1-dicarboxylate. This method has long steps, a cumbersome process, is not environmentally friendly, and has a high cost.

[0007] The literature [Org. Lett., 2009, 11, 3523] also reported another route for synthesizing tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate starting from epibromohydrin, which involves 8 steps. The starting material epibromohydrin has a high price, and in the first step of preparing 2-benzyloxy-1,3-dibromoethane from epibromohydrin, highly toxic reagent mercuric chloride which causes great pollution to the environment is used, so it is not suitable for industrial production. In addition, lithium aluminum hydride which is very prone to explosion is used in the cyano reduction step, posing a great safety risk.

[0008]

[0009] Therefore, there is a need in the art for a method for synthesizing 6-hydroxy-2-azaspiro[3.3]heptane compounds that is simple to operate, has low raw material cost, produces less waste, has low cost, high yield, and is easy to industrialize. Summary of the Invention

[0010] The object of the present invention is to provide a synthesis method of 6-hydroxy-2-azaspiro[3.3]heptane compounds with simple operation, low raw material cost, less three wastes, low cost, high yield and easy industrial production, so as to solve the problems of cumbersome steps and high cost in the existing synthesis process.

[0011] The present invention provides a synthesis method of 6-hydroxy-2-azaspiro[3.3]heptane compounds, and the method comprises the following steps:

[0012] (1) The compound shown in formula I undergoes a ring closure reaction with the compound shown in formula II to obtain the compound shown in formula III;

[0013] (2) The compound shown in formula III undergoes an ester group reduction reaction to obtain the compound shown in formula IV;

[0014] (3) The hydroxyl group of the compound shown in formula IV undergoes a substitution reaction to obtain the compound shown in formula V;

[0015] (4) The compound shown in formula V undergoes a cyano reduction and a ring closure reaction to obtain the compound shown in formula VI;

[0016] (5) The compound shown in formula VI undergoes a hydroxyl protecting group removal and an amino protection to obtain the compound shown in formula VII,

[0017]

[0018] wherein,

[0019] X is a halogen or OMs, OTs;

[0020] R 1 is MOM, MEM, THP, BOM, PMBM, t-Bu, SEM, TBS, TIPS, TBDPS, Ac or Bz;

[0021] R 2 is a C1-C8 alkyl group;

[0022] Y is OMs, OTs, OTf or a halogen;

[0023] R is Boc, Cbz, Alloc, Fmoc, Ac or Bz.

[0024] In another preferred example, the halogen is F, Cl, Br or I, preferably Br or Cl.

[0025] In another preferred example, MOM is CH 3 OCH 2 -. MEM is CH 3 OCH 2 CH 2 OCH2 -. THP is BOM is PhCH 2 OCH 2 O-. PMBM is MeOC 6 H 4 CH 2 OCH 2 O-. t-Bu is tert-butyl. SEM is Me 3 SiCH 2 CH 2 OCH 2 -. TBS is trimethylsilyl. TIPS is triisopropylsilyl. TBDPS is tert-butyldimethylsilyl. Ac is acetyl. Bz is benzoyl.

[0026] In another preferred example, OMs is methanesulfonyloxy, OTs is p-toluenesulfonyloxy, and OTf is trifluoromethanesulfonyloxy.

[0027] In another preferred example, Boc is tert-butoxycarbonyl. Cbz is benzyloxycarbonyl. Alloc is allyloxycarbonyl. Fmoc is

[0028] In another preferred example, X is Br, Cl, or OTs.

[0029] In another preferred example, R 1 is MOM.

[0030] In another preferred example, R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl, preferably ethyl.

[0031] In another preferred example, Y is OTs.

[0032] In another preferred example, R is Boc.

[0033] In another preferred example, Step 1 includes: in a first solvent, under the action of a first base reagent, the compound shown in Formula I and the compound shown in Formula II undergo a ring-closing reaction to obtain the compound shown in Formula III.

[0034] In another preferred example, in Step 1, the compound shown in Formula II is a C1-C8 alkyl cyanoacetate, preferably selected from methyl cyanoacetate, ethyl cyanoacetate, isopropyl cyanoacetate, n-propyl cyanoacetate, n-butyl cyanoacetate, sec-butyl cyanoacetate, isobutyl cyanoacetate, tert-butyl cyanoacetate, and more preferably ethyl cyanoacetate.

[0035] In another preferred example, in the first step, the molar equivalent of the compound shown in Formula II is 1 to 10 times, preferably 1 to 3 times, such as 1 time or 1.5 times, that of the compound shown in Formula I.

[0036] In another preferred example, in the first step, the first base reagent is selected from one or a combination of sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, sodium hydride, sodium amide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-pentoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, triethylamine, diisopropylethylamine, tripropylamine, tributylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 2,6-dimethyl-4-tert-butylpyridine, DBU, DABCO, MTBD. Preferably selected from potassium carbonate and potassium tert-butoxide.

[0037] In another preferred example, in the first step, the equivalent of the first base reagent is 1 to 5 times, preferably 2 to 4 times, such as 3 times, that of the compound shown in Formula I.

[0038] In another preferred example, in the first step, the first solvent is selected from one or a combination of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, NMP, toluene, xylene, chlorobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane. Preferably N,N-dimethylacetamide.

[0039] In another preferred example, in the first step, the mass-volume fraction of the compound shown in Formula I relative to the first solvent is 100 - 800 g / L, preferably 100 - 500 g / L.

[0040] In another preferred example, the ring-closing reaction is carried out at 20 - 150 °C, preferably 50 - 150 °C, more preferably 80 - 120 °C, such as 100 - 110 °C.

[0041] In another preferred example, in the first step, the reaction time of the ring-closing reaction is 5 - 15 hours, preferably 6 - 12 hours, such as 8 - 10 hours.

[0042] In another preferred example, the first step includes: mixing the first solvent, the first base reagent, the compound shown in Formula I and the compound shown in Formula II, carrying out a ring-closing reaction at a certain temperature, and obtaining the compound shown in Formula III after reacting for a period of time.

[0043] In another preferred example, the first step further includes a post-treatment step. Preferably, the post-treatment step includes: after the reaction is completed, cooling to room temperature, adding dichloromethane and water, separating the layers, and concentrating the organic phase to remove the solvent and then distilling the product under reduced pressure.

[0044] In another preferred example, step two includes: in a second solvent and under the action of a first reducing agent, the compound shown in Formula III undergoes an ester group reduction reaction to obtain the compound shown in Formula IV.

[0045] In another preferred example, in step two, the first reducing agent is selected from sodium borohydride, potassium borohydride, lithium borohydride, lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, borane-tetrahydrofuran, borane-dimethyl sulfide, a combination of sodium borohydride and lithium chloride, a combination of sodium borohydride and calcium chloride, sodium borohydride and boron trifluoride diethyl etherate, a combination of sodium borohydride and aluminum trichloride, a combination of sodium borohydride and iodine, a combination of sodium borohydride and zinc chloride, a combination of sodium borohydride and cobalt chloride, a combination of sodium borohydride and nickel chloride, or a combination thereof. Sodium borohydride is preferred.

[0046] In another preferred example, in step two, the molar equivalent of the first reducing agent is 1 - 5 times the equivalent of the compound shown in Formula III, preferably 2 - 3 times the equivalent.

[0047] In another preferred example, in step two, the second solvent can be a C1-C8 monohydric alcohol solvent or an ether solvent, etc., preferably selected from one or a combination of methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, toluene, acetonitrile, dichloromethane, water. Tetrahydrofuran is preferred.

[0048] In another preferred example, in step two, the mass-volume fraction of the compound shown in Formula III relative to the second solvent is 50 - 500 g / L, preferably 80 - 200 g / L.

[0049] In another preferred example, step two is carried out at 10 - 120 °C, preferably 10 - 80 °C, more preferably 20 - 60 °C, for example 40 - 50 °C.

[0050] In another preferred example, in step two, the reaction time of the ester group reduction reaction is 2 - 15 hours, preferably 3 - 10 hours, for example 5 - 8 hours.

[0051] In another preferred example, step two includes: mixing the second solvent, the first reducing agent, and the compound shown in Formula III, and carrying out an ester group reduction reaction at a certain temperature. After reacting for a period of time, the compound shown in Formula IV is obtained.

[0052] In another preferred example, step two further includes a post-treatment step. Preferably, the post-treatment step includes: after the reaction is completed, adding hydrochloric acid to quench, extracting three times with dichloromethane, concentrating to dryness, and directly feeding it into the next reaction.

[0053] In another preferred example, step two includes: directly feeding the product after the reaction is completed into the next reaction after simple post-treatment.

[0054] In another preferred example, step three includes: in a third solvent, under the action of a second base reagent, the compound shown in formula IV undergoes a substitution reaction of the hydroxyl group with a substitution reagent to obtain the compound shown in formula V.

[0055] In another preferred example, in step three, the substitution reagent is selected from sulfonyl chlorides or sulfonic anhydrides, preferably selected from one of p-toluenesulfonyl chloride, p-toluenesulfonic anhydride, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, and more preferably p-toluenesulfonyl chloride.

[0056] In another preferred example, in step three, the molar equivalent of the substitution reagent is 1 - 5 times the equivalent of the compound shown in formula IV, preferably 1 - 2 times the equivalent, for example 1.2 times the equivalent.

[0057] In another preferred example, in step three, the second base reagent is selected from one or a combination of triethylamine, diisopropylethylamine, tripropylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 2,6-dimethyl-4-tert-butylpyridine, N-methylmorpholine, imidazole, DBU, DABCO, MTBD, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide. Preferably selected from triethylamine.

[0058] In another preferred example, in step three, the molar equivalent of the second base reagent is 0.5 - 5 times that of the substitution reagent, preferably 0.8 - 2 times, for example 1 time.

[0059] In another preferred example, in step three, the third solvent can be a ketone solvent, an ester solvent or an ether solvent, etc., preferably selected from one or a combination of acetone, 2-butanone, 4-methyl-2-pentanone, ethyl acetate, isopropyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethers such as methyl tert-butyl ether, DMF, DMAc, DMSO, NMP, toluene, acetonitrile, dichloromethane, water. Preferably dichloromethane.

[0060] In another preferred example, in step three, the mass-volume fraction of the substitution reagent relative to the third solvent is 50 - 500 g / L, preferably 80 - 200 g / L.

[0061] In another preferred example, step three is carried out at 0 - 100 °C, preferably 5 - 70 °C, more preferably 10 - 50 °C, for example 10 - 20 °C or 15 - 25 °C.

[0062] In another preferred embodiment, in the third step, the reaction time of the substitution reaction is 10 - 48 hours, preferably 15 - 30 hours.

[0063] In another preferred embodiment, the third step includes: mixing a third solvent, a second base reagent, and a compound represented by Formula IV, and performing a substitution reaction at a certain temperature. After reacting for a period of time, a compound represented by Formula V is obtained.

[0064] In another preferred embodiment, the third step further includes a post-treatment step. Preferably, the post-treatment step includes: after the reaction is completed, washing once with saturated sodium bicarbonate aqueous solution and water, and concentrating the organic phase under reduced pressure to remove the solvent to obtain the product.

[0065] In another preferred embodiment, the fourth step includes: in a fourth solvent, under the action of a second reducing agent, a compound represented by Formula V undergoes a cyano reduction reaction to reduce the cyano group to an amino group, and then an intramolecular substitution cyclization reaction is carried out simultaneously to obtain a compound represented by Formula VI.

[0066] In another preferred embodiment, in the fourth step, the second reducing agent is a metal reducing agent.

[0067] In another preferred embodiment, in the fourth step, the second reducing agent is selected from sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, nickel borohydride, cobalt borohydride, lithium aluminum hydride, diisobutylaluminum hydride, lithium triethylborohydride, sodium dihydrobis(2-methoxyethoxy)aluminate, borane tetrahydrofuran, borane dimethyl sulfide, a combination of sodium borohydride and lithium chloride, a combination of sodium borohydride and calcium chloride, a combination of sodium borohydride and boron trifluoride diethyl etherate, a combination of sodium borohydride and aluminum trichloride, a combination of sodium borohydride and iodine, a combination of sodium borohydride and zinc chloride, a combination of sodium borohydride and cobalt chloride, a combination of sodium borohydride and nickel chloride, a combination of sodium borohydride and zirconium chloride, or a combination thereof.

[0068] In another preferred embodiment, in the fourth step, the second reducing agent is a combination of sodium borohydride and cobalt chloride.

[0069] In another preferred embodiment, the molar ratio of sodium borohydride to cobalt chloride is 0.5 - 5:1, preferably 0.8 - 3:1, more preferably 1.5 - 2:1.

[0070] In another preferred embodiment, in the fourth step, the molar equivalent (or total molar equivalent) of the second reducing agent is 1 - 6 times the equivalent of the compound represented by Formula V, preferably 2 - 4 times the equivalent.

[0071] In another preferred example, in the fourth step, the fourth solvent may be a C1-C8 monohydric alcohol solvent or an ether solvent, etc., preferably selected from one or a combination of methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, toluene, acetonitrile, dichloromethane, and water. Tetrahydrofuran is preferred.

[0072] In another preferred example, in the fourth step, the mass-volume fraction of the compound shown in Formula V relative to the fourth solvent is 50-500 g / L, preferably 80-200 g / L, such as 100 g / L.

[0073] In another preferred example, the fourth step is carried out at 10-120 °C, preferably 10-80 °C, more preferably 20-60 °C, such as 30-40 °C.

[0074] In another preferred example, in the fourth step, the reaction time of the reaction is 10-24 hours, preferably 15-20 hours, such as 16-18 hours.

[0075] In another preferred example, the fourth step includes: mixing the fourth solvent, the second reducing agent, and the compound shown in Formula V, and carrying out a cyano reduction reaction and a ring-closing reaction at a certain temperature. After reacting for a period of time, a compound shown in Formula VI is obtained.

[0076] In another preferred example, the fourth step further includes a post-treatment step. Preferably, the post-treatment step includes: after the reaction is completed, cooling to 0 °C, adding a dilute sodium hydroxide aqueous solution to quench the reaction, extracting three times with dichloromethane, washing the organic phase with water once, and concentrating the organic phase to dryness and directly using it for the next step.

[0077] In another preferred example, the fourth step includes: directly feeding the product after simple post-treatment of the completed reaction into the next reaction.

[0078] In another preferred example, the fourth step includes: in a fifth solvent, under the action of a catalyst, under a certain hydrogen pressure, the compound shown in Formula V undergoes a cyano reduction reaction to reduce the cyano group to an amino group, and then an intramolecular substitution ring-closing reaction is carried out simultaneously to obtain a compound shown in Formula VI.

[0079] In another preferred example, in the fourth step, the catalyst is a catalyst for catalytic hydrogenation reduction.

[0080] In another preferred example, in the fourth step, the catalyst is selected from one or more of palladium on carbon, palladium hydroxide on carbon, Raney nickel, Ru / C, and Rh / C, and Raney nickel is preferred.

[0081] In another preferred example, in the fourth step, the mass of the catalyst is 1-50 wt%, preferably 5-30 wt%, and more preferably 10 wt% of the compound shown in Formula V.

[0082] In another preferred example, in the fourth step, the fifth solvent can be a C1-C8 monohydric alcohol solvent, an ester solvent, an ether solvent, etc., and is preferably selected from one or a combination of methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, dichloromethane, acetonitrile, toluene, and acetic acid. Ethanol is preferred.

[0083] In another preferred example, in the fourth step, the mass-volume fraction of the compound shown in Formula V relative to the fifth solvent is 50-500 g / L, preferably 80-200 g / L, such as 100 g / L.

[0084] In another preferred example, in the fourth step, the volume of the fifth solvent relative to the compound shown in Formula V is 2-20 times, preferably 10 times.

[0085] In another preferred example, the fourth step is carried out at 10-150 °C, preferably 20-100 °C, and more preferably 30-80 °C, such as 50 °C.

[0086] In another preferred example, the fourth step is carried out under a certain hydrogen pressure.

[0087] In another preferred example, in the fourth step, the reaction time of the reaction is 10-24 hours, preferably 15-20 hours, such as 16-18 hours.

[0088] In another preferred example, the fourth step includes: mixing the fifth solvent, the catalyst, and the compound shown in Formula V, and carrying out a cyano reduction reaction and a ring-closing reaction under a certain temperature and a certain hydrogen pressurization condition, and obtaining the compound shown in Formula VI after reacting for a period of time.

[0089] In another preferred example, the fourth step further includes a step of adjusting the pH to alkaline.

[0090] In another preferred example, the fourth step further includes a post-treatment step. Preferably, the post-treatment step includes: after the reaction is completed, cooling to room temperature, filtering off the catalyst, adjusting the pH of the filtrate to alkaline with an aqueous sodium hydroxide solution, extracting three times with dichloromethane, and directly concentrating the organic phase under reduced pressure to dryness to obtain the product.

[0091] In another preferred example, step five includes: in a sixth solvent and under the action of an acid reagent, the compound shown in formula VI undergoes a hydroxy protecting group deprotection reaction, and then under the action of a third base reagent, it is mixed with an amino protecting reagent to carry out an amino protection reaction to obtain the compound shown in formula VII.

[0092] In another preferred example, in step five, the acid reagent is an organic acid or an inorganic acid, preferably selected from one or a combination of hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, and preferably hydrochloric acid.

[0093] In another preferred example, in step five, the molar equivalent of the acid reagent is 1 to 5 times the equivalent of the compound shown in formula VI, preferably 1 to 2 times the equivalent, such as 1.1 to 1.5 times the equivalent.

[0094] In another preferred example, in step five, the sixth solvent can be an alcohol solvent, ester solvent, or ether solvent with C1-18, preferably selected from one or a combination of water, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, dichloromethane, acetonitrile, toluene, acetic acid. A combination of tetrahydrofuran and water is preferred.

[0095] In another preferred example, in step five, the mass-volume fraction of the compound shown in formula VI relative to the sixth solvent is 20 - 400 g / L, preferably 50 - 200 g / L.

[0096] In another preferred example, the hydroxy protecting group deprotection reaction in step five is carried out at 10 - 150 °C, preferably 10 - 80 °C, more preferably 10 - 50 °C, such as 20 - 30 °C.

[0097] In another preferred example, in step five, the reaction time of the hydroxy protecting group deprotection reaction is 1 - 10 hours, preferably 3 - 8 hours, such as 5 - 6 hours.

[0098] In another preferred example, in step five, the third base reagent is an inorganic base or an organic acid, preferably selected from one or a combination of sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, triethylamine, diisopropylethylamine, tripropylamine, tributylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 2,6-dimethyl-4-tert-butylpyridine, N-methylmorpholine, imidazole, DBU, DABCO, MTBD. Sodium carbonate is preferred.

[0099] In another preferred example, in step five, the third base reagent is added to the reaction system in the form of an aqueous solution.

[0100] In another preferred embodiment, in the fifth step, the third base reagent is added to make the pH of the reaction system 8-11, preferably 9-10.

[0101] In another preferred embodiment, in the fifth step, the amino protecting reagent is an acid anhydride or an acyl chloride, and preferably the acid anhydride or acyl chloride is Boc 2 O, CbzCl, AllocCl, FmocCl, Ac 2 O, Ac 2 O, BzCl.

[0102] In another preferred embodiment, in the fifth step, the molar equivalent of the amino protecting reagent is 0.5-10 times, preferably 1-5 times, more preferably 1-2 times that of the compound shown in Formula VI.

[0103] In another preferred embodiment, the amino protection reaction in the fifth step is carried out at 10-150 °C, preferably 10-80 °C, more preferably 10-50 °C, for example 20-30 °C.

[0104] In another preferred embodiment, in the fifth step, the reaction time of the amino protection reaction is 10-24 hours, preferably 12-18 hours, for example 15-18 hours.

[0105] In another preferred embodiment, the fifth step includes: mixing a sixth solvent, an acid reagent, and the compound shown in Formula VI, carrying out a hydroxy protecting group deprotection reaction at a certain temperature, adding a third base reagent after reacting for a period of time to adjust the pH, and then adding an amino protecting reagent to carry out an amino protection reaction at a certain temperature, and obtaining the product after post-treatment.

[0106] In another preferred embodiment, the fifth step further includes a post-treatment step. Preferably, the post-treatment step includes: extracting twice with ethyl acetate after the reaction is completed, concentrating under reduced pressure, and purifying by trituration with n-heptane to obtain the product.

[0107] In the second aspect of the present invention, an intermediate is provided, having the structure of Formula III, Formula IV or Formula V:

[0108]

[0109] Wherein,

[0110] R 1 is MOM, MEM, THP, BOM, PMBM, t-Bu, SEM, TBS, TIPS, TBDPS, Ac or Bz;

[0111] R 2 is a C1-C8 alkyl group;

[0112] Y is OMs, OTs, OTf or a halogen.

[0113] In another preferred example, R 1 is MOM.

[0114] In another preferred example, R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl, preferably ethyl.

[0115] In another preferred example, Y is OTs.

[0116] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described hereinafter (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be repeated one by one here. Detailed implementation manners

[0117] Through extensive and in-depth research, the present inventors have first discovered an efficient synthesis method for 6-hydroxy-2-azaspiro[3.3]heptane compounds with easily available raw materials, short steps, mild reaction conditions and high yields. The total yield reaches 41.28%, and only common reagents are used, which are non-toxic and very conducive to industrial production. The present invention has been completed on this basis.

[0118] Terms

[0119] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention belongs.

[0120] As used herein, the terms "comprising", "including", "containing" can be used interchangeably, including not only closed definitions, but also semi-closed and open definitions. In other words, the said terms include "consisting of", "consisting essentially of".

[0121] As used herein, when referring to specific enumerated values, the term "about" means that the value can vary by no more than 1% from the enumerated value. For example, as used herein, the expression "about 100" includes all values between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0122] The synthesis method of the present invention

[0123] The present invention provides a synthesis method for 6-hydroxy-2-azaspiro[3.3]heptane compounds. Specifically, it includes the following steps:

[0124] (1): The compound shown in Formula I undergoes a ring-closing reaction with the compound shown in Formula II to obtain the compound shown in Formula III.

[0125] (2) The compound shown in Formula III undergoes a reduction reaction to obtain the compound shown in Formula IV.

[0126] (3) The hydroxyl group of the compound shown in Formula IV is transformed to obtain the compound shown in Formula V.

[0127] (4) The compound shown in Formula V undergoes a cyano reduction and a ring-closing reaction to obtain the compound shown in Formula VI.

[0128] (5) The compound shown in Formula VI undergoes a deprotection of the hydroxyl protecting group and an amino protection to obtain the compound shown in Formula VII.

[0129]

[0130] The above reaction steps:

[0131] Among them, for Compound I: X = Cl, Br, I; R 1 is MOM, THP, TBS, TIPS, TBDPS, Ac, Bz;

[0132] Among them, for Compound II: R 2 is a C1-C8 alkyl group such as methyl, ethyl, isopropyl, tert-butyl, etc.;

[0133] Among them, for Compound V: Y = OMs, OTs, OTf, Cl, Br, I;

[0134] Among them, for Compound VIII: R is Boc, Cbz, Alloc, Fmoc, Ac, Bz..

[0135] Among them, the ring-closing reaction conditions in step (1) preferably include the following steps: in a certain organic solvent, at a certain temperature, under the action of a certain base, the compound shown in Formula I and the compound shown in Formula II undergo a ring-closing reaction to obtain the compound shown in Formula III.

[0136] Among them, the compound shown in Formula II in the ring-closing reaction is preferably selected from C1-C8 alkyl cyanoacetates such as methyl cyanoacetate, ethyl cyanoacetate, isopropyl cyanoacetate, n-propyl cyanoacetate, n-butyl cyanoacetate, sec-butyl cyanoacetate, isobutyl cyanoacetate, tert-butyl cyanoacetate, etc., and ethyl cyanoacetate is preferred.

[0137] Among them, the molar equivalent of the compound shown in Formula II in the ring-closing reaction is 1-10 times that of the compound shown in Formula I, and 1.5 times is preferred.

[0138] Among them, the base used in the ring - closing reaction is selected from inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, sodium hydride, sodium amide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert - butoxide, potassium tert - butoxide, sodium tert - pentoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc., and organic bases such as triethylamine, diisopropylethylamine, tripropylamine, tributylamine, pyridine, 2 - methylpyridine, 2,6 - dimethylpyridine, 2,6 - dimethyl - 4 - tert - butylpyridine, DBU, DABCO, MTBD, etc., one or a combination thereof. Preferably potassium carbonate.

[0139] Among them, the equivalent of the base used in the ring - closing reaction is 1 - 5 times that of the compound shown in Formula I, preferably 2 - 3 times.

[0140] Among them, the organic solvent used in the ring - closing reaction is selected from one or a combination of solvents such as N,N - dimethylformamide, N,N - dimethylacetamide, dimethyl sulfoxide, NMP, toluene, xylene, chlorobenzene, tetrahydrofuran, 2 - methyltetrahydrofuran, 1,4 - dioxane, etc. Preferably N,N - dimethylacetamide.

[0141] Among them, the reaction temperature of the ring - closing reaction is 20 - 150 °C, preferably 100 - 110 °C.

[0142] Among them, the reduction reaction conditions in step (ii) are conventional reaction methods and conditions in the art, preferably including the following steps: in a certain organic solvent, at a certain temperature, under the action of a certain reducing agent, the compound shown in Formula III undergoes an ester - group reduction reaction to obtain the compound shown in Formula IV.

[0143] Among them, the reducing agent used in the reduction reaction is preferably selected from one or a combination of sodium borohydride, potassium borohydride, lithium borohydride, lithium aluminum hydride, sodium bis(2 - methoxyethoxy)aluminum hydride, borane - tetrahydrofuran, borane - dimethyl sulfide, sodium borohydride / lithium chloride, sodium borohydride / calcium chloride, sodium borohydride / boron trifluoride diethyl etherate, sodium borohydride / aluminum trichloride, sodium borohydride / iodine, sodium borohydride / zinc chloride, sodium borohydride / cobalt chloride, sodium borohydride / nickel chloride. Preferably sodium borohydride.

[0144] Among them, the solvent used in the reduction reaction is one or a combination of C1 - C8 alcohols such as methanol, ethanol, isopropanol, tert - butanol, ethers such as tetrahydrofuran, 2 - methyltetrahydrofuran, methyl tert - butyl ether, 1,4 - dioxane, toluene, acetonitrile, dichloromethane, water, etc. Preferably tetrahydrofuran.

[0145] Among them, the molar equivalent of the reducing agent used in the reduction reaction is 1 - 5 times the equivalent of the compound shown in Formula III, preferably 2 times the equivalent.

[0146] The volume of the solvent used in the reduction reaction is 1 to 20 times the volume of the compound shown in Formula III, preferably 10 times the volume.

[0147] The reaction temperature of the reduction reaction is 10 - 120 °C, preferably 40 - 50 °C.

[0148] The conditions for the conversion of the hydroxyl group in the compound shown in Formula IV to the compound shown in Formula V in step (iii) are conventional methods and reaction conditions in the art. The present invention particularly preferably the following reaction methods and conditions: in a certain organic solvent, at a certain temperature, under the action of a certain base, the compound shown in Formula IV reacts with sulfonyl chloride to obtain the compound shown in Formula V.

[0149] Among them, the sulfonyl chloride used in the reaction is selected from p-toluenesulfonyl chloride, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, and p-toluenesulfonyl chloride is preferred.

[0150] Among them, the base used in the reaction is selected from one or a combination of organic bases such as triethylamine, diisopropylethylamine, tripropylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 2,6-dimethyl-4-tert-butylpyridine, N-methylmorpholine, imidazole, DBU, DABCO, MTBD, etc., and inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc. Triethylamine is preferred.

[0151] Among them, the solvent used in the reaction is one or a combination of ketones such as acetone, 2-butanone, 4-methyl-2-pentanone, esters such as ethyl acetate, isopropyl acetate, butyl acetate, ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, DMF, DMAc, DMSO, NMP, toluene, acetonitrile, dichloromethane, water, etc. Dichloromethane is preferred.

[0152] The molar equivalent of the sulfonyl chloride used in the reaction is 1 to 5 times the equivalent of the compound shown in Formula IV, preferably 1.2 times the equivalent.

[0153] The reaction temperature of the reaction is 0 - 100 °C, preferably 10 - 20 °C.

[0154] The reduction of the cyano group and the ring-closing reaction in step (iv) can be carried out by reducing with an equivalent of a metal reducing agent or by catalytic hydrogenation reduction. For the reduction of the cyano group with a metal reducing agent, the present invention particularly preferably the following reaction methods and conditions: in a certain organic solvent, at a certain temperature, under the action of a certain reducing agent, the cyano group in the compound shown in Formula V is reduced to an amino group while an intramolecular substitution ring-closing reaction occurs to obtain the compound shown in Formula VI.

[0155] Among them, the reducing agent used in the cyano reduction and ring closure reaction is preferably selected from one or a combination of sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, nickel borohydride, cobalt borohydride, lithium aluminum hydride, diisobutylaluminum hydride, lithium triethylborohydride, sodium bis(2-methoxyethoxy)aluminum dihydride, borane-tetrahydrofuran, borane-dimethyl sulfide, sodium borohydride / lithium chloride, sodium borohydride / calcium chloride, sodium borohydride / boron trifluoride diethyl etherate, sodium borohydride / aluminum trichloride, sodium borohydride / iodine, sodium borohydride / zinc chloride, sodium borohydride / cobalt chloride, sodium borohydride / nickel chloride, sodium borohydride / zirconium chloride. Sodium borohydride / cobalt chloride is preferred.

[0156] The solvent used in the cyano reduction and ring closure reaction is one or a combination of C1-C8 alcohols such as methanol, ethanol, isopropanol, tert-butanol, ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, toluene, acetonitrile, dichloromethane, water, etc. Tetrahydrofuran is preferred.

[0157] The molar equivalent of the reducing agent used in the cyano reduction and ring closure reaction is 1-5 times the equivalent of the compound shown in Formula III, preferably 2 times the equivalent.

[0158] The reaction temperature of the cyano reduction and ring closure reaction is 10-120 °C, preferably 30-40 °C.

[0159] For the catalytic hydrogenation reduction of cyano, the present invention particularly preferably the following reaction methods and conditions: in a certain organic solvent, at a certain temperature, under the action of a certain metal catalyst, under a certain hydrogen pressure, the cyano in the compound shown in Formula V is reduced to an amino group while an intramolecular substitution ring closure reaction occurs to obtain the compound shown in Formula VI.

[0160] Among them, the metal catalyst used in the reaction is selected from the following group: one or more of palladium-carbon, palladium hydroxide-carbon, Raney nickel, Ru / C, Rh / C, and Raney nickel is preferred.

[0161] Among them, the organic solvent used in the reaction is selected from alcohol solvents such as methanol, ethanol, isopropanol, ester solvents such as ethyl acetate, isopropyl acetate, ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and dichloromethane, acetonitrile, toluene, acetic acid, etc., and ethanol is preferred.

[0162] The reaction temperature of the reaction is 10-150 °C, preferably 50 °C.

[0163] The dosage of the metal catalyst in the reaction is 1-50 wt% of the compound shown in Formula V, and more preferably 10 wt%.

[0164] Among them, the amount of the reaction solvent for the reaction is 2 to 20 times the volume of the compound shown in Formula V, preferably 10 times the volume.

[0165] Among them, the methods and conditions for the deprotection of the hydroxyl protecting group and the amino protection reaction in the step (v) are all conventional methods and conditions in the art. The present invention particularly preferably the following conditions: the compound shown in Formula VI is in a certain solvent, at a certain temperature, under the action of an acid, the hydroxyl protecting group is removed, and then a certain amount of base and acid anhydride or acyl chloride are added to protect the amino group to obtain the compound shown in Formula VII.

[0166] Among them, the acid used for the hydroxyl deprotection reaction is a common inorganic acid and organic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, etc., preferably hydrochloric acid.

[0167] Among them, the solvent used for the hydroxyl deprotection reaction is selected from one or more of solvents such as water, C1-18 alcohol solvents such as methanol, ethanol, isopropanol, ester solvents such as ethyl acetate and isopropyl acetate, ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and methyl tert-butyl ether, and solvents such as dichloromethane, acetonitrile, toluene, and acetic acid. The combination of tetrahydrofuran and water is preferred.

[0168] Among them, the reaction temperature of the hydroxyl deprotection reaction is 10-150 °C, preferably 20-30 °C.

[0169] Among them, the base used for the amino protection reaction is selected from inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and calcium hydroxide, and organic bases such as triethylamine, diisopropylethylamine, tripropylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 2,6-dimethyl-4-tert-butylpyridine, N-methylmorpholine, imidazole, DBU, DABCO, MTBD, etc. One or a combination thereof. Sodium carbonate is preferred.

[0170] Among them, the acid anhydride or acyl chloride used for the amino protection reaction is Boc 2 O, CbzCl, AllocCl, FmocCl, Ac 2 O, Ac 2 O, BzCl and other common reagents.

[0171] Among them, the molar equivalent of the acid anhydride or acyl chloride used for the amino protection reaction is 0.5 to 10 times the equivalent of the compound shown in Formula VI, preferably 1 to 2 times the equivalent.

[0172] Among them, the reaction temperature of the amino protection reaction is 10-150 °C, preferably 20-30 °C.

[0173] The main advantages of the present invention include:

[0174] For the synthesis method of the present invention, the raw materials are cheap and easily available, the preparation steps are simple, the yield is high, the cost is low, and it is easy to be industrially produced.

[0175] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and weight parts.

[0176] Example 1-1: Synthesis of Ethyl 1-cyano-3-(methoxymethoxy)cyclobutane-1-carboxylate

[0177]

[0178] 508 g of 1-chloro-2-(chloromethyl)-3,5-dioxane, 610 g of potassium carbonate, 230 g of ethyl cyanoacetate, and 2 L of N,N-dimethylacetamide were added to a reaction flask, and the temperature was raised to 100 - 110 °C for reaction for 8 - 10 hours. After the reaction was completed, the temperature was lowered to room temperature, dichloromethane and water were added, and the layers were separated. The organic phase was concentrated to remove the solvent and then the product (303 g) was distilled under reduced pressure, with a yield of 73.0%. 1 H NMR(400MHz,Chloroform-d)δ4.61(m,2H),4.36(m,1H),4.28(m,2H),3.36(m,3H),2.99(m,2H),2.73(m,2H),1.29(m,3H).

[0179] Example 1-2: Synthesis of Ethyl 1-cyano-3-(methoxymethoxy)cyclobutane-1-carboxylate

[0180]

[0181] 337 g of 1-chloro-2-(chloromethyl)-3,5-dioxane, 560 g of potassium tert-butoxide, 230 g of ethyl cyanoacetate, and 2 L of N,N-dimethylacetamide were added to a reaction flask, and the temperature was raised to 100 - 110 °C for reaction for 8 - 10 hours. After the reaction was completed, the temperature was lowered to room temperature, dichloromethane and water were added, and the layers were separated. The organic phase was concentrated to remove the solvent and then the product (282 g) was distilled under reduced pressure, with a yield of 67.9%. 1 HNMR(400MHz,Chloroform-d)δ4.61(m,2H),4.36(m,1H),4.28(m,2H),3.36(m,3H),2.99(m,2H),2.73(m,2H),1.29(m,3H).

[0182] Examples 1 - 3: Synthesis of Ethyl 1 - cyano - 3-(methoxymethoxy)cyclobutane - 1 - carboxylate

[0183]

[0184] Add 865 g of 1 - chloro - 2-(chloromethyl)-3,5 - dioxane, 610 g of potassium carbonate, 230 g of ethyl cyanoacetate, and 2 L of N,N - dimethylformamide to a reaction flask. Heat the mixture to 100 - 110 °C and react for 8 - 10 hours. After the reaction is completed, cool the mixture to room temperature, add dichloromethane and water, separate the layers, concentrate the organic phase to remove the solvent, and then distill the product under reduced pressure to obtain 291 g of the product with a yield of 70.0%. 1 H NMR(400MHz,Chloroform - d)δ4.61(m,2H),4.36(m,1H),4.28(m,2H),3.36(m,3H),2.99(m,2H),2.73(m,2H),1.29(m,3H).

[0185] Example 2: Synthesis of 1-(hydroxymethyl)-3-(methoxymethoxy)cyclobutane - 1 - carbonitrile

[0186]

[0187] Add 100 g of ethyl 1 - cyano - 3-(methoxymethoxy)cyclobutane - 1 - carboxylate, 1000 mL of tetrahydrofuran, and 43 g of sodium borohydride to a reaction flask. Heat the mixture to 40 - 50 °C and react for 5 - 8 hours. After the reaction is completed, add hydrochloric acid to quench the reaction, extract with dichloromethane three times, concentrate, and directly use the product in the next step reaction. 1 H NMR(400MHz,Chloroform - d)δ4.54(s,2H),4.18 - 4.11(m,1H),3.68(s,1H),3.32(s,3H),2.46 - 3.59(m,4H).

[0188] Example 3: Synthesis of (1 - cyano - 3-(methoxymethoxy)cyclobutyl)methyl 4 - benzenesulfonate

[0189]

[0190] Add the compound from the previous step, 900 mL of dichloromethane, 133 g of p - toluenesulfonyl chloride, and 71 g of triethylamine to a reaction flask. React at 15 - 25 °C for 15 - 30 hours. After the reaction is completed, wash the mixture successively with saturated sodium bicarbonate aqueous solution and water. Concentrate the organic phase under reduced pressure to remove the solvent to obtain 106 g of the product with a two - step yield of 76%. 11H NMR (400 MHz, Chloroform-d) δ 7.81 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 4.55 (s, 2H), 4.20 - 4.12 (m, 1H), 4.08 (s, 2H), 3.34 (s, 3H), 2.63 - 2.51 (m, 3H), 2.46 (s, 3H).

[0191] Example 4: Synthesis of 6-(methoxymethoxy)-2-azaspiro[3.3]heptane

[0192]

[0193] Add 100 g of (1-cyano-3-(methoxymethoxy)cyclobutyl)methyl 4-benzenesulfonate, 1000 mL of THF, 24 g of sodium borohydride, and 80 g of cobalt chloride to the reaction flask. Heat the mixture to 30 - 40 °C and react for 16 - 18 hours. After the reaction is completed, cool the mixture to 0 °C, add dilute sodium hydroxide aqueous solution to quench the reaction, extract with dichloromethane three times, wash the organic phase with water once, and concentrate the organic phase to dryness directly for the next step. 1 1H NMR (400 MHz, Chloroform-d) δ 4.50 (s, 2H), 3.99 (s, 3H), 3.92 (m, 1H), 3.30 (m, 4H), 2.53 (m, 2H), 2.08 (m, 2H).

[0194] In another preferred reaction condition, add 100 g of (1-cyano-3-(methoxymethoxy)cyclobutyl)methyl 4-benzenesulfonate, 1000 mL of ethanol, and 10 g of Raney nickel to the hydrogenation flask. Carry out the hydrogenation reaction under hydrogen pressure at 50 °C for 16 - 18 hours. After the reaction is completed, cool the mixture to room temperature, filter off the catalyst, adjust the pH of the filtrate to alkaline with sodium hydroxide aqueous solution, extract with dichloromethane three times, and directly concentrate the organic phase under reduced pressure to dryness to obtain the product. 1 1H NMR (400 MHz, Chloroform-d) δ 4.50 (s, 2H), 3.99 (s, 3H), 3.92 (m, 1H), 3.30 (m, 4H), 2.53 (m, 2H), 2.08 (m, 2H).

[0195] Example 5: Synthesis of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate

[0196]

[0197] 5 g of 6-(methoxymethoxy)-2-azaspiro[3.3]heptane was dissolved in 50 mL of tetrahydrofuran in a reaction flask. 10 mL of 4N hydrochloric acid was added, and the mixture was stirred at 20 - 30 °C for 5 - 6 hours. After the hydrolysis was completed, saturated aqueous sodium carbonate solution was added to adjust the pH to 9 - 10. Then 10 g of Boc anhydride was added, and the mixture was stirred at 20 - 30 °C for 15 - 18 hours. After the reaction was completed, the mixture was extracted twice with ethyl acetate, concentrated under reduced pressure, and purified by trituration with n-heptane to obtain 2.6 g of a white solid product with a yield of 80%. 1 H NMR(400MHz,DMSO-d6)δ5.00(d,J=6.1Hz,1H),3.92(m,1H),3.78(s,2H),3.73(s,2H),2.46-2.30(m,2H),1.96-1.82(m,2H),1.34(s,9H).

[0198] All documents mentioned in the present invention are incorporated herein by reference as if each document was individually incorporated by reference. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

1. A method for synthesizing 6-hydroxy-2-azaspiro[3.3]heptane compounds, characterized in that, the method comprises the following steps: (1) The compound shown in formula I undergoes a ring-closing reaction with the compound shown in formula II to obtain the compound shown in formula III; (2) The compound shown in formula III undergoes an ester group reduction reaction to obtain the compound shown in formula IV; (3) The hydroxyl group of the compound shown in formula IV undergoes a substitution reaction to obtain the compound shown in formula V; (4) The compound shown in formula V undergoes a cyano reduction and a ring-closing reaction to obtain the compound shown in formula VI; (5) The compound shown in formula VI undergoes a hydroxyl protecting group removal and an amino protection to obtain the compound shown in formula VII, wherein, X is a halogen or OMs, OTs; R 1 is MOM, MEM, THP, BOM, PMBM, t-Bu, SEM, TBS, TIPS, TBDPS, Ac or Bz; R 2 is a C1-C8 alkyl group; Y is OMs, OTs, OTf or a halogen; R is Boc, Cbz, Alloc, Fmoc, Ac or Bz.

2. The synthesis method according to claim 1, characterized in that, X is Br, Cl or OTs, and R 1 is MOM, and R 2 is ethyl.

3. The synthesis method according to claim 1, characterized in that, step (1) includes: in a first solvent, under the action of a first base reagent, the compound shown in formula I undergoes a ring-closing reaction with the compound shown in formula II to obtain the compound shown in formula III.

4. The synthesis method according to claim 3, characterized in that, step (1) includes one or more of the following features selected from the group: A. The compound shown in formula II is a C1-C8 alkyl cyanoacetate, preferably selected from methyl cyanoacetate, ethyl cyanoacetate, isopropyl cyanoacetate, n-propyl cyanoacetate, n-butyl cyanoacetate, sec-butyl cyanoacetate, isobutyl cyanoacetate, tert-butyl cyanoacetate, and ethyl cyanoacetate is preferred; B. The molar equivalent of the compound shown in formula II is 1-10 times that of the compound shown in formula I, preferably 1-3 times, such as 1 time, 1.5 times; C. The first base reagent is selected from one or a combination of sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, sodium hydride, sodium amide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-pentoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, triethylamine, diisopropylethylamine, tripropylamine, tributylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 2,6-dimethyl-4-tert-butylpyridine, DBU, DABCO, MTBD; D. The equivalent of the first base reagent is 1-5 times that of the compound shown in formula I, preferably 2-4 times; E. Step (1) is carried out at 20-150 °C, preferably 50-150 °C, more preferably 80-120 °C, such as 100-110 °C.

5. The synthesis method according to claim 1, characterized in that, step (2) includes: in a second solvent, under the action of a first reducing agent, the compound shown in formula III undergoes an ester group reduction reaction to obtain the compound shown in formula IV.

6. The synthesis method according to claim 5, characterized in that, step (2) includes one or more of the following features selected from the group: A. The first reducing agent is selected from sodium borohydride, potassium borohydride, lithium borohydride, lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum dihydride, borane-tetrahydrofuran, borane-dimethyl sulfide, a combination of sodium borohydride and lithium chloride, a combination of sodium borohydride and calcium chloride, sodium borohydride and boron trifluoride diethyl etherate, a combination of sodium borohydride and aluminum trichloride, a combination of sodium borohydride and iodine, a combination of sodium borohydride and zinc chloride, a combination of sodium borohydride and cobalt chloride, a combination of sodium borohydride and nickel chloride, or a combination thereof; B. The molar equivalent of the first reducing agent is 1 - 5 times the equivalent of the compound shown in Formula III, preferably 2 - 3 times the equivalent; C. Step two is carried out at 10 - 120 °C, preferably 10 - 80 °C, more preferably 20 - 60 °C, for example 40 - 50 °C; D. Step two includes: directly inputting the product after the reaction is completed into the next reaction after simple post-treatment.

7. The synthesis method according to claim 1, wherein, Step three includes: in a third solvent, under the action of a second base reagent, the compound shown in Formula IV undergoes a substitution reaction of the hydroxyl group with a substitution reagent to obtain the compound shown in Formula V.

8. The synthesis method according to claim 7, wherein, Step three includes one or more of the following characteristics: A. The substitution reagent is selected from sulfonyl chloride or sulfonic anhydride, preferably one of p-toluenesulfonyl chloride, p-toluenesulfonic anhydride, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, and more preferably p-toluenesulfonyl chloride; B. The molar equivalent of the substitution reagent is 1 - 5 times the equivalent of the compound shown in Formula IV, preferably 1 - 2 times the equivalent, for example 1.2 times the equivalent; C. The second base reagent is selected from one or a combination of triethylamine, diisopropylethylamine, tripropylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 2,6-dimethyl-4-tert-butylpyridine, N-methylmorpholine, imidazole, DBU, DABCO, MTBD, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide; preferably triethylamine; D. The molar equivalent of the second base reagent is 0.5 - 5 times that of the substitution reagent, preferably 0.8 - 2 times, for example 1 time; E. Step three is carried out at 0 - 100 °C, preferably 5 - 70 °C, more preferably 10 - 50 °C, for example 10 - 20 °C or 15 - 25 °C.

9. The synthesis method according to claim 1, wherein, Step four includes: in a fourth solvent, under the action of a second reducing agent, the compound shown in Formula V undergoes a cyano reduction reaction to reduce the cyano group to an amino group, and then an intramolecular substitution cyclization reaction is carried out simultaneously to obtain the compound shown in Formula VI; Or, step four includes: in a fifth solvent, under the action of a catalyst, under a certain hydrogen pressure, the compound shown in Formula V undergoes a cyano reduction reaction to reduce the cyano group to an amino group, and then an intramolecular substitution cyclization reaction is carried out simultaneously to obtain the compound shown in Formula VI.

10. The synthesis method according to claim 1, wherein, Step 5 includes: in a sixth solvent, under the action of an acid reagent, the compound shown in Formula VI undergoes a hydroxyl protecting group deprotection reaction, and then under the action of a third base reagent, it is mixed with an amino protecting reagent to carry out an amino protection reaction to obtain the compound shown in Formula VII.

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