CN103936652B - Intermediate compound IV of anti-hepatitis C medicine Boceprevir and its preparation method and application - Google Patents

Abstract

The present invention relates to the preparation method technical field for anti-hepatitis C medicine Boceprevir.Compounds Ⅳ provided by the invention (F-1) structural formula is as follows.The preparation of this compounds, easy and simple to handle, yield is higher.Using this compounds to can be used for the synthesis of anti-hepatitis C medicine Boceprevir, this is that the synthesis of anti-hepatitis C medicine Boceprevir provides new thinking and method.And convenient with the detection of ultraviolet chromophoric group more original synthetic method in such compound molecule, additionally on hydroxyl, the introducing of benzyl avoids the side reaction caused in condensation step because of hydroxyl nucleophilicity, has certain advantage compared with existing synthetic method.

Description

Intermediate IV of anti-hepatitis C drug Boceprevir and its preparation method and application

technical field

The invention relates to the technical field of preparation methods for anti-hepatitis C drug Boceprevir.

Background technique

Globally, the infection rate of hepatitis C virus (HCV) is about 3%, and the total number of infected people is about 200 million. Because of the high infection rate of HCV and the serious potential complications such as liver cirrhosis and liver cancer, HCV is a serious threat to human life and health. According to the Simmonds naming system, HCV can be divided into six main genotypes, namely I-VI, and each type can be divided into several subtypes (such as Ia, Ib, IIa, IIb, IIIa, IIIb, etc.). There are about 40 million HCV-infected people in my country, 69% of which are type I infections (mainly type Ib). The current treatment for chronic hepatitis C is mainly the combination of pegylated interferon (PEG-IFNα) and ribavirin (RBV). This therapy fails to produce a sustained virological response in about 50% of patients with HCVI. And there are adverse reactions, so it is urgent to develop effective therapeutic drugs. Due to this need, the research and development of new anti-HCV drugs is very active. At present, more than 50 anti-HCV drug candidates are undergoing or have been approved for clinical trials. Among these drugs, Victrelis (boceprevir) was approved by the US FDA on May 13, 2011 in combination with pegylated interferon and ribavirin for the treatment of chronic hepatitis C in adults.

Boceprevir (structure as above) is a chronic hepatitis C treatment drug developed by Schering-Plough in the United States. It is an orally effective HCV NS3 protease inhibitor. The small molecule inhibitor discovered by shortening and modification can capture the serine in the active site of NS3, and the carbonyl carbon on the ketoamide combines with the serine to form a covalent adduct, thereby inactivating NS3. A study published in the "New England Journal of Medicine" showed that for patients with previously untreated chronic HCV genotype I infection, adding Boceprevir to the standard treatment of pegylated interferon-ribavirin was associated with Compared with standard treatment alone, it can significantly increase the sustained virological response rate.

There are two main synthetic strategies of Boceprevir. Patent WO02/08244A2 and J.Med.Chem.2006, 49, 6074-6086 report the synthesis strategy of Boceprevir obtained from three fragments through two condensations and one hydrolysis, and finally oxidation of side chain hydroxyl. details as follows:

Patent WO2008/079216 reports the synthesis strategy of Boceprevir that first oxidizes the hydroxyl group of the side chain and then condenses, as follows:

Other relevant patents or documents are optimized and improved on the basis of the above two synthetic strategies (for details, please refer to US2004/018914, US2006/043950, US2007/025804, etc.). However, the existing synthetic methods all have the same problem: since there is no obvious chromophoric group in the structure of each intermediate, the reaction detection and intermediate control are relatively troublesome. In addition, there are exposed hydroxyl groups in the condensation step of strategy 1, which will inevitably lead to side reactions, which is also the case in the actual operation. The inventors of the present invention have successfully solved the problem of detection difficulties and side reactions in the condensation step by introducing a substituted or unsubstituted benzyl group into an intermediate, while taking into account the limitations of hepatitis C virus ("HCV") protease inhibitors. Of importance, novel intermediates for the preparation of such inhibitors are always of interest.

Contents of the invention

The purpose of the present invention is to solve the problems existing in the above-mentioned existing methods for synthesizing Boceprevir, and to provide a new intermediate compound, which can easily and efficiently prepare Boceprevir or such compounds.

For reaching above-mentioned purpose, the technical scheme that the present invention takes is as follows:

Compound F-1 of the following general formula:

R is a substituent at any position of the benzene ring, and R is hydrogen, alkyl or alkoxy. Preferably R is at the para position; preferably R is hydrogen or C1-C3 alkyl, more preferably hydrogen.

The above-mentioned new general formula compound F-1 can be used to prepare the hepatitis C (HCV) protease inhibitor Boceprevir having the following structure

The compound of formula F-1 can prepare Boceprevir through following reaction route

a) In an organic solvent, compound F-1 is deprotected under acidic conditions to obtain compound F-2

b) In an organic solvent, in the presence of a base and a condensing agent, compound F-2 and compound G-3 are condensed to obtain a compound of formula 1

C) The compound of formula 1 can be easily prepared by hydrogenation reduction to obtain the compound of formula 2, and the compound of formula 2 is oxidized to obtain the final target compound Boceprevir

R is a substituent at any position of the benzene ring, R is hydrogen, alkyl or alkoxy, and A is an acid radical. Preferably R is at the para position; preferably R is hydrogen or C1-C3 alkyl, more preferably hydrogen.

The acid used in step a) includes hydrochloric acid, sulfuric acid, trifluoroacetic acid, preferably hydrochloric acid. Relative to compound F-1, the acid can be used in an amount of 1 to 20 molar equivalents, preferably 1 to 10 molar equivalents, more preferably 1 to 5 molar equivalents. Usable solvents include ether solvents, such as diethyl ether, THF, methyl tert-butyl ether, THP, dioxane, etc.; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, etc. ; Aromatic solvents, such as toluene, benzene, xylene, trimethylbenzene, chlorobenzene, etc.; and ester solvents, such as ethyl acetate, etc. or a suitable mixture thereof. The preferred solvent is an ether solvent, more preferably dioxane. The reaction can be carried out at a temperature of -25°C to 50°C, preferably -10°C to 25°C, more preferably 0°C to 25°C for about 1 hour or until the reaction is complete.

Usable bases for step b) include triethylamine, N,N-diisopropylethylamine, pyridine, N-methylmorpholine, preferably N-methylmorpholine and N,N-diisopropylethylamine. The base can be used in an amount of 2 to 8 molar equivalents, preferably 2 to 5 molar equivalents, more preferably 2 to 4 molar equivalents relative to compound F-2. Condensing agents that can be used include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), benzotriazol-1-yloxytris(dimethylamino) Phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate (PyBOP), N, N'-carbonyldiimidazole (CDI), 2-(7-even Azobenzotriazole)-N,N,N',N'-Tetramethyluronium hexafluorophosphate (HATU), 2-(7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate Phosphate (HATU), ≥99.5% (HPLC) (HBTU), N,N'-dicyclohexylcarbodiimide (DCC), preferably EDCI, BOP, PyBOP, HATU, more preferably EDCI and HATU. The condensing agent can be used in an amount of 1 molar equivalent to 5 molar equivalents, preferably 1 molar equivalent to 3 molar equivalents, more preferably 1 molar equivalent to 2 molar equivalents, relative to compound F-2. In order to promote the reaction, additives can also be added, available additives include 1-hydroxy-7-azobenzotriazole (HOAT), 1-hydroxybenzotriazole (HOBT), ≥99% (HPLC). The additive is used in an amount of 0 to 5 molar equivalents, preferably 1 molar equivalent to 3 molar equivalents, more preferably 1 molar equivalent to 2 molar equivalents, relative to compound F-1. Relative to compound F-2, compound G-3 can be used in an amount of 1 to 2 molar equivalents, preferably 1 to 1.5 molar equivalents, more preferably 1 to 1.2 molar equivalents. Usable solvents include ether solvents, such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, tetrahydropyran, dioxane, etc.; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, dichloromethane Ethane, etc.; aromatic solvents, such as toluene, benzene, xylene, trimethylbenzene, chlorobenzene, etc.; ester solvents, such as ethyl acetate, etc., and other solvents, such as DMF, DMSO, acetonitrile, etc. or their suitable mixtures . Preferred solvents are other solvents, more preferably DMF and acetonitrile.

The method for preparing Boceprevir, the compound of formula 3, from the compound of formula 2 can be found in patents US2006/043950, WO02/08244A2, J.Med.Chem.2006, 49, 6074-6086, and US8188137B2.

The preparation method of the compound of the above-mentioned general formula F-1 is to condense the compound F of the following formula and the compound G-2 in an organic solvent under the conditions of the presence of a base and a condensing agent:

Wherein R is a substituent at any position of the benzene ring, R is hydrogen, alkyl or alkoxy, and A is an acid radical. Preferably R is at the para position; preferably R is hydrogen or C1-C3 alkyl, more preferably hydrogen.

Usable bases include triethylamine, N,N-diisopropylethylamine, pyridine and N-methylmorpholine, preferably N-methylmorpholine and N,N-diisopropylethylamine. Relative to compound F, the amount of the base can be 2 to 8 molar equivalents, preferably 2 to 5 molar equivalents, more preferably 2 to 4 molar equivalents. Useful condensing agents include EDCI, BOP, PyBOP, CDI, HATU, HBTU and DCC, preferably EDCI, BOP, PyBOP and HATU, more preferably EDCI and HATU. Relative to compound F, the amount of the condensing agent can be 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, more preferably 1 to 2 molar equivalents. Step a) can also add additives, additives include HOBT and HOAT and so on. Relative to compound F, the additive can be used in an amount of 0 to 5 molar equivalents, preferably 1 molar equivalent to 3 molar equivalents, more preferably about 1 molar equivalent to 2 molar equivalents. Compound G-2 can generally be used in an amount of about 1 molar equivalent to about 2 molar equivalents, preferably 1 molar equivalent to 1.5 molar equivalents, more preferably 1 molar equivalent to 1.2 molar equivalents, relative to Compound F. Usable solvents include ether solvents, such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, tetrahydropyran, dioxane, etc.; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, dichloromethane Ethane, etc.; aromatic solvents, such as toluene, benzene, xylene, trimethylbenzene, chlorobenzene, etc.; ester solvents, such as ethyl acetate, etc., and other solvents, such as DMF, DMSO, acetonitrile, etc. or their suitable mixtures . Preferred solvents are other solvents, more preferably DMF and acetonitrile. The reaction can be carried out at a temperature of -25°C to 50°C, preferably -10°C to 25°C, more preferably 0°C to 25°C for about 24 hours or until the reaction is complete.

Compound F can be obtained by deprotecting the compound E in an organic solvent under acidic conditions:

Wherein R is a substituent at any position of the benzene ring, and R is hydrogen, alkyl or alkoxy. Preferably R is at the para position; preferably R is hydrogen or C1-C3 alkyl, more preferably hydrogen.

Useful acids include hydrochloric acid, sulfuric acid, trifluoroacetic acid, preferably hydrochloric acid. Relative to compound E, the acid can be used in an amount ranging from 1 molar equivalent to 20 molar equivalents, preferably from 1 molar equivalent to 10 molar equivalents, more preferably from 1 molar equivalent to 5 molar equivalents. Usable solvents include ether solvents, such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, tetrahydropyran, dioxane, etc.; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, dichloromethane Ethane, etc.; aromatic solvents, such as toluene, benzene, xylene, trimethylbenzene, chlorobenzene, etc.; and ester solvents, such as ethyl acetate, etc., or a suitable mixture thereof. The preferred solvent is an ether solvent, more preferably dioxane. The reaction can be carried out at a temperature of -25°C to 50°C, preferably -10°C to 25°C, more preferably 0 to 25°C, for about 1 hour or until the reaction is complete.

Compound E can be obtained by reacting the compound D of the following formula with ethyl chloroformate in an organic solvent under the condition of the presence of a base and directly reacting with concentrated ammonia

Wherein R is a substituent at any position of the benzene ring, and R is hydrogen, alkyl or alkoxy. Preferably R is at the para position; preferably R is hydrogen or C1-C3 alkyl, more preferably hydrogen.

The bases available for the above reaction include triethylamine, N, N-diisopropylethylamine, pyridine, N-methylmorpholine, lithium hydroxide, sodium hydroxide, potassium hydroxide, preferably triethylamine, N, N - diisopropylethylamine and N-methylmorpholine, more preferably triethylamine. Relative to compound D, the recommended amount of the base is 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, more preferably 1 to 2.5 molar equivalents. Relative to compound D, ethyl chloroformate can be used in an amount of 1 molar equivalent to about 5 molar equivalents, preferably 1 molar equivalent to 3 molar equivalents, more preferably 1 molar equivalent to 2.5 molar equivalents. Relative to compound D, the concentrated ammonia water can be used in an amount of 1 to 8 molar equivalents, preferably 1 to 5 molar equivalents, more preferably 1 to 3 molar equivalents. Usable solvents include ether solvents, such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, tetrahydropyran, etc.; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, etc.; aromatic solvents such as toluene, benzene, xylene, trimethylbenzene, chlorobenzene, etc.; and ester solvents such as ethyl acetate, etc. or a suitable mixture thereof. The preferred solvent is an ether solvent, more preferably tetrahydrofuran. The reaction can be carried out at a temperature of -25°C to 50°C, preferably -10°C to 25°C, more preferably 0°C to 25°C, for about 2 hours or until the reaction is complete.

Compound D can be obtained by hydrolyzing compound C in an organic solvent under the action of a base:

Wherein R is a substituent at any position of the benzene ring, and R is hydrogen, alkyl or alkoxy. Preferably R is at the para position; preferably R is hydrogen or C1-C3 alkyl, more preferably hydrogen.

For the above hydrolysis reaction, available bases include potassium hydroxide, sodium hydroxide, lithium hydroxide, preferably sodium hydroxide and lithium hydroxide, more preferably lithium hydroxide. Relative to compound C, the base can be used in an amount of 1 molar equivalent to 10 molar equivalents, preferably 1 molar equivalent to 5 molar equivalents, more preferably 1 molar equivalent to 4 molar equivalents. Usable solvents include ether solvents, such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, tetrahydropyran, etc.; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, etc.; aromatic Solvents, such as toluene, benzene, xylene, trimethylbenzene, chlorobenzene, etc.; and ester solvents, such as ethyl acetate, etc.; protic solvents, such as methanol, ethanol, water, etc. or a suitable mixture thereof. Preferably the solvent is a mixed solvent, more preferably a tetrahydrofuran/methanol mixed solvent. The reaction may be carried out at a temperature of 0°C to 60°C, preferably 0 to 40°C, more preferably 10°C to 25°C, for about 4 hours or until the reaction is complete.

Compound C can be obtained by compound B of the following formula, in an organic solvent, under the action of a catalyst, reacted with di-tert-butyl dicarbonate and then obtained through the action of hydrazine hydrate:

Wherein R is a substituent at any position of the benzene ring, and R is hydrogen, alkyl or alkoxy. Preferably R is at the para position; preferably R is hydrogen or C1-C3 alkyl, more preferably hydrogen.

Usable catalysts may be 4-dimethylaminopyridine, triethylamine, butyllithium, sodium hydroxide, etc., preferably 4-dimethylaminopyridine and triethylamine, more preferably 4-dimethylaminopyridine. Relative to compound B, the amount of the catalyst used is generally 0.2 to 3 molar equivalents, preferably 0.2 to 1 molar equivalent, more preferably 0.2 to 0.5 molar equivalent. Relative to compound B, the amount of di-tert-butyl dicarbonate can generally be used in the range of 1 molar equivalent to 5 molar equivalents, preferably 1 molar equivalent to 3 molar equivalents, more preferably 1 molar equivalent to 2 molar equivalents. Relative to compound B, the amount of hydrazine hydrate can usually be 2 to 10 molar equivalents, preferably 2 to 5 molar equivalents, more preferably 2 to 4 molar equivalents. Solvents that can be used with di-tert-butyl dicarbonate include ether solvents, such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, tetrahydropyran, etc.; halogenated hydrocarbons, such as dichloromethane, chloroform, tetrachloride Carbon, dichloroethane, etc.; aromatic solvents, such as toluene, benzene, xylene, trimethylbenzene, chlorobenzene, etc.; and ester solvents, such as ethyl acetate, etc. or a suitable mixture thereof. The preferred solvent is an ether solvent, more preferably tetrahydrofuran. Available solvents for hydrazinolysis include ether solvents, such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, tetrahydropyran, etc.; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane etc.; aromatic solvents such as toluene, benzene, xylene, trimethylbenzene, chlorobenzene, etc.; protic solvents such as methanol, ethanol, water, etc. or suitable mixtures thereof. The solvent is preferably a mixed solvent, more preferably a tetrahydrofuran/methanol mixed solvent. The reaction of compound B and di-tert-butyl dicarbonate can be carried out at 25°C to reflux temperature, preferably 50°C to reflux temperature, more preferably at reflux temperature, for about 8 hours or until the reaction is complete; the hydrazinolysis reaction can be carried out at -25°C ~50°C, preferably -10°C to about 25°C, more preferably 10°C to 25°C, for about 4 hours or until the reaction is complete.

Compound B can be obtained by reacting compound A of the following formula with a substituted or unsubstituted benzyl halide in an organic solvent in the presence of a base:

Wherein R is a substituent at any position of the benzene ring, and R is hydrogen, alkyl or alkoxy. Preferably R is at the para position; preferably R is hydrogen or C1-C3 alkyl, more preferably hydrogen.

X in the above-mentioned substituted or unsubstituted benzyl halides can be chlorine or bromine, preferably X is bromine; R can be hydrogen, C1-C6 alkyl or C1-C6 alkoxy, preferably R is hydrogen or C1-C3 alkyl ; R can be at any unsubstituted position on the benzene ring, preferably R is at the para position. The amount of the substituted or unsubstituted benzyl halide can generally be used in the range of 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, more preferably 1 to 1.3 molar equivalents relative to compound A. Useful bases include potassium tert-butoxide, sodium hydride, potassium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, diiso Lithium propylamide, butyllithium, preferably potassium tert-butoxide, sodium hydride, lithium bis(trimethylsilyl)amide, more preferably sodium hydride. The base can usually be used in an amount of 1 molar equivalent to 5 molar equivalents, preferably 1 molar equivalent to 3 molar equivalents, more preferably 1 molar equivalent to 1.5 molar equivalents, relative to compound A. Usable solvents include ether solvents such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, tetrahydropyran, etc.; aromatic solvents such as toluene, benzene, xylene, trimethylbenzene, chlorobenzene, etc.; and ester solvents , such as ethyl acetate, etc. or a suitable mixture thereof. The preferred solvent is an ether solvent, more preferably tetrahydrofuran. The reaction can be carried out at a temperature of -25°C to 25°C, preferably -10°C to 10°C, more preferably -5°C to 0°C, for about 2 hours or until the reaction is complete.

The compound A of the present invention can be prepared by methods known in the art, see Chinese patent application 201210200429.6 for details.

The invention provides a new compound F-1. The preparation of this type of compound has simple reaction operation and high yield. The compound can be used for the synthesis of the anti-hepatitis C drug Boceprevir, which provides a new idea and method for the synthesis of the anti-hepatitis C drug Boceprevir. Moreover, the ultraviolet chromogenic group in the molecule of this type of compound is more convenient to detect than the original synthesis method. In addition, the introduction of the benzyl group on the hydroxyl group avoids the side reaction caused by the nucleophilicity of the hydroxyl group in the condensation step, which is different from the existing synthetic method. Compared with certain advantages.

detailed description

The following are the reaction steps involved in the preferred embodiments of the present invention. Unless otherwise noted, all the chemicals and solvents of the present invention were obtained from commercial sources without further purification before use.

Embodiment 1-9: R is the preparation of formula 1 compound of hydrogen

Embodiment 1: the preparation of compound B

Compound A (5g, 20.6mmol) was dissolved in 40ml of DMF and added to a three-neck flask, cooled to -5°C; NaH (60%, 1.1g, 26.8mmol) was added in batches and stirred for 1h, and 40ml of BnBr was added dropwise at -5°C (4.2g, 24.7mmo) DMF solution, after the dropwise addition, stir at this temperature for 2h, add ice water to quench the reaction, extract with ethyl acetate, a small amount of times, combine the organic phases, wash with saturated brine and anhydrous Drying over sodium sulfate and distilling off the solvent gave a yellow oil, and column chromatography gave 6.2g of compound B as a white solid, yield 90.4%, m/z (MH+) 334.16, 1HNMR (400MHz, CDCl3) δ1.31(t, 3H ), 1.41-1.57(m, 4H), 1.64-1.74(m, 2H), 1.77(s, 3H), 1.96-2.06(m, 2H), 2.25-2.29(m, 1H), 3.95(d, 1H ), 4.19-4.25 (m, 3H), 4.28 (d, 1H), 4.81 (d, 1H), 5.63 (d, 1H), 7.30-7.35 (m, 5H).

Embodiment 2: the preparation of compound C

Compound B (5g, 15mmol), DMAP (0.37g, 3mmol) was dissolved in 60ml of THF, after adding (Boc) ₂ O (6.88ml, 30mmol), the temperature was raised to reflux, and after reflux for about 8h, the temperature was lowered to room temperature, and 60ml of methanol and hydrazine hydrate were added (3g, 60mmol) was stirred for 4h and then diluted with 200ml dichloromethane. The reaction solution was washed with 1N HCl, copper sulfate solution, saturated sodium bicarbonate solution and saturated brine successively. After drying over anhydrous sodium sulfate, the solvent was evaporated to obtain a yellow oil. , column chromatography obtained 4.4g compound C as a white solid, yield 75.0%, m/z (MNa+) 414.06, 1HNMR (400MHz, CDCl ) δ 1.32 (t, 3H), 1.44 (s, 9H), 1.48- 1.68(m, 4H), 1.78-1.87(m, 2H), 2.02-2.11(m, 2H), 2.33-2.37(m, 1H), 3.98(m, 1H), 4.20-4.32(m, 3H), 4.43 (d, 1H), 4.65 (d, 1H), 4.81 (d, 1H), 7.30-7.37 (m, 5H).

Embodiment 3: the preparation of compound D

Compound C (2g, 5mmol) was dissolved in 20ml of MeOH/THF (v/v1:1) solution, added 20ml of 1M LiOH solution, stirred at room temperature for 4h, added 1M potassium bisulfate solution to adjust the pH to 2, extracted with dichloromethane, and combined the organic phases , the organic phase was washed successively with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate and evaporated to obtain compound D as a white solid 1.91 g, yield 100%, m/z (MNa+) 386.13.

Embodiment 4: the preparation of compound E

Compound D (1.91g, 5mmol) was dissolved in 30ml of anhydrous THF and cooled to 0°C, triethylamine (1.9ml, 12.5mmol) was added followed by ethyl chloroformate (1.2ml, 11mmol), stirred at 0°C for 15min Then add 30% ammonia water (2ml, 13.5mmol) and stir at 0°C for 30min, add 50ml of ethyl acetate and stir for 20min, remove the solid by suction filtration, and wash the filtrate with 1M potassium hydrogensulfate, saturated sodium bicarbonate and saturated saline solution successively After washing and drying with anhydrous sodium sulfate, a white solid was obtained after distilling off the solvent, and 3.30 g of compound E was obtained as a white solid by column chromatography, with a yield of 71.2%. m/z (MNa+) 385.16, 1HNMR (400MHz, CDCl3) δ1.44 (s, 9H), 1.61-1.70 (m, 4H), 1.76-1.90 (m, 2H), 2.03-2.10 (m, 2H), 2.34-2.40(m, 1H), 3.80-3.98(m, 1H), 4.47(s, 1H), 4.60-4.67(m, 2H), 5.50(s, 1H), 6.46(s, 1H), 7.28- 7.41 (m, 5H).

Embodiment 5: the preparation of compound F

Compound E (422mg, 1.12mmol) was dissolved in 5ml 4NHCl/dioxane and stirred for 1h, the volatile matter of the above reaction solution was evaporated to dryness, and then 10ml of dichloromethane was added to continue to concentrate. Repeat 4 times to obtain 350mg of Compound F as a white solid, which was collected Yield 100%, m/z (MH+) 263.13.

Embodiment 6: the preparation of formula 1 compound

G-1 (136mg, 0.37mmol), EDCI (105mg, 0.59mmol), HOBt (100mg, 0.59mmol) were dissolved in 8ml of DMF, cooled in an ice-water bath, NMM (0.23mml, 1.56mmol) was added, stirred for 30min, compound F ( 117mg, 0.37mmol) was added to 8ml of DMF, this solution was added to the reaction solution of G-1, stirred at 0°C for 2 days, 50ml of water was added to the reaction solution, the reaction solution was extracted with ethyl acetate, and the organic phase was successively washed with 1N hydrochloric acid Washed with saturated sodium bicarbonate solution, then washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent to obtain a yellow oil, column chromatography obtained 177mg of the compound of formula 1 as a white solid, yield 78.0%, m /z(MNa+)634.34, 1HNMR(400MHz, DMSO-d)δ0.89(m, 9H), 0.82-1.00(m, 6H), 1.17(s, 9H), 1.26(m, 1H), 1.43(m , 1H), 1.65-1.74(m, 4H), 1.78-1.94(m, 2H), 2.01-2.08(m, 2H), 2.36-2.40(m, 1H), 3.74-3.76(m, 2H), 3.92 -3.97(m, 1H), 4.11(d, 1H), 4.26(s, 1H), 4.47(s, 1H), 4.60-4.67(m, 2H), 5.52(s, 1H), 6.44(s, 1H ), 7.28-7.46 (m, 5H), 7.76-8.04 (br, 2H), 8.20-8.30 (s, 1H).

Embodiment 7: the preparation of compound F-1

G-2 (94mg, 0.37mmol), EDCI (105mg, 0.59mmol), HOBt (100mg, 0.59mmol) were dissolved in 8ml of DMF, cooled in an ice-water bath, NMM (0.23mml, 1.56mmol) was added and stirred for 30min; Compound F ( 120mg, 0.37mmol) was added to 8ml of DMF, this solution was added to the reaction solution of G-2, and stirred at 0°C for 2 days; 50ml of water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate, and the organic phase was successively washed with 1N hydrochloric acid Washed with saturated sodium bicarbonate solution, then washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to obtain a yellow oily substance. Column chromatography gave 146mg of compound F-1 as a white solid, with a yield of 79.2%. m/z (MNa+) 522.30, 1HNMR (400MHz, DMSO-d) δ0.92-1.03 (m, 6H), 1.23-1.26 (m, 1H), 1.44 (s, 9H), 1.46-1.50 (m, 1H ), 1.64-1.74(m, 4H), 1.75-1.92(m, 2H), 2.03-2.08(m, 2H), 2.38-2.44(m, 1H), 3.54-3.72(m, 2H), 3.91-3.97 (m, 1H), 4.13(d, 1H), 4.49(s, 1H), 4.60-4.69(m, 2H), 5.52(s, 1H), 6.44(s, 1H), 7.25-7.49(m, 5H ).

Embodiment 8: the synthesis of compound F-2

Dissolve compound F-1 (140mg, 0.28mmol) in 3ml 4NHCl/dioxane and stir for 1h, evaporate the volatile matter of the above reaction solution to dryness, add 10ml dichloromethane to continue concentration, repeat 4 times to obtain 120mg compound F-2 as a White solid, yield 100%, m/z (MH+) 400.30.

Embodiment 9: the preparation of formula 1 compound

Dissolve G-3 (78mg, 0.34mmol), HATU (128mg, 0.34mmol) in 8ml of DMF, cool in an ice-water bath, add DIEA (0.18mml, 1.00mmol), and stir for 30min; compound F-2 (120mg, 0.28mmol) Add to 8ml of DMF, add this solution to the reaction solution of G-2, stir overnight at 0°C; add 50ml of water to the reaction solution, extract the reaction solution with ethyl acetate, and wash the organic phase with 1N hydrochloric acid and saturated sodium bicarbonate solution successively Washing, and then washing with saturated brine, drying over anhydrous sodium sulfate, evaporation of the solvent to obtain a yellow oil, column chromatography to obtain 118 mg of the compound of formula 1 as a white solid, yield 68.7%.

Embodiment 10-18: R is the preparation of the compound of formula 1 that R is methyl and R is in para position

Embodiment 10: the preparation of compound B

Compound A (2g, 8.23mmol) was dissolved in 10ml of DMF and added to a three-neck flask, cooled to -5°C, NaH (60%, 0.43g, 10.70mmol) was added in batches and stirred for 1h, and 10ml of DMF solution of methyl benzyl bromide (1.83g, 9.88mmo), after the dropwise addition, stir at this temperature for 2h, add ice water to quench the reaction, extract with ethyl acetate, a small amount of multiple times, combine the organic phases, and wash with saturated saline After washing, it was dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain a yellow oil, and column chromatography obtained 2.4 g of compound B as a white solid, with a yield of 82.5%, 1HNMR (400MHz, CDCl3) δ1.31 (t, 3H), 1.43- 1.64(m, 4H), 1.74-1.78(m, 2H), 1.83(s, 3H), 1.97-2.05(m, 2H), 2.25-2.29(m, 1H), 2.34(s, 3H), 4.00( d, 2H), 4.17-4.33 (m, 4H), 4.77 (d, 1H), 5.58 (d, 1H), 7.16 (d, 2H), 7.23 (d, 2H).

Embodiment 11: Preparation of Compound C

Compound B (1.8g, 5.19mmol) and DMAP (0.13g, 1.04mmol) were dissolved in 20ml of THF, after adding (Boc) ₂ O (2.4ml, 10.38mmol), the temperature was raised to reflux, and after reflux for about 8h, the temperature was lowered to room temperature and 20ml was added Methanol and hydrazine hydrate (1.04g, 20.76mmol) were stirred for 4h, then diluted with 100ml of dichloromethane, the reaction solution was washed with 1N HCl, copper sulfate solution, saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, evaporated Remove solvent to obtain yellow oil, column chromatography obtains 1.34g compound C as white solid, yield 63.7%, m/z (MNa+) 428.06, 1HNMR (400MHz, CDCl ) δ 1.32 (t, 3H), 1.43 (s , 9H), 1.50-1.67(m, 4H), 1.76-1.91(m, 2H), 2.00-2.10(m, 2H), 2.30-2.33(m, 1H), 2.35(s, 3H), 3.94-3.98 (m, 1H), 4.00(d, 1H), 4.17-4.38(m, 3H), 4.64(d, 1H), 4.79(d, 1H), 7.17(d, 2H), 7.27(d, 2H).

Embodiment 12: Preparation of Compound D

Compound C (1.2g, 2.96mmol) was dissolved in 20ml of MeOH/THF (v/v1:1) solution, added 20ml of 1M LiOH solution, stirred at room temperature for 4h, added 1M potassium bisulfate solution to adjust the pH to 2, extracted with dichloromethane, combined The organic phase was washed successively with saturated sodium bicarbonate and saturated brine, dried and evaporated over anhydrous sodium sulfate, and the solvent was used to obtain 1.2g of compound D as a white solid with a yield of 100%, m/z (MNa+) 400.13.

Embodiment 13: Preparation of Compound E

Compound D (1.2g, 3.19mmol) was dissolved in 20ml of anhydrous THF and cooled to 0°C, after adding triethylamine (1.1ml, 7.98mmol), ethyl chloroformate (0.7ml, 7.02mmol) was added, and at 0°C After stirring for 15min, add 30% ammonia water (1ml, 8.61mmol) and stir at 0°C for 30min, add 50ml of ethyl acetate and stir for 20min, remove the solid by suction filtration, and wash the filtrate with 1M potassium bisulfate, saturated sodium bicarbonate and saturated Wash with saline solution, dry over anhydrous sodium sulfate, evaporate the solvent to obtain a white solid, column chromatography to obtain 831 mg of compound E as a white solid, yield 69.3%, m/z (MNa+) 399.16, 1HNMR (400MHz, CDCl3) δ1.43(s, 9H), 1.60-1.71(m, 4H), 1.77-1.93(m, 2H), 2.00-2.10(m, 2H), 2.35(s, 3H), 2.36-2.40(m, 1H ), 3.83-3.98(m, 1H), 4.50(s, 1H), 4.62-4.69(m, 2H), 5.50(s, 1H), 6.47(s, 1H), 7.18(d, 2H), 7.25( d, 2H).

Embodiment 14: Preparation of Compound F

Compound E (400mg, 1.06mmol) was dissolved in 5ml 4NHCl/dioxane and stirred for 1h. After evaporating the volatile matter of the above reaction solution to dryness, 10ml of dichloromethane was added to continue concentrating. Repeat 4 times to obtain 330mg of Compound F as a white solid. Yield 100%, m/z (MH+) 277.13.

Embodiment 15: Preparation of compound 1

G-1 (136mg, 0.37mmol), EDCI (105mg, 0.59mmol), HOBt (100mg, 0.59mmol) were dissolved in 8ml of DMF, cooled in an ice-water bath, NMM (0.23mml, 1.56mmol) was added, stirred for 30min, compound F ( 120mg, 0.38mmol) was added to 8ml of DMF, this solution was added to the reaction solution of G-1, stirred at 0°C for 2 days, 50ml of water was added to the reaction solution, the reaction solution was extracted with ethyl acetate, and the organic phase was successively washed with 1N hydrochloric acid Washed with saturated sodium bicarbonate solution, then washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent to obtain a yellow oil, and column chromatography obtained 173mg of the compound of formula 1 as a white solid, yield 72.7%, m /z (MNa+) 648.34, 1HNMR (400MHz, DMSO-d) δ0.88-0.92 (m, 9H), 0.81-1.02 (m, 6H), 1.18 (s, 9H), 1.27 (m, 1H), 1.45 (m, 1H), 1.68-1.75(m, 4H), 1.81-1.94(m, 2H), 2.03-2.09(m, 2H), 2.33-2.41(m, 1H), 2.35(s, 3H), 3.75 -3.77(m, 2H), 3.92-3.97(m, 1H), 4.13(d, 1H), 4.25(s, 1H), 4.44(s, 1H), 4.61-4.67(m, 2H), 5.48(s , 1H), 6.42(s, 1H), 7.17(d, 2H), 7.23(d, 2H), 7.77-8.04(br, 2H), 8.20-8.28(s, 1H).

Embodiment 16: Preparation of Compound F-1

G-2 (94mg, 0.37mmol), EDCI (105mg, 0.59mmol), HOBt (100mg, 0.59mmol) were dissolved in 8ml of DMF, cooled in an ice-water bath, NMM (0.23mml, 1.56mmol) was added, stirred for 30min, compound F ( 120mg, 0.38mmol) was added to 8ml of DMF, this solution was added to the reaction solution of G-2, stirred at 0°C for 2 days, 50ml of water was added to the reaction solution, the reaction solution was extracted with ethyl acetate, and the organic phase was successively washed with 1N hydrochloric acid Washed with saturated sodium bicarbonate solution, then washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to obtain a yellow oily substance. Column chromatography gave 139mg of compound F-1 as a white solid, with a yield of 73.1%. m/z (MNa+) 536.30, 1HNMR (400MHz, DMSO-d) δ0.90-1.03(m, 6H), 1.22-1.26(m, 1H), 1.44(s, 9H), 1.48-1.51(m, 1H ), 1.62-1.71(m, 4H), 1.75-1.92(m, 2H), 2.03-2.08(m, 2H), 2.34(s, 3H), 2.37-2.44(m, 1H), 3.54-3.70(m , 2H), 3.90-3.97(m, 1H), 4.13(d, 1H), 4.52(s, 1H), 4.60-4.69(m, 2H), 5.52(s, 1H), 6.44(s, 1H), 7.18(d, 2H), 7.23(d, 2H).

Embodiment 17: the synthesis of compound F-2

Dissolve compound F-1 (139mg, 0.27mmol) in 3ml 4NHCl/dioxane and stir for 1h, evaporate the volatile matter of the above reaction solution to dryness, add 10ml dichloromethane to continue concentration, repeat 4 times to obtain 120mg compound F-2 as a White solid, yield 100%, m/z (MH+) 414.30.

Embodiment 18: the preparation of formula 1 compound

G-3 (78mg, 0.34mmol), HATU (128mg, 0.34mmol) were dissolved in 8ml of DMF, cooled in an ice-water bath, added DIEA (0.18mml, 1.00mmol), stirred for 30min, compound F-2 (120mg, 0.27mmol) was added To 8ml of DMF, add this solution to the reaction solution of G-3, stir overnight at 0°C, add 50ml of water to the reaction solution, extract the reaction solution with ethyl acetate, and wash the organic phase with 1N hydrochloric acid and saturated sodium bicarbonate solution successively , and then washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to obtain a yellow oily substance. Column chromatography gave 102 mg of the compound of formula 1 as a white solid, with a yield of 60.2%.

Embodiment 19-27: R is the preparation of the compound of formula 1 that R is methoxy and R is in para position

Embodiment 19: Preparation of Compound B

Compound A (4g, 16.46mmol) was dissolved in 10ml of DMF and added to a three-neck flask, cooled to -5°C; NaH (60%, 0.86g, 21.40mmol) was added in batches and stirred for 1h; 10ml was added dropwise at -5°C The DMF solution of p-methoxybenzyl chloride (3.08g, 19.75mmol), after the dropwise addition, stirred at this temperature for 2h; added ice water to quench the reaction, extracted with ethyl acetate, a small amount of multiple times, combined the organic phases, and saturated After washing with brine, drying with anhydrous sodium sulfate and distilling off the solvent gave a yellow oil; column chromatography gave 2.3 g of Compound B as a white solid, yield 37.9%, m/z (MH+) 364.16

Embodiment 20: Preparation of Compound C

Compound B (2.0g, 5.51mmol), DMAP (134mg, 1.10mmol) was dissolved in 20ml of THF, after adding (Boc) ₂ O (2.5ml, 11.02mmol), the temperature was raised to reflux, and after reflux for about 8h, it was cooled to room temperature and 20ml of methanol was added and hydrazine hydrate (1.10g, 22.04mmol) were stirred for 4h, then diluted with 100ml of dichloromethane, the reaction solution was washed with 1N HCl, copper sulfate solution, saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, evaporated The solvent gave a yellow oil, and column chromatography gave 1.51 g of compound C as a white solid, with a yield of 65.3%, (MNa+) 444.06.

Embodiment 21: Preparation of Compound D

Compound C (1g, 2.57mmol) was dissolved in 20ml of MeOH/THF (v/v1:1) solution, added 20ml of 1M LiOH solution, stirred at room temperature for 4h, added 1M potassium bisulfate solution to adjust the pH to 2, extracted with dichloromethane, combined organic The organic phase was washed successively with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate and evaporated to obtain 50 mg of compound D as a white solid, yield 100%, m/z (MNa+) 416.13.

Embodiment 22: Preparation of Compound E

Compound D (900mg, 2.29mmol) was dissolved in 20ml of anhydrous THF and cooled to 0°C, added triethylamine (0.8ml, 5.73mmol) and ethyl chloroformate (0.5ml, 5.04mmol), stirred at 0°C After 15min, add 30% ammonia water (0.7ml, 8.61mmol) and stir at 0°C for 30min, add 50ml of ethyl acetate and stir for 20min, remove the solid by suction filtration, and then wash the filtrate with 1M potassium bisulfate, saturated sodium bicarbonate and saturated Washed with saline solution, dried over anhydrous sodium sulfate, and evaporated to obtain a white solid. Column chromatography gave 587 mg of compound E as a white solid, yield 65.4%, m/z (MNa+) 415.16.

Embodiment 23: Preparation of Compound F

Compound E (950mg, 2.42mmol) was dissolved in 5ml 4NHCl/dioxane and stirred for 1h, the volatile matter of the above reaction solution was evaporated to dryness, and then 10ml of dichloromethane was added to continue concentrating. Repeat 4 times to obtain 795mg of compound F as a white solid. Yield 100%, m/z (MH+) 293.13.

Embodiment 24: Preparation of compound 1

G-1 (136mg, 0.37mmol), EDCI (105mg, 0.59mmol), HOBt (100mg, 0.59mmol) were dissolved in 8ml of DMF, cooled in an ice-water bath, NMM (0.23mml, 1.56mmol) was added, stirred for 30min, compound F ( 120mg, 0.37mmol) was added to 8ml of DMF, this solution was added to the reaction solution of G-1, stirred at 0°C for 2 days, 50ml of water was added to the reaction solution, the reaction solution was extracted with dichloromethane, and the organic phase was successively washed with 1N hydrochloric acid Washed with saturated sodium bicarbonate solution, then washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent to obtain a yellow oil, column chromatography obtained 145mg of the compound of formula 1 as a white solid, yield 61.3%, m /z(MNa+)664.34, 1HNMR(400MHz, DMSO-d)δ0.87-0.92(m, 9H), 0.82-1.02(m, 6H), 1.18(s, 9H), 1.28(m, 1H), 1.44 (m, 1H), 1.66-1.75(m, 4H), 1.82-1.94(m, 2H), 2.03-2.09(m, 2H), 2.33-2.41(m, 1H), 3.75-3.77(m, 2H) , 3.83(s, 3H), 3.92-3.97(m, 1H), 4.13(d, 1H), 4.25(s, 1H), 4.44(s, 1H), 4.61-4.67(m, 2H), 5.48(s , 1H), 6.42(s, 1H), 6.90(d, 2H), 6.99(d, 2H), 7.77-8.04(br, 2H), 8.20-8.28(s, 1H).

Example 25: Preparation of Compound F-1

G-2 (94mg, 0.37mmol), EDCI (105mg, 0.59mmol), HOBt (100mg, 0.59mmol) were dissolved in 8ml of DMF, cooled in an ice-water bath, NMM (0.23mml, 1.56mmol) was added, stirred for 30min, compound F ( 120mg, 0.37mmol) was added to 8ml of DMF, this solution was added to the reaction solution of G-2, stirred at 0°C for 2 days, 50ml of water was added to the reaction solution, the reaction solution was extracted with ethyl acetate, and the organic phase was successively washed with 1N hydrochloric acid Washed with saturated sodium bicarbonate solution, then washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to obtain a yellow oily substance. Column chromatography gave 126 mg of compound F-1 as a white solid, with a yield of 64.6%. m/z (MNa+) 552.30, 1HNMR (400MHz, DMSO-d) δ0.91-1.03 (m, 6H), 1.20-1.26 (m, 1H), 1.44 (s, 9H), 1.48-1.51 (m, 1H) ), 1.62-1.71(m, 4H), 1.75-1.92(m, 2H), 2.03-2.08(m, 2H), 2.38-2.44(m, 1H), 3.54-3.70(m, 2H), 3.84(s , 3H), 3.91-3.97(m, 1H), 4.11(d, 1H), 4.52(s, 1H), 4.63-4.70(m, 2H), 5.52(s, 1H), 6.44(s, 1H), 6.91 (d, 2H), 7.02 (d, 2H).

Example 26: Synthesis of Compound F-2

Dissolve compound F-1 (120mg, 0.23mmol) in 3ml 4NHCl/dioxane and stir for 1h, evaporate the volatile matter of the above reaction solution to dryness, add 10ml dichloromethane to continue concentrating, repeat 4 times to obtain 105mg compound F-2 as a White solid, yield 100%, m/z (MH+) 430.30.

Embodiment 27: the preparation of formula 1 compound

G-3 (30mg, 0.13mmol), HATU (50mg, 0.13mmol) were dissolved in 8ml of DMF, cooled in an ice-water bath, DIEA (0.1ml, 0.57mmol) was added, stirred for 30min, compound F-2 (50mg, 0.11mmol) was added Add the solution to 8ml of DMF, add the solution to the reaction solution of G-2, stir overnight at 0°C, add 50ml of water to the reaction solution, extract the reaction solution with ethyl acetate, and wash the organic phase with 1N hydrochloric acid and saturated sodium bicarbonate solution successively , then washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent to obtain a yellow oil, column chromatography to obtain 40mg of the compound of formula 1 as a white solid, yield 57.2%

Embodiment 28: Preparation of formula 2 compound with R as hydrogen compound of formula 1

Dissolve the compound of formula 1 (50 mg, 0.08 mmol) in 20 ml of methanol, add 10 mg of 10% palladium carbon, place it at 40 ° C, stir overnight in a hydrogen atmosphere of 0.7 MP, filter the palladium carbon with diatomaceous earth, and obtain the filtrate After concentration, 39 mg of the compound of formula (2) was obtained as a white solid with a yield of 92.3%, m/z (MNa+) 544.42, and a purity of 91.2% as shown by HPLC.

Example 5

Example 29: Preparation of Formula 2 Compound with R as Methyl and R in Para-position Formula 1 Compound

Dissolve the compound of formula 1 (50 mg, 0.08 mmol) in 20 ml of methanol, add 10 mg of 10% palladium carbon, place it at 40 ° C, stir overnight in a hydrogen atmosphere of 0.7 MP, filter the palladium carbon with diatomaceous earth and concentrate the obtained filtrate Finally, 37 mg of the compound of formula (2) was obtained as a white solid with a yield of 89.5%, m/z (MNa+) 544.42, and a purity of 90.3% as shown by HPLC.

Claims (25)

1. following general formula compound F-1:

R is the optional position substituent group of phenyl ring, and R is hydrogen, C1-C3 alkyl or alkoxyl.

2. general formula compound F-1 as claimed in claim 1, it is characterised in that: R is in para-position.

3. general formula compound F-1 as claimed in claim 1 or 2, it is characterised in that: R is the alkyl of hydrogen or C1-C3.

4. general formula compound F-1 as claimed in claim 3, it is characterised in that: R is hydrogen.

5. the application of any described compound F-1 of claim 1-4, it is characterised in that: for preparing the compound 2 of following formula

6. the application of compound F-1 as claimed in claim 5, it is characterised in that: compound 2 preparation process is as follows:

A) in organic solvent, make compound F-1 deprotection base under acid condition, obtain compound F-2

B) in organic solvent, alkali and under condensing agent existence condition, make compound F-2 and compound G-3 condensation obtain formula 1 compound

C) namely formula 1 compound obtains formula 2 compound through hydro-reduction

R is the optional position substituent group of phenyl ring, and R is hydrogen, C1-C3 alkyl or alkoxyl, and A is acid group.

7. the application of compound F-1 as claimed in claim 6, it is characterised in that: the acid that step a) uses is hydrochloric acid, sulphuric acid or trifluoroacetic acid.

8. the application of compound F-1 as claimed in claim 6, it is characterised in that: the alkali that step b) uses is triethylamine, DIPEA, pyridine or N-methylmorpholine.

9. the application of compound F-1 as claimed in claim 6, it is characterised in that: the condensing agent that step b) uses is EDCI, BOP, PyBOP, CDI, HATU, HBTU or DCC.

10. the application of compound F-1 as claimed in claim 6, it is characterised in that: step b) adds additive HOBT or HOAT.

11. the preparation method of any described compound F-1 of claim 1-4, the method is in organic solvent, alkali and under condensing agent existence condition, makes following formula: compound F and compound G-2 condensation obtain

Wherein R is the substituent group of phenyl ring optional position, and R is hydrogen, C1-C3 alkyl or alkoxyl, and A is acid group.

12. the preparation method of compound F-1 described in claim 11, it is characterised in that: the alkali of use is triethylamine, DIPEA, pyridine or N-methylmorpholine.

13. the preparation method of compound F-1 described in claim 11, it is characterised in that: the condensing agent of use is EDCI, BOP, PyBOP, CDI, HATU, HBTU or DCC.

14. the preparation method of compound F-1 described in claim 11, it is characterised in that: add additive HOBT or HOAT.

15. claim 11-14 arbitrarily as described in the preparation method of compound F-1, it is characterised in that: by compound E in organic solvent, under acid condition, deprotection base obtains compound F

Wherein R is the substituent group of phenyl ring optional position, and R is hydrogen, C1-C3 alkyl or alkoxyl, and A is acid group.

16. the preparation method of compound F-1 as claimed in claim 15, it is characterised in that: described acid is hydrochloric acid, sulphuric acid or trifluoroacetic acid.

17. the preparation method of compound F-1 as claimed in claim 15, it is characterised in that: compound E be compound D in organic solvent, under alkali existence condition, direct after react with ethyl chloroformate be obtained by reacting with strong aqua ammonia

Wherein R is the substituent group of phenyl ring optional position, and R is hydrogen, C1-C3 alkyl or alkoxyl.

18. the preparation method of compound F-1 as claimed in claim 17, it is characterised in that: described alkali is triethylamine, DIPEA, pyridine, N-methylmorpholine, Lithium hydrate, sodium hydroxide or potassium hydroxide.

19. the preparation method of compound F-1 as claimed in claim 17, it is characterised in that: described strong aqua ammonia mass concentration is 28-35%.

20. the preparation method of compound F-1 as claimed in claim 17, it is characterised in that: compound D is in organic solvent, under alkali effect, makes compound C hydrolysis obtain

Wherein R is the substituent group of phenyl ring optional position, and R is hydrogen, C1-C3 alkyl or alkoxyl.

21. the preparation method of compound F-1 as claimed in claim 20, it is characterised in that: described alkali is potassium hydroxide, sodium hydroxide or Lithium hydrate.

22. the preparation method of compound F-1 as claimed in claim 20, it is characterised in that: compound C is by the compound B of following formula, in organic solvent, under catalyst action, obtains then through hydrazine hydrate effect after reacting with Bis(tert-butoxycarbonyl)oxide

Wherein R is the substituent group of phenyl ring optional position, and R is hydrogen, C1-C3 alkyl or alkoxyl.

23. the preparation method of compound F-1 as claimed in claim 22, it is characterised in that: described catalyst is DMAP, triethylamine, butyl lithium or sodium hydroxide.

24. the preparation method of compound F-1 as claimed in claim 22, it is characterised in that: compound B is by the compound A of following formula, in organic solvent, under alkali existence condition, is obtained by reacting with substituted or unsubstituted benzyl halide

Wherein R is the substituent group of phenyl ring optional position, and R is hydrogen, C1-C3 alkyl or alkoxyl, and X is chlorine or bromine.

25. the preparation method of compound F-1 as claimed in claim 24, it is characterised in that: described alkali is potassium tert-butoxide, sodium hydride, hydrofining, double; two (trimethyl silicon based) Lithamide., double; two (trimethyl silicon based) Sodamide., double; two (trimethyl silicon based) potassamide, lithium diisopropylamine or butyl lithium.