HK1029790B - Processes and intermediates for preparing anti-cancer compounds - Google Patents

Description

Process and intermediates for preparing anticancer compounds

The present invention relates to processes and intermediates for preparing compounds useful in the treatment of hyperproliferative diseases such as cancer in mammals.

U.S. patent 5,747,498 issued 5/5 in 1998 and incorporated by reference in its entirety in this specification relates to a series of novel quinazoline derivatives, including [6, 7-bis (2-methoxyethoxy) -quinazolin-4-yl ] - (3-ethynylphenyl) amine hydrochloride, which are inhibitors of erbB class oncogenic and proto-oncoprotein tyrosine kinases, such as Epidermal Growth Factor Receptor (EGFR), and, therefore, are useful in the treatment of proliferative diseases, such as human cancer. U.S. patent application entitled "N- (3-ethynylphenylamino) -6, 7-bis (2-methoxyethoxy) -4-quinazolinamine mesylate anhydrate or monohydrate" filed on 29.4.1998 (inventor T. Norris, D.Santafianos, D.J.M.Allen, R.M.Shanker, and J.M.Raggon, attorney docket PC10074, which is incorporated herein by reference in its entirety) is directed to N- (3-ethynylphenylamino) -6, 7-bis (2-methoxyethoxy) -4-quinazolinamine mesylate anhydrate and hydrate having the same anticancer uses as the corresponding hydrochloride described above. The present invention relates to processes and intermediates for the preparation of anticancer compounds referred to in the above-mentioned U.S. patents and U.S. patent applications.

The invention relates to a preparation formula1Methods of compounds and pharmaceutically acceptable salts and solvates thereof,

in the formula:

R¹and R²Are each selected from C₁-C₁₀Alkyl and C₁-C₁₀Alkoxy, wherein alkyl and alkoxy are independently selected from hydroxy and C by up to 2₁-C₆The substituent of alkoxy is optionally substituted;

R¹⁵is H, C₁-C₁₀Alkyl, or- (CH)₂)_q(C₆-C₁₀Aryl) wherein q is an integer from 0 to 4;

the method comprises the following steps2Compound (I)

In the formula R¹⁵、R¹And R²As defined above, and G is selected from the group consisting of-C (OH) R³R⁴and-SiR³R⁴R⁵A protecting group of (a);

R³、R⁴and R⁵Each is C₁-C₆An alkyl group; in which (a) G is-C (OH) R³R⁴When containing hydroxy-substituted C₁-C₁₀Treating with alkali metal or alkaline earth metal hydroxide in the solvent of alkyl; or in (b) G is-SiR³R⁴R⁵When using tetra (C) fluoride in aprotic solvents₁-C₆Alkyl) ammonium treatment.

In a preferred embodiment, where G is-C (OH) R³R⁴When the solvent is a secondary alcohol, such as butan-2-ol or isopropanol, and the alkali or alkaline earth metal hydroxide is selected from sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide or potassium hydroxide, most preferably sodium hydroxide.

In another preferred embodiment, where G is-SiR³R⁴R⁵When the fluorinated tetra (C)₁-C₆Alkyl) ammonium compound is tetra-n-butyl fluorideThe alkylammonium, and the aprotic solvent are selected from Tetrahydrofuran (THF), diethyl ether, Dimethoxyethane (DME), toluene, dichloromethane, chloroform, or a mixture of two or more of the foregoing solvents, most preferably THF.

The invention also relates to the above formula2A process for the preparation of a compound which comprises reacting a compound of formula3Compound (I)

In the formula R¹And R²As defined above, by formula4Treatment of compounds

In which G and R¹⁵The same as above2And (4) compound definition.

In a preferred embodiment of the above process, the compound of formula (II) is3A compound of the formula4The compound is treated in an organic solvent such as Dimethylformamide (DMF), Dimethylsulfoxide (DMSO), THF, acetonitrile (MeCN), or a mixture of two or more of the foregoing solvents, more preferably acetonitrile

The invention also relates to the above formula3A process for the preparation of a compound which comprises reacting a compound of formula5Compound (I)

Treated with thionyl chloride in anhydrous dichloromethane.

In a preferred embodiment of each of the above reactions, R¹And R²Are both 2-methoxyethoxy, and R¹⁵Is H.

The invention also relates to6And7and pharmaceutically acceptable salts and solvates thereof

In the formula R¹⁵As defined above, R⁶Is C₁-C₁₀Alkyl or- (CH)₂)_mO(CH₂)_nCH₃；

R⁷Is C₁-C₁₀Alkyl or- (C)₁-C₆Alkyl) (C₆-C₁₀Aryl) in which R is as defined above⁷The group is optionally substituted with 1 to 3 substituents selected from the group consisting of: halogen, nitro, trifluoromethyl, trifluoromethoxy, (C)₁-C₆Alkyl) sulfonyl, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₆-C₁₀Aryloxy radical or C₆-C₁₀An arylsulfonyl group;

each m is independently an integer from 1 to 6, and n is an integer from 0 to 3;

the method comprises the following steps8Compound (I)

In the formula G¹is-C (OH) R³R⁴And R¹⁵、R⁶、R³And R⁴As defined above, the above-mentioned definition,

with the formula R in the presence of alkali metal or alkaline earth metal hydroxides⁷Primary or secondary alcohol treatment of-OH, wherein R⁷As defined above, the alkali metal or alkaline earth metal hydroxide is, for example, sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide or potassium hydroxide, most preferably sodium hydroxide.

In a preferred embodiment of the above reaction, R⁶Is 2-methoxyethoxy and said formula R⁷the-OH alcohol is preferably a secondary alcohol.

The invention also relates to the preparation formula9Methods of compounds and pharmaceutically acceptable salts and solvates thereof,

in the formula R¹⁵、R⁶And R⁷The same as defined above;

R⁸、R⁸and R¹⁰Are respectively selected from H, C₁-C₁₀Alkyl, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -OR¹¹、-C(O)R¹¹、-C(O)OR¹¹、-NR¹²C(O)OR¹⁴、-OC(O)R¹¹、-NR¹²SO₂R¹⁴、-SO₂NR¹¹R¹²、-NR¹²C(O)R¹¹、-C(O)NR¹¹R¹²、-NR¹¹R¹²、-S(O)_j(CH₂)_q(C₆-C₁₀Aryl), -S (O)_j(C₁-C₆Alkyl) where j is an integer of 0 to 2, - (CH)₂)_q(C₆-C₁₀Aryl), -O (CH)₂)_q(C₆-C₁₀Aryl), -NR-¹²(CH₂)_q(C₆-C₁₀Aryl), and- (CH)₂)_q(4-10 membered heterocycle), wherein q is an integer of 0-4; said alkyl group optionally containing a substituent selected from the group consisting of O, -S (O)_j-and-N (R)¹²) -wherein j is an integer from 0 to 2, provided that two O atoms, two S atoms, or O and S atoms are not directly connected to each other; said aryl and heterocyclyl being optionally fused to C₆-C₁₀Aryl radical, C₅-C₈Saturated cyclic groups, or 4-10 membered heterocyclic groups; and said alkyl, aryl and heterocyclyl are optionally substituted by 1-5 substituents each independently selected fromSubstituent group substitution: halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR¹²SO₂R¹⁴、-SO₂NR¹¹R¹²、-C(O)R¹¹、-C(O)OR¹¹、-OC(O)R¹¹、-NR¹²C(O)OR¹⁴、-NR¹²C(O)R¹¹、-C(O)NR¹¹R¹²、-NR¹¹R¹²、-OR¹¹、C₁-C₁₀Alkyl, - (CH)₂)_q(C₆-C₁₀Aryl), and- (CH)₂)_q(4-10 membered heterocyclic) group, wherein q is an integer of 0 to 4;

each R¹¹Each is selected from H, C₁-C₁₀Alkyl, - (CH)₂)_q(C₆-C₁₀Aryl), and- (CH)₂)_q(4-10 membered heterocyclic) group, wherein q is an integer of 0 to 4; said alkyl group optionally containing 1 or 2 members selected from the group consisting of O, -S (O)_j-and-N (R)¹²) -wherein j is an integer from 0 to 2, with the proviso that two O atoms, two S atoms or O and S atoms are not directly connected to each other; said aryl and heterocyclic ring R¹¹Radicals optionally condensed on C₆-C₁₀Aryl radical, C₅-C₈Saturated cyclic groups or 4-to 10-membered heterocyclic groups; and the above R¹¹Substituents, other than H, are optionally substituted with 1-5 substituents independently selected from the group consisting of: halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -C (O) R¹²、C(O)OR¹²、-OC(O)R¹²、-NR¹²C(O)R¹³、-C(O)NR¹²R¹³、-NR¹²R¹³Hydroxy, C₁-C₆An alkyl group; and C₁-C₆An alkoxy group;

R¹²and R¹³Each is H or C₁-C₆An alkyl group; and

R¹⁴is selected from R¹¹Substituents specified in the definition, only R¹⁴Is not H;

the process comprises reacting a compound of formula (I) in the presence of an alkali or alkaline earth metal hydroxide10Compound (I)

In the formula R¹⁵、R⁶、R⁸、R⁹And R¹⁰As defined above, the above-mentioned definition,

with the formula R⁷Primary or secondary alcohol treatment of-OH, wherein R⁷As defined above, primary alcohols are preferred, and the alkali metal or alkaline earth metal hydroxide is, for example, sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide or potassium hydroxide, most preferably sodium hydroxide.

The above formula1， 6， 7And9the compounds are useful for treating hyperproliferative diseases, such as cancer, in mammals.

The invention also relates to the above formula1In the preparation of compounds of formula2An intermediate.

The term "halogen" as used herein, unless otherwise indicated, includes fluorine, chlorine, bromine or iodine, preferably halogen is fluorine, chlorine and bromine.

The term "alkyl" as used herein, unless otherwise specified, includes saturated monovalent hydrocarbon radicals containing straight, branched or cyclic moieties, or combinations of the foregoing. Of course, the cyclic moiety contained in the alkyl group needs to have at least 3 carbon atoms

The term "aryl" as used herein, unless otherwise specified, includes organic groups resulting from the removal of one hydrogen atom from an aromatic hydrocarbon, such as phenyl or naphthyl.

The term "4-to 10-membered heterocyclyl" as used herein, unless otherwise specified, includes aromatic and non-aromatic heterocyclyl groups containing one or more heteroatoms selected from O, S and N, wherein each heterocyclyl group contains from 4 to 10 atoms in its ring system. Non-aromatic heterocyclic groups include groups containing only 4 atoms in their ring system, but aromatic heterocyclic groups must contain at least 5 atoms in their ring system. The heterocyclic group includes benzo-fused ring systems and ring systems substituted with one or more oxo groups. An example of a quaternary heterocyclic group is azetidinyl (derived from azetidine). An example of a five-membered heterocyclic ring is thiazolyl, and an example of a ten-membered heterocyclic ring is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thienylalkyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homoazacyclohexyl, oxaheptenyl, thiepinyl, oxazepinyl, diazepinyl, thiaazepinyl, 1, 2, 3, 6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolyl, indolinyl, 2H-pyranyl, 4H-hydropyranyl, dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithiapentyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, 3H-indolyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, piperazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, o-diazanaphthyl, indazolyl, indolizinyl, 2, 3-diazanaphthyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, 1, 5-diazanaphthyl, and furylpyridinyl. The abovementioned radicals derived from the compounds listed above may, where possible, be C-linked or N-linked. For example, the pyrrole-derived group may be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked).

The term "pharmaceutically acceptable salt" as used herein, unless otherwise indicated, includes salts of acidic or basic groups that may be present in the compounds of the present invention. The compounds prepared according to the invention, which are basic in nature, are capable of forming a wide variety of salts with various inorganic or organic acids. Acids which can be used for the preparation of pharmaceutically acceptable acid addition salts of the basic compounds are those which form non-toxic acid addition salts, i.e. salts containing pharmaceutically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulphate, bisulphate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, glucarate, formate, benzoate, glutamate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate [ i.e. 1, 1' -methylene-bis (2-hydroxy-3-naphthoate) ]. The compounds containing a basic moiety such as an amino group prepared according to the present invention can form pharmaceutically acceptable salts with various amino acids other than the above-mentioned acids.

Those compounds prepared according to the present invention that are acidic in nature are capable of forming basic salts with a variety of pharmaceutically acceptable cations. Examples of such salts include the alkali or alkaline earth metal salts of the compounds of the invention, especially the calcium, magnesium and potassium salts.

The compounds prepared according to the invention have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. The present invention relates to all optical isomers and stereoisomers and mixtures thereof prepared according to the invention. The compounds of formula 1 may also exist in tautomeric forms. The invention also relates to the use of all said tautomers and mixtures thereof.

The invention also includes isotopically-labelled compounds prepared according to the invention and pharmaceutically acceptable salts thereof, which are related to formula (la)1The compounds specified in (1) are identical, but the fact that one or more atoms are different in atomic mass or number of protons from the atoms normally found in natureAtomic mass or number of protons. Examples of isotopes which can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example each⁺H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³⁵S、¹⁸F and³⁶and (4) Cl. The compounds prepared according to the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs, which contain the aforementioned isotopes and/or other isotopes of other atoms, are within the scope of the present invention. Some isotopically-labelled compounds of the invention, e.g. by introducing a radioactive isotope such as³H and¹⁴c for use in a drug and/or stromal tissue distribution assay. Tritium, i.e.³H, and carbon-14, i.e.¹⁴The C isotope is particularly preferred because of its ease of preparation and detectability. In addition, with heavier isotopes such as tritium, i.e²H replacement can result in some therapeutic advantages from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and is therefore preferred in some circumstances. The invention is of1The isotopically labeled compounds of (a) and prodrugs thereof can generally be prepared by carrying out the procedures described in the schemes below and/or in the examples and preparations, substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

Detailed description of the invention

Reaction scheme 1

Reaction formula 2

Reaction formula 3

The process of the present invention may be referred to the above reaction scheme1-3 is described. In the reactions described below, all reactions were carried out at atmospheric pressure and room temperature (about 20 to 25 ℃ C.), unless otherwise specified. In addition, unless otherwise indicated, the substituents R¹-R¹⁰，R¹⁵G and G¹As defined above.

In the reaction formula1In the formula1The compounds can be prepared by first treating the starting formula with thionyl chloride in anhydrous dichloromethane at reflux temperature (about 38-42 ℃ at atmospheric pressure)5A compound of the formula5The compounds may be prepared according to methods well known to those skilled in the art) to give compounds of formula (la)3A compound is provided. Followed by treatment in an organic solvent (e.g. DMF, DMSO, THF, MeCN, or a mixture of two or more of the above solvents, preferably MeCN) at a temperature of 50 deg.C to reflux temperature, preferably reflux temperature, with the compound of formula4Compound treatment formula3Compound (I) can give2A compound is provided. The above abbreviations are as defined in the summary of the invention, with reference to the above definitions. Formula (II)1The compounds may be prepared by reaction of a compound wherein G is-C (OH) R³R⁴When containing C substituted by at least one hydroxy group₁-C₁₀In a solvent for the alkyl group of the formula2The compound being treated with an alkali or alkaline earth metal hydroxide, or being-SiR at G³R⁵When in an aprotic solvent2Tetrafluorotetrakis (C) for use as compound₁-C₆Alkyl) ammonium compound. In which G is-C (OH) R³R⁴When the solvent is preferably a secondary alcohol, such as butan-2-ol or isopropanol, the alkali or alkaline earth metal hydroxide may be selected from sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide or potassium hydroxide, preferably sodium hydroxide, and the reaction is preferably carried out at a temperature of about 100 ℃ to 150 ℃.In which G is-SiR³R⁴R⁵When is fluorinated tetra (C)₁-C₆Alkyl) ammonium compound is preferably tetra-n-butylammonium fluoride, the aprotic solvent is selected from THF, diethyl ether, DMF, toluene, dichloromethane, chloroform, or a mixture of two or more of the above solvents, preferably THF, and the reaction is preferably carried out at a temperature of about room temperature to about 70 ℃. Formula (II)1The anticancer compound of (a) can be converted into a pharmaceutically acceptable salt as described below.

In the reaction formula2By using a compound of the formula R in the presence of an alkali metal or alkaline earth metal hydroxide at a temperature of from about 100 ℃ to about 150 ℃⁷Primary or secondary alcohol treatment of-OH8Wherein R is⁷As defined above, can be prepared6And 7, such as sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide or potassium hydroxide, preferably sodium hydroxide. Using the formula R⁷The secondary alcohol of-OH will convert to the formula7To minimize asymmetric analogs, using the formula R⁷The primary alcohol of the-OH group will be of increasing formula7Relative concentration of the asymmetric analog of (a). Thus, primary or secondary alcohols may be preferred, depending on the preferred analogue. Formula (II)6And7the compounds may be isolated by a variety of methods, such as chromatography, which are well known to those skilled in the art. Formula (II)6And7the compounds may be converted into the following pharmaceutically acceptable salts.

In the reaction formula3In the formula9The compounds may be according to the above reaction scheme2By the process described in (1) with the formula R⁷Primary or secondary alcohol treatment of-OH10Compound (iv). Due to the reaction formula3The purpose of the reaction is to prepare asymmetric analogs, so the use of formula R is preferred⁷-primary alcohols of OH. The compound of formula 9 can be converted into a pharmaceutically acceptable salt as described below.

Certain of the compounds prepared according to the present invention described above may have asymmetric carbon atoms. Compounds containing isomeric mixtures of one or more centers may exist as mixtures of diastereomers, which mixtures may be separated into the individual diastereomers on the basis of differences in their physicochemical properties by methods known to those skilled in the art, e.g., chromatography or fractional crystallization. All such isomers, including diastereomeric mixtures, are considered part of the invention.

The compounds described above, which are basic in nature, are capable of forming a wide variety of salts with a variety of inorganic and organic acids. Although the salts must be pharmaceutically acceptable for mammalian administration, it is often desirable in practice to isolate the compounds of the invention from the reaction mixture first in the form of a pharmaceutically unacceptable salt and then convert the latter to the free base compound by treatment with an alkaline agent, followed by conversion of the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of the present invention are readily prepared by treating the basic compound with substantially equivalent amounts of the selected inorganic or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily available. The desired acid addition salts can also be precipitated from the solution by adding a suitable inorganic or organic acid to the free base solution in an organic solvent.

Those compounds that are acidic in nature can form base salts with a variety of pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly sodium and potassium salts. All these salts are prepared by the general procedure. Chemical bases useful as reagents for preparing the pharmaceutically acceptable base salts of the present invention are those that form non-toxic base salts with the acidic compounds of the present invention. These non-toxic base salts include those derived from the pharmaceutically acceptable cations, such as sodium, potassium, calcium, magnesium, and the like. These salts can be readily prepared by the following method: the corresponding acidic compound is treated with an aqueous solution containing the desired alkali metal alkoxide or metal hydroxide and the resulting solution is evaporated to dryness, preferably under reduced pressure. Alternatively, these salts can also be prepared by the following method: the lower alcohol solution of the acidic compound and the desired alkali metal alkoxide or metal hydroxide are mixed together and the resulting solution is evaporated to dryness in the same manner as before. In both cases, it is preferred to use stoichiometric amounts of reagents in order to ensure complete reaction and maximum yield of the desired end product.

The following examples further illustrate the processes and intermediates of this invention, although the scope of the invention is not limited by the following examples.

Example 1

3- [ (trimethylsilyl) ethynyl group]Preparation of nitrobenzene

A mixture of 1-bromo-3-nitrobenzene (10.0g, 49.45mmol) and trimethylsilylacetylene (8.4ml, 59.34mmol) was treated with triethylamine (33ml) to give a small amount of white precipitate. The resulting mixture was treated with bis (triphenylphosphine) palladium II dichloride (7mg, 0.01mmol) and copper (1) iodide (8.5mg, 0.04mmol) and heated at 80-85 deg.C (oil bath temperature) for 4 hours. The bright yellow mixture was cooled to room temperature. The solid was isolated by filtration through triethylamine (33 ml). The shell yellow solution was concentrated by evaporation and dried under vacuum at room temperature overnight to give the title product (11.11g, 102%) as a dark brown oil. gc/MS represents 100% purity of the final compound, M/e 219(M + H)⁺。

Example 2

3- [ (trimethylsilyl) ethynyl group]Preparation of anilines

The nitro compound, 3- [ (trimethylsilyl) ethynyl, prepared as described above is reacted with a suitable solvent]A mixture of nitrobenzene (0.86g, 3.92mmol) in 2-propanol (30ml) was degassed with nitrogen and treated with 5% platinum on alumina (268 mg). The mixture was shaken on a Parr shaker under hydrogen pressure (30psi) for 22 hours. The reaction mixture is passed through short Celite^TMThe pad was filtered and concentrated by evaporation to give an oil which was dried under vacuum overnight to give the title product (692mg, 93%) as a yellow brown oil.

δ_H(300MHz；CDCl₃)0.24(9H，s)，3.56(2H，bs)，6.62(1H，ddd，J＝1.0，2.3 & 8.0)，6.78(1H，t，J＝2.2)，6.87(1H，dt，J＝7.7 & 1.2)，7.07(1H，t，J＝7.8)；d_c(75.5MHz；CDCl₃)93.4，105.4，115.6，118.2，122.4，123.8，129.2，146.2；m/e 190(M+H)⁺。

Example 3

6, 7-bis (2-methoxyethoxy) -N- [3- [ (trimethylsilyl)

Ethynyl group]Phenyl radical]Preparation of (E) -4-quinazolinamine, monohydrochloride

4-chloro 6, 7-bis (2-methoxyethoxy) quinazoline (942mg, 3.01mmol) was treated with a solution of aniline (645mg, 3.41mmol) in 2-propanol (14ml) and heated at reflux for 2.5 h. The mixture was cooled to room temperature and stirred for 1 hour. The solid was collected by filtration, washed with 2-propanol (5ml) and dried under vacuum overnight to give the title product (1.33g, 88%) as a white solid.

δ_H(400MHz；CDCl₃)0.21(9H，s)，3.38(3H，s)，3.41(3H，s)，3.72(2H，m)，3.77(2H，m)，4.10(2H，s)，4.53(2H，s)，7.20(1H，t，J＝7.8)，7.23-7.28(2H，m)，7.75(1H，d，J 7.8)，7.88(1H，s)，8.20(1H，s)，8.42(1H，s)；m/e 466(M+H)⁺。

Example 4

N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy)

Preparation of (E) -4-quinazolinamine monohydrochloride

A slurry of the silyl compound prepared above, 6, 7-bis (2-methoxyethoxy) -N- [3- [ (trimethylsilyl) ethynyl ] phenyl ] -4-quinazolinamine monohydrochloride (1.22g, 2.43mmol) in tetrahydrofuran (6.1ml) was treated with a 1M solution of tetra-N-butylammonium fluoride in tetrahydrofuran (2.6ml, 2.55mmol) and stirred at room temperature for 1 hour. The resulting solution was treated with 2-propanol (12.2ml), the oil concentrated by evaporation in 2-propanol (20ml) was treated with concentrated hydrochloric acid (0.2ml) to give a precipitate mixture which was stirred at room temperature for 1 hour. The solid was collected by filtration, washed with 2-propanol (2ml) and dried in vacuo to give the title product (747mg, 72%) as an off-white solid (mp 226-.

δ_H(300MHz；d₆-DMSO)3.36(6H，s)，3.77-3.80(4H，m)，4.30(1H，s)，7.39(1H，s)，7.41(1H，d，J＝7.8)，7.50(1H，t，J＝7.9)，7.79(1H，d，J＝8.1)，7.88(1H，s)，8.40(1H，s)，8.86(1H，s)，11.48(1H，bs)；δ_c(100MHz；d₆-DMSO)58.4，58.5，68.7，69.2，69.7，67.0，81.3，83.0，100.3，105.2，107.2，121.9，125.4，127.6，128.9，129.2，135.2，137.7，148.3，149.2，155.4，158.0；m/e 394(M+H)⁺。

Example 5

4- [3- [ [6, 7-bis (2-methoxyethoxy) -4-quinazolinyl]

Amino group]Phenyl radical]-2-methyl-3-butyn-2-ol monohydrochloride

4-chloro-6, 7-bis (2-methoxyethoxy) quinazoline (15g, 48mmol), 4- (3-aminophenyl) -2-methyl-3-butyn-2-ol (9.2g, 52.8mmol) and acetonitrile (225ml) were heated at reflux for 5 hours. The resulting mixture was cooled to 5-10 ℃ and stirred for 1 hour. The solid was collected by filtration, washed with acetonitrile (15ml) and dried under vacuum overnight to give the title product (23.4g, 100%) as a white solid.

δ_H(400MHz；d₆-DMSO)1.44(6H，s)，3.31-3.32(6H，m)，3.69-3.75(4H，m)，4.24-4.30(2H，m)，4.35-4.37(2H，m)，7.25(1H，m)，7.39(2H，m)，7.72-7.74(2H，m)ijio，8.47(1H，s)，8.79(1H，s)，11.64(1H，s)；m/e 452(M+H)⁺。

Example 6

4- [3- [ [6, 7-bis (2-methoxyethoxy) -4-quinazolinyl]

Amino group]Phenyl radical]Preparation of (E) -2-methyl-3-butyn-2-ol

4- [3- [ [6, 7-bis (2-methoxyethoxy) -4-quinazolinyl ] amino ] phenyl ] -2-methyl-3-butyn-2-ol monohydrochloride (19.0g, 39.7mmol), water (95ml) and ethyl acetate (380ml) prepared above were stirred together at room temperature to form a mixture. The pH of the mixture was adjusted to pH10-12 with 50% aqueous sodium hydroxide solution, resulting in two clear layers. The organic layer was separated from the aqueous layer and concentrated under vacuum to a volume of-190 ml. Crystallization of the title product after granulation in an ice bath, filtration and drying yielded the product (15.13g, 86%).

δ_H(400MHz；CDCl₃)1.56(6H，s)，3.35(3H，s)，3.37(3H，s)，3.7-3.71(4H，m)，4.13-4.19(4H，m)，7.0(1H，m)，7.13-7.17(2H，m)，7.3(1H，m)，7.6(2H，m)，8.55(1H，s)；m/e 452(M+H)⁺

Example 7

N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy)

Preparation of (E) -4-quinazolinamine monohydrochloride

4- [3- [ [6, 7-bis (2-methoxyethoxy) -4-quinazolinyl ] amino ] phenyl ] -2-methyl-3-butyn-2-ol monohydrochloride (32.4g, 66.3mmol) prepared above, water (300ml) and butan-1-ol (600ml) were stirred together at room temperature to form a mixture. The pH of the mixture was adjusted to 10-12 with 50% aqueous sodium hydroxide to give two clear layers. The organic layer was separated from the aqueous layer and concentrated at atmospheric pressure to allow azeotropic separation of water from the butan-1-ol solution. The final volume of the butan-1-ol solution was about 300 ml. Anhydrous solid sodium hydroxide (0.13g, 3.3mmol) was added to the azeotropically dried but-1-ol solution and the resulting mixture was heated at 115 ℃ and 120 ℃ under reflux for 24 hours. The butan-1-ol (150ml) was isolated by distillation and the concentrated reaction mixture was cooled to 15-25 ℃. Concentrated hydrochloric acid (6.1ml) and butan-1-ol (60ml) were added to the cooled concentrate and the mixture was granulated overnight at 20-25 ℃ for crystallisation. The title product crystals were isolated by filtration and dried at 45-50 ℃ under vacuum to remove butan-1-ol. The product was obtained (21.0g, 73.7%). Purity by HPLC 96.5%.

Example 8

N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy)

Preparation of (E) -4-quinazolinamine mesylate

4- [3- [ [6, 7-bis (2-methoxyethoxy) -4-quinazolinyl ] amino ] phenyl ] -2-methyl-3-butyn-2-ol monohydrochloride (32.4g, 66.3mmol) prepared above, water (300ml) and butan-1-ol (600ml) were stirred together at room temperature to form a mixture. The pH of the mixture was adjusted to pH10-12 with 50% aqueous sodium hydroxide solution, resulting in two clear layers. The organic layer was separated from the aqueous layer and concentrated at atmospheric pressure to allow azeotropic separation of water from the butan-1-ol solution. The final volume of the butan-1-ol solution was about 300 ml. Anhydrous solid sodium hydroxide (0.13g, 3.3mmol) was added to the azeotropically dried but-1-ol solution and the resulting mixture was heated at 115 ℃ and 120 ℃ under reflux for 24 hours. The reaction mixture was cooled to 15-25 ℃. Methanesulfonic acid (4.6ml) was added and the mixture was granulated at 20-25 ℃ overnight for crystallization. The title product crystals were isolated by filtration, washed with butan-1-ol (25ml) and dried at 45-50 ℃ under vacuum to remove butan-1-ol. The product was obtained (29.16g, 90%) with a purity of 96.7% by HPLC.

Example 9

N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy)

Preparation of (E) -4-quinazolinamine monohydrochloride

4- [3- [ [6, 7-bis (2-methoxyethoxy) -4-quinazolinyl ] amino ] phenyl ] -2-methyl-3-butyn-2-ol (20.0g, 44.3mmol) prepared above, anhydrous solid sodium hydroxide (0.09g, 2.2mmol) and butan-2-ol (400ml) were stirred together and heated at 100 ℃ and 102 ℃ under reflux for 36 hours. The resulting reaction mixture was cooled to 15-25 ℃ and concentrated hydrochloric acid (4.1ml) was added. The resulting mixture was granulated at 20-25 ℃ overnight for crystallization. The title product crystals were isolated by filtration, washed with butan-2-ol (25ml) and dried at 40-45 ℃ under vacuum to remove butan-2-ol. The product was obtained (17.7g, 93%). Purity by HPLC 99.1%.

Example 10

N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy)

Preparation of (E) -4-quinazolinamine monohydrochloride

4- [3- [ [6, 7-bis (2-methoxyethoxy) -4-quinazolinyl ] amino ] phenyl ] -2-methyl-3-butyn-2-ol (20.0g, 44.3mmol) prepared above, anhydrous solid sodium hydroxide (260mg, 6.5mmol) and butan-2-ol (400ml) were stirred together and heated in a pressure vessel at 135 ℃ 140 ℃ for 32 hours. The resulting reaction mixture was cooled to 60-65 ℃ and concentrated hydrochloric acid (4.8ml) was added. The resulting mixture was granulated at 20-25 ℃ overnight for crystallization. The mixture was treated with water (10ml), stirred at 58-60 ℃ for 21 hours, cooled to 15-20 ℃ and granulated for 2 hours. The title product crystals were isolated by filtration, washed with propan-2-ol (2X 30ml) and dried under vacuum at 45-50 ℃ to remove propan-2-ol. The product was obtained (17.6g, 92%).

Example 11

Preparation of N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) -4-quinazolinamine monohydrochloride

4- [3- [ [6, 7-bis (2-methoxyethoxy) -4-quinazolinyl ] amino ] phenyl ] -2-methyl-3-butyn-2-ol (5.0g, 11mmol) prepared above, anhydrous solid sodium hydroxide (44mg, 11mmol) and 2-methoxyethanol (50ml) were stirred together and heated at reflux for 47 hours. The resulting reaction mixture was cooled to 15-25 ℃ and concentrated hydrochloric acid (1.1ml) was added. The resulting mixture was granulated at 20-25 ℃ for 1 hour to crystallize. The title product crystals were isolated by filtration, washed with 2-methoxyethanol (10ml) and dried under vacuum at 40-45 ℃ to remove 2-methoxyethanol. The product was obtained (3.73g, 78%).

Example 12

N- (3-ethynylphenyl) -6, 7-bis (2-methoxy

Preparation of ethoxy) -4-quinazolinamine mesylate

4- [3- [ [6, 7-bis (2-methoxyethoxy) -4-quinazolinyl ] amino ] phenyl ] -2-methyl-3-butyn-2-ol (20.0g, 44.3mmol) prepared above, anhydrous solid sodium hydroxide (0.09g, 2.2mmol) and butan-2-ol (400ml) were stirred together, heated at 100 ℃ and 120 ℃ under reflux for 36 hours, and the resulting reaction mixture was cooled to 15-25 ℃ and methanesulfonic acid (5.1g, 53.2mmol) was added. The resulting mixture was granulated at 20-25 ℃ overnight for crystallization. The title product crystals were isolated by filtration, washed with butan-2-ol (25ml) and dried at 40-45 ℃ under vacuum to remove butan-2-ol. The product was obtained (19.45g, 90%). Purity by HPLC 98.5%.

Example 13

Preparation of N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) -4-quinazolinamine

4-chloro-6, 7-bis (2-methoxyethoxy) quinazoline (50g, 160mmol), 3-ethylaniline (21.34g, 176mmol) and propan-2-ol (500ml) were heated at 78-82 ℃ for 16 h. The resulting mixture was cooled to 5-10 ℃ and stirred for 1 hour. The solid was collected by filtration and combined with water (200ml) and ethyl acetate (500 ml). The mixture was adjusted to pH10-12 with 50% aqueous sodium hydroxide to give a clear layer. The organic layer was separated, washed with water (200ml), brine (200ml), dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The oil was solidified and dried at 20-25 ℃ under vacuum to give the title product (57.2g, 90%) as a white solid, mp 72-74 ℃.

δ_H(300MHz；CDCl₃)1.16(3H，t，J＝7.6)，2.58(2H，q，J＝7.6)，3.32(3H，s)，3.34(3H，s)，2.01-2.47(2H，m)，2.08-2.54(2H，m)，4.07-4.12(4H，m)，6.91(1H，d，J＝7.6)，7.11(1H，s)，7.21(1H，t，J＝7.8)，7.35(1H，s)，7.42(1H，s)，7.48(1H，d，J＝8.0)，8.13(1H，bs)，8.58(1H，s)；δ_c(75.5MHz；CDCl₃)15.4，28.8，59.1，68.2，68.9，70.4，70.8，103.0，108.3，109.3，119.7，121.7，123.9，128.8，138.6，145.1，147.0，148.6，153.6，154.4，156.9；ν_max(KBr)cm^-1 3136(s)，1624(s)，1575(s)，1535(s)，1487(s)；m/z 398(M+H)⁺(Found：C，65.64；H，6.96；N，10.32.C₂₂H₂₇N₃O₄·0.25H₂O requires C，65.73；H，6.90；N，10.45％).

Example 14

Preparation of N- (3-ethylphenyl) -6- (2-methoxyethoxy) -7-benzyloxy-4-quinazolinamine

N- (3-ethylphenyl) -6, 7-bis (2-methoxyethoxy) -4-quinazolinamine (4.0g, 10mmol), solid sodium hydroxide (104mg, 2.6mmol) and benzyl alcohol (20ml) prepared as described above were heated at 150 ℃ 152 ℃ for 23 hours. The resulting reaction mixture was cooled to room temperature and purified by silica gel column chromatography eluting with a gradient containing ethyl acetate/hexanol eluent to give a white solid which was dried at 45-50 deg.C under vacuum to give the title product (2.52g, 58%), mp 156-.

δ_H(300MHz；CDCl₃)1.17(3H，t，J 7.6)，2.58(2H，q，J 7.6)，3.33(3H，s)，3.65-3.68(2H，m)，4.07-4.11(2H，m)，5.11(2H，s)，6.93(1H，d，J 7.7)，7.18-7.29(5H，m)，7.35-7.42(4H，m)，7.50(1H，d，J 8.0)，8.20(1H，bs)，8.61(1H，s)；δ_c(75.5MHz；CDCl₃)14.2，15.4，28.8，59.2，69.2，70.7，70.8，103.2，109.1，109.4，119.7，121.7，124.0，127.3，128.1，128.5，128.8，135.8，138.6，145.1，147.0，148.9，153.7，154.2，156.9；ν_max(KBr)cm^-1 1625，1611，1576；m/z430(M+H)⁺；(Found：C，71.42；H，6.50；N，9.48.C₂₆H₂₇N₃O₃ requires C，72.70；H，6.34；N，9.78％)。

Example 15

Preparation of N- (3-ethylphenyl) -6- (2-methoxyethoxy) -7-butoxy-4-quinazolinamine

N- (3-ethylphenyl) -6, 7-bis (2-methoxyethoxy) -4-quinazolinamine (4.0g, 10mmol) prepared above, solid sodium hydroxide (94mg, 2.36mmol) and butan-1-ol (20ml) were heated at reflux for 12 days. The resulting reaction mixture was cooled to room temperature and purified by silica gel column chromatography eluting with a gradient containing ethyl acetate/hexanol eluent to give a white solid which was dried at 45-50 deg.C under vacuum to give the title product (2.57g, 65%), mp90-92 deg.C.

δ_H(300MHz；CDCl₃)0.93(3H，t，J 7.4)，1.19(3H，t，J 7.6)，1.45(2H，sextet，J 7.5)，1.79(2H，pentet，J 6.9)，2.61(2H，q，J 7.6)，3.39(3H，s)，3.70-3.74(2H，m)，4.00(2H，t，J 6.6)，4.12-4.15(2H，m)，6.94(1H，d，J 7.7)，7.15(1H，s)，7.24(1H，t，J 7.8)，7.34(1H，s)，7.44(1H，s)，7.51(1H，d，J 8.0)，7.95(1H，bs)，8.60(1H，s)；δ_c(75.5MHz；CDCl₃)13.8，15.4，19.2，28.8，30.8，59.3，68.7，69.3，70.9，103.2，108.2，108.9，119.6，121.6，124.0，128.9，138.6，145.2，147.2，148.8，153.6，154.9，156.8；ν_max(KBr)cm^-1 1618，1576，1519；m/z 396(M+H)⁺；(Found：C，70.90；H，7.56；N，10.66.C₂₃H₂₉N₃O₃ requires C，69.85；H，7.39；N，10.63％)。

Example 16

Preparation of N- (4-methoxyphenyl) -6, 7-bis (2-methoxyethoxy) -4-quinazolinamine

4-chloro-6, 7-bis (2-methoxyethoxy) quinazoline (25g, 79.9mmol), 4-methoxyaniline (9.8g, 79.9mmol) and propan-2-ol (250ml) were heated at 78-82 ℃ for 16 h. The resulting mixture was cooled to 5-10 ℃ and stirred for 1 hour. The solid was collected by filtration and washed with propan-2-ol (25 ml). The isolated solid was recrystallized from ethanol/water and dried in a vacuum oven at 40-50 deg.C overnight. The recrystallized solid was mixed with water (100ml) and ethyl acetate (250 ml). The mixture was adjusted to pH10-12 with 50% aqueous sodium hydroxide to give a clear layer. The organic layer was separated, washed with water (200ml), brine (200ml), dried over anhydrous magnesium sulfate, filtered, and concentrated to give a white solid which was dried at 40-45 ℃ and under vacuum to give the title product (20.86g, 65%), mp186-187 ℃.

δ_H(300MHz；CDCl₃)3.31(3H，s)，3.35(3H，s)，3.62-3.65(2H，m)，3.70-3.72(2H，m)，3.74(3H，s)，4.04-4.11(4H，m)，6.83(2H，d，J 9.0)，7.09(1H，s)，7.33(1H，s)，7.46(2H，d，J9.0)，8.12(1H，bs)，1H，s)；δ_c(75.5MHz；CDCl₃)55.4，59.2，68.2，69.0，70.4，70.8，103.1，108.3，109.1，114.2，124.7，131.4，146.8，148.6，153.7，154.3，156.7，157.3；ν_max(KBr)cm^-11619，1590，1582，1511；m/z 400(M+H)⁺；(Found：C，63.30；H，6.37；N，10.47.C₂₁H₂₅N₃O₅requires C，63.42；H，6.31；N，10.52％).

Example 17

N- (4-methoxyphenyl) -6- (2-methoxyethoxy) -7-benzyloxy-4-quinazolinamine

N- (4-methoxyphenyl) -6, 7-bis (2-methoxyethoxy) -4-quinazolinamine (2.0g, 4.6mmol), solid anhydrous sodium hydroxide (104mg, 2.6mmol) and benzyl alcohol (20ml) prepared above were heated at 145 ℃ for 18 hours. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography eluting with a gradient containing ethyl acetate/hexanol eluent to give a white solid which was dried at 45-50 deg.C under vacuum to give the product (0.915g, 42%) mp208-209 deg.C.

δ_H(300MHz；CDCl₃)3.34(3H，s)，3.91(2H，t，J 4.2)，3.74(3H，s)，4.10(2H，bs)，5.13(2H，s)，6.83(2H，d，J 8.9)，7.20-7.30(5H，m)，7.36-7.38(3H，m)，7.47(2H，d，J 8.9)，8.10(1H，bs)，8.54(1H，s)；δ_c(75.5MHz；CDCl₃)55.5，59.3，69.2，70.7，70.9，103.3，109.0，109.1，114.2，124.6，127.3，128.1，128.5，131.3，135.8，146.8，148.8，153.7，154.2，154.2，156.8，157.2；ν_max(KBr)cm^-1 1619，1580，1511；m/z 432(M+H)⁺；(Found：C，69.48；H，5.85；N，9.68.C₂₅H₂₅N₃O₄ requires C，69.59；H，5.84；N，9.74％)。

Example 18

Preparation of N-phenyl-N-methyl-6, 7-bis (2-methoxyethoxy) -4-quinazolinamine

4-chloro-6, 7-bis (2-methoxyethoxy) quinazoline (10g, 31.97mmol), N-methylaniline (3.5ml, 31.97mmol) and acetonitrile (100ml) were heated at 78-82 ℃ for 24 hours. The resulting mixture was cooled to 5-10 ℃ and stirred for 0.5 hour. The solid was collected by filtration and dried in a vacuum oven at 50-55 deg.C for 5 hours. The separated solid was mixed with water (50ml) and ethyl acetate (200 ml). The mixture was adjusted to pH10-12 with 50% aqueous sodium hydroxide to give a clear layer. The organic layer was separated, washed with water (50ml), brine (50ml), dried over anhydrous magnesium sulfate, filtered and concentrated to give a white solid which was dried at 50-55 ℃ under vacuum to give the product (8.55g, 70%), mp109-111 ℃.

δ_H(300MHz；CDCl₃)3.33(3H，s)，3.39(3H，s)，3.42-3.45(2H，m)，3.48-3.51(2H，m)，3.58(3H，s)，3.74-3.78(2H，m)，4.16-4.20(2H，m)，6.33(1H，s)，7.11-7.20(4H，m)，7.83(2H，t，J 7.8)，8.68(1H，s)；δ_c(75.5MHz；CDCl₃)42.0，59.2，59.3，67.6，68.2，70.3，70.4，106.5，107.9，110.9，125.8，126.0，129.9，147.0，148.4，148.7，153.0，153.4，160.4；ν_max(KBr)cm^-11615，1571，1497；m/z 384(M+H)⁺；(Found：C，65.85；H，6.52；N，11.01.C₂₁H₂₅N₃O₄ requiresC，65.78；H，6.57；N，10.96％)。

Example 19

Preparation of N-phenyl-N-methyl-6- (2-methoxyethoxy) -7-butoxy-4-quinazolinamine

N-methyl-N-phenyl-6, 7-bis (2-methoxyethoxy) -4-quinazolinamine (1.0g, 2.61mmol), solid anhydrous sodium hydroxide (97.5mg, 2.43mmol) and butan-1-ol (10ml) prepared as described above were heated at reflux for 24 h. The resulting reaction mixture was cooled to room temperature and purified by silica gel column chromatography eluting with a gradient containing ethyl acetate/hexane eluent to give a white solid which was dried at 45-50 deg.C under vacuum to give the product (517g, 52%), mp62-63 deg.C.

δ_H(300MHz；CDCl₃)0.93(3H，t，J 7.4)，1.45(2H，sextet，J 7.4)，1.80(2H，pentet，J6.7)，3.35(3H，s)，3.44-3.52(4H，m)，3.59(3H，s)，4.05(2H，t，J 6.7)，6.34(1H，s)，7.12-7.21(4H，m)，7.34(2H，t，J 7.7)，8.69(1H，s)；δ_c(75.5MHz；CDCl₃)13.8，19.2，30.7，42.0，59.2，67.8，68.6，70.4，106.5，107.7，110.6，125.8，125.9，129.9，147.0，148.6，153.0，153.8，160.4；ν_max(KBr)cm^-1 1616，1572，1543；m/z 382(M+H)⁺；(Found：C，69.39；H，7.38；N，10.86.C₂₂H₂₇N₃O₃ requires C，69.27；H，7.14；N，11.02％)。

Claims (14)

1. Preparation formula1A method of treatment of a compound or a pharmaceutically acceptable salt or solvate thereof,

in the formula:

R¹and R²Are each selected from C₁-C₁₀Alkyl and C₁-C₁₀Alkoxy, wherein alkyl and alkoxy are independently selected from hydroxy and C by up to 2₁-C₆Taking alkoxy groupsThe substituent is optionally substituted;

R¹⁵is H, C₁-C₁₀Alkyl, or- (CH)₂)_q(C₆-C₁₀Aryl) wherein q is an integer from 0 to 4; the method comprises the following steps2Compound (I)

In the formula R¹⁵、R¹And R²As defined above, and G is selected from the group consisting of-C (OH) R³R⁴and-SiR³R⁴R⁵A protecting group of (a);

R³、R⁴and R⁵Each is C₁-C₆An alkyl group;

in which (a) G is-C (OH) R³R⁴When containing hydroxy-substituted C₁-C₁₀Treating with alkali metal or alkaline earth metal hydroxide in the solvent of alkyl; or in (b) G is-SiR³R⁴R⁵When using tetra (C) fluoride in aprotic solvents₁-C₆Alkyl) ammonium treatment.

2. The method of claim 1, wherein G is-C (OH) R³R⁴When the solvent is a secondary alcohol, and the alkali metal or alkaline earth metal hydroxide is selected from sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide or potassium hydroxide,

3. the process of claim 2 wherein the solvent is butan-2-ol or isopropanol, or a mixture of the two solvents, and the alkali or alkaline earth metal hydroxide is sodium hydroxide.

4. The method of claim 1, wherein G is-SiR³R⁴R⁵Said fluorinated tetrakis (C)₁-C₆Alkyl) ammonium compound is tetra-n-butylammonium fluoride, and the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, dimethoxyethane, toluene, and mixtures thereof,Dichloromethane, chloroform, and mixtures of two or more of the foregoing solvents.

5. The method of claim 1, wherein R¹And R²Is 2-methoxyethoxy and R⁵Is H.

6. The process of claim 1 wherein said formula (la)2The preparation of the compound comprises3Compound (I)

In the formula R¹And R²As defined in claim 1, by the formula4Treatment of compounds

In the formula R¹⁵And G is as defined in claim 1.

7. The process of claim 6 wherein the compound of formula (la)3A compound of the formula4The compound is treated in an organic solvent selected from the group consisting of dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetonitrile, and mixtures of two or more of the foregoing solvents.

8. The process of claim 7, wherein the solvent is acetonitrile, R¹And R²Are both 2-methoxyethoxy, and R¹⁵Is H.

9. The process of claim 6 wherein formula (la)3The preparation of the compound comprises5The compound is in anhydrous dichloromethane

Treated with thionyl chloride.

10. The method of claim 9, wherein R¹、R²Are all 2-methoxyethoxy.

11. Preparation formula6Or 7 or a pharmaceutically acceptable salt or solvate thereof

In the formula: r⁶Is C₁-C₁₀Alkyl or- (CH)₂)_mO(CH₂)_nCH₃；

R⁷Is C₁-C₁₀Alkyl or- (C)₁-C₆Alkyl) (C₆-C₁₀Aryl) in which the R is⁷Optionally substituted with 1-3 substituents each selected from: halogen, nitro, trifluoromethyl, trifluoromethoxy, (C)₁-C₆Alkyl) sulfonyl, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₆-C₁₀Aryloxy radical or C₆-C₁₀An arylsulfonyl group;

each m is independently an integer from 1 to 6, and n is an integer from 0 to 3;

R¹⁵is H, C₁-C₁₀Alkyl, or- (CH)₂)_q(C₆-C₁₀Aryl) wherein q is an integer from 0 to 4;

the method comprises the following steps8Compound (I)

In the formula: r⁶And R¹⁵The same as defined above;

G¹is-C (OH) R³R⁴And R³And R⁴Are respectively C₁-C₆Alkyl in alkali metal or alkaline earth metal hydroxideIn the presence of compounds with the formula R⁷Primary or secondary alcohol treatment of-OH, wherein R⁷Is C₁-C₁₀Alkyl or- (C)₁-C₆Alkyl) (C₆-C₁₀Aryl) and the above R⁷Optionally substituted with 1-3 substituents each selected from: halogen, nitro, trifluoromethyl, trifluoromethoxy, (C)₁-C₆Alkyl) sulfonyl, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₆-C₁₀Aryloxy radical, C₆-C₁₀An arylsulfonyl group.

12. The process of claim 11 wherein the alkali or alkaline earth metal hydroxide is selected from the group consisting of sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, or potassium hydroxide.

13. The process of claim 12 wherein the alkali or alkaline earth metal hydroxide is sodium hydroxide, R⁶Is 2-methoxyethoxy, R¹⁵Is H, and said formula R⁷the-OH alcohol is a secondary alcohol.

14. Formula (II)2Compound (I)

In the formula R¹And R²Are each selected from C₁-C₁₀Alkyl and C₁-C₁₀Alkoxy, wherein the alkyl and alkoxy are independently selected from the group consisting of hydroxy and C by up to 2₁-C₆The substituent of alkoxy is optionally substituted;

g is selected from-C (OH) R³R⁴And SiR³R⁴R⁵A protecting group of (a);

R³，R⁴and R⁵Each is C₁-C₆An alkyl group; and

R¹⁵is H, C₁-C₁₀Alkyl, or- (CH)₂)_q(C₆-C₁₀Aryl) group, wherein q is an integer from 0 to 4.