CN101389614A

CN101389614A - Process for the preparation of 3-[5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-oxo-2-substituted-2, 3-dihydro-1, 2-benzisoxazol-6-yl) methoxy] phenyl] propionic ester and intermediates for use in the process

Info

Publication number: CN101389614A
Application number: CNA2007800061836A
Authority: CN
Inventors: 米泽健治; 高松保; 青木直克; 桥本智宏; 竹林正弘; 铃木敬亮; 大西裕司
Original assignee: Toyama Chemical Co Ltd
Current assignee: Toyama Chemical Co Ltd
Priority date: 2006-02-21
Filing date: 2007-02-19
Publication date: 2009-03-18
Anticipated expiration: 2027-02-19
Also published as: CN101389614B; ZA200807190B

Abstract

Disclosed is a production process using, as an intermediate, a 6-(halomethyl)-1,2-benzisooxazol-3(2H)-one derivative represented by the general formula: Wherein R<5> represents a methyl group substituted by at least one phenyl group which may be substituted, or an oxygenated heterocyclic ring which may be substituted; and X represents a halogen atom. The process is useful for the production of 3-[5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl]propionic acid, which is useful as an antirheumatic agent, in a high yield and in a safe and simple manner.

Description

Process for the preparation of 3-[5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-oxo-2-substituted-2, 3-dihydro-1, 2-benzisoxazol-6-yl) methoxy] phenyl] propionic ester and intermediates for use in the process

Technical field

[0001]

The present invention relates to 3-{5-[4-(cyclopentyloxy)-2-hydroxy benzoyl]-2-[(3-oxo-2-replace-2,3-dihydro-1,2-benzoisoxazole-6-yl) methoxyl group] phenyl the preparation method of propionic ester and its intermediate.

Background technology

[0002]

3-{5-[4-(cyclopentyloxy)-2-hydroxy benzoyl]-2-[(3-hydroxyl-1; 2-benzoisoxazole-6-yl) methoxyl group] phenyl } propionic acid (after this being called T-5224) has excellent arthritis effect and has folding bone restraining effect; in addition; it is very safe, has excellent medicine kinetics and is valuable (non-patent literature 1) as rheumatism.

T-5224 is by to 3-{5-[4-(cyclopentyloxy)-2-hydroxy benzoyl]-2-[(3-oxo-2-replace-2; 3-dihydro-1,2-benzoisoxazole-6-yl) methoxyl group] phenyl } propionic ester (after this being called the T-5224 intermediate) goes to protect and prepares (patent documentation 1).

This T-5224 intermediate is by making 6-(brooethyl)-2-(methoxymethyl)-1; 2-benzoisoxazole-3 (2H)-ketone (after this be called preparation intermediate 1-1) or 6-(brooethyl)-3-(methoxymethoxy)-1,2-benzoisoxazole (after this being called preparation intermediate 1-2) and 3-{5-[4-cyclopentyloxy)-the 2-hydroxy benzoyl]-the 2-hydroxy phenyl } propionic acid methyl ester (after this being called preparation intermediate 2) (patent documentation 1) reaction prepares.

Yet, preparation intermediate 1-1 and preparation intermediate 1-2 all have defective for example they all (a) be oil substances and (b) have low purity and stability.

The preparation method of preparation intermediate 1-1 and preparation intermediate 1-2 has defective, and for example their (c) require for example silica gel column chromatography of complicated program, (d) have low productive rate and (e) use dangerous and have the starting material of high toxicity (chloromethyl methyl ether).

The preparation method of preparation intermediate 2 have defective for example its (f) require complicated program for example distillation and column chromatography and (g) use extremely expensive, inflammable and autoreaction reagent (the azo dicarbonyl compound is azoethane dicarboxylic ester and di-isopropyl azodicarboxylate for example) and (h) generation require a large amount of aluminum chloride waste liquids of complex process.

By making preparation intermediate 1-1 or preparation intermediate 1-2 and 2 reactions of preparation intermediate, the T-5224 intermediate of preparation has defective, and for example they all are (i) oil substances, (j) and for segregation they, require for example silica gel column chromatography of complicated process.

Use preparation intermediate 1-1, preparation intermediate 1-2 and preparation intermediate 2, the method for preparing the T-5224 intermediate is not satisfied.

[0003]

Intermediate product 2 can be by 2-oxo-2H-chromene carboxylic acid or the preparation of its salt.The preparation method's of 2-oxo-2H-chromene carboxylic acid or its salt example comprises, for example, (A) wherein with 6-methyl-2H-chromen-2-one bromination and with the vulkacit H reaction after be hydrolyzed method (patent documentation 2) with oxidation; (B) make the method for laurate closed loop, this laurate obtains (non-patent literature 2) by several methods by P-hydroxybenzoic acid or its ester; (C) make the method (non-patent literature 3) of P-hydroxybenzoic acid or its ester closed loop; (D) wherein after the Knoevenagel condensation of carrying out 3-formyl radical-4-hydroxy-benzoic acid and toxilic acid, heat and decarboxylized method (non-patent literature 4).

Yet preparation method (A) has defective, and for example its (k) requires complicated program, and (1) exists the reaction reagent of many types and they is expensive.

Preparation method (B) have defective for example (m) ring-closure reaction at high temperature (n) have many steps and (o) have the reaction reagent of many types and they are expensive.

Preparation method (C) have defective for example (p) it have low productive rate.

Preparation method (D) has defective, and for example (q) initial substance is expensive and (r) the decarboxylation reaction is at high temperature.

The industrial production process of 2-oxo-2H-chromene carboxylic acid or its salt is also unsatisfactory.

[0004]

Patent documentation 1: international open WO03/042150 brochure

Patent documentation 2: international open WO2004/050082 brochure

Non-patent literature 1:Arthritis Rheum, 2006 Vol.54 (9), S232

Non-patent literature 2:Chem.Pharm.Bull., 1994, Vol.42, p.2170-2173

Non-patent literature 3:J.Org.Chem.1951, Vol.16, p.253-261.

Non-patent literature 4:Annali di Chimica (Rome) 1966 Vol.56 (6), p.700-716

[0005]

Still wish a kind of preparation method strongly, this method can easily be used cheap starting material to prepare T-5224 in a large number and human body is safe and does not have big environmental influence.

Summary of the invention

[0006]

Under these conditions, the contriver furthers investigate, and the result finds

(1) benzophenone derivative or its salt of representing by following general formula [1]:

[general formula 1]

R wherein ¹Expression hydrogen atom and R ²Expression alkoxyl group, or R ¹And R ²Key of expression connects together; R ³Representative ring alkyl and R ⁴Expression hydrogen atom, or R ³And R ⁴Be identical and represent hydrogen atom or alkyl separately that condition is to work as R ¹Be hydrogen atom and R ²When being alkoxyl group, R ³Representative ring alkyl and R ⁴The expression hydrogen atom, be the preparation intermediate 2 preparation in important preparation intermediate;

(2) benzophenone derivative or its salt of representing by following general formula [2]:

[general formula 6]

R wherein ^2aThe expression alkoxyl group; R ^3bThe representative ring alkyl can easily be prepared as follows: make the benzophenone derivative by following general formula [1a] expression

[general formula 2]

R wherein ^3aAnd R ^4aThe expression alkyl, carry out dealkylation reaction and obtain benzophenone derivative or its salt by following general formula [1b] expression:

[general formula 3]

The benzophenone derivative or its salt that make this benzophenone derivative or its salt in the presence of alkali, carry out alkylated reaction then and obtain to represent by following general formula [1c]:

[general formula 4]

R wherein ^3bAs surface defined, make this benzophenone derivative or its salt in the presence of alkali, carry out ring-opening reaction then and obtain benzophenone derivative or its salt by following general formula [1d] expression:

[general formula 5]

R wherein ^2aAnd R ^3bAs surface defined, make this benzophenone derivative or its salt carry out reduction reaction then;

(3) 6-(monochloromethyl)-1 that represents by following general formula [3], 2-benzoisoxazole-3 (2H)-ketone derivatives

[general formula 7]

R wherein ⁵Expression is substituted with the methyl of the phenyl of one or more optional replacements, or the optional oxygen heterocyclic ring group that replaces; X represents halogen atom, is valuable as the preparation intermediate of T-5224, specifically, and R wherein ⁵The compound (a) that is the optional trityl that replaces or tetrahydrochysene-2H-pyrans-2-base is can the easy to handle solid, (b) has high purity and stability, (c) do not using complicated process for example to prepare under the situation of silica gel column chromatography, (d) with produced in high yields, (e) to human body safety, (g) do not have big environmental influence, (h) can use cheap starting material to prepare in a large number, and be better than known preparation intermediate 1-1 and preparation intermediate 1-2;

(4) 6-(monochloromethyl)-1 that represents by following general formula [3], 2-benzoisoxazole-3 (2H)-ketone derivatives

[general formula 9]

R wherein ⁵With X as surface defined; can easily be prepared as follows: with the methyl of the phenyl that is substituted with one or more optional replacements; or the optional oxygen heterocyclic ring group protection 6-methyl isophthalic acid that replaces; 2 of 2-benzoisoxazole-3-alcohol and obtain 6-methyl isophthalic acid by following general formula [4] expression, 2-benzoisoxazole-3 (2H)-ketone:

[general formula 8]

R wherein ⁵As mentioned above, then halogenation;

(5) 6-(monochloromethyl)-1 that represents by following general formula [3], 2-benzoisoxazole-3 (2H)-ketone derivatives

[general formula 13]

R wherein ⁵With X as mentioned above, can easily be prepared as follows: make (methylol) benzoic ether or its salt by following general formula [5] expression:

[general formula 10]

R wherein ⁶The expression alkyl obtains (methylol) benzohydroxamic acid derivative or its salt by following general formula [6] expression with azanol or its reactant salt:

[general formula 11]

Make the reaction of this (methylol) benzohydroxamic acid derivative or its salt and thionyl halide then, the compound or its salt that makes gained then carries out intramolecular cyclization reaction and obtains 6-(monochloromethyl)-1 by following general formula [7] expression, 2-benzoisoxazole-3-alcohol or its salt in the presence of alkali:

[general formula 12]

Wherein X as mentioned above, then with the methyl of phenyl that is substituted with one or more optional replacements, or the optional oxygen heterocyclic ring group that replaces protects this 6-(monochloromethyl)-1,2-benzoisoxazole-3-alcohol derivate or its salt 2;

(6) the T-5224 intermediate by the compound of the compound or its salt of general formula [2] and general formula [3] is the easy to handle solid;

(7) 2-oxo-2H-chromene carboxylic acid or its salt of representing by general formula [10]

[general formula 16]

Can easily be prepared as follows: will be by the methyl-2H-chromen-2-one oxidation of following general formula [8] expression with Manganse Dioxide

[general formula 14]

And 2-oxo-2H-chromene formaldehyde that acquisition is represented by following general formula [9]:

[general formula 15]

Use this compound of salt oxidation of halous acid then, and specifically, in the presence of sulfuric acid and water, use the compound of Manganse Dioxide oxidation general formula [8], the compound of general formula [9] prepares under high yield, and dissolves by reaction solvent because of the manganese that is by product, so do not need special procedure to remove demanganize, and in addition, prepare compound or its salt by simple program with highly purified general formula [10], and the compound of general formula [9] of needn't emanating, and finished the present invention.

[0007]

Adopt compound of the present invention and preparation method of the present invention, prepared T-5224 easily and with technical scale.

Preparation method of the present invention is characterised in that: (1) complicated purifying procedure for example distill with column chromatography be unnecessary, (2) do not use danger and have toxic reaction reagent that (the azo dicarbonyl compound is azoethane dicarboxylic ester and di-isopropyl azodicarboxylate for example; Chloromethyl methyl ether), (3) response procedures is simple etc.In other words, preparation method of the present invention is safe to human body and has low environmental influence and can be used as the simple preparation method of a large amount of preparations of T-5224.

Compound of the present invention (1) is the easy to handle solid, (2) has high purity and stability, (3) do not needing complicated process for example to prepare under the situation of silica gel column chromatography, (4) high productivity preparation, (5), have low environmental influence and can use cheap starting material to prepare in a large number to human body safety.

The compound of the application of the invention can easily prepare T-5224.

Preferred forms of the present invention

[0008]

The present invention will be described in detail belows.

When this uses, except as otherwise noted, halogen atom is meant chlorine atom, bromine atoms and iodine atom; Alkyl is meant straight chain or branching C _1-6Base, for example methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl and amyl group; Cycloalkyl is meant C _3-8Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl for example; Alkoxyl group is meant straight chain or branching C _1-6Alkoxyl group is methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy and isopentyloxy for example; Alkylsulfonyloxy is meant C _1-6Alkylsulfonyloxy, for example sulfonyloxy methyl oxygen base, trifluoromethyl sulfonyloxy and ethyl sulfonyloxy; Aryl-sulfonyl oxygen is meant for example phenylsulfonyloxy and tosyloxy.

The example of leavings group comprises halogen atom, alkylsulfonyloxy and aryl-sulfonyl oxygen.

[0009]

R ⁵The ＂ methyl ＂ that is substituted with the phenyl of one or more optional replacements be benzyl, diphenyl-methyl and trityl, wherein this phenyl can be chosen wantonly and be substituted with one or more groups that are selected from halogen atom, nitro, alkyl, alkoxyl group etc.

R ⁵The optional oxygen heterocyclic ring group ＂ that replaces of ＂ contain Sauerstoffatom as the heterocyclic group that becomes ring hetero atom, for example tetrahydrochysene-2H-pyrans-2-is basic and tetrahydrochysene-2H-furans-2-base, and this heterocyclic group can be chosen wantonly and be substituted with one or more groups that are selected from halogen atom, alkyl and alkoxyl group etc.

[0010]

As for the compound or its salt by general formula [1] expression, preferred examples for compounds is following compound.

R wherein ¹Be hydrogen atom and R ²Be the compound of methoxy or ethoxy and R wherein ¹And R ²The compound that forms key that connects together is preferred.R wherein ¹Be hydrogen atom and R ²Be the compound of methoxyl group and R wherein ¹And R ²The compound that forms key that connects together is preferred.

R wherein ³And R ⁴Be identical and each is the compound of hydrogen atom, methyl or ethyl and R wherein ³Be cycloalkyl and R ⁴The compound that is hydrogen atom is preferred.R wherein ³And R ⁴Be identical and each is the compound of hydrogen atom or methyl and R wherein ³Be cyclopentyl and R ⁴The compound that is hydrogen atom is preferred.

Work as R ¹Be hydrogen atom and R ²When being alkoxyl group, R wherein ³Be cycloalkyl and R ⁴The compound that is hydrogen atom is preferred.Work as R ¹Be hydrogen atom and R ²When being methoxy or ethoxy, R wherein ³Be cyclopentyl and R ⁴The compound that is hydrogen atom is preferred.

As for the compound or its salt by general formula [1] expression, preferred salt comprises sodium salt.

[0011]

The example of the preferred preparation method of the compound or its salt of general formula [2] comprises following method.

In preferred manufacturing procedure, the R of the compound of general formula [1a] ^3aAnd R ^4aBe identical and each is an alkyl; The R of the compound of general formula [1c] and [1d] ^3bIt is cycloalkyl; The R of the compound of general formula [1d] ^2aIt is alkoxyl group.

In preferred preparation method, the R of the compound of general formula [1a] ^3aAnd R ^4aBe identical and each is methyl or ethyl; The R of the compound of general formula [1c] and [1d] ^3bIt is cyclopentyl; The R of the compound of general formula [1d] ^2aIt is methoxy or ethoxy.

In preferred preparation method, the R of the compound of general formula [1a] ^3aAnd R ^4aBe identical and each is a methyl; The R of the compound of general formula [1c] and [1d] ^3bIt is cyclopentyl; The R of the compound of general formula [1d] ^2aIt is methoxyl group.

[0012]

As for the compound by general formula [3] expression, preferred compound comprises following example.

R wherein ⁵The compound that is optional trityl that replaces or the optional tetrahydrochysene-2H-pyrans-2-base that replaces is preferred.R wherein ⁵The compound that is the optional trityl that replaces is preferred.R wherein ⁵The compound that is trityl is preferred, and this trityl can be chosen wantonly and be substituted with halogen atom or methoxyl group.R wherein ⁵The compound that is trityl is even is preferred.

Wherein X is that the compound of chlorine atom or bromine atoms is preferred.

[0013]

Preferred manufacturing procedure as for the compound of general formula [3] provides following example.

In a kind of preferred manufacturing procedure, use wherein R ⁵It is the compound of optional trityl that replaces or the optional tetrahydrochysene-2H-pyrans-2-base that replaces.In a kind of preferred preparation method, use wherein R ⁵It is the compound of the optional trityl that replaces.In a kind of even preferred preparation method, use wherein R ⁵Be the compound of trityl, this trityl can be chosen wantonly and be substituted with halogen atom or methoxyl group.In a kind of even preferred preparation method, use wherein R ⁵It is the compound of trityl.In a kind of preferred manufacturing procedure, using wherein, X is the compound of chlorine atom or bromine atoms.

[0014]

As for the preferred preparation method of the compound or its salt of general formula [10], given following example.

In a kind of preferred manufacturing procedure, in the presence of sulfuric acid and water with the compound oxidation of Manganse Dioxide, and after the compound of preparation general formula [9], with this compound of salt oxidation of halous acid with general formula [8].

The method that the preferably use therein Manganse Dioxide of preparation method is activated manganese dioxide.

This preparation method preferably wherein vitriolic concentration (with respect to sulfuric acid and water) be 10-99% (w/w), more preferably 35-75% (w/w), even the more preferably method of 45-65% (w/w).

The preparation method preferably compound of its formula of [8] is the method for 6-methyl-2H-chromen-2-one or 7-methyl-2H-chromen-2-one, and more preferably wherein this compound is the method for 6-methyl-2-oxo-2H-chromene.

The compound segregation and the purifying of general formula [9] still preferably, can be used for ensuing reaction under not by isolating situation.

[0015]

As for wherein with the isolating method of crystal of the compound or its salt of general formula [10], the crystalline method is preferred from following solvent: ketone is the mixed solvent of methyl iso-butyl ketone (MIBK) etc. and water for example, and alcohol is the mixed solvent of methyl alcohol etc. and water or the sulfoxide mixed solvent of dimethyl sulfoxide (DMSO) etc. and water for example for example.The crystalline method is preferred from the mixed solvent of the mixed solvent of first alcohol and water or dimethyl sulfoxide (DMSO) and water.

[0016]

As for the preferred manufacturing procedure of T-5224 intermediate, provide following example.

In a kind of preferred manufacturing procedure, the R of the compound of general formula [2] ^2aBe alkoxyl group, R ^3bIt is cycloalkyl; The R of the compound of general formula [3] ⁵Be optional trityl or the tetrahydrochysene-2H-pyrans-2-base that replaces.

In a kind of preferred preparation method, the R of the compound of general formula [2] ^2aBe methoxy or ethoxy, R ^3bIt is cyclopentyl; The R of general formula [3] ⁵It is the optional trityl that replaces.

In a kind of even preferred preparation method, the R of the compound of general formula [2] ^2aBe methoxyl group, R ^3bIt is cyclopentyl; The R of general formula [3] ⁵It is trityl.

In a kind of preferred manufacturing procedure, the X of the compound of general formula [3] is chlorine atom or bromine atoms.

[0017]

Next, preparation method of the present invention will be described.

[preparation method 1]

In this general formula, L represents leavings group; R ^2a, R ^3a, R ^3bAnd R ^4aAs mentioned above.

[0018]

(1-1)

Compound by mutual-through type [1a] carries out dealkylation and reacts the compound or its salt for preparing general formula [1b].

For example, by Protective Groups In Organic Synthesis, T.W.Greene, John Wiley ﹠amp; Sons, Inc.1999, the third edition, the method for describing in p.249-276 or carry out this reaction corresponding to the method for this method.

[0019]

The example (being not particularly limited as long as it does not influence reaction) that is used for the solvent of this reaction comprises aliphatic hydrocrbon for example hexane and hexanaphthene; Aromatic hydrocarbon is benzene, toluene and dimethylbenzene for example; Halohydrocarbon is methylene dichloride, chloroform, 1 for example, 2-ethylene dichloride, chlorobenzene and dichlorobenzene; Ether is diox, tetrahydrofuran (THF), glycol dimethyl ether and diethylene glycol dimethyl ether for example; Sulfoxide is dimethyl sulfoxide (DMSO) for example; Ester is methyl acetate and ethyl acetate for example; Acid amides is 1-Methyl-2-Pyrrolidone, N for example, dinethylformamide and N,N-dimethylacetamide; Ketone is acetone and 2-butanone for example; Alcohol is methyl alcohol, ethanol, 2-propyl alcohol and 2-methyl-2-propyl alcohol and nitrile acetonitrile for example for example.These solvents can use separately or can use two or more solvents in combination.Preferred solvent comprises the mixed solvent of acid amides and aromatic hydrocarbon.The mixed solvent of 1-Methyl-2-Pyrrolidone and toluene is preferred.The usage quantity of solvent (but not being limited to especially) is 1-50 times (v/w) of the amount of the compound of general formula [1a] preferably, more preferably 1-15 times (v/w).

[0020]

The example that is used for the dealkylation agent of this reaction comprises the salt of mineral acid and organic bases.Representative examples of mineral pigments comprises hydrochloric acid, Hydrogen bromide and hydroiodic acid HI.The example of organic bases comprises dimethyl aminopyridine, triethylamine and pyridine.Preferred dealkylation agent comprises the salt of mineral acid and pyridine, and the salt of hydrochloric acid and pyridine is preferred.With respect to the compound of general formula [1a], with 2-10 doubly, more preferably 4-10 mol ratio is doubly used this salt.

In addition, the salt of mineral acid and organic bases can produce in this reaction system.With respect to the compound of general formula [1a], with 2-10 doubly, more preferably 4-10 mol ratio is doubly used this mineral acid.With respect to the compound of general formula [1a], with 2-10 doubly, more preferably 4-10 mol ratio is doubly used this organic bases.

[0021]

Temperature of reaction is (but not being limited to especially) 150-250 ℃, preferred 180-220 ℃.Reaction times is not particularly limited, but is 10 minutes-50 hours, preferred 30 minutes-24 hours.

[0022]

The compound or its salt of the general formula of Huo Deing [1b] can be used for ensuing reaction under not isolating situation like this.

[0023]

(1-2)

The compound or its salt of general formula [1c] is prepared as follows: make the compound of general formula [11] and the compound or its salt of general formula [1b] carry out alkylated reaction in the presence of alkali.

For the compound of general formula [11], for example, cyclopentyl bromide or analogue are commercially available.

[0024]

The example (being not particularly limited as long as it does not influence reaction) that is used for the solvent of this reaction comprises aromatic hydrocarbon for example benzene, toluene and dimethylbenzene; Ether is diox, tetrahydrofuran (THF), glycol dimethyl ether and diethylene glycol dimethyl ether for example; Acid amides is 1-Methyl-2-Pyrrolidone, N for example, dinethylformamide and N,N-dimethylacetamide; Ketone is acetone and 2-butanone for example; With halohydrocarbon for example methylene dichloride, chloroform, 1,2-ethylene dichloride, chlorobenzene and dichlorobenzene.These solvents can use separately or can use two or more solvents in combination.Preferred solvent comprises acid amides, and N, and dinethylformamide is further preferred.The usage quantity of solvent (but not being limited to especially) is 1-50 times (v/w) of the amount of the compound or its salt of general formula [1b] preferably, more preferably 1-15 times (v/w).

[0025]

The example that is used for the alkali of this reaction comprises organic bases for example dimethyl aminopyridine, triethylamine and pyridine; Alkalimetal hydride is sodium hydride for example; With alkaline carbonate for example salt of wormwood and yellow soda ash.Preferred alkali comprises alkaline carbonate for example salt of wormwood and yellow soda ash, and salt of wormwood is preferred.With respect to the compound or its salt of general formula [1b], with 0.5-20 doubly, preferred 0.5-5 mol ratio is doubly used this alkali.

[0026]

With respect to the compound or its salt of general formula [1b], with 1-20 doubly, preferred 1-5 mol ratio doubly is used for this reaction with the compound of general formula [11].

[0027]

Temperature of reaction is not particularly limited, but is 0-120 ℃, preferred 50-120 ℃.

Reaction times is not particularly limited, but is 10 minutes-50 hours, preferred 30 minutes-24 hours.

[0028]

The compound or its salt of the general formula of Huo Deing [1c] can still preferably not have to be used for ensuing reaction under the isolating situation through segregation and purifying like this.

[0029]

(1-3)

The compound or its salt of general formula [1d] prepares by allowing the compound of general formula [1c] carry out ring-opening reaction in the presence of alkali.

[0030]

The example (being not particularly limited as long as it does not influence reaction) that is used for the solvent of this reaction comprises aromatic hydrocarbon for example benzene, toluene and dimethylbenzene; Ether is diox, tetrahydrofuran (THF), glycol dimethyl ether and diethylene glycol dimethyl ether for example; Ester is methyl acetate and ethyl acetate for example; Ketone is acetone and 2-butanone for example; Alcohol is methyl alcohol, ethanol, 2-propyl alcohol and 2-methyl-2-propyl alcohol for example; Nitrile is acetonitrile for example; Acid amides is 1-Methyl-2-Pyrrolidone, N for example, dinethylformamide and N,N-dimethylacetamide; Halohydrocarbon is methylene dichloride, chloroform, 1 for example, 2-ethylene dichloride, chlorobenzene and dichlorobenzene.These solvents can use separately or can use two or more solvents in combination.Preferred solvent comprises the mixed solvent of pure and mild aromatic hydrocarbon, and the mixed solvent of methyl alcohol and toluene is further preferred.The usage quantity of solvent (but not being limited to especially) is 1-50 times (v/w) of the amount of the compound or its salt of general formula [1c] preferably, more preferably 1-15 times (v/w).

[0031]

The example that is used for the alkali of this reaction comprises metal alkoxide for example sodium methylate, sodium ethylate, potassium tert.-butoxide and sodium tert-butoxide.Preferred alkali comprises sodium methylate and sodium ethylate, and sodium methylate is preferred.With respect to the compound or its salt of general formula [1c], with 1-20 doubly, preferred 1-5 mol ratio is doubly used this alkali.Alkali can be dissolved in organic solvent and use.If alkali to be used is sodium methylate, then preferably it is dissolved in methyl alcohol and use.When the alkali that uses is sodium ethylate, preferably it is dissolved in ethanol and use.

[0032]

Temperature of reaction is not particularly limited, but is 0-100 ℃, preferred 30-80 ℃.

[0033]

The compound or its salt of the general formula of Huo Deing [1d] can be used as the sodium salt segregation like this, but can not have to be used for ensuing reaction under the isolating situation.

[0034]

(1-4)

The compound or its salt of the compound or its salt of general formula [2] by mutual-through type [1d] carries out reduction reaction and prepares.

For this reduction reaction, example is included in hydrogen source and has the catalytic hydrogenation of using catalyzer down.

[0035]

The example (being not particularly limited as long as it does not influence reaction) that is used for the solvent of this reaction comprises alcohol for example methyl alcohol, ethanol, 2-propyl alcohol and 2-methyl-2-propyl alcohol; Acid amides is 1-Methyl-2-Pyrrolidone, N for example, dinethylformamide and N,N-dimethylacetamide; Halohydrocarbon is methylene dichloride, chloroform, 1 for example, 2-ethylene dichloride, chlorobenzene and dichlorobenzene; Aromatic hydrocarbon is benzene, toluene and dimethylbenzene for example; Ether is diox, tetrahydrofuran (THF), glycol dimethyl ether and diethylene glycol dimethyl ether for example; Nitrile is acetonitrile for example; Ketone is acetone and 2-butanone for example; Ester is methyl acetate and ethyl acetate for example; Carboxylic acid is acetate and water for example.These solvents can use separately or can use two or more solvents in combination.Preferred solvent comprises that water and one or more are selected from the mixed solvent of the solvent of alcohol, ketone and ether.The mixed solvent of 2-third alcohol and water is preferred.The usage quantity of solvent (but not being limited to especially) is 1-50 times (v/w) of the amount of the compound or its salt of general formula [1d] preferably, more preferably 1-15 times (v/w).

[0036]

The example that is used for this catalyst for reaction comprises palladium catalyst for example carbon palladium, Palladous chloride, acid chloride and palladium black; Nickel catalyzator is Raney Ni (Raney nickel) and platinum oxide for example.The amount of catalyzer to be used is the 0.010-1 doubly (w/w) of amount of the compound or its salt of general formula [1d], and preferred 0.01-0.5 is (w/w) doubly.

[0037]

The example that is ready to use in the hydrogen source of this reaction comprises hydrogen; Formic acid; Formate is sodium formiate and ammonium formiate for example, and sodium hypophosphite.Hydrogen, formic acid and formate are preferred hydrogen sources.Formic acid and formate are preferred.Formic acid, sodium formiate and ammonium formiate are even are preferred.

[0038]

When formic acid or formate during as hydrogen source, with respect to the compound or its salt of general formula [1d], with 1-20 doubly, preferred 1-5 mol ratio is doubly used formic acid or formate.

[0039]

When using hydrogen as hydrogen source, hydrogen pressure is a 1-30 normal atmosphere, preferred 1-10 normal atmosphere.

[0040]

In addition, preferably in this reaction, add acid to suppress by product.

The example of acid comprises for example for example hydrochloric acid and sulfuric acid of acetate and formic acid and mineral acid of organic acid.With respect to the compound or its salt of general formula [1d], with 1-20 doubly, preferred 1-5 mol ratio is doubly used this acid.

[0041]

[0042]

[preparation method 2]

In this general formula, R ⁵With X as surface defined.

[0043]

(2-1)

The compound of general formula [4] is prepared as follows: with the methyl of the phenyl that is substituted with one or more optional replacements or protect 2 of compound or its salt of general formula [12] with the optional oxygen heterocyclic ring group that replaces.

The compound or its salt of general formula [12] prepares by the method for describing in open WO03/042150 brochure in for example world or the U.S. Patent Application Publication No. 2005/0143434.In addition, the compound or its salt of general formula [12] can be by the preparation method A preparation of describing after a while.

[0044]

Work as R ⁵When being the trityl that can replace, for example, by Protective Groups InOrganic Synthesis, T.W.Greene, John Wiley ﹠amp; Sons Inc., 1999, the third edition, p.86-113, the method for describing among the 573-586 prepares the compound of general formula [4].

More specifically say, in the presence of alkali, make the compound or its salt and the reaction of trityl halogen of general formula [12].

[0045]

The example that is used for the alkali of this reaction comprises for example for example salt of wormwood and yellow soda ash of dimethyl aminopyridine, triethylamine, pyridine and N-methylmorpholine and alkaline carbonate of organic bases.For this alkali, organic bases is preferred, and pyridine is preferred.With respect to the compound or its salt of general formula [12], with 1-20 doubly, preferred 1-10 mol ratio is doubly used this alkali.

[0046]

The example that is ready to use in the trityl halogen of this reaction comprises trityl chloride, trityl bromide, (4-p-methoxy-phenyl) diphenyl-chloromethane, (4,4 '-Dimethoxyphenyl) phenyl methyl chlorine and (2-chloro-phenyl-) diphenyl-chloromethane.Trityl chloride and trityl bromide are preferred, and trityl chloride is preferred.With respect to the compound or its salt of general formula [12], with 1-10 doubly, preferred 1-3 mol ratio is doubly used this trityl halogen.

[0047]

The example (being not particularly limited as long as it does not influence reaction) that is used for the solvent of this reaction comprises for example acetonitrile of nitrile; Aromatic hydrocarbon is benzene,toluene,xylene and sym-trimethylbenzene for example; Ether is diox, tetrahydrofuran (THF), phenylmethylether, glycol dimethyl ether and diethylene glycol dimethyl ether for example; Aliphatic hydrocrbon is hexane and hexanaphthene for example; Halohydrocarbon is chloroform, methylene dichloride, chlorobenzene and dichlorobenzene for example; Ester is methyl acetate, ethyl acetate and butylacetate for example; Acid amides is N for example, dinethylformamide and N,N-dimethylacetamide; With sulfoxide dimethyl sulfoxide (DMSO) for example.They can use in combination.Preferred solvent comprises halohydrocarbon, and methylene dichloride is preferred.The usage quantity of solvent (but not being limited to especially) is 1-50 times (v/w) of the amount of the compound or its salt of general formula [12] preferably, more preferably 1-15 times (v/w).

[0048]

Temperature of reaction is not particularly limited, but is-50 to 150 ℃, preferred-30 to 100 ℃.

Reaction times is not particularly limited, but is 5 minutes-50 hours, preferred 5 minutes-24 hours.

[0049]

Work as R ⁵When being the tetrahydrochysene-2H-pyrans that can replace-2-base, for example, by ProtectiveGroups In Organic Synthesis, T.W.Greene, John Wiley ﹠amp; SonsInc., 1999, the third edition, p.27-58, the method for describing among the 249-280 prepares the compound of general formula [4].

More specifically say, for example, the compound or its salt of general formula [12] is reacted in the presence of catalyzer with dihydropyrane.

[0050]

The example that is used for this catalyst for reaction comprises acid for example hydrochloric acid, sulfuric acid and tosic acid; Salt is tosic acid pyridine, Hydrogen bromide triphenylphosphine, cupric chloride (I), Tai-Ace S 150 and zeolite for example.Preferred catalyzer comprises salt, and the tosic acid pyridine is preferred.With respect to the compound or its salt of general formula [12], with 0.01-10 doubly, preferred 0.01-3 mol ratio is doubly used this catalyzer.

[0051]

The example that is used for the dihydropyrane of this reaction comprises 3,4-dihydro-2H-pyrans, 3,4-dihydro-2-methoxyl group-2H-pyrans and 5,6-dihydro-4-methoxyl group-2H-pyrans.3,4-dihydro-2H-pyrans is preferred.With respect to the compound or its salt of general formula [12], with 1-20 doubly, preferred 1-5 mol ratio is doubly used this dihydropyrane.

[0052]

The example (being not particularly limited as long as it does not influence reaction) that is used for the solvent of this reaction comprises aromatic hydrocarbon for example benzene,toluene,xylene and sym-trimethylbenzene; Ether is diox, tetrahydrofuran (THF), phenylmethylether, glycol dimethyl ether and diethylene glycol dimethyl ether for example; Ester is methyl acetate, ethyl acetate and butylacetate for example; Nitrile is acetonitrile for example; Acid amides is N for example, dinethylformamide and N,N-dimethylacetamide; With halohydrocarbon for example chloroform, methylene dichloride, chlorobenzene and dichlorobenzene etc.They can use in combination.Preferred solvent comprises halohydrocarbon, and methylene dichloride is preferred.The usage quantity of solvent (but not being limited to especially) is 1-50 times (v/w) of the amount of the compound or its salt of general formula [12] preferably, more preferably 1-15 times (v/w).

[0053]

Temperature of reaction is not particularly limited, but is-50 to 100 ℃, preferred-30 to 50 ℃.

[0054]

The compound of the general formula of Huo Deing [4] can not have to be used for ensuing reaction under the isolating situation like this.

[0055]

(2-2)

Prepare the compound of general formula [3] by compound halogenation with general formula [4].

[0056]

The example (but being not particularly limited, as long as it is can be used for the halogenated halogenating agent of the alkyl group side chain of aromatic substance) that is used for the halogenating agent of this reaction comprises element halogen for example chlorine, bromine and iodine; Imide is N-chlorosuccinimide, N-bromosuccinimide, N-chloro phthalimide and N-bromo phthalimide for example; Glycolylurea for example 1,3-two bromo-5,5-T10 and 1,3 dichloro 5,5 dimethyl hydantoin; And SULPHURYL CHLORIDE.Preferred halogenating agent comprises imide, and N-bromosuccinimide is preferred.With respect to the compound of general formula [4], with 1 or bigger multiple, preferred 1-3 mol ratio is doubly used halogenating agent, but is not particularly limited.

[0057]

Preferably in the presence of radical initiator, carry out this reaction.The example of radical initiator (but unrestricted, needing only it is the radical initiator of using always) comprises dialkyl for example di-t-butyl peroxide, peroxidation two tert-pentyls and peroxidation two (2-methyl-2-amyl group); The peroxidation diacyl is dibenzoyl peroxide, dicumyl peroxide and peroxidation two phthalyls for example; The hydroperoxidation alkyl is t-butyl hydroperoxide and hydroperoxidation cumyl for example; Percarboxylic acids, for example peroxybenzoic acid, a peroxide phthalic acid, peroxyformic acid and peracetic acid; Inorganic peroxy compounds is persulfuric acid for example; With organic azo-compound for example 2,2 '-azobis isobutyronitrile, 2,2 '-azo two (2, the 4-methyl pentane nitrile), 2,2 '-azo two (2-methylbutyronitrile), 2,2 '-the two isovaleronitriles, 1 of azo, 1 '-azo two (cyclohexane nitrile), 2,2 '-azo two (4-methoxyl group-2,4-methyl pentane nitrile), 2,2 '-two (2-amidine propane) dihydrochlorides and 2,2 of azo '-the two isopropylformic acid dimethyl esters of azo.Organic azo-compound is preferred radical initiator, and more preferably 2,2 '-azobis isobutyronitrile, 2,2 '-azo two (2, the 4-methyl pentane nitrile) and 2,2 '-azo pair (4-methoxyl group-2,4-methyl pentane nitrile).With respect to the compound of general formula [4], with 0.01 or bigger multiple, preferred 0.05-1 mol ratio is doubly used radical initiator, but is not particularly limited.

[0058]

The example (being not particularly limited as long as it does not influence reaction) that is used for the solvent of this reaction comprises aliphatic hydrocrbon for example hexane, hexanaphthene and heptane; Ether is diox, tetrahydrofuran (THF), phenylmethylether, glycol dimethyl ether and diethylene glycol dimethyl ether for example; Ester is methyl acetate, ethyl acetate and butylacetate for example; Halohydrocarbon is chloroform, methylene dichloride, chlorobenzene and dichlorobenzene for example.They can use in combination.Preferred solvent comprises ester and halohydrocarbon.Methylene dichloride and chlorobenzene are preferred.The usage quantity of solvent (but not being limited to especially) is 1-50 times (v/w) of the amount of the compound of general formula [4] preferably, more preferably 1-15 times (v/w).

[0059]

Temperature of reaction is not particularly limited, but is 0-200 ℃, preferred 0-100 ℃.

[0060]

In this reaction, the methyl that may have the compound of its formula of [4] is dihalide and three halogenated by-product compounds.In this case, for example, adopt Synthesis, 2001, Vol.14, the p.2078-2080 method of Miao Shuing, and more particularly, by make the dialkyl phosphonate reaction in the presence of alkali, wherein methyl is the compound that dihalide or three halogenated compounds can be transformed into general formula [3].

[0061]

The example that is used for the alkali of this reaction comprises organic bases for example triethylamine, N, N-diisopropylethylamine; The oxyhydroxide of basic metal or alkaline-earth metal is sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and hydrated barta for example; The carbonate of basic metal or alkaline-earth metal is yellow soda ash, salt of wormwood and barium carbonate for example.Preferred alkali comprises the carbonate of basic metal or alkaline-earth metal, and salt of wormwood is preferred.With respect to the compound of general formula [4], with 0.5 or bigger multiple, more preferably 0.5-10 mol ratio is doubly used this alkali.

[0062]

The example that is used for the dialkyl phosphonate of this reaction comprises dimethyl phosphine acid esters, diethyl phosphonate, di-isopropyl phosphonic acid ester and dibutyl phosphonic acid ester; Dimethyl phosphine acid esters and diethyl phosphonate are preferred.With respect to the compound of general formula [4], with 0.5 or bigger multiple, more preferably 0.5-10 mol ratio is doubly used this dialkyl phosphonate.

[0063]

The example (being not particularly limited as long as it does not influence reaction) that is used for the solvent of this reaction comprises ether for example diox, tetrahydrofuran (THF), phenylmethylether, glycol dimethyl ether and diethylene glycol dimethyl ether; With halohydrocarbon for example methylene dichloride, chloroform, 1,2-ethylene dichloride, chlorobenzene and dichlorobenzene.They can use in combination.Preferred solvent comprises halohydrocarbon.Methylene dichloride is preferred.The usage quantity of solvent (but not being limited to especially) is 1-50 times (v/w) of the amount of the compound of general formula [4] preferably, more preferably 1-20 times (v/w).

[0064]

Temperature of reaction is not particularly limited, but is 0-200 ℃, preferred 0-100 ℃.Reaction times is not particularly limited, but is 1-50 hour, preferred 1-24 hour.

[0065]

[preparation method 3]

In this general formula, R ⁵, R ⁶With X as surface defined.

As the example of the compound or its salt of general formula [5], 2-hydroxyl-4-(methylol) benzoic acid methyl ester is known.In addition, for example, prepare the compound or its salt of general formula [5] by the method for describing in open WO2004/113281 brochure in the world or the Japanese Patent No. 3197011.

In addition, the compound or its salt of general formula [5] can be by the preparation method B preparation of describing after a while.

[0066]

(3-1)

The compound or its salt of general formula [6] is by in the presence of the alkali or do not having to allow the compound or its salt of general formula [5] and azanol or its reactant salt prepare under the situation of alkali.

[0067]

Be used for the azanol of this reaction or the example of its salt and comprise azanol, azanol hydrosulfate, hydroxylamine hydrochloride and azanol oxalate.Hydroxylamine hydrochloride is preferred.Azanol or its salt can be dissolved in solvent for example in water and the methyl alcohol and use.With respect to the compound or its salt of general formula [5], with 1 or bigger multiple, preferred 1-5 mol ratio is doubly used this azanol or its salt.

[0068]

Preferably in the presence of alkali, carry out this reaction.The oxyhydroxide that the example of alkali comprises basic metal or alkaline-earth metal is sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and hydrated barta for example; Alkali-metal supercarbonate is sodium bicarbonate and saleratus for example; The carbonate of basic metal or alkaline-earth metal is yellow soda ash, salt of wormwood and barium carbonate for example; Aluminate compound is sodium aluminate and potassium aluminate for example; Metal alkoxide is sodium methylate, sodium ethylate and potassium tert.-butoxide for example.Adopt them, can use two or more types in combination.In addition, if necessary, alkali can be dissolved in solvent for example in water and the methyl alcohol and use.Preferred alkali comprises metal alkoxide.Sodium methylate is preferred.When using sodium methylate as alkali, it preferably uses as methanol solution.With respect to the compound or its salt of general formula [5], with 1 or bigger multiple, preferred 1-10 mol ratio is doubly used this alkali.

[0069]

The example (being not particularly limited as long as it does not influence reaction) that is used for the solvent of this reaction comprises aromatic hydrocarbon for example benzene,toluene,xylene and sym-trimethylbenzene; Ether is diox, tetrahydrofuran (THF), phenylmethylether, glycol dimethyl ether and diethylene glycol dimethyl ether for example; Halohydrocarbon is chloroform, methylene dichloride, chlorobenzene and dichlorobenzene for example; Alcohol is methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol and butanols for example; Acid amides is N for example, dinethylformamide and N,N-dimethylacetamide; And water.They can use in combination.Preferred solvent comprises alcohol, and methyl alcohol is preferred.The usage quantity of solvent (but not being limited to especially) is 1-50 times (v/w) of the amount of the compound or its salt of general formula [5] preferably, more preferably 1-15 times (v/w).

[0070]

[0071]

The compound or its salt of the general formula of Huo Deing [6] can not have to be used for ensuing reaction under the isolating situation like this, but preferably with its segregation.

[0072]

(3-2)

The compound or its salt by making general formula [6] and the compound or its salt of thionyl halide prepared in reaction general formula [13].

[0073]

The example that is ready to use in the thionyl halide of this reaction comprises thionyl chloride and thionyl bromide, and thionyl chloride is preferred.With respect to the compound or its salt of general formula [6], with 1 or bigger multiple, preferred 1-10 mol ratio is doubly used this thionyl halide.

[0074]

The example (being not particularly limited as long as it does not influence reaction) that is used for the solvent of this reaction comprises aromatic hydrocarbon for example benzene,toluene,xylene and sym-trimethylbenzene; Ether is diox, tetrahydrofuran (THF), phenylmethylether, glycol dimethyl ether and diethylene glycol dimethyl ether for example; Halohydrocarbon is chloroform, methylene dichloride, chlorobenzene and dichlorobenzene for example; And thiotetrole.They can use in combination.Preferred solvent comprises halohydrocarbon, and methylene dichloride is preferred.The usage quantity of solvent (but not being limited to especially) is 1-50 times (v/w) of the amount of the compound or its salt of general formula [6] preferably, more preferably 1-15 times (v/w).

[0075]

Preferably in the presence of catalyzer, carry out this reaction.The example of catalyzer comprises N, dinethylformamide.With respect to the compound or its salt of general formula [6], with 0.001-1 doubly, preferred 0.01-0.5 mol ratio is doubly used this catalyzer.

[0076]

Temperature of reaction is not particularly limited, but is 0 to 100 ℃, preferred 0 to 50 ℃.

[0077]

The compound or its salt of the general formula of Huo Deing [13] is not preferably having to be used for ensuing reaction under the isolating situation like this.

[0078]

(3-3)

Be prepared as follows the compound or its salt of general formula [7]: the compound or its salt and thionyl halide reaction in the presence of alkali, carrying out the then intramolecular cyclization reaction that make general formula [13].

[0079]

The example that is ready to use in the thionyl halide of this reaction comprises thionyl chloride and thionyl bromide, and thionyl chloride is preferred.With respect to the compound or its salt of general formula [13], with 1 or bigger multiple, preferred 1-10 mol ratio is doubly used this thionyl halide.

[0080]

The example that is used for the alkali of this reaction comprises organic bases for example triethylamine, N, N-diisopropylethylamine, pyridine, dimethyl aminopyridine, N-methylmorpholine and 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU); With mineral alkali for example sodium hydroxide, potassium hydroxide, yellow soda ash and salt of wormwood.Preferred alkali is organic bases, and pyridine is preferred.With respect to the compound or its salt of general formula [13], with 1 or bigger multiple, preferred 1-5 mol ratio is doubly used this alkali.

[0081]

The example (being not particularly limited as long as it does not influence reaction) that is used for the solvent of this reaction comprises aromatic hydrocarbon for example benzene,toluene,xylene and sym-trimethylbenzene; Ether is diox, tetrahydrofuran (THF), phenylmethylether, glycol dimethyl ether and diethylene glycol dimethyl ether for example; Halohydrocarbon is chloroform, methylene dichloride, chlorobenzene and dichlorobenzene for example; And thiotetrole.They can use in combination.Preferred solvent comprises halohydrocarbon, and methylene dichloride is preferred.

The usage quantity of solvent (but not being limited to especially) is 1-50 times (v/w) of the amount of the compound or its salt of general formula [13] preferably, more preferably 1-15 times (v/w).

[0082]

Temperature of reaction is not particularly limited, but is 0-100 ℃, preferred 0-50 ℃.

[0083]

The compound or its salt of the general formula of Huo Deing [7] is not preferably having to be used for ensuing reaction under the isolating situation like this.

[0084]

(3-4)

The compound of general formula [3] is prepared as follows: with the methyl of the phenyl that is substituted with one or more optional replacements or protect 2 of compound or its salt of general formula [7] with the optional oxygen heterocyclic ring group that replaces.Carry out this reaction according to preparation method (2-1).

[0085]

[preparation method 4]

[0086]

(4-1)

The compound of general formula [9] is prepared as follows: the compound of using Manganse Dioxide oxidation general formula [8] in the presence of sulfuric acid and water.

As for the compound of general formula [8], for example, 6-methyl-2H-chromen-2-one is commercially available.

[0087]

Be ready to use in the sulfuric acid of this reaction and the amount of water and be not particularly limited, but the 1-50 of the amount of the compound of general formula [8] doubly (v/w) preferably, more preferably 3-15 doubly (v/w).With respect to the sulfuric acid concentration of sulfuric acid and water 10-99% (w/w) preferably, more preferably 35-75% (w/w), even more preferably 45-65% (w/w).

[0088]

Can add the solvent that does not influence reaction.The example of solvent (unrestricted as long as it does not influence reaction) comprises aliphatic halogenated hydrocarbons for example methylene dichloride, chloroform and ethylene dichloride; With aromatic halohydrocarbons for example chlorobenzene and dichlorobenzene.They can use in combination.Preferred solvent comprises aromatic halohydrocarbons, and chlorobenzene is preferred.The usage quantity of solvent (but not being limited to especially) is 0.1-10 times (v/w) of the amount of the compound of general formula [8] preferably, more preferably 0.5-3 times (v/w).

[0089]

The Manganse Dioxide that is used for this reaction is not particularly limited, but preferred activated manganese dioxide.Can make the currently known methods of manganous sulfate and potassium permanganate reaction obtain activated manganese dioxide by wherein for example.In addition, can use commercially available activated manganese dioxide, and can use industrial a large amount of preparation to be used for the Manganse Dioxide of battery.

The usage quantity of this Manganse Dioxide is the 0.5-10 doubly (w/w) of amount of the compound of general formula [8], more preferably 1-3 doubly (w/w).

Can once add Manganse Dioxide, add, more preferably press 8-20 aliquots containig and add but preferably press 2-50 aliquots containig.

[0090]

Temperature of reaction is not particularly limited, but is 0-150 ℃, preferred 50-90 ℃.

Reaction times is not particularly limited, but is 10 minutes-50 hours, preferred 30 minutes-20 hours.

[0091]

The compound of the general formula of Huo Deing [9] is not preferably having to be used for ensuing reaction under the isolating situation like this.

[0092]

(4-2)

The compound or its salt of general formula [10] prepares by the compound with the salt oxidation general formula [9] of halous acid.

The example (being not particularly limited as long as it does not influence reaction) that is used for the solvent of this reaction comprises aliphatic halogenated hydrocarbons for example methylene dichloride, chloroform and ethylene dichloride; Aromatic halohydrocarbons is chlorobenzene and dichlorobenzene for example; Ether is diox, tetrahydrofuran (THF), glycol dimethyl ether and diethylene glycol dimethyl ether for example; Acid amides is N for example, dinethylformamide, N,N-dimethylacetamide and 1-Methyl-2-Pyrrolidone; Sulfoxide is dimethyl sulfoxide (DMSO) for example; Alcohol is methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol and butanols for example; Ketone is acetone and 2-butanone for example; Nitrile is acetonitrile for example; Ester is methyl acetate and ethyl acetate for example; Nitro-compound is Nitromethane 99Min. and oil of mirbane for example; Aromatic hydrocarbon is benzene, toluene and dimethylbenzene for example; And water.These solvents can use in combination.Preferred solvent comprises the mixed solvent of ketone, sulfoxide and water, and the mixed solvent of 2-butanone, dimethyl sulfoxide (DMSO) and water is preferred.The usage quantity of solvent (but not being limited to especially) is 1-50 times (v/w) of the amount of the compound of general formula [9] preferably, more preferably 3-30 times (v/w).

[0093]

The example of salt that is used for the halous acid of this reaction comprises chlorite, bromite and iodite.The example of described salt comprises for example salt of sodium and potassium and alkaline earth salt calcium salt for example of an alkali metal salt.More particularly, chlorite is preferred, and alkali metal chlorite is preferred, and Textone is even is preferred.These salt can be used as the aqueous solution and use.

With respect to the compound of general formula [9], with 1 or bigger multiple, preferred 1-2 mol ratio is doubly used the salt of halous acid.

[0094]

Generally speaking, preferably carry out this reaction in the presence of one or more halogen scavenging agents, described halogen scavenging agent is selected from dimethyl sulfoxide (DMSO), thionamic acid, hydrogen peroxide and 2-methyl-2-butene etc.Preferred halogen scavenging agent comprises dimethyl sulfoxide (DMSO).

With respect to the amount of the compound of general formula [9], the amount of halogen scavenging agent to be used is 0.4 times (v/w) of this amount, and preferred 0.4-4 is (v/w) or bigger multiple doubly.

[0095]

In addition, this reaction preferably under acidic conditions by adding acid or buffer reagent carries out, more preferably under pH value 4.0-7.0, carry out.For this acid, example comprises for example for example hydrochloric acid and sulfuric acid of acetate and formic acid and mineral acid of organic acid.Mineral acid for example hydrochloric acid and sulfuric acid is preferred, and hydrochloric acid is preferred.For buffer reagent, example comprises SODIUM PHOSPHATE, MONOBASIC or potassium primary phosphate.

In addition, when under not by isolating situation, the compound of general formula [9] being used for this reaction, can in this reaction, adding alkali and under pH value 4.0-7.0, carry out.For this alkali, example comprises organic bases for example triethylamine and N, N-diisopropylethylamine; The oxyhydroxide of basic metal or alkaline-earth metal is sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and hydrated barta for example; And ammoniacal liquor.Preferred alkali comprises sodium hydroxide, potassium hydroxide and ammoniacal liquor, and ammoniacal liquor is preferred.

[0096]

Temperature of reaction is not particularly limited, but is-20 to 120 ℃, preferred 0 to 50 ℃.

[0097]

[preparation method 5]

In this general formula, R ^3aAnd R ^4aAs mentioned above.

As for the compound of general formula [14], for example, 1,3-dimethoxy benzene and 1, the 3-diethoxybenzene is commercially available.

[0098]

(5-1)

Be prepared as follows the compound of general formula [1a]: in the presence of acid, make the compound reaction of the compound or its salt and the general formula [14] of general formula [10a].

[0099]

The example that is ready to use in the acid of this reaction comprises for example mixture of methanesulfonic, trifluoromethayl sulfonic acid and methanesulfonic and Vanadium Pentoxide in FLAKES of strong organic acid.The mixture of methanesulfonic and Vanadium Pentoxide in FLAKES is preferred.Adopt the mixture of methanesulfonic and Vanadium Pentoxide in FLAKES, the amount of the methanesulfonic of use is the 1-50 doubly (v/w) of amount of the compound or its salt of general formula [10a], and preferred 2-20 is (v/w) doubly.With respect to the compound or its salt of general formula [10a], with 0.5-10 mol ratio doubly, preferred 0.5-4 mol ratio is doubly used Vanadium Pentoxide in FLAKES.

[0100]

Can add the solvent that does not influence reaction.Solvent is not particularly limited, as long as it does not influence reaction.Yet example comprises halohydrocarbon for example methylene dichloride, chloroform, 1,2-ethylene dichloride, chlorobenzene and dichlorobenzene; Aliphatic hydrocrbon is hexane and hexanaphthene for example; Nitro-compound is Nitromethane 99Min. and oil of mirbane for example; And dithiocarbonic anhydride.Adopt these solvents, can use one type or can use two or more in combination.Preferred solvent comprises halohydrocarbon, and chlorobenzene is preferred.The usage quantity of solvent (but being not particularly limited) is 0.05-10 times (v/w) of the amount of the compound or its salt of general formula [10a] preferably, more preferably 0.1-3 times (v/w).

[0101]

With respect to the compound or its salt of general formula [10a], with 1-10 doubly, preferred 1-2 mol ratio is doubly used the compound of general formula [14].

[0102]

Temperature of reaction is not particularly limited, but is 30-150 ℃, preferred 50-100 ℃.

[0103]

The compound of the general formula of Huo Deing [1a] can not have to be used for ensuing reaction under the isolating situation like this.

[0104]

(5-2)

Carrying out Fu's row Dare-Kerafyrm thatch reaction (Friedel-Crafts reaction) between the reactive derivatives of the compound or its salt of the compound of general formula [1a] by making general formula [10a] and the compound of general formula [14] prepares.

[0105]

The example (being not particularly limited as long as it does not influence reaction) that is used for the solvent of this reaction comprises halohydrocarbon for example methylene dichloride, chloroform, 1,2-ethylene dichloride, chlorobenzene and dichlorobenzene; Aliphatic hydrocrbon is hexane and hexanaphthene for example; Nitro-compound is Nitromethane 99Min. and oil of mirbane for example; And dithiocarbonic anhydride.Adopt these solvents, can use one type or can use two or more in combination.Preferred solvent comprises nitro-compound and halohydrocarbon, and Nitromethane 99Min. and methylene dichloride are preferred.The usage quantity of solvent (but being not particularly limited) is 1-50 times (v/w) of the amount of the compound or its salt of general formula [10a] preferably, more preferably 1-15 times (v/w).

[0106]

As for the reactive derivatives of the compound or its salt of the general formula that is used for this reaction [10a], example comprises carboxylic acid halides or acid anhydrides.

The carboxylic acid halides or the acid anhydrides of the compound or its salt of general formula [10a] are prepared as follows: make the compound or its salt and for example thionyl chloride, oxalyl chloride, phosphorus pentachloride, diacetyl oxide and the reaction of carbonochloridic acid ethyl ester of activator of general formula [10a].With respect to the compound or its salt of general formula [10a], with 1-10 doubly, preferred 1-3 mol ratio is doubly used activator.In addition, in the reaction of the carboxylic acid halides of the compound or its salt that obtains general formula [10a], with respect to the compound or its salt of general formula [10a], with 0.001-1 doubly, preferred 0.001-0.5 mol ratio is doubly added N, and dinethylformamide is as catalyzer.

[0107]

For the acid that is used for this reaction, example comprises tin tetrachloride, aluminum chloride, trifluoroboranes and zinc chloride.With respect to the compound or its salt of general formula [10a], with 1-10 doubly, preferred 1-5 mol ratio is doubly used acid.

[0108]

[0109]

Temperature of reaction is not particularly limited, still-78 to 100 ℃, and preferred-50 to 70 ℃.

Reaction times is not particularly limited, but is 10 minutes-50 hours, preferred 10 minutes-24 hours.

[0110]

[preparation method 6]

In this general formula, R ^2a, R ^3b, R ⁵With X as mentioned above.

The compound or its salt by making general formula [2] and the compound of general formula [3] react the compound or its salt for preparing general formula [20].

[0111]

Carry out the compound or its salt that alkylated reaction prepares general formula [20] between the compound or its salt by making general formula [2] and the compound of general formula [3].

[0112]

The example (being not particularly limited as long as it does not influence reaction) that is used for the solvent of this reaction comprises aromatic hydrocarbon for example benzene, toluene and dimethylbenzene; Ether is diox, tetrahydrofuran (THF), glycol dimethyl ether and diethylene glycol dimethyl ether for example; Acid amides is 1-Methyl-2-Pyrrolidone, N for example, dinethylformamide and N,N-dimethylacetamide; Ketone is acetone and 2-butanone for example; Halohydrocarbon is methylene dichloride, chloroform, 1 for example, 2-ethylene dichloride, chlorobenzene and dichlorobenzene.These solvents can use separately or can use two or more solvents in combination.Preferred solvent comprises ketone, and acetone and 2-butanone are preferred.The usage quantity of solvent (but being not particularly limited) is 1-50 times (v/w) of the amount of the compound or its salt of general formula [2] preferably, more preferably 1-15 times (v/w).

[0113]

The example that is used for the alkali of this reaction comprises organic bases for example dimethyl aminopyridine, triethylamine and pyridine; Alkalimetal hydride is sodium hydride for example; With alkaline carbonate for example salt of wormwood and yellow soda ash.Preferred alkali comprises alkaline carbonate for example salt of wormwood and yellow soda ash etc., and salt of wormwood is preferred.With respect to the compound or its salt of general formula [2], with 0.5-20 doubly, preferred 0.5-5 mol ratio is doubly used alkali.

[0114]

With respect to the compound or its salt of general formula [2], with 1-20 doubly, preferred 1-5 mol ratio doubly is used for this reaction with the compound of general formula [3].

[0115]

[0116]

Next, use description to the preparation method of the compound or its salt of the general formula [5] of the present invention preparation and general formula [12].These compounds still for example, can prepare them by following preparation method by known method combination is prepared.

[0117]

[preparation method A]

For example, prepare the compound or its salt of general formula [15] by the method for describing in open WO03/042150 brochure in the world or the Application No. 2005/0143434.

[0118]

Be prepared as follows the compound or its salt of general formula [12]: the compound or its salt of general formula [15] and thionyl halide are reacted then, in the presence of alkali, carry out intramolecular cyclization reaction.

[0119]

For the thionyl halide that is used for this reaction, example comprises thionyl chloride and thionyl bromide, and thionyl chloride is preferred.With respect to the compound or its salt of general formula [15], with 1 or bigger multiple, preferred 1-10 mol ratio is doubly used this thionyl halide.

[0120]

The example that is used for the alkali of this reaction comprises organic bases for example triethylamine, N, N-diisopropylethylamine, Tributylamine, pyridine, dimethyl aminopyridine, N-methylmorpholine and 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU); With mineral alkali for example sodium hydroxide, potassium hydroxide, yellow soda ash and salt of wormwood.Preferred alkali is organic bases, and Tributylamine is preferred.With respect to the compound or its salt of general formula [15], with 1 or bigger multiple, preferred 1-5 mol ratio is doubly used alkali.

[0121]

The example (being not particularly limited as long as it does not influence reaction) that is used for the solvent of this reaction comprises aromatic hydrocarbon for example benzene,toluene,xylene and sym-trimethylbenzene; Ether is diox, tetrahydrofuran (THF), t-butyl methyl ether, cyclopentyl-methyl ether, phenylmethylether, glycol dimethyl ether and diethylene glycol dimethyl ether for example; Halohydrocarbon is chloroform, methylene dichloride, chlorobenzene and dichlorobenzene for example; And thiotetrole.They can use in combination.Preferred solvent comprises ether, and t-butyl methyl ether is preferred.The usage quantity of solvent (but being not particularly limited) is 1-50 times (v/w) of the amount of the compound or its salt of general formula [15] preferably, more preferably 1-15 times (v/w).

[0122]

Temperature of reaction is not particularly limited, still-30 to 30 ℃, and preferred-20 to 20 ℃.

[0123]

The compound or its salt of the general formula of Huo Deing [12] can not have to be used for ensuing reaction under the isolating situation like this, but preferably with its segregation, for example, for example extracts and crystallization by ordinary method.

[0124]

[preparation method B]

In this general formula, R ⁶As mentioned above.

As for the compound or its salt of general formula [16], for example 2-hydroxy-4-methyl benzoic acid methyl ester is known.

[0125]

(B-1)

The compound of general formula [17] can be for example, by Protective Groups In OrganicSynthesis, T.W.Greene, John Wiley ﹠amp; Sons, Inc.1999, the third edition, p.149-179, the method preparation of describing among the 276-280.More particularly, for example, compound or its salt by making general formula [16] in the presence of alkali and benzoyl halogen react and prepare it.

[0126]

The example that is used for the alkali of this reaction comprises organic bases for example dimethyl aminopyridine, triethylamine, pyridine and N-methylmorpholine; With alkaline carbonate for example salt of wormwood and yellow soda ash.Preferred alkali is organic bases, and triethylamine is preferred.With respect to the compound or its salt of general formula [16], with 1-20 doubly, preferred 1-5 mol ratio is doubly used alkali.

[0127]

As for the benzoyl halogen that is used for this reaction, example comprises benzoyl chloride and benzoyl bromide, and benzoyl chloride is preferred.With respect to the compound or its salt of general formula [16], with 1-10 doubly, preferred 1-3 mol ratio is doubly used benzoyl halogen.

[0128]

The example (being not particularly limited as long as it does not influence reaction) that is used for the solvent of this reaction comprises for example acetonitrile of nitrile; Aromatic hydrocarbon is benzene,toluene,xylene and sym-trimethylbenzene for example; Ether is diox, tetrahydrofuran (THF), phenylmethylether, glycol dimethyl ether and diethylene glycol dimethyl ether for example; Aliphatic hydrocrbon is hexane and hexanaphthene for example; Halohydrocarbon is chloroform, methylene dichloride, chlorobenzene and dichlorobenzene for example; Ester is methyl acetate, ethyl acetate and butylacetate for example; Acid amides is N for example, dinethylformamide and N,N-dimethylacetamide; With sulfoxide dimethyl sulfoxide (DMSO) for example.They can use in combination.Preferred solvent comprises aromatic hydrocarbon, and toluene is preferred.The usage quantity of solvent (but being not particularly limited) is 1-50 times (v/w) of the amount of the compound or its salt of general formula [16] preferably, more preferably 1-15 times (v/w).

[0129]

[0130]

(B-2)

Prepare the compound of general formula [18] by compound bromination with general formula [17].Carry out this reaction according to preparation method (2-2).

[0131]

(B-3)

For example, make the compound of general formula [18] and acetate react the compound for preparing general formula [19].

[0132]

As for the acetate that is used for this reaction, example comprises potassium acetate and sodium acetate, and potassium acetate is preferred.With respect to the compound of general formula [18], with 1-10 doubly, preferred 1-3 mol ratio is doubly used acetate.

In addition, can prepare acetate on the spot.

[0133]

The example (being not particularly limited as long as it does not influence reaction) that is used for the solvent of this reaction comprises for example acetonitrile of nitrile; Aromatic hydrocarbon is benzene,toluene,xylene and sym-trimethylbenzene for example; Ether is diox, tetrahydrofuran (THF), phenylmethylether, glycol dimethyl ether and diethylene glycol dimethyl ether for example; Aliphatic hydrocrbon is hexane and hexanaphthene for example; Halohydrocarbon is chloroform, methylene dichloride, chlorobenzene and dichlorobenzene for example; Ester is methyl acetate, ethyl acetate and butylacetate for example; Acid amides is N for example, dinethylformamide and N,N-dimethylacetamide; With sulfoxide dimethyl sulfoxide (DMSO) for example.They can use in combination.Preferred solvent comprises the mixed solvent of ester and acid amides, and ethyl acetate and N, and the mixed solvent of dinethylformamide is preferred.The usage quantity of solvent (but being not particularly limited) is 1-50 times (v/w) of the amount of the compound of general formula [18] preferably, more preferably 1-15 times (v/w).

[0134]

[0135]

(B-4)

Prepare the compound or its salt of general formula [5] by the compound hydrolysis that makes general formula [19].More particularly, for example, compound by making general formula [19] and metal alkoxide react and prepare it.

[0136]

For the metal alkoxide that is used for this reaction, example comprises sodium methylate and sodium ethylate, and sodium methylate is preferred.When the metal alkoxide that uses was sodium methylate, it preferably used as methanol solution.With respect to the compound of general formula [19], with 2-10 doubly, preferred 2-3 mol ratio is doubly used metal alkoxide.

[0137]

The example (being not particularly limited as long as it does not influence reaction) that is used for the solvent of this reaction comprises for example acetonitrile of nitrile; Aromatic hydrocarbon is benzene,toluene,xylene and sym-trimethylbenzene for example; Ether is diox, tetrahydrofuran (THF), phenylmethylether, glycol dimethyl ether and diethylene glycol dimethyl ether for example; Aliphatic hydrocrbon is hexane and hexanaphthene for example; Halohydrocarbon is chloroform, methylene dichloride, chlorobenzene and dichlorobenzene for example; Alcohol is methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol and butanols for example; Acid amides is N for example, dinethylformamide and N,N-dimethylacetamide; With sulfoxide dimethyl sulfoxide (DMSO) for example; And water.They can use in combination.Preferred solvent comprises the mixed solvent of aromatic hydrocarbon and alcohol, and the mixed solvent of toluene and methyl alcohol is preferred.The usage quantity of solvent (but being not particularly limited) is 1-50 times (v/w) of the amount of the compound of general formula [19] preferably, more preferably 1-15 times (v/w).

[0138]

Temperature of reaction is not particularly limited, but is 0-150 ℃, preferred 0-100 ℃.

[0139]

Can will emanate by the compound of above-mentioned preparation method's acquisition and pass through for example extraction of ordinary method, crystallization, distillation and column chromatography purification.

In addition, employing is used for above-mentioned preparation method's compound, when having isomer (for example, optically active isomer, geometrical isomer and tautomer), can use all these isomer, and can use metal-salt in addition, hydrate, solvate and all crystal formations.

[0140]

Next, will quote embodiment and prepare embodiment and describe the present invention, but the invention is not restricted to them.

For silica gel,, use B.W.Silica gel BW-127ZH (Fuji Silysia Chemical Ltd.) if do not stipulate in addition.

Mixture ratio in the eluent is a volume ratio.

For each embodiment and preparation embodiment, every kind of abbreviation is defined as follows.

Me: methyl; THP: THP trtrahydropyranyl; Tr: trityl; DMSO-d ₆: the deuterate dimethyl sulfoxide (DMSO)

[0141]

Embodiment 1-1

17L water is dropwise added in 79L 62.5% sulfuric acid, and after adding 13.0kg 6-methyl-2H-chromen-2-one and 13L chlorobenzene, 20.8kg Manganse Dioxide is divided into 8 parts and interpolation under 70-90 ℃.Under 70-90 ℃, dropwise add other 10L 62.5% sulfuric acid, and stirred 1 hour down at 80-90 ℃.Behind this reaction mixture of cooling, add 75L water, and add 22L 25% ammoniacal liquor.Next, add 26L ethyl acetate and 52L 2-butanone, and remove water layer.In the reaction mixture of gained, add 111L 2-butanone and 13L water, and separate organic layer, and add 7.8L dimethyl sulfoxide (DMSO) and 3.9L hydrochloric acid.Under 15-40 ℃, dropwise add 26L 25% sodium chlorite aqueous solution, and under uniform temp, stirred 30 minutes.After 74-80 ℃ of following this reaction mixture of stirring 15 minutes, separate organic layer.65L water is added in this organic layer, and under 30-40 ℃, dropwise add 13L 25% ammoniacal liquor, and separate water layer.The 52L dimethyl sulfoxide (DMSO) is added in this water layer, and under 30-40 ℃, dropwise add 8L hydrochloric acid, and under 65-75 ℃, dropwise add after the other 8L hydrochloric acid, under uniform temp, stirred 30 minutes.With this reaction mixture cooling, and cross filter solid, obtain 9.03kg light yellowish brown solid 2-oxo-2H-chromene-6-carboxylic acid.

¹H-NMR(DMSO-d ₆)δ：6.59(1H，d，J＝9.6Hz)，7.49(1H，d，J＝8.6Hz)，8.12(1H，dd，J＝8.6，1.9Hz)，8.20(1H，d，J＝9.6Hz)，8.36(1H，d，J＝1.9Hz)，13.22(1H，brs)

[0142]

Embodiment 1-2

260mL water is dropwise added in 1220mL 62.5% sulfuric acid, and after adding 200g6-methyl-2H-chromen-2-one and 200mL chlorobenzene, 320g Manganse Dioxide is divided into 8 parts and interpolation under 70-90 ℃.Under 70-90 ℃, dropwise add other 160mL 62.5% sulfuric acid, and stirred 30 minutes down at 80-90 ℃.Behind this reaction mixture of cooling, add 1160mL water, and dropwise add 340mL 25% ammoniacal liquor.Next, add 400mL ethyl acetate and 800mL 2-butanone, and remove water layer.In the reaction mixture of gained, add 1700mL2-butanone and 200mL water, and separate organic layer, and add 120mL dimethyl sulfoxide (DMSO) and 800mL water.Dropwise add 80mL 25% ammoniacal liquor.Under 25-40 ℃, dropwise add 360mL 25% sodium chlorite aqueous solution, and under uniform temp, stirred 1 hour.Next, under 25-35 ℃, dropwise 108mL 25% ammoniacal liquor is added in the reaction mixture, and separate water layer.600mL methyl alcohol is added in the water layer, and dropwise add 40mL hydrochloric acid.Next, add the 15.7g S-WAT by two parts down at 25-30 ℃, and stirred 30 minutes.Under 40-50 ℃, drip after the other 200mL hydrochloric acid,, and filter and collect solid, obtain 144g light yellowish brown solid 2-oxo-2H-chromene-6-carboxylic acid this reaction mixture cooling.

At DMSO-d ₆In ¹H-NMR is identical with the value of embodiment 1-1.

[0143]

Embodiment 2

7mL water is dropwise added in 31mL 62.5% sulfuric acid, and after adding 5.00g 7-methyl-2H-chromen-2-one and 5mL chlorobenzene, 8.00g Manganse Dioxide is divided into 8 parts and interpolation under 70-90 ℃.Under 70-90 ℃, dropwise add other 4mL 62.5% sulfuric acid, and stirred 1 hour down at 80-90 ℃.Behind this reaction mixture of cooling, add 29mL water, and dropwise add 9mL 25% ammoniacal liquor.Next, add 10mL ethyl acetate and 20mL 2-butanone, and remove water layer.In the reaction mixture of gained, add 43mL 2-butanone and 5mL water, and separate organic layer, and add 3mL dimethyl sulfoxide (DMSO) and 2mL hydrochloric acid.Under 15-40 ℃, dropwise add 10mL 25% sodium chlorite aqueous solution, and under uniform temp, stirred 30 minutes.At 74-80 ℃ of following stirred reaction mixture, and separate organic layer.40mL water and 15mL 2-butanone are added in the organic layer.Under 30-40 ℃, dropwise add 5mL 25% ammoniacal liquor, and separate water layer.The 30mL dimethyl sulfoxide (DMSO) is added in this water layer, and under 30-40 ℃, dropwise add 3mL hydrochloric acid.After the 5mL hydrochloric acid that under 65-75 ℃, drips other, under uniform temp, stirred 30 minutes.With this reaction mixture cooling, and filter and collect this solid, obtain 1.67g light yellowish brown solid 2-oxo-2H-chromene-7-carboxylic acid.

¹H-NMR(DMSO-d ₆)δ：6.63(1H，d，J＝9.5Hz)，7.80-7.90(3H，m)，8.14(1H，d，J＝9.5Hz)

[0144]

Embodiment 3

The 6.85kg Vanadium Pentoxide in FLAKES is added in the 46L methanesulfonic, and after 70-80 ℃ is stirred 1 hour down, add 17.0kg 2-oxo-2H-chromene-6-carboxylic acid and 1.7L chlorobenzene, and under 70-80 ℃, dropwise add 13.0kg 1, the 3-dimethoxy benzene, and under uniform temp, stirred 3 hours.Behind this reaction mixture of cooling, add the 94L 2-butanone, and dropwise add 34L water 55L 25% ammoniacal liquor then.Next, this reaction mixture is heated to 65-75 ℃, and separates organic layer.26L 2-butanone and 34L water are added in this organic layer, and dropwise add 2.6L 25% ammoniacal liquor.This reaction mixture is heated to 65-75 ℃, and separates organic layer.Heat this organic layer, and under atmospheric pressure distill out the 77L solvent.The 17L 4-methyl-2 pentanone is added in this reaction mixture, and under 40-65 ℃, dropwise add 60L methyl alcohol 120L water then.After 10-25 ℃ is stirred down this reaction mixture 30 minutes, filter and collect solid, obtain 19.0kg light yellowish brown solid 6-(2,4-dimethoxy benzoyl)-2H-chromen-2-one.

¹H-NMR(CDCl ₃)δ：3.69(3H，s)，3.89(3H，s)，6.47(1H，d，J＝9.8Hz)，6.52(1H，d，J＝2.2Hz)，6.59(1H，dd，J＝8.5，2.2Hz)，7.35(1H，d，J＝8.5Hz)，7.45(1H，d，J＝8.5Hz)，7.74(1H，d，J＝9.8Hz)，7.91(1H，dd，J＝8.5，2.0Hz)，7.95(1H，d，J＝2.0Hz)

[0145]

Embodiment 4

478g 6-(2,4-dimethoxy benzoyl)-2H-chromen-2-one is added in the mixture solution of 480mL pyridine, 240mL1-N-methyl-2-2-pyrrolidone N-and 480mL toluene.Next, dropwise add 454mL hydrochloric acid.Heat this reaction mixture, and when carrying out azeotropic dehydration, stirred this reaction mixture 2 hours down at 200-210 ℃.After reaction mixture is to 85-110 ℃, add 480 mL N, dinethylformamide dropwise adds 2.4L water under 85-95 ℃.After 10-25 ℃ of following this reaction mixture of stirring 30 minutes, filter and collect solid.Obtained 421g light color yellowish brown solid 6-(2,4-dihydroxy-benzene formyl radical)-2H-chromen-2-one.

¹H-NMR(DMSO-d ₆)δ：6.38-6.42(2H，m)，6.60(1H，d，J＝9.5Hz)，7.41(1H，d，J＝8.8Hz)，7.53(1H，d，J＝8.5Hz)，7.86-7.88(1H，m)，8.06(1H，d，J＝2.0Hz)，8.18(1H，d，J＝9.5Hz)，10.69(1H，s)，11.82(1H，s)

[0146]

Embodiment 5-1

Add 9.25kg salt of wormwood, 21.0kg 6-(2,4-dihydroxy-benzene formyl radical)-2H-chromen-2-one and 16.6kg cyclopentyl bromide to 63L N, in the dinethylformamide, and under 90-100 ℃, stirred 2 hours.Behind this reaction mixture of cooling, add 63L toluene, 21L2-butanone and 84L water.Next, add 1.26kg salt of wormwood, and separate organic layer.After adding 11L methyl alcohol and 21L toluene in this organic layer, under atmospheric pressure distill out the 63L solvent.Under 55-65 ℃, dropwise 33.0kg 28% sodium methylate/methanol solution is added in the reaction mixture of gained.Under uniform temp, stirred 1 hour.With this reaction mixture cooling, and after order is added 16L hydrochloric acid and 32L toluene, under 60-70 ℃, dropwise add 63L water.Separate organic layer, and after adding 21L toluene, under atmospheric pressure distill out the 42L solvent.After 75-85 ℃ of following this reaction mixture of stirring 30 minutes, under 10-25 ℃, dropwise add 42L hexanaphthene and 42L water.After under uniform temp, stirring 30 minutes, filter and collect solid, obtain 20.3kg light color yellowish brown solid (E)-3-{5-[4-cyclopentyloxy)-the 2-hydroxy benzoyl]-2-coumarinic acid methyl ester.

¹H-NMR(DMSO-d ₆)δ：1.50-1.80(6H，m)，1.90-2.00(2H，m)，3.72(3H，s)，4.85-4.95(1H，m)，6.48-6.50(2H，m)，6.68(1H，d，J＝16.1Hz)，7.05(1H，d，J＝8.5Hz)，7.44-7.47(1H，m)，7.59-7.61(1H，m)，7.86(1H，d，J＝16.1Hz)，7.92(1H，d，J＝2.2Hz)，11.20(1H，brs)，11.94(1H，s)

Embodiment 5-2

Add 8.81g salt of wormwood, 20.0g 6-(2,4-dihydroxy-benzene formyl radical)-2H-chromen-2-one and 15.8g cyclopentyl bromide to 60mL N, in the dinethylformamide, and under 90-100 ℃, stirred 2.5 hours.Behind this reaction mixture of cooling, add 60mL toluene and 80mL water.Next, add 2.40g salt of wormwood, and separate organic layer.After adding to 10mL methyl alcohol and 30mL toluene in this organic layer, under atmospheric pressure distill out the 60mL solvent.Under 55-65 ℃, dropwise 31.4g 28% sodium methylate/methanol solution is added in the reaction mixture of gained.After under identical temperature, stirring 1 hour, under atmospheric pressure distill out the 10mL solvent.With this reaction mixture cooling, and under 10-25 ℃, dropwise add the 100mL 2-butanone.After stirring 30 minutes under the identical temperature, filter and collect solid.Next, this solid is added in the mixture solution of 80mL 2-propyl alcohol, 5.44g formic acid, 7.23g acetate and 16mL water.In addition, add 1.50g, and stirred this suspension 3 hours down at 40-45 ℃ at the suspension of 10% palladium in 10mL water on the carbon.After this reaction mixture of cooling is to 25-35 ℃, adds 1.0g diatomite, and after under uniform temp, stirring 5 minutes, leach insoluble substance.Mixture solution with 20mL 2-propyl alcohol and 14mL water washs this filter cake.This filtrate and washings are mixed, and are adding 30mL water and 20mg 3-{5-[4-(cyclopentyloxy)-2-hydroxy benzoyl]-the 2-hydroxy phenyl } after the propionic acid methyl ester, stirred 1 hour down at 10-20 ℃.Under 10-25 ℃, dropwise 100mL water is added in the reaction mixture; and after 10-20 ℃ is stirred 30 minutes down; cross filter solid, obtain 15.7g light color yellowish brown solid 3-{5-[4-(cyclopentyloxy)-2-hydroxy benzoyl]-the 2-hydroxy phenyl } the propionic acid methyl ester.

At DMS0-d ₆In ¹H-NMR is consistent with the value of embodiment 8.

[0147]

Embodiment 6

Add 13.3mL cyclopentyl bromide and 17.1g salt of wormwood the 75mL N of 25.0g 6-(2,4-dihydroxy-benzene formyl radical)-2H-chromen-2-one to, in the dinethylformamide solution.Stirred 4 hours down at 78-82 ℃.Behind this reaction mixture of cooling, add 125mL water and 50mL toluene, and it is heated to 40-50 ℃, and separate organic layer.After adding to 125mL 2-propyl alcohol in this organic layer, heat and make the dissolving of this solid.Stir this reaction mixture 30 minutes down and after 10 ℃ are stirred 1 hour down, filter and collect this solid at 40-45 ℃, obtain 22.8g light color yellowish brown solid 6-[4-(cyclopentyloxy)-2-hydroxy benzoyl]-the 2H-chromen-2-one.

¹H-NMR(DMSO-d ₆)δ：1.55-1.80(6H，m)，1.90-2.05(2H，m)，4.85-5.00(1H，m)，6.50-6.53(2H，m)，6.59(1H，d，J＝9.5Hz)，7.45(1H，d，J＝8.8Hz)，7.54(1H，d，J＝8.5Hz)，7.87-7.90(1H，m)，8.08(1H，d，J＝2.2)，8.18(1H，d，J＝9.5)，11.67(1H，brs)

[0148]

Embodiment 7

Add 33.0g 28% sodium methylate/methanol solution to 30.0g 6-[4-(cyclopentyloxy)-2-hydroxy benzoyl]-suspension of 2H-chromen-2-one in 60mL toluene and 60mL methyl alcohol in.Under refluxing, its was heated 3 hours.After this reaction mixture is ice-cooled, add 90mL water, and it is adjusted to pH value 1.2 with hydrochloric acid.Next, add the 90mL ethyl acetate, and separate organic layer.After adding to the 30mL ethyl acetate in this organic layer, under atmospheric pressure distill out the 140mL solvent.Under 70-75 ℃, dropwise add the 90mL hexanaphthene in this reaction mixture.Stirring 30 minutes under 65-70 ℃ and after 10 ℃ are stirred 1 hour down, filtering and collect this solid, obtain the light yellowish brown solid (E) of 24.2g-3-{5-[4-(cyclopentyloxy)-2-hydroxy benzoyl]-2-coumarinic acid methyl ester.

At DMSO-d ₆In ¹H-NMR is identical with the value of embodiment 5-1.

[0149]

Embodiment 8

With 20.5kg (E)-3-{5-[4-(cyclopentyloxy)-2-hydroxy benzoyl]-the 2-hydroxy phenyl } methyl acrylate, 5.47kg acetate and 5.47kg sodium formiate add in the 62L 2-propyl alcohol.Add 3.08kg at the suspension of 5% palladium in 21L water on the carbon, and stirred this suspension 7 hours down at 40-45 ℃.After this reaction mixture of cooling is to 25-35 ℃, add 2kg diatomite.After under uniform temp, stirring 5 minutes, leach insoluble substance, and wash this filter cake with the mixture solution of 41L 2-propyl alcohol and 20L water.Filtrate and washings are mixed, and separate organic layer.After interpolation 31L water is in this organic layer, stirred 1 hour down at 10-20 ℃.Under 10-25 ℃, dropwise 82L water is added in this reaction mixture; and after 10-20 ℃ is stirred 1 hour down; filter and collect solid, obtain 18.0kg light color yellowish brown solid 3-{5-[4-(cyclopentyloxy)-2-hydroxy benzoyl]-the 2-hydroxy phenyl } the propionic acid methyl ester.

¹H-NMR(DMSO-d ₆)δ：1.50-1.80(6H，m)，1.85-2.00(2H，m)，2.61(2H，t，J＝7.6Hz)，2.83(2H，t，J＝7.6Hz)，3.58(3H，s)，4.85-4.95(1H，m)，6.45-6.49(2H，m)，6.92(1H，d，J＝8.3Hz)，7.42-7.47(3H，m)，10.40(1H，brs)，12.07(1H，s)

[0150]

Embodiment 9

With 20.0g 6-methyl isophthalic acid, 2-benzoisoxazole-3-alcohol, 9.93g pyridine and 35.0g trityl chloride add in the 100mL methylene dichloride, and stir 1 hour down at 35-45 ℃.40mL water and 24mL 20% aqueous sodium hydroxide solution are added in this reaction mixture, and separate organic layer.With 20mL dichloromethane extraction water layer, and, under atmospheric pressure distill out the 70mL solvent, and add 100mL 2-propyl alcohol, and under atmospheric pressure distill out the 40mL solvent the organic layer merging.40mL water is added in this reaction mixture, and after 10-25 ℃ is stirred 30 minutes down, filter and collect solid, obtain 46.0g light color yellow solid 6-methyl-2-trityl-1,2-benzoisoxazole-3 (2H)-ketone.

¹H-NMR(DMSO-d ₆)δ：2.36(3H，s)，7.03(1H，d，J＝8.0Hz)，7.18-7.33(10H，m)，7.43-7.47(7H，m)

[0151]

Embodiment 10

With 24.0kg 6-methyl-2-trityl-1,2-benzoisoxazole-3 (2H)-ketone and 18.6kg N-bromosuccinimide add in the 48L chlorobenzene.Under 70-80 ℃, dropwise added two (2, the 4-methyl pentane nitrile) solution in the 4.8L methylene dichloride of 0.30kg 2,2 '-azo 5 times every 1 hour.After finishing dropping, restir is 1 hour under same temperature.96L methylene dichloride, 2.40kg diatomite, 24L 20% aqueous sodium hydroxide solution, 0.77kg S-WAT and 48L water are added in this reaction mixture.Leach insoluble substance, and with this filter cake of 72L washed with dichloromethane.Filtrate and washings are merged, and separate organic layer.24L methylene dichloride, 12.7kg salt of wormwood and 6.07kg dimethyl phosphonate are added in this organic layer, and stirred 4 hours down at 40-50 ℃.48L water and 14L 20% aqueous sodium hydroxide solution are added in this reaction mixture, and separate organic layer.With this water layer of 24L dichloromethane extraction, merge organic layer, add the 24L methylene dichloride, and under atmospheric pressure distill out the 210L solvent.24L acetone is added in this reaction mixture, and under atmospheric pressure distill out the 40L solvent.Dropwise add 96L 2-propyl alcohol and 24L water, and filter and collect solid, obtain 25.2kg white solid 6-(brooethyl)-2-trityl-1,2-benzoisoxazole-3 (2H)-ketone.

¹H-NMR(DMSO-d ₆)δ：4.72(2H，s)，7.22-7.49(17H，m)，7.58(1H，d，J＝8.0Hz)

[0152]

Embodiment 11

350g 2-hydroxyl-4-(methylol) benzoic acid methyl ester and 160g hydroxylamine hydrochloride are added in the 700mL methyl alcohol.Under reflux, dropwise add 1.11kg 28% sodium methylate/methanol solution, and stirred 3 hours.To wherein adding 2.1L water and under atmospheric pressure distilling out the 850mL solvent.Then, add 196mL hydrochloric acid down at 40-50 ℃.Under uniform temp, stir product 30 minutes, and dropwise add 116mL hydrochloric acid.After crossing filter solid, obtain to be the 291g N of ivory buff solid form, 2-dihydroxyl-4-(methylol) benzamide.

¹H-NMR(DMSO-d ₆)δ：4.46(2H，d，J＝5.8Hz)，5.26(1H，t，J＝5.8Hz)，6.78(1H，d，J＝8.2Hz)，6.85(1H，s)，7.62(1H，d，J＝8.2Hz)，9.28(1H，s)，11.39(1H，s)，12.25(1H，s)

[0153]

Embodiment 12

With 10.0g N, 2-dihydroxyl-4-(methylol) benzamide is suspended in the 50mL methylene dichloride.To wherein adding 0.21mL N, dinethylformamide.With its cooling and in the ice-cooled 8.36mL thionyl chloride of dropwise adding down.Under reflux, stir after 2 hours, under atmospheric pressure distill out the 13mL solvent.In this reaction mixture, add the 13mL methylene dichloride, under 20-30 ℃, dropwise add the 4.64mL pyridine, and under uniform temp, stirred product 1 hour.After adding 20mL water and 50mL acetone, under atmospheric pressure distill out the 50mL solvent, cross filter solid, and obtain to be the 6.45g 6-(chloro methyl)-1 of ivory buff solid form, 2-benzoisoxazole-3-alcohol.

¹H-NMR(DMSO-d ₆)δ：4.91(2H，s)，7.39(1H，dd，J＝8.1，1.1Hz)，7.65(1H，s)，7.76(1H，d，J＝8.1Hz)，12.41(1H，s)

[0154]

Embodiment 13

(1) with 1.00g 6-(chloro methyl)-1,2-benzoisoxazole-3-alcohol is suspended in the 20mL methylene dichloride, and to wherein adding 27.0mg tosic acid pyridine and 0.596mL 3,4-dihydro-2H-pyrans.At room temperature stirred 24 hours.Distilling off solvent under reduced pressure, and by silica gel column chromatography (eluent; Hexane: the residue that ethyl acetate=3:1) purifying obtained.As a result, obtain be white in color 6-(chloro the methyl)-2-(tetrahydrochysene-2H-pyrans-2-yl)-1 of solid form of 1.10g, 2-benzoisoxazole-3 (2H)-ketone.It plays the seed crystal effect.

(2) in the 75mL methylene dichloride, suspension 5.00g 6-(chloro methyl)-1,2-benzoisoxazole-3-alcohol, and to wherein adding 0.137g tosic acid pyridine and 2.98mL3,4-dihydro-2H-pyrans.At room temperature stirred 8 hours.In this reaction mixture, add 30mL water and separate organic layer.With 10mL dichloromethane extraction water layer, and wash this water layer and organic layer and use anhydrous sodium sulfate drying with moisture saturated nacl aqueous solution.Distilling off solvent under reduced pressure, and the 20mL diisopropyl ether added in the residue that is obtained.After adding seed crystal and at room temperature stirring 30 minutes, cross filter solid and obtain 6-(chloro methyl)-2-(tetrahydrochysene-2H-pyrans-2-yl)-1 that 6.65g is the ivory buff solid form, 2-benzoisoxazole-3 (2H)-ketone.

¹H-NMR(DMSO-d ₆)δ：1.45-1.55(2H，m)，1.62-1.77(1H，m)，1.85-2.00(2H，m)，2.00-2.15(1H，m)，3.57-3.64(1H，m)，3.89-3.93(1H，m)，4.89(2H，s)，5.47-5.50(1H，m)，7.42(1H，d，J＝8.0Hz)，7.62(1H，s)，7.83(1H，d，J＝8.0Hz)

[0155]

Embodiment 14

Suspension 5.00g 6-(chloro methyl)-1 in the 50mL methylene dichloride, 2-benzoisoxazole-3-alcohol, 7.59g trityl chloride and 2.20mL pyrido at room temperature stirred 5 hours.In this reaction mixture, add 15mL water and 15mL methylene dichloride, and under backflow and heating, stirred product 5 minutes.Behind this reaction mixture of cooling, add 2.50g silica gel.After leaching insoluble substance, wash this filter cake with the 10mL methyl chloride.Filtrate and washings are merged and after adding 8mL methylene dichloride and 15mL water, under atmospheric pressure distill out the 45mL solvent.In this reaction mixture, add 35mL acetone and under atmospheric pressure distill out the 33mL solvent.After adding 20mL water, cross filter solid, obtain to be 11.3g 6-(chloro the methyl)-2-trityl-1 of ivory buff solid form, 2-benzoisoxazole-3 (2H)-ketone.

¹H-NMR(DMSO-d ₆)δ：4.79(2H，s)，7.19-7.50(17H，m)，7.60(1H，d，J＝8.0Hz)

[0156]

Embodiment 15

With 10.5kg N, 2-dihydroxyl-4-(methylol) benzamide and 0.10kg N, dinethylformamide adds in the 105L methylene dichloride.Under reflux,, under uniform temp, stirred product 6 hours then to wherein dropwise adding the 14.3kg thionyl chloride.Then, under atmospheric pressure distill out 11L solvent and add down 24L methylene dichloride and 13.6kg trityl chloride at 20-30 ℃.Stirred 4 hours under uniform temp to wherein dropwise adding the 4.31kg pyrido.In this reaction mixture, add 21L water, and separate organic layer.With 11L dichloromethane extraction water layer.To wherein adding 21L water and 2.10kg diatomite and this organic layer.Then, under 20-30 ℃, dropwise add 12.6L 20% aqueous sodium hydroxide solution.After leaching insoluble substance, with this filter cake of 21L washed with dichloromethane.Merging filtrate and washings also under atmospheric pressure distill out the 57L solvent.In this reaction mixture, add 53L 2-propyl alcohol, and under atmospheric pressure distill out the 53L solvent.In this reaction mixture, add 53L 2-propyl alcohol.Under atmospheric pressure distill out after the 46L solvent, under 15-20, stirred product 30 minutes.Cross filter solid then and obtain to be 17.6kg 6-(chloro the methyl)-2-trityl-1 of ivory buff solid form, 2-benzoisoxazole-3 (2H)-ketone.

DMSO-d ₆In ¹The value of H-NMR and embodiment 14 is coincide.

[0157]

Embodiment 16

With 30.0g 6-(brooethyl)-2-trityl-1,2-benzoisoxazole-3 (2H)-ketone and 13.9mL diethylamine add 90mL N to, in the dinethylformamide.At room temperature stirred 50 minutes.Ethyl acetate, methylene dichloride and water are added in the reaction mixture, and separate organic layer.Water and hydrochloric acid are added in the organic layer, and separate water layer.Water extraction organic layer also adds 180mL acetone and also dropwise adds 13mL 20% aqueous sodium hydroxide solution together with this water layer.Cross filter solid and obtain 6-(diethylamino) methyl-2-trityl-1 that 22.2g is the ivory buff solid form, 2-benzoisoxazole-3 (2H)-ketone.

¹H-NMR(DMSO-d ₆)δ：0.94(6H，t，J＝7.1Hz)，2.42(4H，q，J＝7.1Hz)，3.56(2H，s)，7.18-7.34(11H，m)，7.45-7.51(7H，s)

[0158]

Embodiment 17

With 20.0g 6-(diethylamino) methyl-2-trityl-1,2-benzoisoxazole-3 (2H)-ketone and 5.1mL Vinyl chloroformate add in the 60mL methylene dichloride.At room temperature stirred then 3 hours, and dropwise 140mL 2-propyl alcohol is added in this reaction mixture in during 30 minutes.Down stirred product 2 hours and cross filter solid and obtain to be 16.6g 6-(chloro the methyl)-2-trityl-1 of ivory buff solid form, 2-benzoisoxazole-3 (2H)-ketone at 5-15 ℃.

¹H-NMR(DMSO-d ₆)δ：4.80(2H，s)，7.18-7.50(17H，m)，7.60(1H，d，J＝8.0Hz)

[0159]

Embodiment 18

With 10.0g 6-(chloro methyl)-2-trityl-1,2-benzoisoxazole-3 (2H)-ketone, 35mL monobromethane and 2.42g Sodium Bromide add in the 80mL N-N-methyl-2-2-pyrrolidone N-, and stir 1.5 hours down at 55-60 ℃.Behind this reaction mixture of cooling, dropwise add 20mL 2-propyl alcohol and 50mL water and also cross filter solid and obtain white solid.The white solid, 35mL monobromethane and the 2.42g Sodium Bromide that are obtained are added in the 80mL N-N-methyl-2-2-pyrrolidone N-, and stirred 1 hour down at 55-60 ℃.Behind this reaction mixture of cooling, dropwise add 20mL 2-propyl alcohol and 50mL water and cross filter solid and obtain be white in color 6-(the brooethyl)-2-trityl-1 of solid form of 9.04g, 2-benzoisoxazole-3 (2H)-ketone.

¹H-NMR(DMSO-d ₆)δ：4.72(2H，s)，7.20-7.51(17H，m)，7.58(1H，d，J＝8.0Hz)

[0160]

Embodiment 19

With 50.0g N, 2-dihydroxyl-4-methyl benzamide adds in the 350mL t-butyl methyl ether, and dropwise adds the 38.1g thionyl chloride under-1 to 0 ℃.Under identical temperature, stirred 30 minutes.Then, under-5 to-3 ℃, dropwise add the 164mL Tributylamine, and stirred 1.5 hours down at-5 to 5 ℃.In this reaction mixture, add 200mL 20% aqueous sodium hydroxide solution, separate organic layer, and add 100mL water, 42mL 20% aqueous sodium hydroxide solution and 5.0g diatomite.After leaching insoluble substance, with this filter cake of 100mL water washing.Merging filtrate is with washings and separate water layer.In this water layer, adding 10mL acetone and 50mL acetate under 40-50 ℃.After under uniform temp, stirring 30 minutes, cross filter solid and obtain the 6-methyl isophthalic acid that 40.1g is the light yellow solid form, 2-benzoisoxazole-3-alcohol.

¹H-NMR(CDCL ₃)δ：2.51(3H，s)，7.13(1H，d，J＝8.0Hz)，7.21(1H，s)，7.65(1H，d，J＝8.0Hz)

[0161]

Embodiment 20

With 12.5kg 3-{5-[4-(cyclopentyloxy)-2-hydroxy benzoyl]-the 2-hydroxy phenyl } propionic acid methyl ester, 15.6kg 6-(brooethyl)-2-trityl-1,2-benzoisoxazole-3 (2H)-ketone and 4.49kg salt of wormwood add in the 125L acetone.Under reflux, stirred 5 hours.Behind this reaction mixture of cooling, add 29L water, dropwise add 2.9L hydrochloric acid, and cross filter solid.Obtain 3-{5-[4-(cyclopentyloxy)-2-hydroxy benzoyl that 19.7kg is the ivory buff solid form like this]-2-[(3-oxo-2-trityl-2,3-dihydro-1,2-benzoisoxazole-6-yl) methoxyl group] phenyl } the propionic acid methyl ester.

¹H-NMR(DMSO-d ₆)δ：1.55-1.78(6H，m)，1.90-2.00(2H，m)，2.63(2H，t，J＝7.6Hz)，2.93(2H，t，J＝7.6Hz)，3.49(3H，s)，4.88-4.94(1H，m)，5.33(2H，s)，6.46-6.51(2H，m)，7.13(1H，d，J＝8.3Hz)，7.22-7.25(3H，m)，7.30-7.34(7H，m)，7.42-7.56(10H，m)，7.63(1H，d，J＝8.0Hz)，12.00(1H，s)

[0162]

Preparation embodiment 1

(1) with 300g 3-{5-[4-(cyclopentyloxy)-2-hydroxy benzoyl]-2-[(3-oxo-2-trityl-2; 3-dihydro-1,2-benzoisoxazole-6-yl) methoxyl group] phenyl } the propionic acid methyl ester adds in 1200mL methyl iso-butyl ketone (MIBK) and the 600mL methanol mixture.At the ice-cooled 43.5mL sulfuric acid that dropwise adds down.Under water-cooled, stirred 1 hour, at room temperature stirred then 1 hour 30 minutes.After adding 1200mL water and 200mL 20% aqueous sodium hydroxide solution; at room temperature stir product 30 minutes and cross filter solid and obtain 3-{5-[4-(cyclopentyloxy)-2-hydroxy benzoyl that 167g is the ivory buff solid form]-2-[(3-hydroxyl-1,2-benzoisoxazole-6-yl) methoxyl group] phenyl } the propionic acid methyl ester.

(2) in 182mL methyl alcohol, suspension 26.0g 3-{5-[4-(cyclopentyloxy)-2-hydroxy benzoyl]-2-[(3-hydroxyl-1,2-benzoisoxazole-6-yl) methoxyl group] phenyl } the propionic acid methyl ester.At room temperature drip after the 78mL water of 10.5g sodium hydroxide, under uniform temp, stirred product 30 minutes.This reaction mixture is added in the water.After being adjusted to pH value 1.5, cross filter solid with 6mol/L hydrochloric acid.The solid that is obtained is dissolved in chloroform and the methanol mixture solution.After washing with water, under reduced pressure distilling off solvent and obtain to be 22.5g 3-{5-[4-(the cyclopentyloxy)-2-hydroxy benzoyl of light light yellow solid form]-2-[(3-hydroxyl-1,2-benzoisoxazole-6-yl) methoxyl group] phenyl propionic acid.

Claims

1. the benzyl propionate derivant of representing by following general formula or the preparation method of its salt:

[general formula 15]

R wherein ^2aThe expression alkoxyl group; R ^3bThe representative ring alkyl; And R ⁵Expression is substituted with the methyl of the phenyl of one or more optional replacements, or the optional oxygen heterocyclic ring group that replaces, and comprising:

Make benzophenone derivative or its salt represented by following general formula

[general formula 9]

R wherein ^2aAnd R ^3bAs surface defined, with the 6-that represents by following general formula (monochloromethyl)-1,2-benzoisoxazole-3 (2H)-ketone derivatives reaction:

[general formula 14]

Wherein X represents halogen atom; And R ⁵As surface defined;

Be prepared as follows this benzophenone derivative: the methyl of in the presence of sulfuric acid and water, representing by following general formula-2H-chromen-2-one with the Manganse Dioxide oxidation

[general formula 1]

And 2-oxo-2H-chromene formaldehyde that acquisition is represented by following general formula:

[general formula 2]

Salt by halous acid obtains this compound oxidation 2-oxo-2H-chromene carboxylic acid or its salt represented by following general formula then:

[general formula 3]

Then change into its reactive derivatives, make this reactive derivatives and the compound reaction of representing by following general formula then:

[general formula 4]

R wherein ^3aAnd R ^4aExpression alkyl, and the benzophenone derivative that acquisition is represented by following general formula:

[general formula 5]

R wherein ^3aAnd R ^4aAs surface defined, make this benzophenone derivative carry out dealkylation reaction then and the benzophenone derivative or its salt that obtain to represent by following general formula:

[general formula 6]

The benzophenone derivative or its salt that make this benzophenone derivative or its salt in the presence of alkali, carry out alkylated reaction then and obtain to represent by following general formula:

[general formula 7]

R wherein ^3bAs surface defined, make this benzophenone derivative or its salt in the presence of alkali, carry out ring-opening reaction then and the benzophenone derivative or its salt that obtain to represent by following general formula:

[general formula 8]

R wherein ^2aAnd R ^3bAs surface defined, make this benzophenone derivative or its salt carry out reduction reaction then; With

This 6-(monochloromethyl)-1,2-benzoisoxazole-3 (2H)-ketone derivatives are according to any preparation in following method (1) or (2):

(1) method that may further comprise the steps: with the methyl of the phenyl that is substituted with one or more optional replacements; or the optional oxygen heterocyclic ring group protection 6-methyl isophthalic acid that replaces; 2 of 2-benzoisoxazole-3-alcohol and obtain the 6-methyl isophthalic acid represented by following general formula, 2-benzoisoxazole-3 (2H)-ketone derivatives:

[general formula 10]

R wherein ⁵As surface defined, then halogenation;

(2) method that may further comprise the steps: make (methylol) benzoate derivatives or its salt represented by following general formula:

[general formula 11]

R wherein ⁶The expression alkyl obtains (methylol) benzohydroxamic acid derivative or its salt represented by following general formula with azanol or its reactant salt:

[general formula 12]

Make the reaction of this (methylol) benzohydroxamic acid derivative or its salt and thionyl halide then, the compound or its salt that makes gained then carries out intramolecular cyclization reaction and the 6-(monochloromethyl)-1 that obtains to be represented by following general formula in the presence of alkali, 2-benzoisoxazole-3-alcohol or its salt:

[general formula 13]

Wherein X as mentioned above, then with the methyl of phenyl that is substituted with one or more optional replacements, or the optional oxygen heterocyclic ring group that replaces protects this 6-(monochloromethyl)-1,2 of 2-benzoisoxazole-3-alcohol derivate.

2. the benzophenone derivative of representing by following general formula or the preparation method of its salt:

[general formula 20]

R wherein ^2aThe expression alkoxyl group; And R ^3bThe representative ring alkyl comprises: make the benzophenone derivative of being represented by following general formula

[general formula 16]

R wherein ^3aAnd R ^4aThe expression alkyl, carry out dealkylation reaction and the benzophenone derivative or its salt that obtain to be represented by following general formula:

[general formula 17]

[general formula 18]

[general formula 19]

R wherein ^2aAnd R ^3bAs surface defined, make this benzophenone derivative or its salt carry out reduction reaction then.

3. the benzophenone derivative of representing by following general formula or the preparation method of its salt:

[general formula 22]

R wherein ^2aThe expression alkoxyl group; And R ^3bThe representative ring alkyl comprises: make benzophenone derivative or its salt represented by following general formula

[general formula 21]

R wherein ^2aAnd R ^3bAs surface defined, carry out reduction reaction.

4. the benzyl propionate derivant of representing by following general formula or the preparation method of its salt:

[general formula 25]

R wherein ^2aThe expression alkoxyl group; R ^3bThe representative ring alkyl; And R ⁵Expression is substituted with the methyl of the phenyl of one or more optional replacements, or the optional oxygen heterocyclic ring group that replaces, and comprising: make benzophenone derivative or its salt represented by following general formula

[general formula 23]

[general formula 24]

R wherein ⁵As surface defined; X is a halogen atom.

5. according to each preparation method among the claim 1-4, wherein R ^2aBe methoxyl group, R ^3bIt is cyclopentyl.

6. the 6-that represents by following general formula (monochloromethyl)-1, the preparation method of 2-benzoisoxazole-3 (2H)-ketone derivatives:

[general formula 27]

Wherein X represents halogen atom; And R ⁵Expression is substituted with the methyl of the phenyl of one or more optional replacements; or the optional oxygen heterocyclic ring group that replaces; comprise: with the methyl of the phenyl that is substituted with one or more optional replacements; or the optional oxygen heterocyclic ring group protection 6-methyl isophthalic acid that replaces; 2 of 2-benzoisoxazole-3-alcohol and obtain the 6-methyl isophthalic acid represented by following general formula, 2-benzoisoxazole-3 (2H)-ketone derivatives:

[general formula 26]

R wherein ⁵As surface defined, then halogenation.

7. the 6-that represents by following general formula (monochloromethyl)-1, the preparation method of 2-benzoisoxazole-3 (2H)-ketone derivatives:

[general formula 31]

R wherein ⁵Expression is substituted with the methyl of the phenyl of one or more optional replacements, or the optional oxygen heterocyclic ring group that replaces; With X be halogen atom, comprising: make (methylol) benzoate derivatives or its salt represented by following general formula:

[general formula 28]

R wherein ⁶Be alkyl, with azanol or its reactant salt and obtain (methylol) benzohydroxamic acid derivative or its salt represented by following general formula:

[general formula 29]

Make the reaction of this (methylol) benzohydroxamic acid derivative and thionyl halide then, the compound or its salt that makes gained then carries out intramolecular cyclization reaction and the 6-(monochloromethyl)-1 that obtains to be represented by following general formula in the presence of alkali, 2-benzoisoxazole-3-alcohol derivate or its salt:

[general formula 30]

Wherein X as mentioned above, then with the methyl of phenyl that is substituted with one or more optional replacements, or the optional oxygen heterocyclic ring group that replaces protects this 6-(monochloromethyl)-1,2-benzoisoxazole-3-alcohol derivate or its salt 2.

8. according to each preparation method in the claim 1,4,5,6 and 7, wherein X is chlorine atom or bromine atoms.

9. according to each preparation method in the claim 1,4,5,6,7 and 8, wherein R ⁵Be optional trityl or the tetrahydrochysene-2H-pyrans-2-base that replaces.

10. the 2-oxo-2H-chromene carboxylic acid represented by following general formula or the preparation method of its salt:

[general formula 34]

Comprise:

The methyl of in the presence of sulfuric acid and water, representing by following general formula-2H-chromen-2-one with the Manganse Dioxide oxidation

[general formula 32]

[general formula 33]

Salt by halous acid is with this compound oxidation then.

11. according to the preparation method of claim 1 or claim 10, wherein Manganse Dioxide is activated manganese dioxide; And sulfuric acid is 35-75% (w/w) with respect to the concentration of sulfuric acid and water.

12. according to the preparation method of claim 10 or claim 11, wherein methyl-2H-chromen-2-one is 6-methyl-2H-chromen-2-one or 7-methyl-2H-chromen-2-one.

13. by the 6-(monochloromethyl)-1 that following general formula is represented, 2-benzoisoxazole-3 (2H)-ketone derivatives:

[general formula 35]

R wherein ⁵Expression is substituted with the methyl of the phenyl of one or more optional replacements, or the optional oxygen heterocyclic ring group that replaces; With X be halogen atom.

14. according to the 6-(monochloromethyl)-1 of claim 13,2-benzoisoxazole-3 (2H)-ketone derivatives, wherein X is chlorine atom or bromine atoms.

15. according to the 6-(monochloromethyl)-1 of claim 13 or 14,2-benzoisoxazole-3 (2H)-ketone derivatives, wherein R ⁵Be optional trityl or the tetrahydrochysene-2H-pyrans-2-base that replaces.

16. according to each 6-(monochloromethyl)-1 in the claim 13,14 and 15,2-benzoisoxazole-3 (2H)-ketone derivatives, wherein R ⁵It is the optional trityl that replaces.

17. according to the 6-(monochloromethyl)-1 of claim 13,2-benzoisoxazole-3 (2H)-ketone derivatives, wherein R ⁵It is trityl; X is chlorine atom or bromine atoms.

18. the benzophenone derivative that following general formula is represented or its salt:

[general formula 36]

R wherein ¹Be hydrogen atom and R ²Be alkoxyl group,

Or R ¹And R ²The formation key connects together; R ³Representative ring alkyl and R ⁴Expression hydrogen atom, or R ³And R ⁴Be identical and represent hydrogen atom or alkyl separately that condition is to work as R ¹Be hydrogen atom and R ²When being alkoxyl group, R ³Representative ring alkyl and R ⁴The expression hydrogen atom.

19. benzophenone derivative or its salt, wherein R according to claim 18 ¹Be hydrogen atom and R ²Be methoxy or ethoxy, or R ¹And R ²The formation key connects together; R ³Representative ring amyl group and R ⁴Expression hydrogen atom, or R ³And R ⁴Be identical and represent hydrogen atom, methyl or ethyl separately that condition is to work as R ¹Be hydrogen atom and R ²When being methoxy or ethoxy, R ³Be cyclopentyl and R ⁴It is hydrogen atom.

20. benzophenone derivative or its salt, wherein R according to claim 18 ¹It is hydrogen atom; R ²It is methoxy or ethoxy; R ³It is cyclopentyl; R ⁴It is hydrogen atom.