CN107188875B - Preparation method and intermediate of substituted phthalide compound - Google Patents

Preparation method and intermediate of substituted phthalide compound Download PDF

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CN107188875B
CN107188875B CN201610149259.1A CN201610149259A CN107188875B CN 107188875 B CN107188875 B CN 107188875B CN 201610149259 A CN201610149259 A CN 201610149259A CN 107188875 B CN107188875 B CN 107188875B
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CN107188875A (en
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邹本立
谢四维
袁利
崔燕
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Lianhe Chemical Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/06—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic

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Abstract

The invention discloses a preparation method of a substituted phthalide compound and an intermediate thereof. The preparation method of the substituted phthalide compound comprises the following steps: and (3) carrying out cyclization reaction on the compound B in water under an acidic condition to obtain a compound A. The method has the advantages of simple process, low cost, less three wastes and suitability for industrial production.

Description

Preparation method and intermediate of substituted phthalide compound
Technical Field
The invention relates to a preparation method of a substituted phthalide compound and an intermediate thereof.
Background
5-phenoxy isobenzofuran-1- (3H) -ketone is an important intermediate for increasing the content of nitrogen-containing heteroaryl compounds of endogenous erythropoietin, and the synthesis methods reported at present at home and abroad are few. The currently reported methods all use 5-bromophenylphthalide as an initial raw material, and the initial raw material is subjected to coupling reaction with phenol to obtain:
Figure BDA0000941973470000011
the 5-bromophenylphthalide is used as a key intermediate for synthesizing 5-phenoxyisobenzofuran-1- (3H) -ketone, and the synthesis method mainly comprises the following steps:
mono, phthalimide process
Figure BDA0000941973470000012
According to the method, phthalimide is used as an initial raw material, ester is formed through nitration, reduction and selective reduction, and diazotization is carried out to obtain 5-bromophenylphthalide. The method has the advantages of long steps, much discharge of three wastes, low yield and overhigh cost, and is not suitable for large-scale industrial production.
Reduction method of di, 4-bromobenzene anhydride
Figure BDA0000941973470000013
The method takes 4-bromophthalic anhydride as a starting material, obtains 5-bromophenylphthalide through selective reduction, has low selectivity of reduction of 4-bromophenylphthalide in the reaction although the steps are short, and has the ratio of the target product to the isomer of only 6: 4 in the document reported by Oren et al, so that the yield of the first step is only 38%. Therefore, the method has limited economic benefits and is not suitable for large-scale production.
Tri, o-xylene process
Figure BDA0000941973470000021
The method takes o-xylene as an initial raw material, and obtains 5-bromophenylphthalide through bromination, oxidation and ring closure, isomers in the bromination reaction are difficult to separate, the yield is low, glacial acetic acid and water are used as solvents in the second step of reaction, cobalt acetate and manganese acetate are used for catalysis, three wastes are more, the yield is low, and the method is not suitable for large-scale production.
Tetra, 4-bromo-2-methylbenzoic acid process
Figure BDA0000941973470000022
The 4-bromo-2-methylbenzoic acid in the route is used as an initial raw material, although the steps are short, the initial raw material is expensive, the reaction time is too long, and three wastes are large. The existing literature report process of the route has limited economic benefit and is not suitable for large-scale preparation and production.
In a word, the existing process for preparing 5-phenoxyl isobenzofuran-1- (3H) -ketone takes 5-bromophenylphthalide as a starting material, and the synthesis of the 5-bromophenylphthalide serving as a key intermediate has the defects of complex process, excessive three wastes, high cost, unsuitability for large-scale industrial production and the like.
Therefore, a new method for preparing 5-phenoxyisobenzofuran-1- (3H) -ketone with simple process, low cost and less three wastes is needed in the field.
Disclosure of Invention
The invention aims to overcome the defects of complex process, excessive three wastes, overhigh cost and the like of the existing preparation method of the 5-phenoxyisobenzofuran-1- (3H) -ketone, and provides a preparation method of a substituted phthalide compound and an intermediate thereof.
The invention provides a preparation method of a substituted phthalide compound shown as a formula A, which comprises the following steps: in water, under an acidic condition, carrying out cyclization reaction on the compound B to obtain a compound A;
Figure BDA0000941973470000031
wherein R is1Hydrogen or alkali metal.
In the ring closure reaction, the alkali metal may be an alkali metal conventional in the art, such as sodium or potassium.
In the cyclization reaction, the volume mol ratio of the water to the compound B can be a volume mol ratio conventional in the cyclization reaction in the field, such as 0.5-1.3L/mol (further, for example, 0.65L/mol, 1.0L/mol, 1.05L/mol or 1.1L/mol).
In the cyclization reaction, the acidic conditions may be those conventional in the art for such cyclization reactions, for example, the reaction system has a pH of 2 or less (further, for example, a pH of 1 or less). The acidic conditions can be achieved by the addition of an acid. The acid may be an acid conventional in the art for such cyclization reactions, such as sulfuric acid or HCl. The molar ratio of the acid to the compound B may be a molar ratio (for example, 1.5 to 3.0) conventionally used in the cyclization reaction in the art, and is preferably 1.5 to 2.0.
In the cyclization reaction, the temperature of the cyclization reaction can be a temperature (for example, 50 to 100 ℃) which is conventional in the cyclization reaction in the field, preferably 70 to 100 ℃, and more preferably 80 to 95 ℃.
In the cyclization reaction, the progress of the cyclization reaction can be monitored by a conventional monitoring method in the field (such as TLC, HPLC or NMR), and the reaction time can be 1 h-2 h, wherein the compound B is generally used as a reaction end point when no longer reacting.
The preparation method of the compound A can also comprise the following steps: in water, in the presence of alkali and zinc, carrying out hydrolysis/reduction reaction on the compound C to obtain a compound B;
Figure BDA0000941973470000041
wherein, R is2Is hydrogen or C1～C4Alkyl group of (1).
In the hydrolysis/reduction reaction, the C1～C4The alkyl group of (a) may be a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl group, for example a methyl group.
In the hydrolysis/reduction reaction, the volume mol ratio of the water to the compound C may be a volume mol ratio conventional in the hydrolysis reaction of this type in the art, for example, 0.8 to 1.1L/mol (further, for example, 1.0 to 1.05L/mol).
In the hydrolysis/reduction reaction, the base may be a base conventional in the hydrolysis reaction of this type in the art, such as sodium hydroxide or potassium hydroxide.
In the hydrolysis/reduction reaction, the molar ratio of the base to the compound C may be a molar ratio conventional in the hydrolysis reaction of this type in the art, for example, 1.1 to 6.0 (e.g., 1.4, 1.5, 2, 2.5, 3, 3.5, or 4.5).
In the hydrolysis/reduction reaction, the zinc may be in the form of zinc powder.
In the hydrolysis/reduction reaction, the molar ratio of the zinc to the compound C may be a molar ratio conventional in the hydrolysis reaction of this type in the art, for example, 3.0 to 5.0 (e.g., 4.5 to 4.8).
In the hydrolysis/reduction reaction, the temperature of the hydrolysis/reduction reaction may be a temperature that is conventional in the field for such hydrolysis reactions, for example, 50 to 100 ℃ (e.g., 80 ℃, 85 ℃, 95 ℃).
In the hydrolysis/reduction reaction, the progress of the hydrolysis/reduction reaction can be monitored by a conventional monitoring method in the art (such as TLC, HPLC or NMR), and the reaction time can be 5h to 17h, generally taking compound C as a reaction end point when no longer reacting.
In the method for preparing the compound A, preferably, after the hydrolysis/reduction reaction is completed, the compound B is not separated (i.e., the compound B is not separated and purified, or a mixture containing the compound B is obtained; for example, the reaction solution of the hydrolysis/reduction reaction is not subjected to post-treatment, or the reaction solution of the hydrolysis/reduction reaction is subjected to simple post-treatment, etc., to obtain a mixture containing the compound B; the simple post-treatment may be filtration, pH adjustment, etc.), and then the cyclization reaction is performed; for example, the reaction solution of the hydrolysis/reduction reaction is filtered (may contain a filter cake), and the cyclization reaction is carried out directly after the reaction solution is adjusted to acidic conditions.
The preparation method of the compound A can also comprise the following steps: in water, in the presence of alkali, carrying out reduction reaction on the compound D and zinc to obtain a compound C;
Figure BDA0000941973470000051
wherein R is3Hydrogen or alkali metal.
In the reduction reaction, the alkali metal may be an alkali metal conventional in the art, such as sodium or potassium.
In the reduction reaction, the volume mol ratio of the water to the compound D can be a volume mol ratio which is conventional in the reduction reaction in the field, such as 0.7 to 1.1L/mol (for example, 0.8 to 1.0L/mol).
In the reduction reaction, the base may be a base conventional to the type of reduction reaction in the art, such as sodium hydroxide or potassium hydroxide.
In the reduction reaction, the molar ratio of the base to the compound D may be a molar ratio conventional in the art for such reduction reactions, such as 1.1 to 6.0 (e.g., 1.4, 1.5, 1.8, 2, 2.4, 2.5, 3, 3.5, or 4.5).
In the reduction reaction, the molar ratio of the zinc to the compound D may be a molar ratio conventional in the art for such reduction reactions, such as 3-10 (e.g., 4, 5, 5.5, 6, or 7).
In the reduction reaction, the temperature of the reduction reaction may be a temperature conventional in the art, such as 50 to 75 ℃ (e.g., 55 ℃, 65 ℃ or 70 ℃).
In the reduction reaction, the progress of the reduction reaction can be monitored by a conventional monitoring method in the field (such as TLC, HPLC or NMR), and the reaction time can be 5h, generally taking the time when the compound D is not reacted any more as the reaction end point.
In the method for preparing the compound A, preferably, after the reduction reaction is completed, the compound C is not separated (i.e., the compound C is not separated and purified, or a mixture containing the compound C is obtained; for example, the reaction solution of the reduction reaction is not subjected to post-treatment, or the reaction solution of the reduction reaction is subjected to simple post-treatment, etc., to obtain a mixture containing the compound C; the simple post-treatment may be filtration, etc.); for example, the reaction solution of the reduction reaction is directly subjected to the hydrolysis/reduction reaction. More preferably, after the reduction reaction is completed, the material is subjected to a reduction reaction at 90-100 ℃ and the hydrolysis/reduction reaction to obtain the compound B (i.e., the compound B is obtained
Figure BDA0000941973470000061
)。
The preparation method of the compound A can also comprise the following steps: in water, in the presence of alkali, carrying out ring opening reaction on the compound E to obtain a compound D;
Figure BDA0000941973470000062
in the ring-opening reaction, the volume mol ratio of the water to the compound E can be a volume mol ratio which is conventional in the ring-opening reaction of this type in the art, such as 0.5 to 0.8L/mol (e.g., 0.55 to 0.60L/mol).
In the ring-opening reaction, the base may be a base conventional to such ring-opening reactions in the art, such as sodium hydroxide or potassium hydroxide.
In the ring-opening reaction, the molar ratio of the base to the compound E may be a molar ratio conventional in the art for such ring-opening reactions, such as 1.5 to 6.0 (e.g., 1.8, 2, 2.4, 2.5, 3, 3.5, or 4.5).
In the ring-opening reaction, the temperature of the ring-opening reaction may be a temperature that is conventional for such ring-opening reactions in the art, such as-5 to 70 ℃ (e.g., 0 ℃, 5 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃ or 40 ℃).
In the ring-opening reaction, the progress of the ring-opening reaction can be monitored by a conventional monitoring method in the art (such as TLC, HPLC or NMR), and generally, the reaction time can be 1 to 5 hours (such as 2 hours) with the compound E no longer reacting as a reaction end point.
In the method for preparing the compound A, preferably, after the ring-opening reaction is completed, the compound D is not separated (i.e., the compound D is not separated and purified, or a mixture containing the compound D is obtained; for example, the reaction solution of the ring-opening reaction is not subjected to post-treatment, or the reaction solution of the ring-opening reaction is subjected to simple post-treatment, such as adding zinc, adding water, etc.), and then the reduction reaction is carried out; for example, the reaction solution of the ring-opening reaction is added with zinc and/or waterDirectly carrying out the reduction reaction at 50-70 ℃ to obtain the compound C; for example, the compound B may be obtained by adding zinc and/or water to the reaction solution of the ring-opening reaction, and then directly performing the reduction reaction and the hydrolysis/reduction reaction at 90 to 100 ℃. More preferably, the zinc powder and/or water is added during the ring-opening reaction charging, the amount of the zinc powder and/or water is referred to the reduction reaction, and then the ring-opening reaction and the reduction reaction are directly carried out at 50-70 ℃ to obtain the compound C (namely, the compound C is obtained
Figure BDA0000941973470000071
) (ii) a Or adding the zinc powder and/or the water during the ring-opening reaction feeding, wherein the dosage refers to the reduction reaction, and then directly carrying out the ring-opening reaction, the reduction reaction and the hydrolysis/reduction reaction at 90-100 ℃ to obtain the compound B (namely, the compound B is obtained
Figure BDA0000941973470000072
)。
In the method for preparing compound a, preferably, the zinc may be added before the ring-opening reaction is performed (i.e., the zinc does not affect the ring-opening reaction), and after the ring-opening reaction is completed, the reduction reaction may be directly performed by adding only water (or not adding water) to the reaction solution of the ring-opening reaction.
The preparation method of the compound A can also comprise the following steps: in an organic solvent, carrying out substitution reaction on a compound F and a compound H in the presence of cuprous salt and a ligand to obtain a compound E; the ligand is one or more of L-proline, acetylacetone, N-methylglycine and N, N-dimethylglycine;
Figure BDA0000941973470000081
wherein X is bromine or chlorine, R4Is hydrogen or an alkali metal; when said R is4In the case of hydrogen, the substitution is carried out in the presence of a baseIn the presence of (a).
In the substitution reaction, the alkali metal may be an alkali metal conventional in the art, such as sodium or potassium.
In the substitution reaction, the organic solvent may be an organic solvent conventional in the art for such substitution reactions, such as one or more of acetonitrile, tetrahydrofuran, polyethylene glycol, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, and dimethylsulfoxide, preferably 1, 4-dioxane.
In the substitution reaction, the moisture content of the organic solvent may be a moisture content conventionally used in the art for organic solvents of this type of substitution reaction, for example, 500ppm or less.
In the substitution reaction, the volume mol ratio of the organic solvent to the compound F can be the volume mol ratio which is conventional in the substitution reaction of this type in the field, for example, 0.45L/mol
In the substitution reaction, the base may be a base conventional in the art for such substitution reactions, such as one or more of sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate and dipotassium hydrogen phosphate, preferably potassium carbonate.
In the substitution reaction, the molar ratio of the base to the compound F can be a molar ratio (for example, 1 to 3) conventional in the substitution reaction of this type in the art, and is preferably 1.2 to 1.5.
In the substitution reaction, the cuprous salt may be a cuprous salt conventional in the substitution reaction in this field, such as one or more of cuprous chloride, cuprous bromide and cuprous iodide, preferably cuprous iodide or cuprous bromide.
In the substitution reaction, the molar ratio of the cuprous salt to the compound F can be a molar ratio (e.g., 0.05 to 0.2), preferably 0.07 to 0.15, and more preferably 0.1 to 0.12, which is conventional in the substitution reaction in this field.
In the substitution reaction, the ligand is preferably N, N-dimethylglycine.
In the substitution reaction, the molar ratio of the ligand to the compound F can be a molar ratio conventional in the substitution reaction in the art (e.g., 0.05 to 0.2), preferably 0.07 to 0.15 (e.g., 0.075 or 0.1).
In the substitution reaction, the molar ratio of the compound H to the compound F can be a molar ratio (for example, 1.0 to 2.5), preferably 1.5 to 2.0, which is conventional in the substitution reaction of this type in the art.
In the substitution reaction, the temperature of the substitution reaction may be a temperature that is conventional in the art, such as 60 to 100 ℃ (e.g., 75 ℃, 80 ℃, 85 ℃ or 95 ℃).
In the substitution reaction, the progress of the substitution reaction can be monitored by a conventional monitoring method in the art (such as TLC, HPLC or NMR), and the reaction time can be 24h, generally taking compound F as the reaction end point when no longer reacting.
The preparation method of the compound A can also comprise the following steps: carrying out substitution reaction on the compound G and the compound H in a polar solvent to obtain a compound E;
Figure BDA0000941973470000091
wherein R is4Is hydrogen or an alkali metal; when said R is4In the case of hydrogen, the substitution is carried out in the presence of a base.
In the substitution reaction, the substitution reaction is preferably carried out under the protection of a protective gas. The protective gas is a protective gas conventional in the substitution reaction of the type in the art, such as nitrogen.
In the substitution reaction, the alkali metal may be an alkali metal conventional in the art, such as sodium or potassium.
In the substitution reaction, the polar solvent may be an organic solvent conventional in the art for such substitution reactions, such as one or more of dimethylsulfoxide, N-dimethylformamide, N-methylpyrrolidone, t-butanol, and polyethylene glycol.
In the substitution reaction, the moisture content of the polar solvent may be a moisture content conventionally used in the art for polar solvents of this type of substitution reaction, for example, 500ppm or less.
In the substitution reaction, the volume molar ratio of the polar solvent to the compound G can be a volume molar ratio which is conventional in the substitution reaction of this type in the art, for example, 0.40L/mol.
In the substitution reaction, the base may be a base conventional in the substitution reaction of this type in the art, and is preferably an inorganic base. The inorganic base may be an inorganic base conventional in the art for such substitution reactions, such as one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, dipotassium hydrogen phosphate, potassium phosphate, and potassium fluoride. The base may be first reacted with the compound H (e.g. potassium phenofluoride complex, sodium or potassium phenoxide).
The molar ratio of the base to the compound G in the substitution reaction may be a molar ratio conventional in this type of substitution reaction in the art, for example, 1.0.
In the substitution reaction, the molar ratio of the compound H to the compound G may be a molar ratio (e.g., 0.5 to 4.0) conventional in the art for the substitution reaction, and is preferably 1.0 to 2.5 (e.g., 1.4, 1.8, or 2.0).
In the substitution reaction, the temperature of the substitution reaction may be a temperature conventional in the art, such as 80 to 140 ℃ (e.g., 90 ℃, 100 ℃, or 120 ℃).
In the substitution reaction, the progress of the substitution reaction can be monitored by a conventional monitoring method in the art (such as TLC, HPLC or NMR), and the reaction time can be 24h, generally taking the compound G no longer reacting as the reaction end point.
Preferably, the preparation route of the compound A is as follows:
Figure BDA0000941973470000111
the invention also provides a preparation method of the compound shown as the formula B, which comprises the following steps: in water, in the presence of alkali and zinc, carrying out hydrolysis/reduction reaction on the compound C to obtain a compound B;
Figure BDA0000941973470000112
wherein R is1Is hydrogen or an alkali metal, R2Is hydrogen or C1～C4Alkyl group of (1).
The reaction conditions for the hydrolysis/reduction reaction are as described above.
The preparation method of the compound B can also comprise the following steps: in water, in the presence of alkali, carrying out reduction reaction on the compound D and zinc to obtain a compound C;
Figure BDA0000941973470000113
wherein R is3Hydrogen or alkali metal.
The reaction conditions for the reduction reaction are as described above.
In the method for preparing the compound B, preferably, after the reduction reaction is completed, the compound C is not separated (i.e., the compound C is not separated and purified, or a mixture containing the compound C is obtained; for example, the reaction solution of the reduction reaction is not subjected to post-treatment, or the reaction solution of the reduction reaction is subjected to simple post-treatment, etc., to obtain a mixture containing the compound C; the simple post-treatment may be filtration, etc.); for example, the hydrolysis reaction is directly performed in the reaction solution of the reduction reaction. Preferably, after the reduction reaction is completed, the material is subjected to reduction reaction at 90-100 ℃ and the hydrolysis/reduction reaction to obtain the compound B.
The preparation method of the compound B can also comprise the following steps: in water, in the presence of alkali, carrying out ring opening reaction on the compound E to obtain a compound D;
Figure BDA0000941973470000121
the reaction conditions for the ring-opening reaction are as described above.
In the method for preparing the compound B, preferably, after the ring-opening reaction is completed, the compound D is not separated (i.e., the compound D is not separated and purified, or a mixture containing the compound D is obtained; for example, the reaction solution of the ring-opening reaction is not subjected to post-treatment, or the reaction solution of the ring-opening reaction is subjected to simple post-treatment, such as adding zinc, adding water, etc.), and then the reduction reaction is carried out; for example, after zinc and/or water are/is added into the reaction solution of the ring-opening reaction, the reduction reaction is directly carried out at 50-70 ℃ to obtain the compound C; for example, the compound B may be obtained by adding zinc and/or water to the reaction solution of the ring-opening reaction, and then directly performing the reduction reaction and the hydrolysis/reduction reaction at 90 to 100 ℃. Preferably, the zinc powder and/or water is added during the ring-opening reaction feeding, the amount of the zinc powder and/or water is referred to the reduction reaction, and then the ring-opening reaction and the reduction reaction are directly carried out at 50-70 ℃ to obtain the compound C; or adding the zinc powder and/or the water during the ring-opening reaction feeding, wherein the amount of the zinc powder and/or the water refers to the reduction reaction, and then directly carrying out the ring-opening reaction, the reduction reaction and the hydrolysis/reduction reaction at 90-100 ℃ to obtain the compound B.
In the method for producing the compound B, preferably, the zinc may be added before the ring-opening reaction is performed (i.e., the zinc does not affect the ring-opening reaction), and after the ring-opening reaction is completed, the reduction reaction may be directly performed by adding only water to the reaction solution of the ring-opening reaction.
The preparation method of the compound B can also comprise the following steps: in an organic solvent, carrying out substitution reaction on a compound F and a compound H in the presence of cuprous salt and a ligand to obtain a compound E; the ligand is one or more of L-proline, acetylacetone, N-methylglycine and N, N-dimethylglycine;
Figure BDA0000941973470000131
wherein X is bromine or chlorine, R4Is hydrogen or an alkali metal; when said R is4In the case of hydrogen, the substitution is carried out in the presence of a base. The reaction conditions for the substitution reaction are as described above.
The preparation method of the compound B can also comprise the following steps: carrying out substitution reaction on the compound G and the compound H in a polar solvent to obtain a compound E;
Figure BDA0000941973470000132
wherein R is4Is hydrogen or an alkali metal; when said R is4In the case of hydrogen, the substitution is carried out in the presence of a base. The reaction conditions for the substitution reaction are as described above.
Preferably, the preparation route of the compound B is as follows:
Figure BDA0000941973470000141
the invention also provides a preparation method of the compound shown in the formula C, which comprises the following steps: in water, in the presence of alkali, carrying out reduction reaction on the compound D and zinc to obtain a compound C;
Figure BDA0000941973470000142
wherein R is2Is hydrogen or C1～C4Alkyl of (2)，R3Hydrogen or alkali metal.
The reaction conditions for the reduction reaction are as described above.
The preparation method of the compound C can also comprise the following steps: in water, in the presence of alkali, carrying out ring opening reaction on the compound E to obtain a compound D;
Figure BDA0000941973470000143
the reaction conditions for the ring-opening reaction are as described above.
In the method for preparing the compound C, preferably, after the ring-opening reaction is completed, the compound D is not separated (i.e., the compound D is not separated and purified, or a mixture containing the compound D is obtained; for example, the reaction solution of the ring-opening reaction is not subjected to post-treatment, or the reaction solution of the ring-opening reaction is subjected to simple post-treatment, such as adding zinc, adding water, etc.), and then the reduction reaction is carried out; for example, after zinc and/or water is added to the reaction solution of the ring-opening reaction, the reduction reaction is directly carried out at 50 to 70 ℃ to obtain the compound C. Preferably, the zinc powder and/or water is added during the ring-opening reaction feeding, the amount of the zinc powder and/or water is referred to the reduction reaction, and then the ring-opening reaction and the reduction reaction are directly carried out at 50-70 ℃ to obtain the compound C.
In the method for producing compound C, preferably, the zinc may be added before the ring-opening reaction is performed (i.e., the zinc does not affect the ring-opening reaction), and after the ring-opening reaction is completed, the reduction reaction may be directly performed by adding only water to the reaction solution of the ring-opening reaction.
The preparation method of the compound C can also comprise the following steps: in an organic solvent, carrying out substitution reaction on a compound F and a compound H in the presence of cuprous salt and a ligand to obtain a compound E; the ligand is one or more of L-proline, acetylacetone, N-methylglycine and N, N-dimethylglycine;
Figure BDA0000941973470000151
wherein X is bromine or chlorine, R4Is hydrogen or an alkali metal; when said R is4In the case of hydrogen, the substitution is carried out in the presence of a base. The reaction conditions for the substitution reaction are as described above.
The preparation method of the compound C can also comprise the following steps: carrying out substitution reaction on the compound G and the compound H in a polar solvent to obtain a compound E;
Figure BDA0000941973470000161
wherein R is4Is hydrogen or an alkali metal; when said R is4In the case of hydrogen, the substitution is carried out in the presence of a base. The reaction conditions for the substitution reaction are as described above.
Preferably, the preparation route of the compound C is as follows:
Figure BDA0000941973470000162
the invention also provides a preparation method of the compound shown in the formula D, which comprises the following steps: in water, in the presence of alkali, carrying out ring opening reaction on the compound E to obtain a compound D;
Figure BDA0000941973470000163
wherein R is2Is hydrogen or C1～C4Alkyl of R3Hydrogen or alkali metal.
The reaction conditions for the ring-opening reaction are as described above.
The preparation method of the compound D can also comprise the following steps: in an organic solvent, carrying out substitution reaction on a compound F and a compound H in the presence of cuprous salt and a ligand to obtain a compound E; the ligand is one or more of L-proline, acetylacetone, N-methylglycine and N, N-dimethylglycine;
Figure BDA0000941973470000171
wherein X is bromine or chlorine, R4Is hydrogen or an alkali metal; when said R is4In the case of hydrogen, the substitution is carried out in the presence of a base. The reaction conditions for the substitution reaction are as described above.
The preparation method of the compound D can also comprise the following steps: carrying out substitution reaction on the compound G and the compound H in a polar solvent to obtain a compound E;
Figure BDA0000941973470000172
wherein R is4Is hydrogen or an alkali metal; when said R is4In the case of hydrogen, the substitution is carried out in the presence of a base. The reaction conditions for the substitution reaction are as described above.
Preferably, the preparation route of the compound D is as follows:
Figure BDA0000941973470000173
the invention also provides a compound shown as formula B, C or D,
Figure BDA0000941973470000181
wherein R is1、R2And R3The definitions of (A) and (B) are as described above.
It has also been found that the yield is significantly reduced if the analogous reaction is carried out with the phenoxy group in compound E replaced by another group, such as methyl, methoxy, etc.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the preparation method has the advantages of simple process, low cost and less three wastes, and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
In the embodiment of the invention, the room temperature is 15-30 ℃.
EXAMPLE 14 Synthesis of phenoxy-phthalimide
200mL of dimethyl sulfoxide (water content less than 500ppm) was added to a three-neck reaction flask equipped with a stirrer under the protection of nitrogen at room temperature, then 100g of 4-nitrophthalimide and 121g of sodium phenolate were added, and the mixture was heated to 120 ℃ to react for 24 hours. Cooling to room temperature, slowly adding the reaction solution into 600mL of ice water, stirring for 30 minutes, filtering, washing a filter cake with 100mL of water 3, taking out the filter cake, and drying to obtain 119g of a product, wherein the yield is 96% and the HPLC purity is 97%. (Ms: M/z 240(M + H)
EXAMPLE 24 Synthesis of phenoxy-phthalimide
200ml of DMF (moisture content is less than 500ppm) is added into a three-mouth reaction bottle with stirring under the protection of nitrogen at room temperature, then 100g of 4-nitrophthalimide and 121g of sodium phenolate are added, and the mixture is heated to 120 ℃ for reaction for 24 hours. Cooling to room temperature, slowly adding the reaction solution into 600mL of ice water, stirring for 30 minutes, filtering, washing a filter cake with 100mL of water 3, taking out the filter cake, and drying to obtain 113g of a product, wherein the yield is 91%, and the HPLC purity is 96%. (Ms: M/z 240(M + H)
EXAMPLE 34 Synthesis of phenoxy-phthalimide
200ml of DMF (moisture content < 500ppm) was added to a stirred three-neck reaction flask under nitrogen protection at room temperature, then 100g of 4-nitrophthalimide and 159g of phenol potassium fluoride complex were added, and the mixture was heated to 120 ℃ to react for 24 hours. Cooling to room temperature, slowly adding the reaction liquid into 600mL ice water, stirring for 30 minutes, filtering, washing a filter cake with 100mL of water 3, taking out the filter cake, and drying to obtain 111g of a product, wherein the yield is 89%, and the HPLC purity is 97%. (Ms: M/z 240(M + H)
EXAMPLE 44 Synthesis of phenoxy-phthalimide
Sequentially adding 100g of 4-bromophthalimide, 62g of phenol, 92g of potassium carbonate, 6.5g of cuprous bromide, 7g of N, N-dimethylglycine and 200mL of 1, 4-dioxane into a three-opening reaction bottle with a stirrer, raising the temperature of a system to 85 ℃ for reaction under the protection of N2, completely reacting the raw materials after 24 hours, and removing the dioxane by reduced pressure distillation; adding 300mL of dichloromethane to dissolve the product, and filtering the product by silica gel; after the filtrate is evaporated to dryness, 100mL of methanol is added, and the mixture is heated to 40 ℃ and stirred for 1 hour; the temperature of the system is reduced to-5-0 ℃, and after stirring for 5 hours, the white crystalline solid is filtered and dried to obtain 85g, the yield is 80 percent, and the HPLC purity is 98 percent. (Ms: M/z 240(M + H)
EXAMPLE 54 Synthesis of phenoxy-phthalimide
Adding 100g of 4-bromophthalimide, 62g of phenol, 92g of potassium carbonate, 9.5g of cuprous iodide, 7g of N, N-dimethylglycine and 200mL of 1, 4-dioxane into a three-opening reaction bottle with a stirrer in sequence, raising the temperature of a system to 85 ℃ for reaction under the protection of N2, completely reacting the raw materials after 24 hours, and removing the dioxane by reduced pressure distillation; adding 300mL of dichloromethane to dissolve the product, and filtering the product by silica gel; after the filtrate is evaporated to dryness, 100mL of methanol is added, and the mixture is heated to 40 ℃ and stirred for 1 hour; the temperature of the system is reduced to-5-0 ℃, and the white crystalline solid is obtained by filtering and drying after stirring for 5 hours, wherein the white crystalline solid is 88g, the yield is 83 percent, and the HPLC purity is 97 percent. (Ms: M/z 240(M + H)
EXAMPLE 6 Synthesis of N-methyl-4-phenoxy-phthalimide
300mL of dimethyl sulfoxide (water content < 500ppm) was added to a stirred three-neck reaction flask under nitrogen protection at room temperature, 150g N-methyl-4-nitrophthalimide and 169g of sodium phenolate were added, and the mixture was heated to 120 ℃ to react for 24 hours. Cooling to room temperature, slowly adding the reaction liquid into 900mL ice water, stirring for 30 minutes, filtering, washing a filter cake with 150mL x 3 of water, taking out the filter cake, and drying to obtain 171g of a product, wherein the yield is 93%, and the HPLC purity is 98%. (Ms: M/z 254(M + H)
EXAMPLE 7 Synthesis of N-methyl-4-phenoxy-phthalimide
300mL of dimethyl sulfoxide (water content < 500ppm) was added to a three-neck reaction flask equipped with a stirrer under nitrogen protection at room temperature, 150g N-methyl-4-nitrophthalimide and 221g of phenol potassium fluoride complex were then added, and the mixture was heated to 120 ℃ to react for 24 hours. Cooling to room temperature, slowly adding the reaction liquid into 900mL of ice water, stirring for 30 minutes, filtering, washing a filter cake with 150mL of water 3, taking out the filter cake, and drying to obtain 175g of a product, wherein the yield is 95% and the HPLC purity is 96%. (Ms: M/z 254(M + H)
EXAMPLE 8 Synthesis of N-methyl-4-phenoxy-phthalimide
300mL of t-butanol (moisture < 500ppm) was added under nitrogen protection at room temperature to a three-necked stirred reaction flask, followed by addition of 150g N, -methyl-4-nitrophthalimide and 221g of potassium phenolfluoride complex, and the mixture was heated to 120 ℃ for reaction for 24 hours. After the reaction was complete, the solvent was removed under reduced pressure, the residue was added to 300mL of water, stirred for 2 hours, filtered, the filter cake was washed with 150mL of water 3, the filter cake was dried to yield 155g of product in 84% yield and 95% purity by HPLC. (Ms: M/z 254(M + H)
EXAMPLE 9 Synthesis of N-methyl-4-phenoxy-phthalimide
106g N-methyl-4-bromophthalimide, 62g of phenol, 92g of potassium carbonate, 6.5g of cuprous bromide, 7g N, N-dimethylglycine and 200mL of 1, 4-dioxane are sequentially added into a three-opening reaction bottle with a stirrer, the temperature is increased to 85 ℃ for reaction under the protection of N2, the raw materials are completely reacted after 24 hours, and the dioxane is removed by reduced pressure distillation; adding 300mL of dichloromethane to dissolve the product, spreading silica gel and filtering; after the filtrate is evaporated to dryness, 100mL of methanol is added, and the mixture is heated to 40 ℃ and stirred for 1 hour; the temperature of the system is reduced to-5-0 ℃, and after stirring for 5 hours, the white crystalline solid is filtered and dried to obtain 98g, the yield is 87%, and the HPLC purity is 98%. (Ms: M/z 254(M + H)
EXAMPLE synthesis of 102- (methylcarbamoyl) -5-phenoxybenzoic acid
Adding 47g of sodium hydroxide into a three-mouth reaction bottle with a stirrer, adding 400mL of water for dissolving, cooling to 0-5 ℃, then adding 200g of the intermediate N-methyl-4-phenoxy-phthalimide prepared in the previous step in batches for about 1 hour, and preserving heat at 0-5 ℃ for 1-2 hours. And (3) tracking by using a thin-layer chromatography until the raw material disappears, adding hydrochloric acid to adjust the pH value to 4-5, filtering, washing a filter cake with 100mL of water, pumping to dry, adding the filter cake into 350mL of methanol, stirring for half an hour at room temperature, filtering, washing the filter cake with 30mL of methanol 2, taking out and drying to obtain 203g of a product, wherein the yield is 95%, and the HPLC purity is 98%. (Ms: M/z 272(M + H)
EXAMPLE 112 Synthesis of carbamoyl-5-phenoxybenzoic acid
Adding 47g of sodium hydroxide into a three-mouth reaction bottle with stirring, adding 400mL of water for dissolving, cooling to 0-5 ℃, then adding 189g of the intermediate 4-phenoxy-phthalimide prepared in the previous step in batches for about 1 hour, and preserving heat at 0-5 ℃ for 1-2 hours. And (3) tracking by using a thin-layer chromatography until the raw material disappears, adding hydrochloric acid to adjust the pH value to 4-5, filtering, washing a filter cake with 100mL of water, pumping to dry, adding the filter cake into 350mL of methanol, stirring for half an hour at room temperature, filtering, washing the filter cake with 30mL of methanol 2, taking out and drying to obtain 191g of a product, wherein the yield is 94%, and the HPLC purity is 98%. (Ms: M/z 258(M + H)
EXAMPLE 122 Synthesis of carbamoyl-5-phenoxybenzaldehyde
Adding 120g of 4-phenoxy-phthalimide into a three-mouth reaction bottle with a stirrer at room temperature, then adding 300mL of water, then adding 160g of 30% sodium hydroxide solution, stirring uniformly, then adding 130g of activated zinc powder, reacting for one hour at room temperature, then heating to 70 ℃, and preserving heat for 5 hours. Cooling to room temperature after the raw materials disappear by thin-layer chromatography, adding hydrochloric acid to adjust the pH to 7-8, adding 800mL of dichloromethane, filtering, standing the filtrate for layering, separating an organic phase, extracting the aqueous phase with 400mL of dichloromethane once, combining dichloromethane, adding sodium sulfate, drying, filtering, and concentrating to obtain 103g of a product with the yield of 85% and the HPLC purity of 93% (Ms: M/z is 242(M + H)
EXAMPLE synthesis of 132- (methylcarbamoyl) -5-phenoxybenzaldehyde
Adding 127g N-methyl-4-phenoxy-phthalimide into a three-mouth reaction bottle with stirring at room temperature, then adding 300mL of water, then adding 160g of 30% sodium hydroxide solution, stirring uniformly, then adding 130g of activated zinc powder, heating to 70 ℃, and preserving heat for 5 hours. Cooling to room temperature after the raw materials disappear by thin-layer chromatography, adding hydrochloric acid to adjust the pH to 7-8, adding 800mL of dichloromethane, filtering, standing the filtrate for layering, separating an organic phase, extracting the aqueous phase with 400mL of dichloromethane once, combining dichloromethane, adding sodium sulfate, drying, filtering, and concentrating to obtain 108g of a product with the yield of 84% and the HPLC purity of 95% (Ms: M/z is 256(M + H)
EXAMPLE 142 Synthesis of carbamoyl-5-phenoxybenzaldehyde
Adding 129g of 2-carbamoyl-5-phenoxybenzoic acid into a three-mouth reaction bottle with stirring at room temperature, then adding 300mL of water, then adding 120g of 30% sodium hydroxide solution, stirring uniformly, then adding 130g of activated zinc powder, heating to 70 ℃, and preserving heat for 5 hours. Cooling to room temperature after the raw materials disappear by thin-layer chromatography, adding hydrochloric acid to adjust the pH to 7-8, adding 800mL of dichloromethane, filtering, standing the filtrate for layering, separating an organic phase, extracting the aqueous phase with 400mL of dichloromethane once, combining dichloromethane, adding sodium sulfate, drying, filtering, and concentrating to obtain 110g of a product with the yield of 92% and the HPLC purity of 94% (Ms: M/z 242(M + H)
EXAMPLE synthesis of 152- (methylcarbamoyl) -5-phenoxybenzaldehyde
Adding 136g of 2-carbamoyl-5-phenoxybenzoic acid into a three-mouth reaction bottle with stirring at room temperature, then adding 300mL of water, then adding 120g of 30% sodium hydroxide solution, stirring uniformly, then adding 130g of activated zinc powder, heating to 70 ℃, and preserving heat for 5 hours. Cooling to room temperature after the raw materials disappear by thin-layer chromatography, adding hydrochloric acid to adjust the pH to 7-8, adding 800mL of dichloromethane, filtering, standing the filtrate for layering, separating an organic phase, extracting the aqueous phase with 400mL of dichloromethane once, combining dichloromethane, adding sodium sulfate, drying, filtering, and concentrating to obtain a product 116g, wherein the yield is 91%, and the HPLC purity is 96% (Ms: M/z is 256(M + H)
EXAMPLE 162 Synthesis of hydroxymethyl-4-phenoxybenzoic acid
Adding 80g of sodium hydroxide into a three-mouth reaction bottle with a stirrer, adding 400mL of water for dissolving, cooling to 0-5 ℃, then adding 200g of the intermediate N-methyl-4-phenoxy-phthalimide prepared in the previous step in batches for about 1 hour, and preserving heat at 0-5 ℃ for 1-2 hours. And (3) tracking by using the thin-layer chromatography until the raw materials disappear, adding 258g of zinc powder and 400mL of water, heating to 90 ℃, preserving heat for reaction for 5 hours, cooling to room temperature after heat preservation, adding 500mL of dichloromethane, stirring for 30 minutes, filtering, and washing a filter cake by using 50mL of dichloromethane 2. Standing the filtrate for separating liquid, extracting the water phase with 100mL of dichloromethane once again, combining dichloromethane and concentrating to obtain the product. The crude product was added to 150mL methanol, stirred for 30 minutes, filtered, the filter cake washed with 30mL x 2 methanol, dried to 165g and 86% HPLC yield. (Ms: M/z 245(M + H)
Example 172 Synthesis of hydroxymethyl-4-phenoxybenzoic acid
Adding 80g of sodium hydroxide into a three-mouth reaction bottle with a stirrer, adding 400mL of water for dissolving, cooling to 0-5 ℃, then adding 189g of the intermediate 4-phenoxy-phthalimide prepared in the previous step in batches for about 1 hour, and preserving the heat at 0-5 ℃ for 1-2 hours. And (3) tracking by using the thin-layer chromatography until the raw materials disappear, adding 258g of zinc powder and 400mL of water, heating to 100 ℃, preserving heat for reacting for 17 hours, cooling to room temperature after the heat preservation is finished, adding 500mL of dichloromethane, stirring for 30 minutes, filtering, and washing a filter cake by using 50mL of dichloromethane 2. Standing the filtrate for separating liquid, extracting the water phase with 100mL of dichloromethane once again, combining dichloromethane and concentrating to obtain the product. The crude product was added to 150mL methanol, stirred for 30 minutes, filtered, the filter cake washed with 30mL x 2 methanol, dried to yield 167g, 87% yield, 97% HPLC purity. (Ms: M/z 245(M + H)
EXAMPLE 182 Synthesis of hydroxymethyl-4-phenoxybenzoic acid
Adding 40g of sodium hydroxide into a three-mouth reaction bottle with stirring, adding 200mL of water for dissolving, then adding 95g of the intermediate 4-phenoxy-phthalimide prepared in the previous step at one time, heating to 90 ℃, keeping the temperature for 1-2h, adding 129g of zinc powder and 200mL of water after the thin-layer chromatography tracking till the raw materials disappear, keeping the temperature for reacting for 17h, cooling to room temperature after the heat preservation is finished, adding 250mL of dichloromethane, stirring for 30 min, filtering, and washing a filter cake with 30mL of dichloromethane 2. Standing the filtrate for separating liquid, extracting the water phase with 60mL of dichloromethane again, combining dichloromethane, and concentrating to obtain the product. The crude product was added to 80mL of methanol, stirred for 30 minutes, filtered, the filter cake washed with 30mL of methanol 2, dried to 85g, yield 88%, HPLC purity 97%. (Ms: M/z 245(M + H)
EXAMPLE 195 Synthesis of phenoxy isobenzofuran-1- (3H) -one
Adding 40g of sodium hydroxide into a three-mouth reaction bottle with a stirrer, adding 200mL of water for dissolving, cooling to 0-5 ℃, then adding 100g of the intermediate N-methyl-4-phenoxy-phthalimide prepared in the previous step in batches for about 1 hour, and preserving heat at 0-5 ℃ for 1-2 hours. And (3) tracking by using the thin-layer chromatography until the raw materials disappear, adding 130g of zinc powder and 200mL of water, heating to 90 ℃, preserving heat, reacting for 5 hours, cooling to room temperature after heat preservation, filtering, and washing a filter cake by using 50mL of x 2. And (3) adding hydrochloric acid into the filtrate to adjust the pH value to 1, heating to 80 ℃, preserving heat for 1-2h, cooling to room temperature after heat preservation is finished, adjusting the pH value to 5-7 by using 30% sodium hydroxide, filtering, washing a filter cake by using water, draining, adding the filter cake into 150mL of methanol, stirring for half an hour at room temperature, filtering, washing the filter cake by using 30mL of methanol 2, taking out and drying to obtain 75g of a product, wherein the yield is 85%, and the HPLC purity is 99%. Ms: 227(M + H) M/z,1HNMR(CDCl3)：5.21(s，2H)，6.92(s，1H)，7.11(m，3H)，7.22(t，1H，J＝7.6Hz)，7.43(m，2H)，7.81(d，1H，J＝8.4Hz)
EXAMPLE 205 Synthesis of phenoxy isobenzofuran-1- (3H) -one
Adding 40g of sodium hydroxide into a three-mouth reaction bottle with a stirrer, adding 200mL of water for dissolving, cooling to 0-5 ℃, then adding 94g of the intermediate 4-phenoxy-phthalimide prepared in the previous step in batches for about 1 hour, and preserving heat at 0-5 ℃ for 1-2 hours. After the thin-layer chromatography tracking is carried out until the raw materials disappear, 130g of zinc powder and 200mL of water are added, and liter is addedAnd (3) heating to 90 ℃, preserving the temperature for 5h, cooling to room temperature after the heat preservation is finished, filtering, and washing a filter cake by 50ml of x 2. And (3) adding hydrochloric acid into the filtrate to adjust the pH value to 1, heating to 80 ℃, preserving heat for 1-2h, reducing the temperature to 5-7 by using 30% sodium hydroxide, filtering, washing a filter cake by using water, draining, adding the filter cake into 150mL of methanol, stirring for half an hour at room temperature, filtering, washing the filter cake by using 30mL of methanol 2, taking out and drying to obtain 74g of a product, wherein the yield is 83% and the HPLC purity is 98%. Ms: 227(M + H) M/z,1HNMR(CDCl3)：5.21(s，2H)，6.92(s，1H)，7.11(m，3H)，7.22(t，1H，J＝7.6Hz)，7.43(m，2H)，7.81(d，1H，J＝8.4Hz)
EXAMPLE 215 Synthesis of phenoxy isobenzofuran-1- (3H) -one
Adding 22g of sodium hydroxide into a three-mouth reaction bottle with a stirrer, adding 200mL of water at room temperature for dissolving, then adding 100g of 2- (methylcarbamoyl) -5-phenoxybenzoic acid, 120g of zinc powder and 200mL of water, heating to 90 ℃, preserving heat for reaction for 5 hours, cooling to room temperature after heat preservation, filtering, and washing a filter cake with 50mL of x 2. And (3) adding hydrochloric acid into the filtrate to adjust the pH value to 1, heating to 80 ℃, preserving heat for 1-2h, reducing the temperature to 5-7 by using 30% sodium hydroxide, filtering, washing a filter cake by using water, draining, adding the filter cake into 150mL of methanol, stirring for half an hour at room temperature, filtering, washing the filter cake by using 30mL of methanol 2, taking out and drying to obtain 74g of a product, wherein the yield is 89%, and the HPLC purity is 99%. Ms: 227(M + H) M/z,1HNMR(CDCl3)：5.21(s，2H)，6.92(s，1H)，7.11(m，3H)，7.22(t，1H，J＝7.6Hz)，7.43(m，2H)，7.81(d，1H，J＝8.4Hz)
EXAMPLE 225 Synthesis of phenoxy isobenzofuran-1- (3H) -one
Adding 23g of sodium hydroxide into a three-mouth reaction bottle with a stirrer, adding 200mL of water at room temperature for dissolving, then adding 100g of 2-carbamoyl-5-phenoxybenzoic acid, 127g of zinc powder and 200mL of water, heating to 90 ℃, preserving heat for reaction for 5 hours, cooling to room temperature after heat preservation is finished, filtering, and washing a filter cake with 50mL of 2. Adding hydrochloric acid into the filtrate to adjust pH to 1, heating to 80 deg.C, maintaining for 1-2h, cooling after maintaining, adjusting pH to 5-7 with 30% sodium hydroxide, filtering, washing the filter cake with water, draining, adding into 150mL methanol, stirring at room temperatureStirring for half an hour, filtering, washing a filter cake with 30mL of methanol 2, taking out and drying to obtain 76g of a product, wherein the yield is 87%, and the HPLC purity is 98%. Ms: 227(M + H) M/z,1HNMR(CDCl3)：5.21(s，2H)，6.92(s，1H)，7.11(m，3H)，7.22(t，1H，J＝7.6Hz)，7.43(m，2H)，7.81(d，1H，J＝8.4Hz)
EXAMPLE 235 Synthesis of Phenoxyisobenzofuran-1- (3H) -one
Adding 22g of sodium hydroxide into a three-mouth reaction bottle with a stirrer, adding 200mL of water at room temperature for dissolving, then adding 127g of 2- (methylcarbamoyl) -5-phenoxybenzaldehyde, 98g of zinc powder and 200mL of water, heating to 90 ℃, preserving heat for reaction for 5 hours, cooling to room temperature after heat preservation is finished, filtering, and washing a filter cake with 50mL of 2. And (3) adding hydrochloric acid into the filtrate to adjust the pH value to 1, heating to 80 ℃, preserving heat for 1-2h, reducing the pH value to 5-7 by using 30% sodium hydroxide after the heat preservation is finished, filtering, washing a filter cake by using water, draining, adding the filter cake into 150mL of methanol, stirring for half an hour at room temperature, filtering, washing the filter cake by using 30mL of methanol 2, taking out and drying to obtain 103g of a product, wherein the yield is 91%, and the HPLC purity is 99%. Ms: 227(M + H) M/z,1HNMR(CDCl3)：5.21(s，2H)，6.92(s，1H)，7.11(m，3H)，7.22(t，1H，J＝7.6Hz)，7.43(m，2H)，7.81(d，1H，J＝8.4Hz)
EXAMPLE 245 Synthesis of phenoxy isobenzofuran-1- (3H) -one
Adding 22g of sodium hydroxide into a three-mouth reaction bottle with a stirrer, adding 200mL of water at room temperature for dissolving, then adding 120g of 2-carbamoyl-5-phenoxybenzaldehyde, 98g of zinc powder and 200mL of water, heating to 90 ℃, preserving heat for reaction for 5 hours, cooling to room temperature after heat preservation is finished, filtering, and washing a filter cake with 50mL of 2. And (3) adding hydrochloric acid into the filtrate to adjust the pH value to 1, heating to 80 ℃, preserving heat for 1-2h, reducing the temperature to 5-7 by using 30% sodium hydroxide, filtering, washing a filter cake by using water, draining, adding the filter cake into 150mL of methanol, stirring for half an hour at room temperature, filtering, washing the filter cake by using 30mL of methanol 2, taking out and drying to obtain 104g of a product, wherein the yield is 92%, and the HPLC purity is 98%. Ms: 227(M + H) M/z,1HNMR(CDCl3)：5.21(s，2H)，6.92(s，1H)，7.11(m，3H)，7.22(t，1H，J＝7.6Hz)，7.43(m，2H)，7.81(d，1H，J＝8.4Hz)
EXAMPLE 255 Synthesis of Phenoxyisobenzofuran-1- (3H) -one
Adding 200mL of water into a three-mouth reaction bottle with stirring, then adding 100g of 2-hydroxymethyl-5-phenoxybenzoic acid and 68mL of concentrated hydrochloric acid, heating to 80 ℃, preserving heat for 1-2h, cooling after the heat preservation is finished, adjusting the pH to 5-7 by using 30% sodium hydroxide, filtering, washing a filter cake by using water, pumping to dryness, adding into 180mL of methanol, stirring at room temperature for half an hour, filtering, washing the filter cake by using 30mL of methanol 2, taking out and drying to obtain 89g of a product, wherein the yield is 95%, and the HPLC purity is 99%. Ms: 227(M + H) M/z,1HNMR(CDCl3)：5.21(s，2H)，6.92(s，1H)，7.11(m，3H)，7.22(t，1H，J＝7.6Hz)，7.43(m，2H)，7.81(d，1H，J＝8.4Hz)
comparative example 15 Synthesis of Methoxyisobenzofuran-1- (3H) -one
Adding 50g of sodium hydroxide into a three-mouth reaction bottle with a stirrer, adding 250mL of water for dissolving, cooling to 0-5 ℃, adding 94g N-methyl-5-methoxy-phthalimide in batches, after about 1h, and keeping the temperature at 0-5 ℃ for 1-2 h. And (3) tracking by thin-layer chromatography until the raw materials disappear, adding 162g of zinc powder and 250mL of water, heating to 90 ℃, preserving heat, reacting for 5 hours, cooling to room temperature after heat preservation, filtering, and washing a filter cake by 70mL of 2. And (3) adding hydrochloric acid into the filtrate to adjust the pH value to 1, heating to 80 ℃, preserving heat for 1-2h, cooling to room temperature after heat preservation is finished, adjusting the pH value to 5-7 by using 30% sodium hydroxide, filtering, washing a filter cake by using water, draining, adding into 200mL of methanol, stirring for half an hour at room temperature, filtering, washing the filter cake by using 30mL of methanol 2, taking out and drying to obtain 45g of a product, wherein the yield is 56%, and the HPLC purity is 99%. M/z 165(M + H)1H-NMR (DMSO-d 6): 3.85(s, 3H,), 5.35(s, 2H), 7.29(s, 1H), 7.33(d, J ═ 8.3Hz), 7.57(d, 1H, J ═ 8.3Hz)
Comparative example 25 Synthesis of methyl Isobenzofuran-1- (3H) -one
Adding 60g of sodium hydroxide into a three-mouth reaction bottle with a stirrer, adding 300mL of water for dissolving, cooling to 0-5 ℃, adding 123g N-methyl-5-methyl-phthalimide in batches, keeping the temperature for 1-2 hours at 0-5 ℃ after about 1 hour. Tracking by thin layer chromatography until the raw materials disappear, adding 195g of zinc powder and 300mL of water, heating to 90 ℃, and keeping the temperatureAnd reacting for 5h, cooling to room temperature after heat preservation is finished, filtering, and washing a filter cake by using 100ml of 2. Adding hydrochloric acid into the filtrate to adjust the pH to 1, heating to 80 ℃, preserving heat for 1-2H, cooling to room temperature after heat preservation is finished, adjusting the pH to 5-7 by using 30% sodium hydroxide, filtering, washing a filter cake by using water, draining, adding the filter cake into 250mL of methanol, stirring for half an hour at room temperature, filtering, washing the filter cake by using 50mL of methanol 2, taking out and drying to obtain 53g of a product with the yield of 51%, and the HPLC purity of 99% M/z to 149(M + H)1H NMR(CDCl3)：：7.81(d，J＝7.6Hz，1H)，7.36(d，J＝7.6Hz，1H)，7.31(s，1H)，5.29(s，2H)，2.52(s，3H)。

Claims (3)

1. A process for the preparation of compound B, characterized in that it comprises the following steps: in water, in the presence of alkali and zinc, carrying out hydrolysis/reduction reaction on the compound C to obtain a compound B;
Figure FDA0002637902780000011
wherein, R is2Is hydrogen or C1～C4Alkyl groups of (a);
R1hydrogen or alkali metal.
2. The method of claim 1, wherein the alkali metal is sodium or potassium.
3. The method according to claim 1 or 2, wherein R is R in the hydrolysis/reduction reaction2In (b), the C1～C4The alkyl group of (a) is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
and/or in the hydrolysis/reduction reaction, the volume mol ratio of the water to the compound C is 0.8-1.1L/mol;
and/or, in the hydrolysis/reduction reaction, the alkali is sodium hydroxide or potassium hydroxide;
and/or, in the hydrolysis/reduction reaction, the molar ratio of the alkali to the compound C is 1.1-6.0;
and/or, in said hydrolysis/reduction reaction, said zinc is in the form of zinc powder;
and/or, in the hydrolysis/reduction reaction, the molar ratio of the zinc to the compound C is 3.0-5.0;
and/or in the hydrolysis/reduction reaction, the temperature of the hydrolysis/reduction reaction is 50-100 ℃;
and/or, in the hydrolysis/reduction reaction, the hydrolysis/reduction reaction takes the compound C as a reaction end point when no longer reacting.
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