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CN109503499A - A kind of Fan get Ta Ni intermediate and preparation method thereof - Google Patents

A kind of Fan get Ta Ni intermediate and preparation method thereof Download PDF

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CN109503499A
CN109503499A CN201811645549.0A CN201811645549A CN109503499A CN 109503499 A CN109503499 A CN 109503499A CN 201811645549 A CN201811645549 A CN 201811645549A CN 109503499 A CN109503499 A CN 109503499A
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reaction
sodium
fan
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吴学平
储贻结
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Nanjing Tian Yue Star Biotechnology Co Ltd
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Nanjing Tian Yue Star Biotechnology Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/59—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C205/60—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms in ortho-position to the carboxyl group, e.g. nitro-salicylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/64—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring the carbon skeleton being further substituted by singly-bound oxygen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
    • 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
    • C07C65/01—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 hydroxy or O-metal groups
    • C07C65/03—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 hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
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    • C07C67/00—Preparation of carboxylic acid esters
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/14—Acetic acid esters of monohydroxylic compounds
    • C07C69/145—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols
    • C07C69/157—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols containing six-membered aromatic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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    • C07—ORGANIC CHEMISTRY
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms

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Abstract

The present invention provides a kind of Fan get Ta Ni intermediate and preparation method thereof, the Fan get Ta Ni intermediate by compound 8 the sodium methoxide or lithium metal, sodium, potassium the effects of under obtain through 9 acidifications:

Description

A kind of Fan get Ta Ni intermediate and preparation method thereof
Technical field:
The present invention relates to a kind of preparation methods of Fan get Ta Ni intermediate, belong to pharmaceutical technology field.
Background technique:
Fan get Ta Ni (vandetanib) chemical name: 4- (4- bromo-2-fluoroanilino) -6- methoxyl group -7- [(1- methyl piperazine Pyridine -4- base) methoxyl group] quinazoline, it is a kind of oral small molecule multiple target point butyric acid kinase inhibitor, has to non-small cell lung cancer There is good therapeutic effect, is researched and developed by AstraZeneca pharmaceutical Co. Ltd, Britain (AstraZeneca).Beauty is obtained in April, 2011 State FDA approval listing, trade name Zactima.The synthesis of Fan get Ta Ni is related to key intermediate as shown in structural formula 1:
More publications include patent WO2003039511, WO2005013988, WO2010028254, CN10253217, CN102070608, CN1876650 and document European Journal of Medicinal Chemistry, 144,740- 750；2018；By Otvagin,Vasilii F.et al,Bioorganic&Medicinal Chemistry Letters,24 (17),4080-4083；2014；By Lim,Chae Jo et al,Jingxi Huagong Zhongjianti,41(6),41- 43；2011；The synthetic route of the reports such as By Li, Long et al all the following steps are included:
Wherein, the synthesis of compound 19 mainly has two lines:
Method one: it connects amine through hydroxyl protection, nitrification, reduction, cyclization, chloro using vanillic acid methyl esters as starting material and is produced Product 19, as follows:
Starting material vanillic acid methyl esters are expensive in the route, and product cost is high, and there are demethyl impurities in route.
Method two: using vanillic aldehyde as starting material, through hydroxyl protection, aldehyde radical itrile group, nitrification, reduction, with DMF-DMA and One step cyclization of amine obtains 19, as follows:
When nitro restores in the route can product cyan-hydrolysis impurity, and the step yield is not high, and product cost is high, equally with Method one can equally have demethyl impurity.
Summary of the invention:
The purpose of the present invention is a kind of preparation method of Fan get Ta Ni intermediate in view of the above problems, reaction conditions Mildly, yield is higher, and supplementary material is cheap and easy to get, is suitble to industrialized production.
Above-mentioned purpose is realized by following technical scheme:
A kind of Fan get Ta Ni intermediate, structural formula are as follows:
Wherein R3For lithium or sodium or potassium.
The preparation method of above-mentioned Fan get Ta Ni intermediate, this method are as follows:
Compound 8 obtains under sodium methoxide or lithium metal, sodium, potassium effect through the acidification of compound 9:
Wherein X is halogen, and R3 is lithium or sodium or potassium；Solvent used in acidization is methanol, and alkali used is first One or more of lithium alkoxide, sodium methoxide, potassium methoxide or lithium metal, metallic sodium, metallic potassium.
The preparation method of the Fan get Ta Ni intermediate, the compound 8 the preparation method comprises the following steps:
(1) it is thrown in acetic acid with P-hydroxybenzoic acid, hydrobromic acid is added, 20~30 DEG C of dropwise addition hydrogen peroxide drip and finish insulation reaction 6 ~10 hours, TLC monitored fully reacting, added water, agitation and filtration, dry compound 1；
(2) 1 benzyl chloride of compound, cylite, iodate benzyl are reacted under acid binding agent effect or are directly reacted with aceticanhydride To compound 2；
(3) compound 2 obtains compound 3 through nitrification；
(4) compound 3 restores to obtain compound 4 through nitro；
(5) compound 4 obtains compound 5 through cyclization；
(6) compound 5 obtains compound 6 through chloro；
(7) compound 6 connects the bromo- 2- fluoroaniline of 4- and obtains compound 7；
(8) deprotection of compound 7 obtains compound 8；
Specific reaction route is as follows:
Wherein X is the halogens such as fluorine, chlorine, bromine, iodine, R1For H or-CH3Or-CH2CH3Or-CH2CH2CH3Or-CH (CH3)2Or- CH2C6H5, R2For-CH2C6H5Or-COCH3；
In the synthesis process of compound 2, lower alcohols of the reaction dissolvent selected from C1~C4, acetone, butanone, one in DMF Kind is a variety of, and 50~150 DEG C of reaction temperature；Acid binding agent used be selected from one of triethylamine, diisopropylethylamine, pyridine or It is a variety of or be selected from one of sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide Or it is a variety of；
In the synthesis process of compound 3, nitrating agent used is in fuming nitric aicd, concentrated nitric acid, dust technology, nitrate One or more, wherein nitrate includes lithium nitrate, sodium nitrate, potassium nitrate；Reaction dissolvent used is selected from methylene chloride, acetic acid One or both of, 20~100 DEG C of reaction temperature；
Non-catalytic hydrogenating reduction system or catalytic hydrogenating reduction system are used in the reaction of the synthesis of compound 4: wherein non- Catalytic hydrogenating reduction system uses iron powder/hydrochloric acid or vulcanized sodium, hydrazine hydrate reduction agent, and reaction dissolvent used is selected from C1~C4 One of lower alcohols solvent or a variety of；Catalyst used in catalytic hydrogenating reduction system is Raney's nickel, palladium carbon, hydrogen-oxygen Change palladium/carbon, platinum carbon or rhodium carbon, the pressure limit of hydrogen is in 0.1~1.0MPa, and the dosage of catalyst is 0.1~10%w/w, instead Answering temperature is 20~60 DEG C, and reaction dissolvent used is selected from one of lower alcohols solvent of C1~C4 or a variety of；
Cyclization reagent is selected from formamidine acetate, formic acid carbonamidine, first formic acid triethyl, Yuan Jia in the reaction of the synthesis of compound 5 One of sour trimethyl is a variety of；Reaction dissolvent be selected from C1~C4 one of lower alcohols, ketone or acids solvent or It is a variety of or；40~100 DEG C of reaction temperature；
In the reaction of the synthesis of compound 6 chlorinating agent be selected from phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, thionyl chloride, One of oxalyl chloride, phosgene, surpalite, triphosgene are a variety of；It includes DMF, triethylamine, two that catalysts, which are selected from organic base, One of wopropyl ethyl amine, pyridine etc. are a variety of；Reaction dissolvent is selected from toluene, tetrahydrofuran, acetonitrile, dioxane, acetic acid One of non-protonic solvents such as ethyl ester are a variety of；Reaction temperature is 20~110 DEG C；
In the reaction of the synthesis of compound 7 catalysts be selected from organic base include DMF, triethylamine, diisopropylethylamine, One of pyridine etc. is a variety of；It is non-proton that reaction dissolvent is selected from toluene, tetrahydrofuran, acetonitrile, dioxane, ethyl acetate etc. One of property solvent is a variety of；Reaction temperature is 20~110 DEG C；
A kind of Fan get Ta Ni intermediate, structural formula are as follows:
Wherein X is halogen, R1For H or-CH3Or-CH2CH3Or-CH2CH2CH3Or-CH (CH3)2 Or-CH2C6H5, R2For-CH2C6H5Or-COCH3。
A kind of Fan get Ta Ni intermediate, structural formula are as follows:
Wherein X is halogen, R1For H or-CH3Or-CH2CH3Or-CH2CH2CH3Or-CH (CH3)2 Or-CH2C6H5, R2For-CH2C6H5Or-COCH3。
A kind of Fan get Ta Ni intermediate, structural formula are as follows:
Wherein X is halogen, R2For-CH2C6H5Or-COCH3。
A kind of Fan get Ta Ni intermediate, structural formula are as follows:
Wherein X is halogen, R2For-CH2C6H5Or-COCH3。
A kind of Fan get Ta Ni intermediate, structural formula are as follows:
Wherein X is halogen, R2For-CH2C6H5Or-COCH3。
A kind of Fan get Ta Ni intermediate, structural formula are as follows:
Wherein X is halogen.
A kind of Fan get Ta Ni intermediate, structural formula are as follows:
Wherein R3For lithium or sodium or potassium.
The utility model has the advantages that
1. the present invention can effectively avoid the side reactions such as demethylation in technical process, be conducive to the control of product quality；
2. the mild condition of preparation I, yield is higher, and supplementary material is cheap and easy to get, is suitble to industrialized production；
3. each step reaction yield of the invention is higher, auxiliary material is less, and overall cost is lower, is suitble to industrialized production；
4. having opened up Fan get Ta Ni important intermediate the present invention provides the intermediate of the new synthesis Fan get Ta Ni of 7 classes Research field.
Specific embodiment:
A kind of Fan get Ta Ni intermediate, structural formula are as follows:
Wherein R3For lithium or sodium or potassium.
The preparation method of above-mentioned Fan get Ta Ni intermediate, this method are as follows:
Compound 8 obtains under sodium methoxide or lithium metal, sodium, potassium effect through the acidification of compound 9:
Wherein X is halogen, and R3 is lithium or sodium or potassium；Solvent used in acidization is methanol, and alkali used is first One or more of lithium alkoxide, sodium methoxide, potassium methoxide or lithium metal, metallic sodium, metallic potassium.
The preparation method of the Fan get Ta Ni intermediate, the compound 8 the preparation method comprises the following steps:
(1) it is thrown in acetic acid with P-hydroxybenzoic acid, hydrobromic acid is added, 20~30 DEG C of dropwise addition hydrogen peroxide drip and finish insulation reaction 6 ~10 hours, TLC monitored fully reacting, added water, agitation and filtration, dry compound 1；
(2) 1 benzyl chloride of compound, cylite, iodate benzyl are reacted under acid binding agent effect or are directly reacted with aceticanhydride To compound 2；
(3) compound 2 obtains compound 3 through nitrification；
(4) compound 3 restores to obtain compound 4 through nitro；
(5) compound 4 obtains compound 5 through cyclization；
(6) compound 5 obtains compound 6 through chloro；
(7) compound 6 connects the bromo- 2- fluoroaniline of 4- and obtains compound 7；
(8) deprotection of compound 7 obtains compound 8；
Specific reaction route is as follows:
Wherein X is the halogens such as fluorine, chlorine, bromine, iodine, R1For H or-CH3Or-CH2CH3Or-CH2CH2CH3Or-CH (CH3)2Or- CH2C6H5, R2For-CH2C6H5Or-COCH3；
In the synthesis process of compound 2, lower alcohols of the reaction dissolvent selected from C1~C4, acetone, butanone, one in DMF Kind is a variety of, and 50~150 DEG C of reaction temperature；Acid binding agent used be selected from one of triethylamine, diisopropylethylamine, pyridine or It is a variety of or be selected from one of sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide Or it is a variety of；
In the synthesis process of compound 3, nitrating agent used is in fuming nitric aicd, concentrated nitric acid, dust technology, nitrate One or more, wherein nitrate includes lithium nitrate, sodium nitrate, potassium nitrate；Reaction dissolvent used is selected from methylene chloride, acetic acid One or both of, 20~100 DEG C of reaction temperature；
Non-catalytic hydrogenating reduction system or catalytic hydrogenating reduction system are used in the reaction of the synthesis of compound 4: wherein non- Catalytic hydrogenating reduction system uses iron powder/hydrochloric acid or vulcanized sodium, hydrazine hydrate reduction agent, and reaction dissolvent used is selected from C1~C4 One of lower alcohols solvent or a variety of；Catalyst used in catalytic hydrogenating reduction system is Raney's nickel, palladium carbon, hydrogen-oxygen Change palladium/carbon, platinum carbon or rhodium carbon, the pressure limit of hydrogen is in 0.1~1.0MPa, and the dosage of catalyst is 0.1~10%w/w, instead Answering temperature is 20~60 DEG C, and reaction dissolvent used is selected from one of lower alcohols solvent of C1~C4 or a variety of；
Cyclization reagent is selected from formamidine acetate, formic acid carbonamidine, first formic acid triethyl, Yuan Jia in the reaction of the synthesis of compound 5 One of sour trimethyl is a variety of；Reaction dissolvent be selected from C1~C4 one of lower alcohols, ketone or acids solvent or It is a variety of or；40~100 DEG C of reaction temperature；
In the reaction of the synthesis of compound 6 chlorinating agent be selected from phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, thionyl chloride, One of oxalyl chloride, phosgene, surpalite, triphosgene are a variety of；It includes DMF, triethylamine, two that catalysts, which are selected from organic base, One of wopropyl ethyl amine, pyridine etc. are a variety of；Reaction dissolvent is selected from toluene, tetrahydrofuran, acetonitrile, dioxane, acetic acid One of non-protonic solvents such as ethyl ester are a variety of；Reaction temperature is 20~110 DEG C；
In the reaction of the synthesis of compound 7 catalysts be selected from organic base include DMF, triethylamine, diisopropylethylamine, One of pyridine etc. is a variety of；It is non-proton that reaction dissolvent is selected from toluene, tetrahydrofuran, acetonitrile, dioxane, ethyl acetate etc. One of property solvent is a variety of；Reaction temperature is 20~110 DEG C；
A kind of Fan get Ta Ni intermediate, structural formula are as follows:
Wherein X is halogen, R1For H or-CH3Or-CH2CH3Or-CH2CH2CH3Or-CH (CH3)2 Or-CH2C6H5, R2For-CH2C6H5Or-COCH3。
A kind of Fan get Ta Ni intermediate, structural formula are as follows:
Wherein X is halogen, R1For H or-CH3Or-CH2CH3Or-CH2CH2CH3Or-CH (CH3)2 Or-CH2C6H5, R2For-CH2C6H5Or-COCH3。
A kind of Fan get Ta Ni intermediate, structural formula are as follows:
Wherein X is halogen, R2For-CH2C6H5Or-COCH3。
A kind of Fan get Ta Ni intermediate, structural formula are as follows:
Wherein X is halogen, R2For-CH2C6H5Or-COCH3。
A kind of Fan get Ta Ni intermediate, structural formula are as follows:
Wherein X is halogen, R2For-CH2C6H5Or-COCH3。
A kind of Fan get Ta Ni intermediate, structural formula are as follows:
Wherein X is halogen.
A kind of Fan get Ta Ni intermediate, structural formula are as follows:
Wherein R3For lithium or sodium or potassium.
The preparation of compound 1:
138g P-hydroxybenzoic acid (1mol) is put into 552ml acetic acid, is added 260ml hydrobromic acid (47%), and temperature control 20~ 30% hydrogen peroxide of 30 DEG C of dropwise addition 170g drips and finishes insulation reaction 6~10 hours, and TLC monitors fully reacting, and 500ml water is added, stirs Mix filtering, dry 182.5g compound 1.
The preparation of compound 2:
80g compound 1 (0.369mol) is put into the DMF of 480ml, 128g (0.928mol) potassium carbonate is added, at room temperature It is added dropwise 157.6g bromobenzyl (0.922mol), drop, which finishes, is warming up to 80~90 DEG C of reactions 10~12 hours, and TLC monitors fully reacting.It crosses Filter, filtrate decompression is concentrated to dryness, and is added 500ml water, agitation and filtration, dry 151g compound 2.
The preparation of compound 3:
90g compound 2 (0.227mol) is put into 540ml methylene chloride, 0~10 DEG C of dropwise addition 19.4g fuming nitric aicd of temperature control (0.296mol) drips and finishes insulation reaction 6~8 hours, and HPLC monitors fully reacting.100ml water, stirring are added into reaction system Layering, the saturated sodium bicarbonate solution of organic layer 100ml × 2 wash, and anhydrous sodium sulfate is dry, are concentrated to dryness slightly Product.
Purifying: 300ml ethyl acetate is added into crude product and 200ml petroleum ether, temperature rising reflux container are cooled to 10~20 DEG C, filtering, dry 73.5g compound 3.
The preparation (catalytic hydrogenation system) of compound 4:
60g compound 3 (0.136mol) is added into autoclave, the 5% palladium charcoal of 1.2g, 240ml methanol finishes, will be anti- It answers kettle nitrogen replacement 2 times, then with after hydrogen displacement 2 times, is reacted at room temperature 6~8 hours after debugging Hydrogen Vapor Pressure to 0.3MPa, TLC Fully reacting is monitored, palladium charcoal is recovered by filtration in reaction solution, and filtrate decompression is concentrated into small size, is cooled to -10~-5 DEG C, and filtering is done It is dry to obtain 53.4g compound 4.
The preparation (catalytic hydrogenation system) of compound 4:
40g compound 3 (0.09mol) is put into 240ml methanol, 40ml acetic acid is added, is warming up to 50~60 DEG C, in batches 16g (0.286mol) iron powder is added in secondary temperature control, finishes insulation reaction 8~10 hours, and TLC monitors fully reacting.It filters, filters while hot Liquid is concentrated to dryness, and 200ml methylene chloride is added, is filtered to remove iron cement, and filtrate decompression is concentrated to dryness, and 40ml methanol is added, It is cooled to -10~-5 DEG C of agitation and filtrations, dry 35.2g compound 4.
Compound 5 must be prepared:
48g compound 4 (0.117mol) is put into 288ml methanol, is added 24.1g formamidine acetate (0.234mol), is risen For temperature to back flow reaction 20~24 hours, TLC monitored fully reacting.It is cooled to room temperature, filtering, dry 35.5g compound 5.
The preparation of compound 6:
30g compound 5 (0.09mol) is put into 180ml toluene, 9.2g triethylamine (0.09mol) and 13.9g tri- is added Chlorethoxyfos (0.09mol) are warming up to 80~90 DEG C and react 4~6 hours, and TLC monitors fully reacting, and reaction product 6 is not taken out, and expect Liquid is cooled to 50~60 DEG C for use.
The preparation of compound 7:
The bromo- 2- fluoroaniline (0.09mol) of 4- of 17.3g is added in batches into above-mentioned 50~60 DEG C of feed liquid, finishes, protects Temperature reaction 1 hour is cooled to room temperature and 180ml isopropanol is added, and stirring washes out solid, filtering, dry 37.9g compound 7.
The preparation of compound 8:
35g compound 7 (0.07mol) is put into 350ml acetic acid, 70ml concentrated hydrochloric acid is added, is warming up to back flow reaction 10 ~12 hours, TLC monitored fully reacting.It is concentrated under reduced pressure into small size, 350ml water is added, filters to obtain wet product.Wet product is put into In 200ml ethyl alcohol, triethylamine tune PH to 7~8, filtering, dry 24.6g compound 8 are added dropwise at room temperature.
I preparation:
20g compound 8 (0.048mol) is put into 200ml methanol, 5g methanol is added in batches at 10~20 DEG C of temperature control Sodium (0.093mol), finishes, and is warming up to 40~50 DEG C and reacts 2~3 hours, TLC monitors fully reacting.It is cooled to 10~20 DEG C of drops Add hydrochloric acid tune PH to 5~6, filtering, washing, dry 13.1g I.
Embodiment 2 is carried out according to following proposal:
The preparation of compound 9:
50g compound 1 (0.23mol) is put into 300ml methanol, 41g thionyl chloride (0.345mol) is added dropwise at room temperature, Drop, which finishes, is warming up to back flow reaction 4~6 hours, is concentrated to dryness, and 200ml ice water agitation and filtration, dry 43.3g chemical combination is added Object 9.
The preparation of compound 10:
By in the DMF of 40g compound 9 (0.173mol) investment 320ml, it is added 35.8g potassium carbonate (0.259mol), room temperature Lower dropwise addition 35.5g bromobenzyl (0.208mol), drop, which finishes, is warming up to 80~90 DEG C of reactions 10~12 hours, and TLC monitors fully reacting.It crosses Filter, filtrate decompression is concentrated to dryness, and is added 500ml water, agitation and filtration, dry 48.7g compound 10.
The preparation of compound 11:
40g compound 10 (0.125mol) is put into 540ml methylene chloride, 0~10 DEG C of dropwise addition 12.3g smoke nitre of temperature control Sour (0.187mol) drips and finishes insulation reaction 6~8 hours, and HPLC monitors fully reacting.100ml water is added into reaction system, stirs Layering is mixed, the saturated sodium bicarbonate solution of organic layer 100ml × 2 washs, and anhydrous sodium sulfate is dry, is concentrated to dryness 41.8g compound 11.
The preparation of compound 12:
40g compound 11 (0.109mol) is added into autoclave, the 5% palladium charcoal of 0.8g, 240ml methanol finishes, will be anti- It answers kettle nitrogen replacement 2 times, then with after hydrogen displacement 2 times, is reacted at room temperature 6~8 hours after debugging Hydrogen Vapor Pressure to 0.3MPa, TLC Fully reacting is monitored, palladium charcoal is recovered by filtration in reaction solution, and filtrate decompression is concentrated into small size, is cooled to -10~-5 DEG C, and filtering is done It is dry to obtain 31.6g compound 11.
The preparation of compound 5:
30g compound 12 (0.089mol) is put into 180ml methanol, is added 13.8g formamidine acetate (0.134mol), is risen For temperature to back flow reaction 20~24 hours, TLC monitored fully reacting.It is cooled to room temperature, filtering, dry 26.8g compound 5.
Embodiment 3 is carried out according to following proposal:
The preparation of compound 13:
50g compound 1 (0.23mol) is put into 300ml acetic acid, is added 47g aceticanhydride (0.461mol), is warming up to reflux Reaction 20~24 hours, TLC detect fully reacting.It is cooled to room temperature, is added 600ml water, filtering, dry 51.4g compound 13。
The preparation of compound 14:
50g compound 13 (0.193mol) is put into 500ml methylene chloride, 0~10 DEG C of dropwise addition 19g fuming nitric aicd of temperature control (0.29mol) drips and finishes insulation reaction 6~8 hours, and HPLC monitors fully reacting.100ml water, stirring are added into reaction system Layering, the saturated sodium bicarbonate solution of organic layer 100ml × 2 wash, and anhydrous sodium sulfate is dry, are concentrated to dryness 53.7g compound 14.
The preparation of compound 15:
50g compound 14 (0.164mol) is added into autoclave, the 5% palladium charcoal of 1g, 300ml methanol is finished, will be reacted Kettle nitrogen replacement 2 times, then with after hydrogen displacement 2 times, reacted at room temperature 6~8 hours after debugging Hydrogen Vapor Pressure to 0.3MPa, TLC prison Fully reacting is controlled, palladium charcoal is recovered by filtration in reaction solution, and filtrate decompression is concentrated into small size, is cooled to -10~-5 DEG C, filtering, drying Obtain 42.5g compound 15.
The preparation of compound 16:
40g compound 15 (0.146mol) is put into 240ml methanol, is added 30g formamidine acetate (0.291mol), heating To back flow reaction 20~24 hours, TLC monitored fully reacting.It is cooled to room temperature, filtering, dry 36.8g compound 16.
The preparation of compound 17:
Will 30g compound 16 (0.106mol) put into 180ml toluene in, be added 10.7g triethylamine (0.106mol) and 16.2g phosphorus oxychloride (0.106mol) is warming up to 80~90 DEG C and reacts 4~6 hours, and TLC monitors fully reacting, reaction product 6 It does not take out, feed liquid is cooled to 50~60 DEG C for use.
The preparation of compound 18:
The bromo- 2- fluoroaniline (0.106mol) of 4- of 20.1g is added in batches into above-mentioned 50~60 DEG C of feed liquid, finishes, It insulation reaction 1 hour, is cooled to room temperature and 180ml isopropanol is added, stirring washes out solid, filtering, dry 41.8g compound 18。
The preparation of compound 8:
40g compound 18 (0.088mol) is put into 200ml methanol and 200ml water, it is molten that potassium hydroxide is added dropwise at room temperature Liquid (dissolution of 60ml water is added in 12.3g potassium hydroxide (0.22mol)), drips and finishes room temperature reaction 10~12 hours, TLC detection has been reacted Entirely.Hydrochloric acid tune PH to 5~6, filtering, dry 31.7g compound 8 are added dropwise at room temperature.
The above is only highly preferred embodiment of the present invention, the method for the present invention includes but be not limited to the above embodiments, the present invention Unaccomplished matter, belong to the common knowledge of those skilled in the art.

Claims (10)

1. a kind of Fan get Ta Ni intermediate, it is characterized in that: its structural formula are as follows:
Wherein R3For lithium or sodium or potassium.
2. a kind of preparation method of Fan get Ta Ni intermediate described in claim 1, it is characterized in that: this method are as follows:
Compound 8 obtains under sodium methoxide or lithium metal, sodium, potassium effect through the acidification of compound 9:
Wherein X is halogen, and R3 is lithium or sodium or potassium；Solvent used in acidization be methanol, alkali used be lithium methoxide, One or more of sodium methoxide, potassium methoxide or lithium metal, metallic sodium, metallic potassium.
3. the preparation method of Fan get Ta Ni intermediate according to claim 2, it is characterized in that: the preparation of the compound 8 Method are as follows:
(1) it is thrown in acetic acid with P-hydroxybenzoic acid, hydrobromic acid is added, 20~30 DEG C of dropwise addition hydrogen peroxide drip and finish insulation reaction 6~10 Hour, TLC monitors fully reacting, adds water, agitation and filtration, dry compound 1；
(2) 1 benzyl chloride of compound, cylite, iodate benzyl acid binding agent effect under react or directly with aceticanhydride reaction Close object 2；
(3) compound 2 obtains compound 3 through nitrification；
(4) compound 3 restores to obtain compound 4 through nitro；
(5) compound 4 obtains compound 5 through cyclization；
(6) compound 5 obtains compound 6 through chloro；
(7) compound 6 connects the bromo- 2- fluoroaniline of 4- and obtains compound 7；
(8) deprotection of compound 7 obtains compound 8；
Specific reaction route is as follows:
Wherein X is the halogens such as fluorine, chlorine, bromine, iodine, R1For H or-CH3Or-CH2CH3Or-CH2CH2CH3Or-CH (CH3)2Or- CH2C6H5, R2For-CH2C6H5Or-COCH3；
In the synthesis process of compound 2, reaction dissolvent be selected from one of the lower alcohols of C1~C4, acetone, butanone, DMF or It is a variety of, 50~150 DEG C of reaction temperature；Acid binding agent used is selected from one of triethylamine, diisopropylethylamine, pyridine or a variety of Or it is selected from one of sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide or more Kind；
In the synthesis process of compound 3, nitrating agent used is selected from one of fuming nitric aicd, concentrated nitric acid, dust technology, nitrate Or it is a variety of, wherein nitrate includes lithium nitrate, sodium nitrate, potassium nitrate；Reaction dissolvent used is in methylene chloride, acetic acid One or two, 20~100 DEG C of reaction temperature；
Non-catalytic hydrogenating reduction system or catalytic hydrogenating reduction system are used in the reaction of the synthesis of compound 4: wherein non-catalytic Hydrogenating reduction system uses iron powder/hydrochloric acid or vulcanized sodium, hydrazine hydrate reduction agent, and reaction dissolvent used is selected from the low of C1~C4 One of grade alcohols solvent is a variety of；Catalyst used in catalytic hydrogenating reduction system is Raney's nickel, palladium carbon, hydroxide Palladium/carbon, platinum carbon or rhodium carbon, for the pressure limit of hydrogen in 0.1~1.0MPa, the dosage of catalyst is 0.1~10%w/w, reaction Temperature is 20~60 DEG C, and reaction dissolvent used is selected from one of lower alcohols solvent of C1~C4 or a variety of；
Cyclization reagent is selected from formamidine acetate, formic acid carbonamidine, first formic acid triethyl, first formic acid three in the reaction of the synthesis of compound 5 One of methyl esters is a variety of；Reaction dissolvent is selected from one of lower alcohols, ketone or acids solvent of C1~C4 or a variety of Or；40~100 DEG C of reaction temperature；
Chlorinating agent is selected from phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, thionyl chloride, oxalyl in the reaction of the synthesis of compound 6 One of chlorine, phosgene, surpalite, triphosgene are a variety of；It includes DMF, triethylamine, diisopropyl that catalysts, which are selected from organic base, One of base ethamine, pyridine etc. are a variety of；Reaction dissolvent is selected from toluene, tetrahydrofuran, acetonitrile, dioxane, ethyl acetate One of equal non-protonic solvents are a variety of；Reaction temperature is 20~110 DEG C；
It includes DMF, triethylamine, diisopropylethylamine, pyridine that catalysts, which are selected from organic base, in the reaction of the synthesis of compound 7 Deng one of or it is a variety of；It is molten that reaction dissolvent is selected from the aprotics such as toluene, tetrahydrofuran, acetonitrile, dioxane, ethyl acetate One of agent is a variety of；Reaction temperature is 20~110 DEG C.
4. a kind of Fan get Ta Ni intermediate, it is characterized in that: its structural formula are as follows:
Wherein X is halogen, R1For H or-CH3Or-CH2CH3Or-CH2CH2CH3Or-CH (CH3)2Or- CH2C6H5, R2For-CH2C6H5Or-COCH3。
5. a kind of Fan get Ta Ni intermediate, it is characterized in that: its structural formula are as follows:
Wherein X is halogen, R1For H or-CH3Or-CH2CH3Or-CH2CH2CH3Or-CH (CH3)2Or- CH2C6H5, R2For-CH2C6H5Or-COCH3。
6. a kind of Fan get Ta Ni intermediate, it is characterized in that: its structural formula are as follows:
Wherein X is halogen, R2For-CH2C6H5Or-COCH3。
7. a kind of Fan get Ta Ni intermediate, it is characterized in that: its structural formula are as follows:
Wherein X is halogen, R2For-CH2C6H5Or-COCH3。
8. a kind of Fan get Ta Ni intermediate, it is characterized in that: its structural formula are as follows:
Wherein X is halogen, R2For-CH2C6H5Or-COCH3。
9. a kind of Fan get Ta Ni intermediate, it is characterized in that: its structural formula are as follows:Wherein X is halogen Element.
10. a kind of Fan get Ta Ni intermediate, it is characterized in that: its structural formula are as follows:Wherein R3For Lithium or sodium or potassium.
CN201811645549.0A 2018-12-30 2018-12-30 A kind of Fan get Ta Ni intermediate and preparation method thereof Pending CN109503499A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114671753A (en) * 2022-03-02 2022-06-28 营口兴福化工有限公司 3-Chloro-4-hydroxybenzoic acid synthesis method

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114671753A (en) * 2022-03-02 2022-06-28 营口兴福化工有限公司 3-Chloro-4-hydroxybenzoic acid synthesis method

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