CN106699578A - Synthesis method of important pharmaceutical and chemical intermediate 4-amino-3-chlorophenol - Google Patents
Synthesis method of important pharmaceutical and chemical intermediate 4-amino-3-chlorophenol Download PDFInfo
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- CN106699578A CN106699578A CN201510779481.5A CN201510779481A CN106699578A CN 106699578 A CN106699578 A CN 106699578A CN 201510779481 A CN201510779481 A CN 201510779481A CN 106699578 A CN106699578 A CN 106699578A
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- PNLPXABQLXSICH-UHFFFAOYSA-N 4-amino-3-chlorophenol Chemical compound NC1=CC=C(O)C=C1Cl PNLPXABQLXSICH-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 239000000126 substance Substances 0.000 title abstract description 5
- 238000001308 synthesis method Methods 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 56
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000003513 alkali Substances 0.000 claims abstract description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 5
- -1 4-acetamino phenyl Chemical group 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 238000010189 synthetic method Methods 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000012320 chlorinating reagent Substances 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 229960000583 acetic acid Drugs 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- PXJJSXABGXMUSU-UHFFFAOYSA-N disulfur dichloride Chemical compound ClSSCl PXJJSXABGXMUSU-UHFFFAOYSA-N 0.000 claims description 2
- 150000002168 ethanoic acid esters Chemical class 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 15
- 239000002994 raw material Substances 0.000 abstract description 9
- 238000000034 method Methods 0.000 abstract description 7
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 abstract 1
- 230000021736 acetylation Effects 0.000 abstract 1
- 238000006640 acetylation reaction Methods 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 229940049953 phenylacetate Drugs 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 238000003756 stirring Methods 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 14
- 239000000543 intermediate Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- UJVWPZIWWKDJNH-UHFFFAOYSA-N (4-acetamido-2-hydroxyphenyl)arsonic acid Chemical compound CC(=O)NC1=CC=C([As](O)(O)=O)C(O)=C1 UJVWPZIWWKDJNH-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- FHIVAFMUCKRCQO-UHFFFAOYSA-N diazinon Chemical compound CCOP(=S)(OCC)OC1=CC(C)=NC(C(C)C)=N1 FHIVAFMUCKRCQO-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- SPMVMDHWKHCIDT-UHFFFAOYSA-N 1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC=1C=C(C)ON=1 SPMVMDHWKHCIDT-UHFFFAOYSA-N 0.000 description 1
- ISPYQTSUDJAMAB-UHFFFAOYSA-N 2-chlorophenol Chemical compound OC1=CC=CC=C1Cl ISPYQTSUDJAMAB-UHFFFAOYSA-N 0.000 description 1
- HORNXRXVQWOLPJ-UHFFFAOYSA-N 3-chlorophenol Chemical class OC1=CC=CC(Cl)=C1 HORNXRXVQWOLPJ-UHFFFAOYSA-N 0.000 description 1
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229960003784 lenvatinib Drugs 0.000 description 1
- WOSKHXYHFSIKNG-UHFFFAOYSA-N lenvatinib Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 WOSKHXYHFSIKNG-UHFFFAOYSA-N 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 229960000940 tivozanib Drugs 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses a synthesis method of important pharmaceutical and chemical intermediate 4-amino-3-chlorophenol, and the method comprises the following steps: acetylation of p-aminophenol, triethylamine and an acylating agent to obtain 4-acetamino phenyl acetate shown as a formula I; chlorination of the formula I compound and a chlorinated reagent to obtain 4-acetamino-3-phenyl chloroacetate shown as a formula II; and reaction of the formula II compound and an alkali at 80-120 DEG C to obtain the 4-amino-3-chlorophenol. The preparation method has the advantages of easy availability of raw materials, low cost, mild condition, high process operability and controllability, high yield and no need of complex post-treatment to obtain the high-purity 4-amino-3-chlorophenol.
Description
Technical field
The invention belongs to technical field of organic synthesis, and in particular to a kind of synthetic method of 4- amino -3- chlorophenols.
Background technology
4- amino -3- chlorophenols are a kind of important pharmaceutical-chemical intermediates, widely apply to antitumor, angiocardiopathy,
In the design synthesis of the medicines such as sacred disease.It is to prepare Novel tyrosine kinase inhibitors for Wo Zhani (Tivozanib) and pleasure
Cut down for the important intermediate of Buddhist nun (Lenvatinib).
The preparation of current 4- amino -3- phenol mainly has two methods, and one kind is through Bamberger by N- (2- chlorphenyls) azanol
Reset and prepare, starting material N- used by the method (2- chlorphenyls) azanol should not be obtained, and used in preparation process high temperature,
The conditions such as high pressure, are not suitable for industrialized production；Another method is to generate diazol through diazotising with p-aminobenzene sulfonic acid, then
There is nucleophilic substitution generation 4- (2- chloro-4-hydroxyls phenylazo) benzene sulfonic acid with 3- chlorophenols, then by zinc powder and ammonium formate
Reduction obtains the chlorophenol of 4- amino -3, and the method needs to use diazol in preparation process, is susceptible to blast, uncomfortable
Close industrialized production.
The content of the invention
There are problems that high cost, high temperature, high pressure, there is provided are a kind of it is an object of the invention to overcome in the prior art
Easy to operate, raw material is easy to get, the 4- amino -3- chlorophenols of the suitable industrialized production of low cost, mild condition, high income
Synthetic method.
The purpose of the present invention can be reached by following measures：
A kind of synthetic method of important pharmaceutical-chemical intermediate 4- amino -3- chlorophenols, it comprises the following steps：
A, para-aminophenol and triethylamine and acylating reagent carry out acetylization reaction, obtain compound of formula I；
B, compound of formula I and chlorinating agent carry out chlorination reaction, obtain Formula II compound；
The reaction of C, Formula II compound and inorganic alkali solution, obtains 4- amino -3- chlorophenols.
Step A is the preparation of compound of formula I 4- acetylaminoacetic acid phenyl esters, acylating reagent in the reaction be selected from acetic anhydride,
One or more in chloroacetic chloride, acetic acid and acetic acid esters.In a kind of preferred scheme, the mole dosage of acylating reagent is
2~10 times of para-aminophenol, the mole dosage of triethylamine is 1~5 times (more preferably 2~4 times) of para-aminophenol.
0~40 DEG C of reaction temperature in step A, preferably 0~30 DEG C, further preferred 20~30 DEG C；Reaction time 1~
15h, preferably 2~10h.
After the completion of reaction in step A, can have to adding water in reaction solution and carrying out a point liquid with water-insoluble organic solvent
Concentration is dried after machine layer washing, you can obtain compound of formula I 4- acetylaminoacetic acid phenyl esters；Preferably use water and ethyl acetate
Carry out extract and separate purification and prepare target product.
A kind of specific course of reaction of step A is as follows：By in para-aminophenol addition triethylamine and acylating reagent, room is risen to
Temperature 2~10h of stirring, is subsequently adding water and ethyl acetate point liquid obtains organic layer, and organic layer is washed with water, and drying is concentrated to give 4-
Acetylaminoacetic acid phenyl ester.
Step B is the preparation of Formula II compound 4- acetylaminohydroxyphenylarsonic acid 3- phenyl chloroacetates, and the chlorinating agent in the reaction may be selected from
One kind or two in chlorine, chlorosuccinimide (NCS), hypochlorous acid, the tertiary fourth fat of hypochlorous acid, sulfur chloride, chlorosulfuric acid
More than kind.In a kind of preferred scheme, the reaction dissolvent of chlorination reaction may be selected from N ' dinethylformamides (DMF), second
Acetoacetic ester, dichloromethane, glacial acetic acid or watery hydrochloric acid, the mole dosage of chlorinating agent are 1~1.5 times of compound of formula I.
Reaction temperature in step B is 0~40 DEG C, preferably 20~30 DEG C；Reaction time is 1~10h, preferably 1~8h.
After the completion of reaction in step B, also a point liquid can be carried out to addition water in reaction solution and with water-insoluble organic solvent,
After organic layer washing, crystallization, filtering is dried, and obtains 4- acetylaminohydroxyphenylarsonic acid 3- phenyl chloroacetates.Ethyl acetate is preferably used to enter
The purification of row extract and separate prepares target product by adding petroleum ether precipitation.
A kind of specific course of reaction of step B is as follows：Intermediate compound I is dissolved in solvent, chlorinating agent, 0~30 DEG C is added
1~8h of stirring, is subsequently adding water and ethyl acetate point liquid obtains organic layer, and organic layer is washed with water, and isometric oil is added dropwise
Ether, crystallization, filtering, dry 4- acetylaminohydroxyphenylarsonic acid 3- phenyl chloroacetates.
To prepare 4- amino -3- chlorophenols, the step preferred formula II compounds are reacted step C with aqueous alkali.One
Plant in preferred scheme, the reaction temperature of step C is 80~120 DEG C, the concentration of aqueous alkali is 2~8mol/L.
Alkali in step C is preferably inorganic base, may be selected from NaOH, potassium hydroxide, lithium hydroxide, potassium carbonate, carbon
One or more in sour sodium, cesium carbonate；The mole dosage of alkali is 2~15 times of Formula II compound, preferably 5~10
Times.
In step C, reaction solution is cooled to room temperature after reaction, with acid for adjusting pH value to 4~7, filtration drying is obtained final product
4- amino -3- chlorophenols, wherein the acid is selected from one or more in concentrated hydrochloric acid, sulfuric acid, phosphoric acid.
A kind of specific course of reaction of step C is as follows：Intermediate II is dissolved in aqueous alkali, 90~110 DEG C are heated to, stirred
4~8h is mixed, room temperature is cooled to, with acid for adjusting pH, the solid for separating out is filtered, filter cake is washed with water, is drying to obtain 4- amino
- 3- chlorophenols.
Beneficial effects of the present invention：Step operation involved in the present invention is convenient, mild condition, does not have high temperature, high pressure, explosive
Etc. harsh conditions, the requirement for equipment in production is greatly reduced.This technique can realize large-scale industrial production, produce
Product yield is high, and purity is high, and energy consumption is low.
Specific embodiment
Synthetic method of the present invention is described in detail below by way of example, but protection scope of the present invention is not limited thereto.
The reaction scheme of following embodiment is as follows：
Embodiment 1：
The first step, the preparation of 4- acetylaminoacetic acid phenyl esters：It is right to being sequentially added in 2000ml four-hole bottles under condition of ice bath
Amino-phenol (100g, 0.92mol), acetic anhydride (500ml), triethylamine (278g, 2.75mol) is gradually increased to
Stirring reaction at room temperature.After stirring reaction 4h, TLC detections, raw material reaction is finished, and 2000ml is added toward reaction solution
Water and 1000ml ethyl acetate, with the separatory funnel point liquid of 5L, upper organic phase is continued to employ, and water is mutually extracted with ethyl acetate 2
Secondary, ethyl acetate distillation and concentration is obtained product by each ethyl acetate 500ml：146g, yield：82.5%.
Second step, the preparation of 4- acetylaminohydroxyphenylarsonic acid 3- phenyl chloroacetates：To sequentially adding intermediate compound I in the single port bottle of 500ml
(30g, 155.3mmol), NCS (21g, 155.3mmol), DMF (300ml), stirring reaction under normal temperature, instead
4h is answered, TLC detections, reaction is finished.1000ml water and 200ml ethyl acetate are added in reaction solution, with separatory funnel point
Liquid obtains organic layer, and organic layer is washed with water 1 time.To 200ml petroleum ethers are slowly added in organic layer, there are a large amount of whites solid
Body is separated out, and filtering, filter cake petroleum ether drip washing, solid dries to obtain product：27g, yield:76.4%, purity 98.3%.
3rd step, the preparation of 4- amino -3- chlorophenols：In to 3000ml four-hole bottles, sequentially add intermediate II (218g,
0.96mol), NaOH solution (6mol/L, 1000ml), dissolution of raw material, in grey black.100~110 DEG C are heated to,
Stirring reaction 5h, reaction is complete.Room temperature is cooled to ice bath, pH to 5~6 is adjusted with concentrated hydrochloric acid, separate out a large amount of grey blacks
Solid, filtering, filter cake adds suitable quantity of water to be beaten, and stirs 15min, and product is dried to obtain in filtering：115g, HPLC purity：
99.0%, yield：83.5%.
Embodiment 2：
The first step, the preparation of 4- acetylaminoacetic acid phenyl esters：It is right to being sequentially added in 2000ml four-hole bottles under condition of ice bath
Amino-phenol (100g, 0.92mol), ethyl acetate (1500mL), triethylamine (185g, 1.83mol), chloroacetic chloride
(108g, 1.37mol), is gradually increased to stirring reaction at room temperature.After stirring reaction 8h, TLC detections, raw material reaction is complete
Finish, 1500ml water is added toward reaction solution, with the separatory funnel point liquid of 5L, obtain ethyl acetate layer, ethyl acetate is steamed
Evaporate and be concentrated to give product：165g, yield：93.4%.
Second step, the preparation of 4- acetylaminohydroxyphenylarsonic acid 3- phenyl chloroacetates：To sequentially adding intermediate compound I in the single port bottle of 1000ml
(90g, 0.46mol), glacial acetic acid (450ml), NCS (62g, 0.46mol), stirring reaction under normal temperature, reaction
2h, TLC detect that reaction is finished.3000ml water and 600ml ethyl acetate are added in reaction solution, with separatory funnel point liquid
Organic layer is obtained, organic layer is washed with water 2 times.To 600ml petroleum ethers are slowly added in organic layer, there are a large amount of white solids
Separate out, filtering, filter cake petroleum ether drip washing, solid dries to obtain product：90g, yield:85.2%, purity 98.5%.
3rd step, the preparation of 4- amino -3- chlorophenols：In to 2000ml four-hole bottles, sequentially add intermediate II (150g,
0.66mol), KOH solution (6mol/L, 700ml), dissolution of raw material, in grey black.90~100 DEG C are heated to, are stirred
Reaction 6h is mixed, reaction is complete.Room temperature is cooled to ice bath, pH to 5~6 is adjusted with concentrated hydrochloric acid, separated out a large amount of grey blacks and consolidate
Body, filtering, filter cake adds suitable quantity of water to be beaten, and stirs 15min, and product is dried to obtain in filtering：79g, HPLC purity：98.7%,
Yield：83.5%.
Embodiment 3:
The first step, the preparation of 4- acetylaminoacetic acid phenyl esters：It is right to being sequentially added in 2000ml four-hole bottles under condition of ice bath
Amino-phenol (100g, 0.92mol), dichloromethane (1000mL), triethylamine (139g, 1.37mol), chloroacetic chloride
(86g, 1.10mol), is gradually increased to stirring reaction at room temperature.After stirring reaction 8h, TLC detections, raw material reaction is complete
Finish, 1500ml water is added toward reaction solution, with the separatory funnel point liquid of 5L, obtain dichloromethane layer, dichloromethane is steamed
Evaporate and be concentrated to give product：164g, yield：92.7%.
Second step, the preparation of 4- acetylaminohydroxyphenylarsonic acid 3- phenyl chloroacetates：To sequentially adding intermediate compound I in the single port bottle of 1000ml
(70g, 0.36mol), ethyl acetate (700ml), NCS (48g, 0.36mol), stirring reaction under normal temperature, instead
2h is answered, TLC detections, reaction is finished.700ml water is added in reaction solution, organic layer is obtained with separatory funnel point liquid, it is organic
Layer is washed with water 2 times.To 700ml petroleum ethers are slowly added in organic layer, there are a large amount of white solids to separate out, filtering, filter
Cake petroleum ether drip washing, solid dries to obtain product：73g, yield:88.4%, purity 98.5%.
3rd step, the preparation of 4- amino -3- chlorophenols：In to 2000ml four-hole bottles, sequentially add intermediate II (150g,
0.66mol), KOH solution (4mol/L, 900ml), dissolution of raw material, in grey black.90~100 DEG C are heated to, are stirred
Reaction 12h is mixed, reaction is complete.Room temperature is cooled to ice bath, pH to 5~6 is adjusted with concentrated hydrochloric acid, separate out a large amount of grey blacks
Solid, filtering, filter cake adds suitable quantity of water to be beaten, and stirs 15min, and product is dried to obtain in filtering：83g, HPLC purity：
98.4%, yield：87.8%.
Each raw material and solvent cited by the present invention can realize the present invention, purity ＞ 98% (HPLC normalization methods),
This is not just enumerated.
Claims (10)
1. a kind of synthetic method of 4- amino -3- chlorophenols, it is characterised in that it comprises the following steps：
A, para-aminophenol and triethylamine and acylating reagent carry out acetylization reaction, obtain compound of formula I；
B, compound of formula I and chlorinating agent carry out chlorination reaction, obtain Formula II compound；
The reaction of C, Formula II compound and inorganic alkali solution, obtains 4- amino -3- chlorophenols.
2. synthetic method according to claim 1, it is characterised in that the acylating reagent is selected from acetic anhydride, chloroacetic chloride, second
One or more in acid and acetic acid esters.
3. synthetic method according to claim 1 and 2, it is characterised in that the mole dosage of acylating reagent is para-aminophenol
2~10 times, the mole dosage of triethylamine is 1~5 times of para-aminophenol.
4. synthetic method according to claim 1, it is characterised in that the reaction temperature in step A is 0~40 DEG C, reaction
1~15h of time.
5. synthetic method according to claim 1, it is characterised in that it is sub- that the chlorinating agent is selected from chlorine, chloro succinyl
One or more in the tertiary fourth fat of amine, hypochlorous acid, hypochlorous acid, sulfur chloride, chlorosulfuric acid.
6. synthetic method according to claim 1 or 5, it is characterised in that in the chlorination reaction of step B, reaction dissolvent is
DMF, ethyl acetate, dichloromethane, glacial acetic acid or watery hydrochloric acid, the mole dosage of chlorinating agent is compound of formula I
1~1.5 times.
7. synthetic method according to claim 1 or 5, it is characterised in that in step B, reaction temperature is 0~40 DEG C,
Reaction time is 1~10h.
8. synthetic method according to claim 1, it is characterised in that in step C, Formula II compound is carried out with aqueous alkali
Reaction, reaction temperature is 80~120 DEG C, and the concentration of aqueous alkali is 2~8mol/L.
9. the synthetic method according to claim 1 or 8, it is characterised in that in step C, the alkali is inorganic base, is selected from
One or more in NaOH, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate.
10. synthetic method according to claim 1, it is characterised in that in step C, lowers the temperature after reaction, uses acid for adjusting pH
To 4~7, filtration drying obtains final product 4- amino -3- chlorophenols to value, wherein the acid is selected from concentrated hydrochloric acid, sulfuric acid, phosphoric acid
One or more.
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Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4520134A (en) * | 1982-08-27 | 1985-05-28 | Rosen Gerald M | N-alkyl-4'-hydroxyacetanilides, pharmaceutical compositions comprising them and their use |
| SU1583355A1 (en) * | 1988-08-29 | 1990-08-07 | Новосибирский институт органической химии СО АН СССР | Method of producing 3,4,4ъ-triaminodiphenyl ester |
| JP2007291096A (en) * | 2006-03-31 | 2007-11-08 | National Institute Of Advanced Industrial & Technology | Selective sequential polyacylation and device therefor |
| CN101085741A (en) * | 2007-06-22 | 2007-12-12 | 健雄职业技术学院 | Method for synthesizing 3,4-diaminophenol |
| CN102304052A (en) * | 2011-07-28 | 2012-01-04 | 浙江大学 | Method for preparing 5-bromo-2-hydroxy-3-nitroacetophenone |
| CN102321041A (en) * | 2011-07-20 | 2012-01-18 | 北京赛科药业有限责任公司 | Preparation method of linezolid |
| CN102424655A (en) * | 2011-10-28 | 2012-04-25 | 杭州迪克化工技术有限公司 | Preparation method of R-(-)-2-acetamido-3-methoxy-N-benzyl propionamide |
| CN102557909A (en) * | 2010-12-30 | 2012-07-11 | 上海恩氟佳科技有限公司 | Preparation method for 5-fluorin-2-hydroxyacetophenone |
| CN105001107A (en) * | 2015-07-07 | 2015-10-28 | 西安交通大学 | Synthetic method for methyl caulophine |
-
2015
- 2015-11-13 CN CN201510779481.5A patent/CN106699578B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4520134A (en) * | 1982-08-27 | 1985-05-28 | Rosen Gerald M | N-alkyl-4'-hydroxyacetanilides, pharmaceutical compositions comprising them and their use |
| SU1583355A1 (en) * | 1988-08-29 | 1990-08-07 | Новосибирский институт органической химии СО АН СССР | Method of producing 3,4,4ъ-triaminodiphenyl ester |
| JP2007291096A (en) * | 2006-03-31 | 2007-11-08 | National Institute Of Advanced Industrial & Technology | Selective sequential polyacylation and device therefor |
| CN101085741A (en) * | 2007-06-22 | 2007-12-12 | 健雄职业技术学院 | Method for synthesizing 3,4-diaminophenol |
| CN102557909A (en) * | 2010-12-30 | 2012-07-11 | 上海恩氟佳科技有限公司 | Preparation method for 5-fluorin-2-hydroxyacetophenone |
| CN102321041A (en) * | 2011-07-20 | 2012-01-18 | 北京赛科药业有限责任公司 | Preparation method of linezolid |
| CN102304052A (en) * | 2011-07-28 | 2012-01-04 | 浙江大学 | Method for preparing 5-bromo-2-hydroxy-3-nitroacetophenone |
| CN102424655A (en) * | 2011-10-28 | 2012-04-25 | 杭州迪克化工技术有限公司 | Preparation method of R-(-)-2-acetamido-3-methoxy-N-benzyl propionamide |
| CN105001107A (en) * | 2015-07-07 | 2015-10-28 | 西安交通大学 | Synthetic method for methyl caulophine |
Non-Patent Citations (5)
| Title |
|---|
| SACHITANAND M. MALI等: "Thioacids Mediated Selective and Mild N-Acylation of Amines", 《J.ORG.CHEM.》 * |
| THEILACKER, WALTER: "Theory of substitution rules. Chlorination of o- and p-aminophenols", 《BERICHTE DER DEUTSCHEN CHEMISCHEN GESELLSCHAFT [ABTEILUNG] B: ABHANDLUNGEN》 * |
| 张志贤: "《实用有机定量分析》", 31 March 1965, 上海科学技术出版社 * |
| 李丽娟 等: "《药物合成反应技术》", 31 July 2007, 化学工业出版社 * |
| 段行信: "《实用精细有机合成手册》", 31 January 2000, 化学工业出版社 * |
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