CN106699578B - A kind of synthetic method of important pharmaceutical-chemical intermediate 4- amino -3- chlorophenol - Google Patents
A kind of synthetic method of important pharmaceutical-chemical intermediate 4- amino -3- chlorophenol Download PDFInfo
- Publication number
- CN106699578B CN106699578B CN201510779481.5A CN201510779481A CN106699578B CN 106699578 B CN106699578 B CN 106699578B CN 201510779481 A CN201510779481 A CN 201510779481A CN 106699578 B CN106699578 B CN 106699578B
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- formula
- amino
- chlorophenol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- PNLPXABQLXSICH-UHFFFAOYSA-N 4-amino-3-chlorophenol Chemical compound NC1=CC=C(O)C=C1Cl PNLPXABQLXSICH-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 238000010189 synthetic method Methods 0.000 title claims abstract description 13
- 239000000126 substance Substances 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- 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 21
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003513 alkali Substances 0.000 claims abstract description 10
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 44
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- 229960000583 acetic acid Drugs 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-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
- 238000001035 drying Methods 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
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 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
- 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- CHWRSCGUEQEHOH-UHFFFAOYSA-N potassium oxide Chemical compound [O-2].[K+].[K+] CHWRSCGUEQEHOH-UHFFFAOYSA-N 0.000 claims 1
- 229910001950 potassium oxide Inorganic materials 0.000 claims 1
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 17
- 239000002994 raw material Substances 0.000 abstract description 9
- 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 abstract description 7
- 238000000034 method Methods 0.000 abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 239000012320 chlorinating reagent Substances 0.000 abstract description 5
- 238000012805 post-processing Methods 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 12
- 238000000926 separation method Methods 0.000 description 11
- 239000007788 liquid Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 7
- 238000001514 detection method Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000012954 diazonium Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 2
- 238000005360 mashing Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- IPBVNPXQWQGGJP-UHFFFAOYSA-N phenyl acetate Chemical compound CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 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
- -1 2- chlorphenyl Chemical group 0.000 description 1
- HORNXRXVQWOLPJ-UHFFFAOYSA-N 3-chlorophenol Chemical compound OC1=CC=CC(Cl)=C1 HORNXRXVQWOLPJ-UHFFFAOYSA-N 0.000 description 1
- GQRUMXSXCFMAQE-UHFFFAOYSA-N 4-[(2-chloro-4-hydroxyphenyl)diazenyl]benzenesulfonic acid Chemical compound ClC1=C(C=CC(=C1)O)N=NC1=CC=C(C=C1)S(=O)(=O)O GQRUMXSXCFMAQE-UHFFFAOYSA-N 0.000 description 1
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical class NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-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
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-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
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- PXJJSXABGXMUSU-UHFFFAOYSA-N disulfur dichloride Chemical compound ClSSCl PXJJSXABGXMUSU-UHFFFAOYSA-N 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
- 150000002148 esters Chemical class 0.000 description 1
- 150000002168 ethanoic acid esters Chemical class 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 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
- JBGGHWCSFZVUFV-UHFFFAOYSA-N n-(2-chlorophenyl)hydroxylamine Chemical compound ONC1=CC=CC=C1Cl JBGGHWCSFZVUFV-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
- 239000012071 phase Substances 0.000 description 1
- 238000000746 purification 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
- 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 invention discloses a kind of synthetic method of important pharmaceutical-chemical intermediate 4- amino -3- chlorophenol, it the steps include: that para-aminophenol and triethylamine and acylating reagent carry out acetylization reaction, obtain compound of formula I 4- acetylaminoacetic acid phenyl ester；Compound of formula I and chlorinating agent carry out chlorination reaction, obtain Formula II compound 4- acetylaminohydroxyphenylarsonic acid 3- phenyl chloroacetate；Formula II compound is reacted at 80~120 DEG C with alkali, obtains 4- amino -3- chlorophenol.The preparation method raw material is easy to get, is at low cost, mild condition, process operability and controllability are strong, high income, and the 4- amino -3- chlorophenol of high-purity can be obtained without complicated post-processing.
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- chlorophenol.
Background technique
4- amino -3- chlorophenol is a kind of important pharmaceutical-chemical intermediate, widely applies to antitumor, cardiovascular disease
In the design synthesis of the drugs such as disease, neurological disease.It is to prepare Novel tyrosine kinase inhibitors for Wo Zhani (Tivozanib)
It cuts down with pleasure for the important intermediate of Buddhist nun (Lenvatinib).
There are mainly two types of methods for the preparation of 4- amino -3- phenol at present, and one is passed through by N- (2- chlorphenyl) azanol
Bamberger resets preparation, and azanol should not be made starting material N- (2- chlorphenyl) used in this method, and use during the preparation process
To conditions such as high temperature, high pressures, be not suitable for industrialized production；Another method is to generate diazonium through diazotising with p-aminobenzene sulfonic acid
Salt, then nucleophilic substitution occurs with 3- chlorophenol and generates 4- (2- chloro-4-hydroxyl phenylazo) benzene sulfonic acid, using zinc powder and
Ammonium formate restores to obtain -3 chlorophenol of 4- amino, and this method needs to use diazonium salt during the preparation process, is easy to happen explosion, no
It is suitble to industrialized production.
Summary of the invention
It is an object of the invention to overcome exist in the prior art at high cost, high temperature, high pressure, it is explosive the problems such as, provide one
It is kind easy to operate, raw material is easy to get, the 4- amino -3- chlorophenol of the suitable industrialized production of at low cost, mild condition, high income
Synthetic method.
The purpose of the present invention can be achieved by the following measures:
A kind of synthetic method of important pharmaceutical-chemical intermediate 4- amino -3- chlorophenol comprising 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；
C, Formula II compound is reacted with inorganic alkali solution, obtains 4- amino -3- chlorophenol.
Step A is the preparation of compound of formula I 4- acetylaminoacetic acid phenyl ester, and the acylating reagent in the reaction is selected from acetic acid
One or more of acid anhydride, chloroacetic chloride, acetic acid and acetic acid esters.In a preferred embodiment, the mole dosage of acylating reagent
It is 2~10 times of para-aminophenol, the mole dosage of triethylamine is 1~5 times (more preferable 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.
In step A after the reaction was completed, water can be added into reaction solution and carry out liquid separation with water-insoluble organic solvent, have
Dry concentration, can be obtained compound of formula I 4- acetylaminoacetic acid phenyl ester after the washing of machine layer；Use of water is preferred and ethyl acetate into
Target product is prepared in row extraction and separation purification.
A kind of specific reaction process of step A is as follows: para-aminophenol being added in triethylamine and acylating reagent, room is risen to
Temperature 2~10h of stirring, is then added water and ethyl acetate liquid separation obtains organic layer, and organic layer is washed with water, and drying is concentrated to give 4- acetyl
Amion acetic acid phenyl ester.
Step B is the preparation of Formula II compound 4- acetylaminohydroxyphenylarsonic acid 3- phenyl chloroacetate, and the chlorinating agent in the reaction is optional
From one or both of chlorine, chlorosuccinimide (NCS), hypochlorous acid, the tertiary fourth rouge of hypochlorous acid, sulfur chloride, chlorosulfuric acid with
On.In a preferred embodiment, the reaction dissolvent of chlorination reaction can be selected from N ' dinethylformamide (DMF), ethyl acetate, two
Chloromethanes, glacial acetic acid or dilute 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.
In step B after the reaction was completed, water can also be added into reaction solution and carry out liquid separation with water-insoluble organic solvent,
After organic layer washing, crystallization is filtered, dry, obtains 4- acetylaminohydroxyphenylarsonic acid 3- phenyl chloroacetate.It is preferable to use ethyl acetate to be extracted
Take separating-purifying that target product is prepared by the way that petroleum ether precipitation is added.
A kind of specific reaction process of step B is as follows: intermediate compound I being dissolved in solvent, addition chlorinating agent, 0~30 DEG C
1~8h is stirred, water then is added and ethyl acetate liquid separation obtains organic layer, organic layer is washed with water, isometric petroleum ether is added dropwise,
Crystallization, filtering, dry 4- acetylaminohydroxyphenylarsonic acid 3- phenyl chloroacetate.
Step C is preparation 4- amino -3- chlorophenol, which is reacted with aqueous alkali.?
In a kind of preferred embodiment, the reaction temperature of step C is 80~120 DEG C, and the concentration of aqueous alkali is 2~8mol/L.
Alkali in step C is preferably inorganic base, can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, carbonic acid
One or more of sodium, cesium carbonate；The mole dosage of alkali is 2~15 times, preferably 5~10 times of Formula II compound.
In step C, reaction solution is cooled to room temperature after reaction, is adjusted with acid pH value to 4~7, filtration drying is to get 4- ammonia
Base -3- chlorophenol, wherein the acid is selected from one or more of concentrated hydrochloric acid, sulfuric acid, phosphoric acid.
A kind of specific reaction process of step C is as follows: intermediate II being dissolved in aqueous alkali, 90~110 DEG C is heated to, stirs
4~8h is mixed, room temperature is cooled to, is adjusted with acid pH, filters the solid of precipitation, filter cake is washed with water, and is drying to obtain 4- amino -3- chlorine
Phenol.
Beneficial effects of the present invention: step operation involved in the present invention is convenient, mild condition, without high temperature, high pressure, explosive
Etc. harsh conditions, greatly reduce requirement for equipment in production.Large-scale industrial production, product may be implemented in this technique
Yield is high, and purity is high, low energy consumption.
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 to
This.
The reaction route of following embodiment is as follows:
Embodiment 1:
The preparation of 4- acetylaminoacetic acid phenyl ester: the first step under condition of ice bath, sequentially adds pair into 2000ml four-hole bottle
Amino-phenol (100g, 0.92mol), acetic anhydride (500ml), triethylamine (278g, 2.75mol) are gradually increased to stir at room temperature
Reaction.After being stirred to react 4h, 2000ml water and 1000ml acetic acid second are added into reaction solution for TLC detection, raw material end of reaction
Ester, with the separatory funnel liquid separation of 5L, upper organic phase is continued to employ, and water phase is extracted with ethyl acetate 2 times, each ethyl acetate 500ml,
Ethyl acetate distillation and concentration is obtained into product: 146g, yield: 82.5%.
The preparation of 4- acetylaminohydroxyphenylarsonic acid 3- phenyl chloroacetate: second step sequentially adds intermediate compound I into the single port bottle of 500ml
(30g, 155.3mmol), NCS (21g, 155.3mmol), DMF (300ml) are stirred to react under room temperature, react 4h, TLC detection,
End of reaction.1000ml water and 200ml ethyl acetate are added in reaction solution, obtains organic layer with separatory funnel liquid separation, organic layer is used
Water washing 1 time.It is slowly added to 200ml petroleum ether into organic layer, there are a large amount of white solids to be precipitated, filtering, filter cake petroleum ether
Elution, solid dry to obtain product: 27g, yield: 76.4%, purity 98.3%.
Third step, the preparation of 4- amino -3- chlorophenol: into 3000ml four-hole bottle, sequentially add intermediate II (218g,
0.96mol), NaOH solution (6mol/L, 1000ml), dissolution of raw material are in grey black.100~110 DEG C are heated to, is stirred to react
5h, fully reacting.It is cooled to room temperature with ice bath, pH to 5~6 is adjusted with concentrated hydrochloric acid, a large amount of grey black solids is precipitated, filter, filter
Cake adds suitable quantity of water to be beaten, and stirs 15min, and product: 115g, HPLC purity is dried to obtain in filtering: 99.0%, yield: 83.5%.
Embodiment 2:
The preparation of 4- acetylaminoacetic acid phenyl ester: the first step under condition of ice bath, sequentially adds pair into 2000ml four-hole bottle
Amino-phenol (100g, 0.92mol), ethyl acetate (1500mL), triethylamine (185g, 1.83mol), chloroacetic chloride (108g,
1.37mol), it is gradually increased to be stirred to react at room temperature.After being stirred to react 8h, TLC detection, raw material end of reaction, into reaction solution
: 165g that 1500ml water is added and obtains ethyl acetate layer with the separatory funnel liquid separation of 5L, ethyl acetate distillation and concentration is obtained product is received
Rate: 93.4%.
The preparation of 4- acetylaminohydroxyphenylarsonic acid 3- phenyl chloroacetate: second step sequentially adds intermediate into the single port bottle of 1000ml
I (90g, 0.46mol), glacial acetic acid (450ml), NCS (62g, 0.46mol) are stirred to react under room temperature, react 2h, TLC detection,
End of reaction.3000ml water and 600ml ethyl acetate are added in reaction solution, obtains organic layer with separatory funnel liquid separation, organic layer is used
Water washing 2 times.It is slowly added to 600ml petroleum ether into organic layer, there are a large amount of white solids to be precipitated, filtering, filter cake petroleum ether
Elution, solid dry to obtain product: 90g, yield: 85.2%, purity 98.5%.
Third step, the preparation of 4- amino -3- chlorophenol: into 2000ml four-hole bottle, sequentially add intermediate II (150g,
0.66mol), KOH solution (6mol/L, 700ml), dissolution of raw material are in grey black.90~100 DEG C are heated to, 6h is stirred to react,
Fully reacting.It is cooled to room temperature with ice bath, pH to 5~6 is adjusted with concentrated hydrochloric acid, a large amount of grey black solids is precipitated, filter, filter cake adds
15min is stirred in suitable quantity of water mashing, and product: 79g, HPLC purity is dried to obtain in filtering: 98.7%, yield: 83.5%.
Embodiment 3:
The preparation of 4- acetylaminoacetic acid phenyl ester: the first step under condition of ice bath, sequentially adds pair into 2000ml four-hole bottle
Amino-phenol (100g, 0.92mol), methylene chloride (1000mL), triethylamine (139g, 1.37mol), chloroacetic chloride (86g,
1.10mol), it is gradually increased to be stirred to react at room temperature.After being stirred to react 8h, TLC detection, raw material end of reaction, into reaction solution
: 164g that 1500ml water is added and obtains dichloromethane layer with the separatory funnel liquid separation of 5L, methylene chloride distillation and concentration is obtained product is received
Rate: 92.7%.
The preparation of 4- acetylaminohydroxyphenylarsonic acid 3- phenyl chloroacetate: second step sequentially adds intermediate into the single port bottle of 1000ml
I (70g, 0.36mol), ethyl acetate (700ml), NCS (48g, 0.36mol) are stirred to react under room temperature, react 2h, TLC inspection
It surveys, end of reaction.700ml water is added in reaction solution, obtains organic layer with separatory funnel liquid separation, organic layer is washed with water 2 times.Xiang You
It is slowly added to 700ml petroleum ether in machine layer, there are a large amount of white solids to be precipitated, filtering, filter cake is eluted with petroleum ether, and solid is dried
Product: 73g, yield: 88.4%, purity 98.5%.
Third step, the preparation of 4- amino -3- chlorophenol: into 2000ml four-hole bottle, sequentially add intermediate II (150g,
0.66mol), KOH solution (4mol/L, 900ml), dissolution of raw material are in grey black.90~100 DEG C are heated to, 12h is stirred to react,
Fully reacting.It is cooled to room temperature with ice bath, pH to 5~6 is adjusted with concentrated hydrochloric acid, a large amount of grey black solids is precipitated, filter, filter cake adds
15min is stirred in suitable quantity of water mashing, and product: 83g, HPLC purity is dried to obtain in filtering: 98.4%, yield: 87.8%.
Each raw material and solvent cited by the present invention can realize the present invention, purity > 98% (HPLC normalization method),
This is just not listed one by one.
Claims (6)
1. a kind of synthetic method of 4- amino -3- chlorophenol, it is characterised in that it includes the following steps:
A, para-aminophenol and triethylamine and chloroacetic chloride carry out acetylization reaction at room temperature, obtain compound of formula I；Triethylamine rubs
Your dosage is 1~5 times of para-aminophenol；
B, compound of formula I and chlorosuccinimide room temperature carry out chlorination reaction, obtain Formula II compound, reaction dissolvent is acetic acid
Ethyl ester or glacial acetic acid；The mole dosage of chlorosuccinimide is 1~1.5 times of compound of formula I；
C, Formula II compound is reacted with inorganic alkali solution, obtains 4- amino -3- chlorophenol.
2. synthetic method according to claim 1, it is characterised in that 1~15h of reaction time in step A.
3. synthetic method according to claim 1 or 2, it is characterised in that in step B, the reaction time is 1~10h.
4. synthetic method according to claim 1, it is characterised in that in step C, Formula II compound and aqueous alkali are carried out
Reaction, reaction temperature are 80~120 DEG C, and the concentration of aqueous alkali is 2~8mol/L.
5. synthetic method according to claim 1, it is characterised in that in step C, the inorganic base is selected from sodium hydroxide, hydrogen
One or more of potassium oxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate.
6. synthetic method according to claim 1, it is characterised in that in step C, cool down after reaction, be adjusted with acid pH value extremely
4~7, filtration drying is to get 4- amino -3- chlorophenol, wherein the acid is selected from one of concentrated hydrochloric acid, sulfuric acid, phosphoric acid or two
Kind or more.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510779481.5A CN106699578B (en) | 2015-11-13 | 2015-11-13 | A kind of synthetic method of important pharmaceutical-chemical intermediate 4- amino -3- chlorophenol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510779481.5A CN106699578B (en) | 2015-11-13 | 2015-11-13 | A kind of synthetic method of important pharmaceutical-chemical intermediate 4- amino -3- chlorophenol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106699578A CN106699578A (en) | 2017-05-24 |
| CN106699578B true CN106699578B (en) | 2019-07-02 |
Family
ID=58930732
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510779481.5A Active CN106699578B (en) | 2015-11-13 | 2015-11-13 | A kind of synthetic method of important pharmaceutical-chemical intermediate 4- amino -3- chlorophenol |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106699578B (en) |
Family Cites Families (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 |
| CN101085741B (en) * | 2007-06-22 | 2010-09-01 | 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 |
| CN102321041B (en) * | 2011-07-20 | 2013-09-25 | 华润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 |
| CN102424655B (en) * | 2011-10-28 | 2014-04-16 | 杭州迪克化工技术有限公司 | Preparation method of R-(-)-2-acetamido-3-methoxy-N-benzyl propionamide |
| CN105001107B (en) * | 2015-07-07 | 2016-08-17 | 西安交通大学 | A kind of method of synthesizing methyl Hongmaoxinjian |
-
2015
- 2015-11-13 CN CN201510779481.5A patent/CN106699578B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN106699578A (en) | 2017-05-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108623486A (en) | A kind of preparation method of V hydrochloride of salbutamol intermediate | |
| CN105884628B (en) | The preparation method of 2,4- di-t-butyl -5- amino phenols | |
| CN106631825B (en) | A kind of preparation method of 3,3,5,5- tetramethyl benzidine | |
| CN103833593B (en) | A kind of preparation method of N-(the 9-fluorenylmethyloxycarbonyl)-O-tert-butyl group-TYR | |
| CN101830793B (en) | Method for preparing hydroxyl-substituted phenylacetic acid compound | |
| CN107522690B (en) | Preparation method of Osimetinib | |
| CN104910135A (en) | Preparation method of new crystal form of dexrabeprazole sodium | |
| CN106699578B (en) | A kind of synthetic method of important pharmaceutical-chemical intermediate 4- amino -3- chlorophenol | |
| CN103588765B (en) | The synthetic method of the synthetic method of Azilsartan or its salt and intermediate and intermediate | |
| CN105198830A (en) | Mirabegron preparation method | |
| CN108440409A (en) | A kind of green high-efficient preparation method of Rebamipide | |
| CN102746235B (en) | Improved method for preparing imidafenacin | |
| CN106588921B (en) | A kind of synthetic method of the methyl formate of 7 azaindole 3 | |
| CN105085595B (en) | A kind of method of deacylation base protection 2,6 halosubstituted purine nucleosides of synthesis | |
| CN105294442A (en) | Preparation method for bicyclo [1.1.1] pentane-1,3-dicarboxylic acid dimethylester | |
| CN101575301B (en) | Preparation method of 2-amino-5-chlorobenzamide | |
| CN104311456B (en) | A kind of preparation method of sulfogaiacol | |
| CN104803846B (en) | The method for preparing bis- [4- (6- acryloyl-oxy hexyl) phenyl] hexamethylene -1,4- dicarboxylic esters | |
| CN110330422B (en) | Preparation method of 2, 6-diethyl-4-methylphenylacetic acid | |
| CN106008323B (en) | A method of preparing half tartrate crystal form C of piperazine Ma Selin | |
| CN107325078B (en) | Preparation method of cilostazol | |
| CN106397416B (en) | A kind of preparation method of Tegafur | |
| CN106316937A (en) | Preparation method of fluazinam | |
| CN106187960B (en) | A kind of preparation method of 2- methoxyiminos -2- furyl acetic acid ammonium salts | |
| CN106279008A (en) | A kind of purifying process of sulfasalazine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20230425 Address after: No. 20 Yaogu Yiheng Road, Xiuying District, Haikou City, Hainan Province, 570311 Patentee after: Xiansheng Zaiming Pharmaceutical Co.,Ltd. Address before: 210042 699 Xuanwu Road, Xuanwu District, Nanjing, Jiangsu -18 Patentee before: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. |
|
| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: No. 20 Yaogu Yiheng Road, Xiuying District, Haikou City, Hainan Province, 570311 Patentee after: Hainan Xiansheng Zaiming Pharmaceutical Co.,Ltd. Country or region after: China Address before: No. 20 Yaogu Yiheng Road, Xiuying District, Haikou City, Hainan Province, 570311 Patentee before: Xiansheng Zaiming Pharmaceutical Co.,Ltd. Country or region before: China |