CN106543080B - A kind of synthetic method of 4- oxos -7- methoxyl groups -1,4- dihydroquinoline -6- methyl formates - Google Patents
A kind of synthetic method of 4- oxos -7- methoxyl groups -1,4- dihydroquinoline -6- methyl formates Download PDFInfo
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- CN106543080B CN106543080B CN201611010792.6A CN201611010792A CN106543080B CN 106543080 B CN106543080 B CN 106543080B CN 201611010792 A CN201611010792 A CN 201611010792A CN 106543080 B CN106543080 B CN 106543080B
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- dihydroquinoline
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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Abstract
The present invention relates to a kind of synthetic methods of 4- oxos -7- methoxyl groups-Isosorbide-5-Nitrae-dihydroquinoline -6- methyl formates, and using 4- nitros-O-Anisic Acid methyl esters as starting material, by Friedel-Crafts reaction, reduction, ammonolysis cyclization obtains target compound.The method of the present invention avoids existing universal method in 180-220 DEG C of decarboxylation ring-forming sequence of diphenyl ether high temperature using classical reaction, solves problem in production, safety and environmental protection is conducive to amplification production.And the method for the present invention has many advantages, such as that reaction efficiency height, high income, purity are high, it is at low cost.
Description
Technical field
The present invention relates to a kind of pleasures to cut down for Buddhist nun's intermediate 4- oxo -7- methoxyl group -1,4- dihydroquinoline -6- methyl formates
Synthetic method belongs to technical field of medicine synthesis.
Background technology
It is happy to cut down for Buddhist nun (Lenvatinib), entitled 4- [the chloro- 4- of 3- (cyclopropyl amino carbonyl) the amino-benzene oxygen] -7- first of chemistry
Oxygroup -6- quinoline formyl amine, structural formula are as follows：
It is a kind of orally active multi-kinase inhibitor of Japanese Wei Cai companies exploitation, the vasoactive endothelium life of targeting ground
Growth factor receptor body (VEGFR) 1-3, fibroblast growth factor acceptor (FGFR) 1-3, stem cell factor receptor and β types
Platelet-derived growth factor receptors (PDGFR).For treating glioma, thyroid adenoma, kidney, liver cancer and ovary
The solid tumors such as cancer, first choice are used for the irremediable differentiated thyroid carcinoma of radioiodine.Obtain U.S. FDA orphan within 2 months 2013
Medicine identification is clinically used for treatment filter blocking, marrow sample, undifferentiated metastatic or Locally Advanced thyroid papillary carcinoma.
4- oxos -7- methoxyl group-Isosorbide-5-Nitrae-dihydroquinoline -6- methyl formates are the happy important intermediates cut down for Buddhist nun of synthesis,
Weiss is generally used at present, and the method for MATTHEW M.et.al et al., route is as follows
The route needs, in 180-220 DEG C of decarboxylation cyclization of diphenyl ether high temperature, very big inconvenience, and higher boiling to be brought to production
Solvent diphenyl ether smell is very big, is unfavorable for environmental protection,
Invention content
The present invention is to overcome above-mentioned the deficiencies in the prior art, provides a kind of 4- oxos -7- methoxyl groups-Isosorbide-5-Nitrae-dihydroquinoline -
The synthetic method of 6- methyl formates, by Friedel-Crafts reaction, is restored using 4- nitros-O-Anisic Acid methyl esters as starting material,
Ammonolysis cyclization obtains target compound.The method of the present invention avoids existing universal method height in diphenyl ether using classical reaction
Warm 180-220 DEG C of decarboxylation ring-forming sequence, solves problem in production, and safety and environmental protection is conducive to amplification production.
The technical scheme is that a kind of synthesis side of 4- oxos -7- methoxyl groups-Isosorbide-5-Nitrae-dihydroquinoline -6- methyl formates
Method, characterized in that include the following steps：
A) 4- nitros-O-Anisic Acid methyl esters (compound I) and chlorallylene acyl chlorides are in organic solvent through Fu Ke
4- nitro -5- chloropropenes acyl group-O-Anisic Acid methyl esters (compound II) is obtained by the reaction；
B) 4- nitros -5- chloropropenes acyl group-O-Anisic Acid methyl esters (compound II) is in the presence of a reducing agent by nitre
Base is reduced into amino and obtains 4- amino -5- chloropropenes acyl group-O-Anisic Acid methyl esters (compound III)；
C) 4- amino -5- chloropropenes acyl group-O-Anisic Acid methyl esters (compound III) carries out ring in the presence of base
Conjunction obtains 4- oxo -7- methoxyl group -1,4- dihydroquinoline -6- methyl formates (compound IV).
Specific reaction equation is as follows,
Above-mentioned synthetic reaction, specifically includes following steps：
A) solvent, 2- methoxyl group -4- nitrobenzene methyls are first put into the reaction vessel, are then cooled to -10 DEG C~0
Chlorallylene acyl chlorides, is finally added dropwise in reaction vessel by DEG C input lewis acid, after dripping off stirring obtain 4- nitre to the reaction was complete
Base -5- chloropropenes acyl group-O-Anisic Acid methyl esters；
B) it by 4- nitro -5- chloropropenes acyl group-O-Anisic Acid methyl esters, puts into reaction vessel, 20% second is added
Alcohol water, ammonium chloride, 45 DEG C of temperature control are to slowly warm up to 80 DEG C~85 DEG C and react 3~4 hours, obtain hereinafter, addition reducing agent after adding
4- amino -5- chloropropenes acyl group-O-Anisic Acid methyl esters；
C) 4- amino -5- chloropropenes acyl group-O-Anisic Acid methyl esters is put into solvent, alkali is added, is warming up to
Reflux obtains target product 4- oxos -7- methoxyl group-Isosorbide-5-Nitrae-dihydroquinoline -6- methyl formates after reaction.
The molar ratio of 2- methoxyl group -4- nitrobenzene methyls and chlorallylene acyl chlorides is 1 in the step a:1.1~1:
1.3；Acyl chlorides can use bromo-derivative, and such as 3- bromopropene acyl chlorides, 3- bromopropene acylbromides replace, 2- methoxyl group -4- nitrobenzoic acid first
Ester is 1 with the molar ratio of 3- bromopropenes acyl chlorides or 3- bromopropene acylbromides:1.1~1:1.3.
Lewis acid is alchlor or boron chloride, preferably alchlor in the step a；2- methoxyl group -4- nitre
Yl benzoic acid methyl esters is 1 with the molar ratio of alchlor or boron chloride:1.2~1:1.7.Solvent is atent solvent, as toluene,
Dichloromethane, dichloroethanes, chloroform, acetonitrile etc..
Reducing agent is reduced iron powder, reduction zinc powder, vulcanized sodium, one kind in hydrazine hydrate, reduction temperature 0- in the step b
100℃.The molar ratio of 4- nitro -5- acryloyls chloro-O-Anisic Acid methyl esters and ammonium chloride is 1:1~1:1.2.4- nitre
The molar ratio of base -5- acryloyls chloro-O-Anisic Acid methyl esters and reducing agent is 1:2~1:3.
Range of reaction temperature in the step c is -5 DEG C~100 DEG C, and alkali can be organic base or inorganic base, preferably
Triethylamine, N, N- diisopropylethylamine, diethylamine, sodium hydroxide, sodium carbonate one kind；4- amino -5- chloropropene acyl group -2- first
The molar ratio of p-methoxybenzoic acid methyl esters and alkali is 1:2~1:3.Solvent can be toluene, dichloromethane, dichloroethanes, three chloromethanes
Alkane, all atent solvents such as acetonitrile.
The present invention has the advantages that compared with prior art：
(1) reaction efficiency height, high income, purity are high.Compound I in step a of the present invention, due to leading to benzene with the presence of nitro
Ring is passivated, but the presence of methoxyl group substantially increases it and aligns the activity of c so that Friedel-Crafts reaction effectively carries out.The present invention is final
Product yield >=95.0%, purity >=96.0%.With Weiss general at present, the receipts of the method for MATTHEW M.et.al et al.
Rate (about 40%-50%) compares, and has pole to significantly improve.
(2) present invention is at low cost.Since each step reaction efficiency of the present invention is all very high：First step products therefrom yield exists
90% or more, second step products therefrom yield can utmostly improve raw material utilization efficiency 80% or more, to greatly
Reduce production cost.
(3) the method for the present invention is more environmentally friendly, and existing universal method is avoided in diphenyl ether high temperature using classical reaction
180-220 DEG C of decarboxylation ring-forming sequence, solves problem in production, and safety and environmental protection is conducive to amplification production.
Specific implementation mode
Embodiment 1,
A) in dry reaction bottle put into toluene 2kg, 2- methoxyl group -4- nitrobenzene methyl 211g, be cooled to 0 DEG C with
Under, aluminum trichloride (anhydrous) 200g is put into, 0-5 DEG C of temperature is controlled, chlorallylene acyl chlorides is added dropwise in reaction bulb for 137 grams, is dripped off
After be to slowly warm up to be stirred at room temperature 16 hours, be cooled to 0-5 DEG C, reaction solution poured into the hydrochloric acid of the cold 6N of 2000ml, stirring 1
Hour, filter to obtain product, purifying is washed to neutrality, 60 DEG C of dry compound II 270g, yield 90%.
B) it by compound II, 299g, puts into reaction bulb, 20% ethanol water 2000g is added, ammonium chloride 60g, control is added
Interior temperature is less than 45 DEG C, and reduced iron powder 160g is added portionwise, and 85 DEG C are to slowly warm up to after adding and is reacted 3 hours, filters iron cement while hot,
Mother liquor is cooled to 0 DEG C or less and filters to obtain product, and 40 DEG C of dryings obtain 216g dry products, yield 80%.
C) compound III 270g are put into 1500g acetonitriles, triethylamine 202g is added, be warming up to reflux, reaction 8 is small
The a large amount of solids of Shi Houyou are precipitated, and the reaction was continued 4 hours, cool the temperature to 25 DEG C, filter, acetonitrile washing, purifying water washing, 80 DEG C
Dry target product, 230g, yield 98.1%, purity 99.1%.
Embodiment 2,
A) in dry reaction bottle, 2- methoxyl group -4- nitrobenzene methyl 220g are put into containing boron chloride
In the dichloromethane 2kg of 183g, 0-5 DEG C of temperature is controlled, chlorallylene acyl chlorides is added dropwise in reaction bulb for 169 grams, rear chamber is dripped off
Temperature stirring 12 hours, is cooled to 0-5 DEG C, reaction solution is poured into the hydrochloric acid of the cold 6N of 2000ml, stirs 1 hour, filters to obtain production
Product, purifying are washed to neutrality, 60 DEG C of dry compound II 281g, yield 90.1%.
B) it by compound II, 299g, puts into reaction bulb, 20% ethanol water 2000g is added, ammonium chloride 64g, control is added
Interior temperature is less than 45 DEG C, and reduction zinc powder 163g is added portionwise, and 80 DEG C are to slowly warm up to after adding and is reacted 4 hours, is filtered while hot, mother liquor
It is cooled to 0 DEG C or less and filters to obtain product, 40 DEG C of dryings obtain 218g dry products, yield 80.7%.
C) compound III 270g are put into 1500g chloroforms, is added, n,N-diisopropylethylamine 280g, risen
Temperature is to flowing back, and reaction has a large amount of solids to be precipitated after 8 hours, the reaction was continued 4 hours, cools the temperature to 25 DEG C, filters, and acetonitrile is washed
It washs, purifies water washing, 80 DEG C of dry target products, 232g, yield 99.1%, purity 99.3%.
Embodiment 3,
A) chloroform 3kg, 2- methoxyl group -4- nitrobenzene methyl 232g are put into dry reaction bottle, be cooled to -
10 DEG C, aluminum trichloride (anhydrous) 219g is put into, 0-25 DEG C of temperature is controlled, chlorallylene acyl chlorides is added dropwise in reaction bulb for 164 grams, is dripped
It is stirred at room temperature after complete 1.2 hours, is to slowly warm up to 45 DEG C and stirs 4.5 hours, be cooled to 1 DEG C, it is cold that reaction solution is poured into 2000ml
6N hydrochloric acid in, stir 1.2 hours, filter to obtain product, purifying is washed to neutrality, and 60 DEG C of dry compound II 301g are received
Rate 91.4%.
B) it by compound II, 300g, puts into reaction bulb, 20% ethanol water 2000g is added, ammonium chloride 62g, control is added
Interior temperature is less than 45 DEG C, and vulcanized sodium 200g is added portionwise, and 83 DEG C are to slowly warm up to after adding and is reacted 3.4 hours, is filtered while hot, mother liquor
It is cooled to 0 DEG C or less and filters to obtain product, 40 DEG C of dryings obtain 223g dry products, yield 82.6%.
C) compound III 300g are put into 1500g acetonitriles, triethylamine 230g is added, be warming up to reflux, reaction 8 is small
The a large amount of solids of Shi Houyou are precipitated, and the reaction was continued 4.6 hours, cool the temperature to 25 DEG C, filter, acetonitrile washing, purifying water washing, and 80
DEG C dry target product, 251g, yield 97.0%, purity 98.7%.
Embodiment 4,
A) in dry reaction bottle put into toluene 2kg, 2- methoxyl group -4- nitrobenzene methyl 211g, be cooled to 0 DEG C with
Under, aluminum trichloride (anhydrous) 200g is put into, 0-25 DEG C of temperature is controlled, 3- bromopropenes acyl chlorides is added dropwise in reaction bulb for 188 grams, is dripped off
After be stirred at room temperature 1.5 hours, be to slowly warm up to 45 DEG C stir 6 hours, be cooled to 2 DEG C, reaction solution poured into the cold 6N of 2000ml
Hydrochloric acid in, stir 1.2 hours, filter to obtain product, purifying is washed to neutrality, 60 DEG C of dry compound II 272g, yield
90.9%.
B) it by compound II, 299g, puts into reaction bulb, 20% ethanol water 2000g is added, ammonium chloride 60g, control is added
Interior temperature is less than 45 DEG C, and reduced iron powder 160g is added portionwise, and 85 DEG C are to slowly warm up to after adding and is reacted 3 hours, filters iron cement while hot,
Mother liquor is cooled to 0 DEG C or less and filters to obtain product, and 40 DEG C of dryings obtain 218g dry products, yield 80.7%.
C) compound III 270g are put into 1500g acetonitriles, triethylamine 202g is added, be warming up to reflux, reaction 8 is small
The a large amount of solids of Shi Houyou are precipitated, and the reaction was continued 4 hours, cool the temperature to 25 DEG C, filter, acetonitrile washing, purifying water washing, 80 DEG C
Dry target product, 230g, yield 98.1%, purity 99.1%.
Claims (7)
1. a kind of synthetic method of 4- oxos -7- methoxyl groups-Isosorbide-5-Nitrae-dihydroquinoline -6- methyl formates, characterized in that including following
Step：
A) solvent, 2- methoxyl group -4- nitrobenzene methyls are first put into the reaction vessel, are then cooled to -10 DEG C~0 DEG C throwing
Enter lewis acid, finally chlorallylene acyl chlorides is added dropwise in reaction vessel, extremely the reaction was complete for stirring after dripping off, and obtains 4- nitros-
5- chloropropenes acyl group-O-Anisic Acid methyl esters；
B) it by 4- nitro -5- chloropropenes acyl group-O-Anisic Acid methyl esters, puts into reaction vessel, 20% ethanol water of addition,
Ammonium chloride, 45 DEG C of temperature control are to slowly warm up to 80 DEG C~85 DEG C and react 3~4 hours, obtain 4- ammonia hereinafter, addition reducing agent after adding
Base -5- chloropropenes acyl group-O-Anisic Acid methyl esters；
C) 4- amino -5- chloropropenes acyl group-O-Anisic Acid methyl esters is put into solvent, alkali is added, is warming up to reflux,
Target product 4- oxo -7- methoxyl group -1,4- dihydroquinoline -6- methyl formates are obtained after reaction；
The step a）The molar ratio of middle 2- methoxyl groups -4- nitrobenzene methyls and chlorallylene acyl chlorides is 1:1.1~1:
1.3。
2. the synthetic method of 4- oxos -7- methoxyl groups-Isosorbide-5-Nitrae-dihydroquinoline -6- methyl formates as described in claim 1, special
Sign is the step a）In chlorallylene acyl chlorides 3- bromopropenes acyl chlorides or 3- bromopropene acylbromides replace；The 2- methoxyl groups-
4- nitrobenzene methyls are 1 with the molar ratio of 3- bromopropenes acyl chlorides or 3- bromopropene acylbromides:1.1~1:1.3.
3. the synthetic method of 4- oxos -7- methoxyl groups-Isosorbide-5-Nitrae-dihydroquinoline -6- methyl formates as claimed in claim 1 or 2,
It is characterized in that the step a）In, lewis acid is alchlor or boron chloride；2- methoxyl group -4- nitrobenzene methyls
It is 1 with the molar ratio of alchlor or boron chloride:1.2~1:1.7.
4. the synthetic method of 4- oxos -7- methoxyl groups-Isosorbide-5-Nitrae-dihydroquinoline -6- methyl formates as claimed in claim 3, special
Sign is the step a）In, lewis acid is alchlor.
5. the synthetic method of 4- oxos -7- methoxyl groups-Isosorbide-5-Nitrae-dihydroquinoline -6- methyl formates as claimed in claim 1 or 2,
It is characterized in that reducing agent is reduced iron powder, reduction zinc powder, vulcanized sodium, one kind in hydrazine hydrate in the step b)；Reduction temperature
It is 0~100 DEG C.
6. the synthetic method of 4- oxos -7- methoxyl groups-Isosorbide-5-Nitrae-dihydroquinoline -6- methyl formates as claimed in claim 1 or 2,
It is characterized in that the step c）Alkali is triethylamine, N, one in N- diisopropylethylamine, diethylamine, sodium hydroxide, sodium carbonate
Kind.
7. the synthetic method of 4- oxos -7- methoxyl groups-Isosorbide-5-Nitrae-dihydroquinoline -6- methyl formates as claimed in claim 1 or 2,
It is characterized in that the solvent is atent solvent.
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Denomination of invention: A synthetic method of methyl 4-oxo-7-methoxy-1,4-dihydroquinoline-6-formate Effective date of registration: 20211207 Granted publication date: 20181109 Pledgee: Qilu bank Limited by Share Ltd. Ji'nan science and technology innovation center sub branch Pledgor: SHANDONG BOYUAN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980014223 |
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Address after: 251400 No. 12, Taixing East Street, Jibei Economic Development Zone, Jiyang District, Jinan City, Shandong Province Patentee after: Shandong Baoyuan Pharmaceutical Co.,Ltd. Address before: Strong in Jiyang County of Ji'nan City, 251400 North Street, Shandong Province Economic Development Zone Patentee before: SHANDONG BOYUAN PHARMACEUTICAL Co.,Ltd. |