CN104876864B - A kind of pleasure cuts down the preparation method for Buddhist nun - Google Patents
A kind of pleasure cuts down the preparation method for Buddhist nun Download PDFInfo
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- CN104876864B CN104876864B CN201510300819.4A CN201510300819A CN104876864B CN 104876864 B CN104876864 B CN 104876864B CN 201510300819 A CN201510300819 A CN 201510300819A CN 104876864 B CN104876864 B CN 104876864B
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- WOSKHXYHFSIKNG-UHFFFAOYSA-N COc1cc2nccc(Oc(cc3)cc(Cl)c3NC(NC3CC3)=O)c2cc1C(N)=O Chemical compound COc1cc2nccc(Oc(cc3)cc(Cl)c3NC(NC3CC3)=O)c2cc1C(N)=O WOSKHXYHFSIKNG-UHFFFAOYSA-N 0.000 description 1
- 0 COc1cc2nccc(Oc3cc(Cl)c(*)cc3)c2cc1C(N)=O Chemical compound COc1cc2nccc(Oc3cc(Cl)c(*)cc3)c2cc1C(N)=O 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The present invention with 4 amino 3 chlorophenol as initiation material, first amido protecting, then docked with 4 chlorine, 7 methoxy quinoline 6 amide; deaminizating protection group, is reacted with cyclopropylamine, prepares pleasure and cuts down for Buddhist nun; this preparation method is simple is easy, high income, and quality is good, is easy to industrialized production.
Description
Technical field
The present invention relates to drug world is and in particular to a kind of pleasure cuts down the preparation method for Buddhist nun.
Background technology
Pleasure is cut down for Buddhist nun Lenvatinib, chemical entitled 4- [the chloro- 4- of 3- (cyclopropyl amino carbonyl) amino-benzene oxygen] -7- methoxy
Base -6- quinoline formyl amine, is a kind of orally active multi-kinase inhibitor of Japanese Wei Cai company exploitation, mainly acts on c-
Multiple target spot such as Kit, Ret and VEGFR-2, real for treating glioma, thyroid tumor, renal carcinoma, hepatocarcinoma and ovarian cancer etc.
Body tumor.2013 2 months obtain U.S. FDA Orphan drug assert, be clinically used for treat filter blocking, marrow sample, undifferentiated transitivity or
Locally Advanced thyroid papillary carcinoma.
The documents such as EP1683785A1, EP1698623A1, EP1797881A1, US7683172A1 describe a kind of happy cutting down and replace
The synthetic method of Buddhist nun, its synthetic route is as follows：
The deficiency of this route is to employ the phenyl chloroformate with certain toxicity as raw material, produces in subsequent reactions
Give birth to the larger phenol of toxicity, furthermore, when not carrying out amido protecting, hydroxyl is not protected, can produce certain miscellaneous
Matter.
Technical scheme
For above-mentioned document weak point, the present invention is redesigned to its synthetic route, with 4- amino -3- chlorobenzene
Phenol is initiation material, first carries out Boc protection to amino, 7- methoxy quinoline -6- amide chloro- with 4- is docked, deaminizating Boc
Protection group, is reacted with cyclopropylamine in the presence of CDI, prepares pleasure and cuts down for Buddhist nun, this preparation method is simple is easy, raw material is easy
It is easy to get, energy consumption is low, high income, quality is good, is easy to industrialized production, synthesis summary route is as follows：
The present invention also synthesizes and has obtained the happy maleate cutting down for Buddhist nun.
The synthesis of (2- chloro-4-hydroxyl-phenyl) t-butyl carbamate (B)：
Add 4- amino -3- chlorophenol (A), Bis(tert-butoxycarbonyl)oxide and triethylamine in dichloromethane, be stirred at room temperature
3-8 hour.Reactant liquor washes with water, adds appropriate normal hexane making beating, anhydrous sodium sulfate drying, decompression steams solvent, is marked
Topic compound (B).
The synthesis of 4- (6- carbamoyl -7- methoxy quinoline -4- epoxide) -2- chloroanilino t-butyl formate (D)：
7- methoxyl group -4- chloroquinoline -6- carboxylic acid amides (C), (2- chloro-4-hydroxyl-phenyl) ammonia is added in dimethyl sulfoxide
Base t-butyl formate (B) and cesium carbonate, at 60-98 DEG C, heated and stirred 8-12 hour, reactant liquor is down to room temperature, reaction
Liquid pours in water, stirs 20-60 minute, filters, is dried to obtain title compound (D).
The synthesis of 4- (4- amino -3- chlorophenoxy) -7- methoxy quinoline -6- carboxamide hydrochloride (E)：
4- (6- carbamoyl -7- methoxy quinoline -4- epoxide) -2- chloroanilino t-butyl formate is added in methanol
(D), appropriate methanol hydrochloride solution, is stirred at room temperature 3-8 hour.Add ether in reactant liquor, stir 20-60 minute, filter,
It is dried to obtain title compound (E).
Pleasure cuts down the synthesis for Buddhist nun (F)：
To in dichloromethane add 4- (4- amino -3- chlorophenoxy) -7- methoxy quinoline -6- carboxamide hydrochloride (E),
Cyclopropylamine, N, N- carbonyl dimidazoles and triethylamine, 40-60 DEG C is heated to reflux stirring 3-12 hour.Reactant liquor washes with water, no
Aqueous sodium persulfate is dried, and decompression steams solvent, recrystallizing methanol, obtains white crystals title compound (F).
Pleasure cuts down the synthesis for Buddhist nun (F)：
To in dichloromethane add 4- (4- amino -3- chlorophenoxy) -7- methoxy quinoline -6- carboxamide hydrochloride (E),
Cyclopropylamine, N, N- carbonyl dimidazoles and triethylamine, CO2Protection, 40-60 DEG C is heated to reflux stirring 3-12 hour.Reactant liquor is used
Water washing, anhydrous sodium sulfate drying, decompression steams solvent, recrystallizing methanol, obtains white crystals title compound (F).
Pleasure cuts down the synthesis of the maleate for Buddhist nun
Pleasure is cut down and is added in maleic acid and the mixed solution of ethanol for Buddhist nun, so that it is dissolved at 30-50 DEG C.After confirming dissolving,
Instill ethyl acetate through 1-4 hour again.After the completion of dropwise addition of ethyl acetate, reactant liquor is stirred at 30-50 DEG C 20-60 and divide
Clock, is then stirred at room temperature 3-10 hour.Filter the crystallization separating out, be dried at 30-80 DEG C, obtain pleasure and cut down the Malaysia for Buddhist nun
The crystallization of hydrochlorate.
The optimization of synthesis technique of the present invention：
The synthesis of (2- chloro-4-hydroxyl-phenyl) t-butyl carbamate (B) preferred
To in 1000ml dichloromethane add 100g 4- amino -3- chlorophenol (A) 183.0g Bis(tert-butoxycarbonyl)oxide and
211.0g triethylamine, is stirred at room temperature 4 hours.Reactant liquor 300ml water washing, adds appropriate normal hexane making beating, anhydrous sodium sulfate
It is dried, decompression steams solvent, obtains 157.0g title compound (B).(yield is 92.5%).
To in 1000ml dichloromethane add 100g 4- amino -3- chlorophenol (A) 183.0g Bis(tert-butoxycarbonyl)oxide and
211.0g diethylamine, is stirred at room temperature 4 hours.Reactant liquor 300m] water washing, add appropriate normal hexane making beating, anhydrous sodium sulfate
It is dried, decompression steams solvent, obtains 75.0g title compound (B).(yield is 41.2%).
The synthesis of 4- (6- carbamoyl -7- methoxy quinoline -4- epoxide) -2- chloroanilino t-butyl formate (D)
Preferably
87.0g 7- methoxyl group -4- chloroquinoline -6- carboxylic acid amides (C), 100.0g (2- is added in 1000ml dimethyl sulfoxide
Chloro- 4- hydroxy-pheny) t-butyl carbamate (B) and 334.0g cesium carbonate, heated and stirred 8 hours at 90 DEG C.Will be anti-
Answer liquid to be down to room temperature, reactant liquor is poured in 3000ml water, stir 30 minutes, filter, be dried to obtain 154.0g title compound
Thing (D).(yield is 93.9%).
87.0g 7- methoxyl group -4- chloroquinoline -6- carboxylic acid amides (C), 100.0g (2- is added in 1000ml dimethyl sulfoxide
Chloro-4-hydroxyl-phenyl) t-butyl carbamate (B) and 334.0g cesium carbonate, heated and stirred 8 hours at 100 DEG C.Will be anti-
Answer liquid to be down to room temperature, reactant liquor is poured in 3000ml water, stir 30 minutes, filter, be dried to obtain 122.0g title compound
Thing (D).(yield is 84.5%).
The synthesis of 4- (4- amino -3- chlorophenoxy) -7- methoxy quinoline -6- carboxamide hydrochloride (E) preferred
100.0g 4- (6- carbamoyl -7- methoxy quinoline -4- epoxide) -2- chlorobenzene ammonia is added in 300ml methanol
Base t-butyl formate (D), with the methanol hydrochloride solution of 500ml 2N, is stirred at room temperature 4 hours.1500ml second is added in reactant liquor
Ether, stirs 30 minutes, filters, is dried to obtain 78.0g title compound (E).(yield is 91.1%).
100.0g 4- (6- carbamoyl -7- methoxy quinoline -4- epoxide) -2- chlorobenzene ammonia is added in 300ml methanol
Base t-butyl formate (D), with the methanol hydrochloride solution of 500ml 4N, is stirred at room temperature 4 hours.1500ml second is added in reactant liquor
Ether, stirs 30 minutes, filters, is dried to obtain 76.0g title compound (E).(yield is 87.2%).
Pleasure cuts down the preferred of the synthesis for Buddhist nun (F)
60.0g 4- (4- amino -3- chlorophenoxy) -7- methoxy quinoline -6- formyl is added in 600ml dichloromethane
Amine hydrochlorate (E), 10.8g cyclopropylamine, 51.2g N, N- carbonyl dimidazoles and 47.8g triethylamine, 50 DEG C are heated to reflux stirring 6
Hour.Reactant liquor 900ml water washing, anhydrous sodium sulfate drying, decompression steams solvent, recrystallizing methanol, obtains white crystals
59.4g title compound (F).Pleasure cuts down the synthesis for Buddhist nun (F)
60.0g 4- (4- amino -3- chlorophenoxy) -7- methoxy quinoline -6- formyl is added in 600ml dichloromethane
Amine hydrochlorate (E), 10.8g cyclopropylamine, 51.2g N, N- carbonyl dimidazoles and 47.8g triethylamine, CO2 protects, 50 DEG C of heating
Return stirring 6 hours.Reactant liquor 900ml water washing, anhydrous sodium sulfate drying, decompression steams solvent, recrystallizing methanol, obtains
White crystals 62.1g title compound (F).
Pleasure cuts down the preferred of the synthesis of maleate for Buddhist nun
Pleasure is cut down and is added in maleic acid (20mg) and the mixed solution of ethanol (2mL) for Buddhist nun (150mg), makes it molten at 40 DEG C
Solution.After confirming dissolving, then instilled ethyl acetate (1.8mL) through 2 hours.After the completion of dropwise addition of ethyl acetate, by reactant liquor 40
Stir 30 minutes at DEG C, be then stirred at room temperature 5 hours.Filter the crystallization separating out, be dried at 60 DEG C, obtain pleasure and cut down for Buddhist nun
Maleate crystallization (176mg).
Pleasure is cut down and is added in maleic acid (20mg) and the mixed solution of methanol (2mL) for Buddhist nun (150mg), makes it molten at 40 DEG C
Solution.After confirming dissolving, then instilled ethyl acetate (1.8mL) through 2 hours.After the completion of dropwise addition of ethyl acetate, by reactant liquor 40
Stir 30 minutes at DEG C, be then stirred at room temperature 5 hours.Filter the crystallization separating out, be dried at 60 DEG C, obtain happy cutting down and replace
The crystallization (123mg) of the maleate of Buddhist nun.
Medicine is made in the crystallization of the present invention itself or dosage form,
The dosage form of the crystallization of the present invention is made medicine, crystallization is mixed with suitable adjuvant additive, makes preparation.
The preferred formulation of the present invention is：Tablet, powder, granule, capsule, syrup, containing tablet, inhalant etc. be administered orally
Preparation；The external preparation such as suppository, ointment, Eye ointments, transdermal agent, eye drop, nasal drop, ear drop, cataplasma, lotion or note
Penetrate agent.
Preferably adjuvant is：Excipient, binding agent, lubricant, disintegrating agent, coloring agent, taste masking rectify olfactory agent, emulsifying agent, table
Face activating agent, cosolvent, suspension agent, isotonic agent, buffer agent, preservative, antioxidant, stabilizer, absorption enhancer etc..
Preferably excipient is：Lactose, white sugar, glucose, corn starch, Mannitol, Sorbitol, starch, α starch,
Dextrin, crystalline cellulose, light silicon anhydride, aluminium silicate, calcium silicates, silicic acid magnesium aluminate, calcium hydrogen phosphate etc..
Preferably binding agent is：Polyvinyl alcohol, methylcellulose, ethyl cellulose, arabic gum, tragacanth gum, gelatin, worm
Glue, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, Polyethylene Glycol etc..
Preferably lubricant is：Magnesium stearate, calcium stearate, stearyl fumarate sodium, Talcum, Polyethylene Glycol, colloidal state two
Silicon oxide etc..
Preferably disintegrating agent is：Crystalline cellulose, agar, gelatin, Calcium Carbonate, sodium bicarbonate, calcium citrate, dextrin, really
Glue, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethylcellulose calcium, cross-linking sodium carboxymethyl cellulose, carboxymethyl form sediment
Powder, carboxymethyl starch sodium etc..
Preferably coloring agent is：Iron sesquioxide, Yellow ferric oxide, carmine, caramel, beta-carotene, oxidation
Titanium, Talcum, Riboflavin Sodium Phosphate etc..
Preferably correctivess are：Cocoa powder, menthol, Oleum menthae, Borneolum Syntheticum, Cortex cinnamomi japonici powder etc..
Preferably emulsifying agent or surfactant are：Octadecyl triethanolamine, sodium lauryl sulphate, dodecyl ammonia
Base propanoic acid, lecithin, glyceryl monostearate, sucrose fatty acid ester, fatty acid glyceride etc..
Preferably cosolvent is：Polyethylene Glycol, propylene glycol, benzoic acid benzyl ester, ethanol, cholesterol, triethanolamine, carbonic acid
Sodium, sodium citrate, Tween 80, nicotiamide etc..
Preferably suspensoid is：Polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxymethyl cellulose, hydroxyl second
The hydrophilic macromolecules such as base cellulose, hydroxypropyl cellulose.
Preferably isotonic agent is：Glucose, sodium chloride, Mannitol, Sorbitol etc..
Preferably buffer agent is：The buffer such as phosphate, acetate, carbonate, citrate.
Preferably preservative is：Methyl parahydroxybenzoate, propyl p-hydroxybenzoate, methaform, benzylalcohol, phenethanol,
Dehydroactic acid, sorbic acid etc..
Preferably antioxidant is：Sulphite, ascorbic acid, alpha-tocopherol etc..
The component of the preferred tablet of the present invention is：10-100g pleasure is cut down and is cut down the knot for Buddhist nun's maleate for the crystallization of Buddhist nun or pleasure
Crystalline substance, 2-10g silicon dioxide, 10-100g potassium dihydrogen phosphate, 2-50g low-substituted hydroxypropyl cellulose, 2-50g hydroxyethyl cellulose,
100-300g Lactose.
The preferred tablet of the present invention is：10-100g pleasure cuts down the crystallization or the happy crystallization cut down for Buddhist nun's maleate for Buddhist nun, 2-
10g silicon dioxide, 10-100g potassium dihydrogen phosphate, 2-50g low-substituted hydroxypropyl cellulose, the mixing of 2-50g hydroxyethyl cellulose,
Then, add appropriate dehydrated alcohol, pelletize；After this granule and 100-300g Lactose are mixed together, using tabletting machine,
Obtain tablet.
The preferred tablet of the present invention is：50g pleasure cuts down the crystallization or the happy crystallization cut down for Buddhist nun's maleate for Buddhist nun, 4g titanium dioxide
Silicon, 40g potassium dihydrogen phosphate, 10g low-substituted hydroxypropyl cellulose, the mixing of 3g hydroxyethyl cellulose, then, add appropriate anhydrous
Ethanol, pelletizes；After this granule and 143g Lactose are mixed together, using tabletting machine, obtain tablet.
The usage amount of the present invention is selected according to symptom, age, administering mode, generally adult be given daily 10 μ g～
10g, divides 1 time or is administered for several times.
The present invention, can be used as angiogenesis inhibitors, antitumor agent, hemangioma cure used as angiogenesis inhibitors
Agent, cancer transfer inhibitor, retinal neovascularization Remedies, diabetic retinopathy therapeutic agent, inflammatory diseases
Agent, the treatment of diseases associated with inflammation including osteoarthrisis deformans knee, rheumatic arthritis, chronic eczema or retardance anaphylaxiss
Agent, atherosclerotic therapeutic agent.
The present invention, as antitumor agent, can treat cancer of pancreas, gastric cancer, colorectal cancer, breast carcinoma, carcinoma of prostate, pulmonary carcinoma, kidney
Cancer, the cerebral tumor, leukemia or ovarian cancer.
The present invention, as c-Kit kinase inhibitor, can treat cancer (the white blood of acute myeloid because of c-Kit kinase activation
Disease, Mast cell leukemia, small cell lung cancer, 6IST, carcinoma of testis, ovarian cancer, breast carcinoma, the cerebral tumor, neural sprout cell cancer or
Colorectal cancer).
The present invention, as c-Kit kinase inhibitor, can treat allergy, asthma.
The source of the primary raw material of the present invention include, without being limited to commercially available, be prepared as follows：
4- amino -3- chlorophenol：《The preparation of 4- amino -3- chlorophenol》,《Chinese Journal of Pharmaceuticals》09 phase in 2013
Bis(tert-butoxycarbonyl)oxide：《Research on Synthesis of Diboc via Diphosgene》,《Shanghai chemical industry》The chloro- 7- first of 02 phase 4- in 2006
Epoxide -6- quinolinecarboxamideas：CAS RN, 417721-36-9
Advantages of the present invention and innovative point are as follows：
1. the present invention selects 4- amino -3- chlorophenol cheap and easy to get is initiation material, first carries out Boc protection to amino,
Simplify reactions steps, improve raw material availability and gross production rate, reagent is all relatively inexpensive, and side reaction is few, yield is high, intermediate
Directly carry out next step reaction, yield is high, the three wastes are few, suitable industrialized production.
2., present invention improves over the step building quinoline female ring, it is that reaction is former with 7- methoxyl group -4- chloroquinoline -6- carboxylic acid amides
The two of material, are introduced directly into quinoline female ring, decrease the generation of side reaction, greatly improve yield.
3. the present invention is reacted with cyclopropylamine in the presence of CDI in the 4th step, prepares pleasure and cuts down for Buddhist nun.This process is actual
On be a two-step reaction, CDI reacts with the amino of title compound (E), the active hydrogen of cyclopropylamine upper band, simultaneously respectively
Lose two imidazoles and generate phosphinylidyne derivant, this step to be completed with " treating different things alike ".
4. the release efficiency of the crystallization of the present invention is high
5. the activity of the compound of the present invention is strong
6. the impurity of the product of the present invention is few
Specific embodiment
Embodiment 1：The synthesis of (2- chloro-4-hydroxyl-phenyl) t-butyl carbamate (B)
To in 1000ml dichloromethane add 100g 4- amino -3- chlorophenol (A) 183.0g Bis(tert-butoxycarbonyl)oxide and
211.0g triethylamine, is stirred at room temperature 4 hours.Reactant liquor 300ml water washing, adds appropriate normal hexane making beating, anhydrous sodium sulfate
It is dried, decompression steams solvent, obtains 157.0g title compound (B).(yield is 92.5%).
1H-NMR (400MHz, d6-DMSO)：1.42 (9H, s), 5.2 (1H, s), 6.63 (1H, d, J=6.4Hz), 6.84
(1H, s), 7.39 (1H, d, J=6.4Hz).
Embodiment 2：4- (6- carbamoyl -7- methoxy quinoline -4- epoxide) -2- chloroanilino t-butyl formate (D)
Synthesis
87.0g 7- methoxyl group -4- chloroquinoline -6- carboxylic acid amides (C), 100.0g (2- is added in 1000ml dimethyl sulfoxide
Chloro-4-hydroxyl-phenyl) t-butyl carbamate (B) and 334.0g cesium carbonate, heated and stirred 8 hours at 90 DEG C.To react
Liquid is down to room temperature, and reactant liquor is poured in 3000ml water, stirs 30 minutes, filters, is dried to obtain 154.0g title compound
(D).(yield is 93.9%).
1H-NMR (400MHz, d6-DMSO)：1.41 (9H, s), 3.82 (3H, s), 6.42 (1H, d, J=8.0Hz),
6.61 (1H, d, J=6.4Hz), 6.80 (1H, s), 7.36 (1H, d, J=6.4Hz), 7.58 (1H, s), 8.62
(1H, d, J=8.0Hz), 8.73 (1H, s).
Embodiment 3：The synthesis of 4- (4- amino -3- chlorophenoxy) -7- methoxy quinoline -6- carboxamide hydrochloride (E)
100.0g 4- (6- carbamoyl -7- methoxy quinoline -4- epoxide) -2- chlorobenzene ammonia is added in 300ml methanol
Base t-butyl formate (D), the methanol hydrochloride solution of 500ml 2N, it is stirred at room temperature 4 hours.1500ml second is added in reactant liquor
Ether, stirs 30 minutes, filters, is dried to obtain 78.0g title compound (E).(yield is 91.1%).1H-NMR (400MHz, d6-
DMSO)：3.82 (3H, s), 6.30 (1H, d, J=6.4Hz), 6.33 (1H, d, J=6.4Hz), 6.42 (1H, d, J=8.0Hz),
6.50 (1H, s), 7.58 (1H, s), 8.62 (1H, d, J=8.0Hz), 8.73 (1H, s).
Embodiment 4：Pleasure cuts down the synthesis for Buddhist nun (F)
60.0g 4- (4- amino -3- chlorophenoxy) -7- methoxy quinoline -6- formyl is added in 600ml dichloromethane
Amine hydrochlorate (E), 10.8g cyclopropylamine, 51.2g N, N- carbonyl dimidazoles and 47.8g triethylamine, 50 DEG C are heated to reflux stirring
6 hours.Reactant liquor 900ml water washing, anhydrous sodium sulfate drying, decompression steams solvent, recrystallizing methanol, obtains white crystals
59.4g title compound (F).(yield is 88.2%).
228～230 DEG C of mp.
1H-NMR (400MHz, d6-DMSO)：0.42 (2H, m), 0.65 (2H, m), 2.56 (1H, m), 2.58 (1H, m),
3.98 (3H, s), 6.50 (1H, d, J=6.1Hz), 7.20 (1H, d, J=3.0Hz), 7.24 (1H, d, J=2.8Hz), 7.49
(1H, d, J=2.8Hz), 7.49 (1H, s), 7.70 (1H, s), 7.82 (1H, s), 7.98 (1H, s), 8.07 (1H, s), 8.24
(1H, d, J=9.0Hz), 8.66 (1H, s), 8.64 (1H, d, J=6.1Hz).
IR(KBr)(cm-1)：3339,3184,3098,3084,2980,1665,1636,1524,1256,1194,916,
851.ESI-MS(m/z)：427[M+H]+, 449 [M+Na]+, 425 [M-H]-.
HPLC：99.5%.
Efficient liquid phase instrument, chromatographic work station
Normalization method：Chromatographic column C18 post；
Mobile phase：Water: acetonitrile: acetic acid=890: 105: 5 (v/v/v)
Detection wavelength 252nm；25 DEG C of column temperature；Flow velocity 0.6ml/min.
Embodiment 5：Pleasure cuts down the synthesis for Buddhist nun (F)
60.0g 4- (4- amino -3- chlorophenoxy) -7- methoxy quinoline -6- formyl is added in 600ml dichloromethane
Amine hydrochlorate (E), 10.8g cyclopropylamine, 51.2g N, N- carbonyl dimidazoles and 47.8g triethylamine, CO2 protects, 50 DEG C of heating
Return stirring 6 hours.Reactant liquor 900ml water washing, anhydrous sodium sulfate drying, decompression steams solvent, recrystallizing methanol, obtains
White crystals 62.1g title compound (F).(yield is 93.1%).
Embodiment 6：Pleasure cuts down the synthesis of the maleate for Buddhist nun
Pleasure is cut down and is added in maleic acid (20mg) and the mixed solution of ethanol (2mL) for Buddhist nun (150mg), makes it molten at 40 DEG C
Solution.After confirming dissolving, then instilled ethyl acetate (1.8mL) through 2 hours.After the completion of dropwise addition of ethyl acetate, by reactant liquor 40
Stir 30 minutes at DEG C, be then stirred at room temperature 5 hours.Filter the crystallization separating out, be dried at 60 DEG C, obtain pleasure and cut down for Buddhist nun
Maleate crystallization (176mg).
Maleate 1H-NMR spectrum (400MHz, DMSO-d6) 6 (ppm)：0.36 (2H, m), 0.63 (2H, m), 2.48
(1H, m), 2.58 (1H, m), 4.00 (3H, s), 6.88 (1H, s), 7.24 (1H, s), 7.37 (1H, d, J=9.0Hz), 7.52
(1H, s), 7.61 (1H, s), 7.88 (1H, s), 7.94 (1H, s), 8.05 (1H, s), 8.36 (1H, d, J=9.0Hz), 8.53
(1H, s), 8.72 (1H, s)
Embodiment 7：Measuring of dissolution velocity is tested
According to rotating disk method (referring to J.H.Wood etc., J.Pharm.Soc., 54,1068 (1955)), using following
The crystallization that condition measures the happy crystallization (crystallization obtaining in embodiment 4) cut down for Buddhist nun's episome, pleasure is cut down for Buddhist nun's episome (is implemented
The crystallization obtaining in example 5), pleasure cut down the dissolution velocity of the crystallization (crystallization obtaining in embodiment 6) of maleate for Buddhist nun.Dissolving
Speed is to keep linear range computation in relation based on dissolving time at initial stage and concentration.
Efficient liquid phase instrument, chromatographic work station
Normalization method：Chromatographic column C18 post；
Mobile phase：Water: acetonitrile: acetic acid=890: 105: 5 (v/v/v)
Detection wavelength 252nm；25 DEG C of column temperature；Flow velocity 0.6ml/min.
Sample size：100μL
Dissolution velocity is as follows.
| Dissolution velocity (μ g/ minute/cm2) | |
| The crystallization of embodiment 4 | 0.9 |
| The crystallization of embodiment 5 | 1.1 |
| The crystallization of embodiment 6 | 122 |
Crystallization with embodiment 4,5 is compared, and the dissolution velocity of the crystallization of embodiment 6 increases substantially.
Embodiment 8：Measure impurity level using HPLC
Add the mixed solution (4: 1) of water and ethanol in the crystallization Crystallization of embodiment 4-6, modulation ultimate density is
The sample solution of 0.1mg/mL.
Using HPLC method, under shown condition determination, sample solution is tested below, measure dissolution peak area, profit
Calculate total impurities with opposite face area method.(the impurity more than or equal to 0.05% for the record.)
(computing formula of total impurities)
The amount (%) of every kind of impurity=(peak area of every kind of impurity) × 100/ ((peak areas of carboxylic acid amides)+(every kind of impurity
Peak area summation))
The summation of the amount of total impurities (%)=every kind of impurity
(HPLC condition determination)
Efficient liquid phase instrument, chromatographic work station
Normalization method：Chromatographic column C18 post；
Mobile phase：Water: acetonitrile: acetic acid=890: 105: 5 (v/v/v)
Detection wavelength 252nm；25 DEG C of column temperature；Flow velocity 0.6ml/min.
Sample size：100μL
Dissolution velocity is as follows.
| Total impurities (%) | |
| The crystallization of embodiment 4 | 1.08 |
| The crystallization of embodiment 5 | 0.61 |
| The crystallization of embodiment 6 | 0.41 |
Embodiment 9：
The crystallization of 50g embodiment 4,4g silicon dioxide, 40g potassium dihydrogen phosphate, 10g low-substituted hydroxypropyl cellulose, 3g hydroxyl
Ethyl cellulose mixes.Then, add appropriate dehydrated alcohol, pelletize；After this granule and 143g Lactose are mixed together, utilize
Tabletting machine, obtains tablet.
Embodiment 10：
The crystallization of 50g embodiment 5,4g silicon dioxide, 40g potassium dihydrogen phosphate, 10g low-substituted hydroxypropyl cellulose, 3g hydroxyl
Ethyl cellulose mixes.Then, add appropriate dehydrated alcohol, pelletize；After this granule and 143g Lactose are mixed together, utilize
Tabletting machine, obtains tablet.
Embodiment 11：
The crystallization of 50g embodiment 6,4g silicon dioxide, 40g potassium dihydrogen phosphate, 10g low-substituted hydroxypropyl cellulose, 3g hydroxyl
Ethyl cellulose mixes.Then, add appropriate dehydrated alcohol, pelletize；After this granule and 143g Lactose are mixed together, utilize
Tabletting machine, obtains tablet.
Embodiment 12：The anti-tumor activity of the present invention
Will be with 1 × 107The concentration of/ml be suspended in PBS VEGF highly express pancreatic cancer cell (KP-1/VEGF) according to
The capacity of 0.1ml is transplanted to the right rib Pericarpium Arecae bottom of female Balb/c (nu/nu) mice of 8 week old.Reach about from gross tumor volume
100mm3When, continuous oral gives measured matter 14 days.Measured matter is suspended in 0.5% methylcellulose, by 0.1ml/kg
Body weight dose is administered.After last dose next day weigh, put to death animal after cut open tumor and weigh.Experiment is according to matched group (solvent control group)
1 group 10, positive controls (5-FU) 1 group 10, measured matter administration group is only carried out for 1 group 10.Calculate tumor by following equation
Suppression ratio.Tumor control rate=(the average knurl weight of the average knurl weight-medicine group of matched group) average knurl weight × 100% of/matched group.
| Dosage (g/kg) | Tumor control rate (%) | |
| Solvent control group | — | — |
| 5-FU group | 0.025 | 62.35 |
| The crystallization group of embodiment 4 | 0.025 | 65.72 |
| The crystallization group of embodiment 5 | 0.025 | 67.31 |
| The crystallization group of embodiment 6 | 0.025 | 68.49 |
Claims (2)
1. a kind of pleasure cut down preparation method for Buddhist nun it is characterised in that：
The synthesis of (2- chloro-4-hydroxyl-phenyl) t-butyl carbamate
Add 4- amino -3- chlorophenol, Bis(tert-butoxycarbonyl)oxide and triethylamine in dichloromethane, 3-8 hour be stirred at room temperature,
Reactant liquor washes with water, adds appropriate normal hexane making beating, anhydrous sodium sulfate drying, decompression steams solvent, obtains (2- chloro- 4- hydroxyl
Base-phenyl) t-butyl carbamate；
The synthesis of 4- (6- carbamoyl -7- methoxy quinoline -4- epoxide) -2- chloroanilino t-butyl formate
7- methoxyl group -4- chloroquinoline -6- carboxylic acid amides, (2- chloro-4-hydroxyl-phenyl) carbamic acid uncle is added in dimethyl sulfoxide
Butyl ester and cesium carbonate, at 60-98 DEG C, heated and stirred 8-12 hour, reactant liquor is down to room temperature, and reactant liquor is poured into water
In, stir 20-60 minute, filter, be dried to obtain 4- (6- carbamoyl -7- methoxy quinoline -4- epoxide) -2- chloroanilino
T-butyl formate；
The synthesis of 4- (4- amino -3- chlorophenoxy) -7- methoxy quinoline -6- carboxamide hydrochloride
Add 4- (6- carbamoyl -7- methoxy quinoline -4- epoxide) -2- chloroanilino t-butyl formate in methanol, fit
The methanol hydrochloride solution of amount, is stirred at room temperature 3-8 hour, adds ether in reactant liquor, stirs 20-60 minute, filters, dry
To 4- (4- amino -3- chlorophenoxy) -7- methoxy quinoline -6- carboxamide hydrochloride；
To in dichloromethane add 4- (4- amino -3- chlorophenoxy) -7- methoxy quinoline -6- carboxamide hydrochloride, cyclopropylamine,
N, N- carbonyl dimidazoles and triethylamine, 40-60 DEG C is heated to reflux stirring 3-12 hour, and reactant liquor washes with water, anhydrous slufuric acid
Sodium is dried, and decompression steams solvent, recrystallizing methanol, obtains pleasure and cuts down for Buddhist nun.
2. a kind of pleasure cut down preparation method for Buddhist nun it is characterised in that：
The synthesis of (2- chloro-4-hydroxyl-phenyl) t-butyl carbamate
100g 4- amino -3- chlorophenol 183.0g Bis(tert-butoxycarbonyl)oxide and 211.0g is added in 1000ml dichloromethane
Triethylamine, is stirred at room temperature 4 hours, reactant liquor 300ml water washing, adds appropriate normal hexane making beating, anhydrous sodium sulfate drying, subtracts
Pressure steams solvent, obtains 157.0g (2- chloro-4-hydroxyl-phenyl) t-butyl carbamate；
The synthesis of 4- (6- carbamoyl -7- methoxy quinoline -4- epoxide) -2- chloroanilino t-butyl formate
87.0g 7- methoxyl group -4- chloroquinoline -6- carboxylic acid amides, 100.0g (2- chloro- 4- hydroxyl is added in 1000ml dimethyl sulfoxide
Base-phenyl) t-butyl carbamate and 334.0g cesium carbonate, at 90 DEG C, heated and stirred 8 hours, reactant liquor is down to room
Temperature, pours into reactant liquor in 3000ml water, stirs 30 minutes, filters, is dried to obtain 154.0g4- (6- carbamoyl -7-
Methoxy quinoline -4- epoxide) -2- chloroanilino t-butyl formate；
The synthesis of 4- (4- amino -3- chlorophenoxy) -7- methoxy quinoline -6- carboxamide hydrochloride
100.0g 4- (6- carbamoyl -7- methoxy quinoline -4- epoxide) -2- chloroanilino first is added in 300ml methanol
Tert-butyl acrylate, the methanol hydrochloride solution of 500ml 2N, it is stirred at room temperature 4 hours, in reactant liquor, adds 1500ml ether, stir 30
Minute, filter, be dried to obtain 78.0g4- (4- amino -3- chlorophenoxy) -7- methoxy quinoline -6- carboxamide hydrochloride,
60.0g 4- (4- amino -3- chlorophenoxy) -7- methoxy quinoline -6- formyl amine salt is added in 600ml dichloromethane
Hydrochlorate, 10.8g cyclopropylamine, 51.2g N, N- carbonyl dimidazoles and 47.8g triethylamine, 50 DEG C are heated to reflux stirring 6 hours, instead
Answer liquid 900ml water washing, anhydrous sodium sulfate drying, decompression steams solvent, recrystallizing methanol, obtain white crystals 59.4g pleasure
Cut down for Buddhist nun.
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| CN105801481A (en) * | 2016-05-20 | 2016-07-27 | 湖南欧亚生物有限公司 | Lenvatinib synthesizing method |
| CN106543080B (en) * | 2016-11-17 | 2018-11-09 | 山东铂源药业有限公司 | A kind of synthetic method of 4- oxos -7- methoxyl groups -1,4- dihydroquinoline -6- methyl formates |
| CN107629001B (en) * | 2017-10-24 | 2020-07-21 | 重庆大学 | Synthesis method of anticancer drug lenvatinib |
| WO2019092625A1 (en) * | 2017-11-09 | 2019-05-16 | Dr. Reddy's Laboratories Limited | Process for the preparation of lenvatinib or its salts thereof |
| CN111574359A (en) * | 2019-02-19 | 2020-08-25 | 愈磐生物科技（苏州）有限公司 | Levatinib-gallic acid eutectic crystal form and application thereof |
| CN116173023A (en) * | 2022-09-09 | 2023-05-30 | 中南民族大学 | New application of lenvatinib in preventing and treating type II diabetes |
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