CN104876864A - Preparation method of lenvatinib - Google Patents
Preparation method of lenvatinib Download PDFInfo
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- CN104876864A CN104876864A CN201510300819.4A CN201510300819A CN104876864A CN 104876864 A CN104876864 A CN 104876864A CN 201510300819 A CN201510300819 A CN 201510300819A CN 104876864 A CN104876864 A CN 104876864A
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- C—CHEMISTRY; METALLURGY
- 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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- 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a preparation method of lenvatinib. The preparation method comprises the following steps : adopting 4-amino-3-irgasan as a starting material, firstly adopting amino groups for protection, then carrying out butt jointing with 4-chloro-7-methoxyquinoline-6-amide, removing amino-group protective groups, reacting with cyclopropylamine and preparing to obtain the lenvatinib. The preparation method disclosed by the invention is simple and easy to implement, high in yield, good in quality and convenient in industrial production.
Description
Technical field
The present invention relates to pharmaceutical field, be specifically related to a kind of pleasure and cut down preparation method for Buddhist nun.
Background technology
Pleasure is cut down for Buddhist nun Lenvatinib, chemistry 4-[the chloro-4-of 3-(cyclopropyl amino carbonyl) amino-benzene oxygen]-7-methoxyl group-6-quinoline formyl amine by name, it is the orally active multi-kinase inhibitor of one of Japanese Wei Cai company exploitation, mainly act on multiple target spot such as c-Kit, Ret and VEGFR-2, be used for the treatment of the solid tumors such as neurospongioma, thyroid tumor, kidney, liver cancer and ovarian cancer.In February, 2013 obtains the identification of U.S. FDA Orphan drug, is clinically used for the treatment of filter blocking, marrow sample, undifferentiated transitivity or Locally Advanced thyroid papillary carcinoma.
The documents such as EP1683785A1, EP1698623A1, EP1797881A1, US7683172A1 describe a kind of pleasure and cut down synthetic method for Buddhist nun, and its synthetic route is as follows:
The deficiency of this route be have employed there is certain toxicity phenyl chloroformate as raw material, in subsequent reactions, create the phenol that toxicity is larger, moreover, when not carrying out amido protecting, hydroxyl is not protected, certain impurity can be produced.
Technical scheme
For above-mentioned document weak point; the present invention redesigns its synthetic route, with 4-amino-3-chlorophenol for starting raw material, first carries out Boc protection to amino; dock with the chloro-7-methoxy quinoline of 4--6-acid amides; deaminizating Boc protecting group, reacts with cyclopropylamine under the effect of CDI, prepares pleasure and cuts down for Buddhist nun; this preparation method is simple and easy to do, raw material is easyly easy to get, energy consumption is low, yield is high; quality is good, is convenient to suitability for industrialized production, and synthesis summary route is as follows:
The present invention also synthesizes the maleate obtaining pleasure and cut down for Buddhist nun.
The synthesis of (2-chloro-4-hydroxyl-phenyl) t-butyl carbamate (B):
4-amino-3-chlorophenol (A), tert-Butyl dicarbonate and triethylamine is added, stirring at room temperature 3-8 hour in methylene dichloride.Reaction solution washes with water, and add the making beating of appropriate normal hexane, anhydrous sodium sulfate drying, decompression steams solvent, obtains title compound (B).
The synthesis of 4-(6-formamyl-7-methoxy quinoline-4-oxygen base)-2-chloroanilino t-butyl formate (D):
7-methoxyl group-4-chloroquinoline-6-carboxylic acid amides (C), (2-chloro-4-hydroxyl-phenyl) t-butyl carbamate (B) and cesium carbonate is added in dimethyl sulfoxide (DMSO), heated and stirred 8-12 hour at 60-98 DEG C, reaction solution is down to room temperature, reaction solution is poured in water, stir 20-60 minute, filter, drying obtains title compound (D).
The synthesis of 4-(4-amino-3-chlorophenoxy)-7-methoxy quinoline-6-carboxamide hydrochloride (E):
4-(6-formamyl-7-methoxy quinoline-4-oxygen base)-2-chloroanilino t-butyl formate (D) is added, appropriate methanol hydrochloride solution, stirring at room temperature 3-8 hour in methyl alcohol.In reaction solution, add ether, stir 20-60 minute, filter, drying obtains title compound (E).
The happy synthesis cut down for Buddhist nun (F):
In methylene dichloride, add 4-(4-amino-3-chlorophenoxy)-7-methoxy quinoline-6-carboxamide hydrochloride (E), cyclopropylamine, N, N-carbonyl dimidazoles and triethylamine, 40-60 DEG C of reflux stirs 3-12 hour.Reaction solution washes with water, anhydrous sodium sulfate drying, and decompression steams solvent, recrystallizing methanol, obtains white crystals title compound (F).
The happy synthesis cut down for Buddhist nun (F):
4-(4-amino-3-chlorophenoxy)-7-methoxy quinoline-6-carboxamide hydrochloride (E), cyclopropylamine, N, N-carbonyl dimidazoles and triethylamine is added, CO in methylene dichloride
2protection, 40-60 DEG C of reflux stirs 3-12 hour.Reaction solution washes with water, anhydrous sodium sulfate drying, and decompression steams solvent, recrystallizing methanol, obtains white crystals title compound (F).
Pleasure cuts down the synthesis of the maleate for Buddhist nun
Happy cutting down adds in the mixing solutions of toxilic acid and ethanol for Buddhist nun, at 30-50 DEG C, make it dissolve.After confirming dissolving, then through 1-4 hour instillation vinyl acetic monomer.After the dropping of vinyl acetic monomer terminates, reaction solution is stirred 20-60 minute at 30-50 DEG C, then at room temperature stir 3-10 hour.Filter the crystallization of separating out, dry at 30-80 DEG C, obtain the crystallization that pleasure cuts down the maleate for Buddhist nun.
The optimization of synthesis technique of the present invention:
The synthesis of (2-chloro-4-hydroxyl-phenyl) t-butyl carbamate (B) preferred
100g 4-amino-3-chlorophenol is added in 1000ml methylene dichloride
183.0g tert-Butyl dicarbonate and 211.0g triethylamine, stirring at room temperature 4 hours.Reaction solution 300ml water washing, add the making beating of appropriate normal hexane, anhydrous sodium sulfate drying, decompression steams solvent, obtains 157.0g title compound (B).(yield is 92.5%).
100g 4-amino-3-chlorophenol is added in 1000ml methylene dichloride
183.0g tert-Butyl dicarbonate and 211.0g diethylamine, stirring at room temperature 4 hours.Reaction solution 300m] water washing, add the making beating of appropriate normal hexane, anhydrous sodium sulfate drying, decompression steams solvent, obtains 75.0g title compound (B).(yield is 41.2%).
The synthesis of 4-(6-formamyl-7-methoxy quinoline-4-oxygen base)-2-chloroanilino t-butyl formate (D) preferred
87.0g 7-methoxyl group-4-chloroquinoline-6-carboxylic acid amides (C), 100.0g (2-chloro-4-hydroxyl-phenyl) t-butyl carbamate (B) and 334.0g cesium carbonate is added, heated and stirred 8 hours at 90 DEG C in 1000ml dimethyl sulfoxide (DMSO).Reaction solution is down to room temperature, reaction solution is poured in 3000ml water, stir 30 minutes, filter, drying obtains 154.0g title compound (D).(yield is 93.9%).
87.0g 7-methoxyl group-4-chloroquinoline-6-carboxylic acid amides (C), 100.0g (2-chloro-4-hydroxyl-phenyl) t-butyl carbamate (B) and 334.0g cesium carbonate is added, heated and stirred 8 hours at 100 DEG C in 1000ml dimethyl sulfoxide (DMSO).Reaction solution is down to room temperature, reaction solution is poured in 3000ml water, stir 30 minutes, filter, drying obtains 122.0g title compound (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-formamyl-7-methoxy quinoline-4-oxygen base)-2-chloroanilino t-butyl formate (D) is added with the methanol hydrochloride solution of 500ml 2N, stirring at room temperature 4 hours in 300ml methyl alcohol.In reaction solution, add 1500ml ether, stir 30 minutes, filter, drying obtains 78.0g title compound (E).(yield is 91.1%).
100.0g 4-(6-formamyl-7-methoxy quinoline-4-oxygen base)-2-chloroanilino t-butyl formate (D) is added with the methanol hydrochloride solution of 500ml 4N, stirring at room temperature 4 hours in 300ml methyl alcohol.In reaction solution, add 1500ml ether, stir 30 minutes, filter, drying obtains 76.0g title compound (E).(yield is 87.2%).
Happy synthesis preferred cut down for Buddhist nun (F)
60.0g 4-(4-amino-3-chlorophenoxy)-7-methoxy quinoline-6-carboxamide hydrochloride (E), 10.8g cyclopropylamine, 51.2g N is added in 600ml methylene dichloride, N-carbonyl dimidazoles and 47.8g triethylamine, 50 DEG C of reflux stir 6 hours.Reaction solution 900ml water washing, anhydrous sodium sulfate drying, decompression steams solvent, recrystallizing methanol, obtains white crystals 59.4g title compound (F).The happy synthesis cut down for Buddhist nun (F)
60.0g 4-(4-amino-3-chlorophenoxy)-7-methoxy quinoline-6-carboxamide hydrochloride (E), 10.8g cyclopropylamine, 51.2g N is added in 600ml methylene dichloride; N-carbonyl dimidazoles and 47.8g triethylamine; CO2 protects, and 50 DEG C of reflux stir 6 hours.Reaction solution 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 the maleate for Buddhist nun
Happy cutting down adds in the mixing solutions of toxilic acid (20mg) and ethanol (2mL) for Buddhist nun (150mg), at 40 DEG C, make it dissolve.After confirming dissolving, then through instillation vinyl acetic monomer (1.8mL) in 2 hours.After the dropping of vinyl acetic monomer terminates, reaction solution is stirred 30 minutes at 40 DEG C, then at room temperature stir 5 hours.Filter the crystallization of separating out, dry at 60 DEG C, obtain the crystallization (176mg) that pleasure cuts down the maleate for Buddhist nun.
Happy cutting down adds in the mixing solutions of toxilic acid (20mg) and methyl alcohol (2mL) for Buddhist nun (150mg), at 40 DEG C, make it dissolve.After confirming dissolving, then through instillation vinyl acetic monomer (1.8mL) in 2 hours.After the dropping of vinyl acetic monomer terminates, reaction solution is stirred 30 minutes at 40 DEG C, then at room temperature stir 5 hours.Filter the crystallization of separating out, dry at 60 DEG C, obtain the crystallization (123mg) that pleasure cuts down the maleate for Buddhist nun.
Medicine is made in crystallization of the present invention itself or formulation,
The formulation of crystallization of the present invention is made medicine, crystallization is mixed with suitable auxiliary material additive, makes preparation.
Preferred formulation of the present invention is: tablet, powder, granule, capsule, syrup, containing the oral preparations such as tablet, inhalation; External preparation or the injections such as suppository, ointment, Eye ointments, transdermal agent, eye drops, nasal drop, ear drop, cataplasma, lotion.
Preferred auxiliary material is: vehicle, tackiness agent, lubricant, disintegrating agent, tinting material, flavoring are rectified and smelt agent, emulsifying agent, tensio-active agent, solubility promoter, suspendible agent, isotonic agent, buffer reagent, sanitas, antioxidant, stablizer, absorption enhancer etc.
Preferred vehicle is: lactose, white sugar, glucose, W-Gum, N.F,USP MANNITOL, Sorbitol Powder, starch, α starch, dextrin, crystalline cellulose, light silicon anhydride, pure aluminium silicate, Calucium Silicate powder, silicic acid magnesium aluminate, secondary calcium phosphate etc.
Preferred tackiness agent is: polyvinyl alcohol, methylcellulose gum, ethyl cellulose, gum arabic, tragacanth gum, gelatin, shellac, HPMC, hydroxypropylcellulose, Xylo-Mucine, Polyvinylpyrolidone (PVP), polyoxyethylene glycol etc.
Preferred lubricant is: Magnesium Stearate, calcium stearate, stearyl fumarate sodium, talcum, polyoxyethylene glycol, colloidal silica etc.
Preferred disintegrating agent is: crystalline cellulose, agar, gelatin, calcium carbonate, sodium bicarbonate, citrate of lime, dextrin, pectin, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethylcellulose, croscarmellose sodium, carboxymethyl starch, sodium starch glycolate etc.
Preferred tinting material is: ferric oxide, Yellow ferric oxide, famille rose, caramel, β-carotene, titanium oxide, talcum, Riboflavin Sodium Phosphate etc.
Preferred correctives is: cocoa powder, menthol, spearmint oil, borneol, Cortex cinnamomi japonici powder etc.
Preferred emulsifying agent or tensio-active agent are: octadecyl trolamine, sodium lauryl sulphate, dodecyl amino propionic acid, Yelkin TTS, Zerol, sucrose fatty ester, glycerol fatty acid ester etc.
Preferred solubility promoter is: polyoxyethylene glycol, propylene glycol, st-yrax acid benzyl ester, ethanol, cholesterol, trolamine, sodium carbonate, Trisodium Citrate, tween 80, niacinamide etc.
Preferred suspensoid is: the hydrophilic macromolecules such as polyvinyl alcohol, Polyvinylpyrolidone (PVP), methylcellulose gum, Walocel MT 20.000PV, Natvosol, hydroxypropylcellulose.
Preferred isotonic agent is: glucose, sodium-chlor, N.F,USP MANNITOL, Sorbitol Powder etc.
Preferred buffer reagent is: the damping fluids such as phosphoric acid salt, acetate, carbonate, Citrate trianion.
Preferred sanitas is: methyl p-hydroxybenzoate, propylparaben, butylene-chlorohydrin, benzylalcohol, phenylethyl alcohol, dehydroacetic acid (DHA), Sorbic Acid etc.
Preferred antioxidant is: sulphite, xitix, alpha-tocopherol etc.
The component of preferred tablet of the present invention is: 10-100g is happy cuts down crystallization for Buddhist nun or the happy crystallization cut down for Buddhist nun's maleate, 2-10g silicon-dioxide, 10-100g potassium primary phosphate, 2-50g low-substituted hydroxypropyl cellulose, 2-50g Natvosol, 100-300g lactose.
Preferred tablet of the present invention is: 10-100g is happy cuts down crystallization for Buddhist nun or the happy crystallization cut down for Buddhist nun's maleate, 2-10g silicon-dioxide, 10-100g potassium primary phosphate, 2-50g low-substituted hydroxypropyl cellulose, 2-50g Natvosol mix, then, add appropriate dehydrated alcohol, granulate; After this particle and 100-300g lactose are mixed together, utilize tabletting machine, obtain tablet.
Preferred tablet of the present invention is: 50g is happy cuts down crystallization for Buddhist nun or the happy crystallization cut down for Buddhist nun's maleate, 4g silicon-dioxide, 40g potassium primary phosphate, 10g low-substituted hydroxypropyl cellulose, 3g Natvosol mix, then, add appropriate dehydrated alcohol, granulate; After this particle and 143g lactose are mixed together, utilize tabletting machine, obtain tablet.
Usage quantity of the present invention is selected according to symptom, age, administering mode, usually adult daily 10 μ g ~ 10g, point 1 time or administration for several times.
The present invention as angiogenesis inhibitors, can as angiogenesis inhibitors, antineoplastic agent, hemangioma cure agent, cancer transfer inhibitor, retinal neovascularization Remedies, diabetic retinopathy therapeutical agent, agents for inflammatory diseases, comprise therapeutical agent, the atherosclerotic therapeutical agent of diseases associated with inflammation of arthritis deformans, rheumatic arthritis, chronic eczema or retardance anaphylaxis.
The present invention, as antineoplastic agent, can treat carcinoma of the pancreas, cancer of the stomach, large bowel cancer, breast cancer, prostate cancer, lung cancer, kidney, cerebral tumor, leukemia or ovarian cancer.
The present invention, as c-Kit kinase inhibitor, can treat the cancer (acute myelogenous leukemia, Mast cell leukemia, small cell lung cancer, 6IST, carcinoma of testis, ovarian cancer, breast cancer, cerebral tumor, neural sprout cell cancer or large bowel cancer) because of c-Kit kinase activation.
The present invention, as c-Kit kinase inhibitor, can treat allergy, asthma.
The source of main raw material of the present invention include, without being limited to commercially available, be prepared as follows:
4-amino-3-chlorophenol: " preparation of 4-amino-3-chlorophenol "; " Chinese Journal of Pharmaceuticals " 09 phase tert-Butyl dicarbonate in 2013: " Research on Synthesis of Diboc via Diphosgene "; " Shanghai chemical industry " the chloro-7-methoxyl group of 02 phase 4--6-quinolinecarboxamideas in 2006: CAS RN, 417721-36-9
Advantage of the present invention and innovative point as follows:
1. the present invention selects 4-amino-3-chlorophenol cheap and easy to get to be starting raw material; first Boc protection is carried out to amino; simplify reactions steps, improve raw material availability and overall yield, reagent is all comparatively cheap; side reaction is few; productive rate is high, and intermediate directly carries out next step reaction, and productive rate is high; the three wastes are few, are applicable to suitability for industrialized production.
2. present invention improves over the step building quinoline female ring, is reaction raw materials two with 7-methoxyl group-4-chloroquinoline-6-carboxylic acid amides, directly introduces quinoline female ring, decreases the generation of side reaction, greatly improve productive rate.
3. the present invention reacts with cyclopropylamine under the 4th effect of step at CDI, prepares happy cutting down for Buddhist nun.This process is actually a two-step reaction, and CDI reacts with the amino of active hydrogen respectively with on title compound (E), cyclopropylamine, and lose two imidazoles Formed acyl derivatives, this step has been come with " treating different things alike " simultaneously.
4. the release efficiency of crystallization of the present invention is high
5. the activity of compound of the present invention is strong
6. the impurity of product of the present invention is few
Specific embodiment
Embodiment 1:(2-chloro-4-hydroxyl-phenyl) synthesis of t-butyl carbamate (B)
100g 4-amino-3-chlorophenol is added in 1000ml methylene dichloride
183.0g tert-Butyl dicarbonate and 211.0g triethylamine, stirring at room temperature 4 hours.Reaction solution 300ml water washing, add the making beating of appropriate normal hexane, anhydrous sodium sulfate drying, decompression steams solvent, obtains 157.0g title compound (B).(yield is 92.5%).
1H-NMR(400MHz，d
6-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)。
The synthesis of embodiment 2:4-(6-formamyl-7-methoxy quinoline-4-oxygen base)-2-chloroanilino t-butyl formate (D)
87.0g 7-methoxyl group-4-chloroquinoline-6-carboxylic acid amides (C), 100.0g (2-chloro-4-hydroxyl-phenyl) t-butyl carbamate (B) and 334.0g cesium carbonate is added, heated and stirred 8 hours at 90 DEG C in 1000ml dimethyl sulfoxide (DMSO).Reaction solution is down to room temperature, reaction solution is poured in 3000ml water, stir 30 minutes, filter, drying obtains 154.0g title compound (D).(yield is 93.9%).
1H-NMR(400MHz，d
6-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)。
The synthesis of embodiment 3:4-(4-amino-3-chlorophenoxy)-7-methoxy quinoline-6-carboxamide hydrochloride (E)
100.0g 4-(6-formamyl-7-methoxy quinoline-4-oxygen base)-2-chloroanilino t-butyl formate (D) is added, the methanol hydrochloride solution of 500ml 2N, stirring at room temperature 4 hours in 300ml methyl alcohol.In reaction solution, add 1500ml ether, stir 30 minutes, filter, drying obtains 78.0g title compound (E).(yield is 91.1%).
1H-NMR(400MHz，d
6-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: the happy synthesis cut down for Buddhist nun (F)
60.0g 4-(4-amino-3-chlorophenoxy)-7-methoxy quinoline-6-carboxamide hydrochloride (E), 10.8g cyclopropylamine, 51.2g N is added in 600ml methylene dichloride, N-carbonyl dimidazoles and 47.8g triethylamine, 50 DEG C of reflux stir 6 hours.Reaction solution 900ml water washing, anhydrous sodium sulfate drying, decompression steams solvent, recrystallizing methanol, obtains white crystals 59.4g title compound (F).(yield is 88.2%).
mp 228～230℃。
1H-NMR(400MHz，d
6-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％。
High performance liquid phase instrument, chromatographic working station
Normalization method: chromatographic column C18 post;
Moving phase: water: acetonitrile: acetic acid=890: 105: 5 (v/v/v)
Determined wavelength 252nm; Column temperature 25 DEG C; Flow velocity 0.6ml/min.
Embodiment 5: the happy synthesis cut down for Buddhist nun (F)
60.0g 4-(4-amino-3-chlorophenoxy)-7-methoxy quinoline-6-carboxamide hydrochloride (E), 10.8g cyclopropylamine, 51.2g N is added in 600ml methylene dichloride; N-carbonyl dimidazoles and 47.8g triethylamine; CO2 protects, and 50 DEG C of reflux stir 6 hours.Reaction solution 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
Happy cutting down adds in the mixing solutions of toxilic acid (20mg) and ethanol (2mL) for Buddhist nun (150mg), at 40 DEG C, make it dissolve.After confirming dissolving, then through instillation vinyl acetic monomer (1.8mL) in 2 hours.After the dropping of vinyl acetic monomer terminates, reaction solution is stirred 30 minutes at 40 DEG C, then at room temperature stir 5 hours.Filter the crystallization of separating out, dry at 60 DEG C, obtain the crystallization (176mg) that pleasure cuts down the maleate for Buddhist nun.
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 (see J.H.Wood etc., J.Pharm.Soc., 54,1068 (1955)), utilize condition below measure happy cut down for Buddhist nun's episome crystallization (crystallization obtained in embodiment 4), happyly to cut down for the crystallization (crystallization obtained in embodiment 5) of Buddhist nun's episome, the happy dissolution rate cutting down the crystallization (crystallization obtained in embodiment 6) of maleate for Buddhist nun.Dissolution rate keeps linear range computation based in the dissolving time at initial stage and the relation of concentration.
High performance liquid phase instrument, chromatographic working station
Normalization method: chromatographic column C18 post;
Moving phase: water: acetonitrile: acetic acid=890: 105: 5 (v/v/v)
Determined wavelength 252nm; Column temperature 25 DEG C; Flow velocity 0.6ml/min.
Sample size: 100 μ L
Dissolution rate is as follows.
| Dissolution rate (μ g/ minute/cm 2) | |
| The crystallization of embodiment 4 | 0.9 |
| The crystallization of embodiment 5 | 1.1 |
| The crystallization of embodiment 6 | 122 |
Compare with the crystallization of embodiment 4,5, the dissolution rate of the crystallization of embodiment 6 increases substantially.
Embodiment 8: utilize HPLC to measure impurity level
In the crystallization Crystallization of embodiment 4-6, add the mixing solutions (4: 1) of water and ethanol, modulation ultimate density is the sample solution of 0.1mg/mL.
Utilize HPLC method, under the condition determination below, sample solution is tested, measure stripping peak area, utilize opposite face area method to calculate total impurities.(record is more than or equal to the impurity of 0.05%.)
(calculation formula of total impurities)
Amount (%)=(peak area of often kind of impurity) × 100/ ((peak area of carboxylic acid amides)+(summation of the peak area of often kind of impurity)) of often kind of impurity
The summation of the amount of total impurities (%)=often kind of impurity
(HPLC condition determination)
High performance liquid phase instrument, chromatographic working station
Normalization method: chromatographic column C18 post;
Moving phase: water: acetonitrile: acetic acid=890: 105: 5 (v/v/v)
Determined wavelength 252nm; Column temperature 25 DEG C; Flow velocity 0.6ml/min.
Sample size: 100 μ L
Dissolution rate 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 primary phosphate, 10g low-substituted hydroxypropyl cellulose, 3g Natvosol mix.Then, add appropriate dehydrated alcohol, granulate; After this particle and 143g lactose are mixed together, utilize tabletting machine, obtain tablet.
Embodiment 10:
The crystallization of 50g embodiment 5,4g silicon-dioxide, 40g potassium primary phosphate, 10g low-substituted hydroxypropyl cellulose, 3g Natvosol mix.Then, add appropriate dehydrated alcohol, granulate; After this particle and 143g lactose are mixed together, utilize tabletting machine, obtain tablet.
Embodiment 11:
The crystallization of 50g embodiment 6,4g silicon-dioxide, 40g potassium primary phosphate, 10g low-substituted hydroxypropyl cellulose, 3g Natvosol mix.Then, add appropriate dehydrated alcohol, granulate; After this particle and 143g lactose are mixed together, utilize tabletting machine, obtain tablet.
Embodiment 12: anti-tumor activity of the present invention
Will with 1 × 10
7the VEGF that the concentration of/ml is suspended in PBS highly expresses pancreatic cancer cell (KP-1/VEGF) is transplanted to female Balb/c (nu/nu) mouse in 8 week age right rib abdomen subcutaneous part according to the capacity of 0.1ml.About 100mm is reached from gross tumor volume
3time, continuous oral gives measured matter 14 days.Measured matter is suspended in 0.5% methylcellulose gum, by the administration of 0.1ml/kg body weight dose.After last administration next day weigh, put to death animal after cut open knurl and weigh.Experiment is according to control group (solvent control group) 1 group 10, and positive controls (5-FU) 1 group 10, measured matter administration group is only carried out for 1 group 10.By following formulae discovery tumor control rate.The average knurl of tumor control rate=(control group average knurl weight-medicine group average knurl weight)/control group heavy × 100%.
| 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 (10)
1. pleasure cuts down the preparation method for Buddhist nun, it is characterized in that: with 4-amino-3-chlorophenol for starting raw material, first amino Boc protection; dock with the chloro-7-methoxy quinoline of 4--6-acid amides; deaminizating Boc protecting group, reacts with cyclopropylamine under the effect of CDI, prepares happy cutting down for Buddhist nun.
2. a kind of pleasure according to claim 1 cuts down the preparation method for Buddhist nun, it is characterized in that: the synthesis of (2-chloro-4-hydroxyl-phenyl) t-butyl carbamate,
4-amino-3-chlorophenol, tert-Butyl dicarbonate and triethylamine is added in methylene dichloride, stirring at room temperature 3-8 hour, reaction solution washes with water, add the making beating of appropriate normal hexane, anhydrous sodium sulfate drying, decompression steams solvent, obtains (2-chloro-4-hydroxyl-phenyl) t-butyl carbamate.
3. a kind of pleasure according to claim 1 cuts down the preparation method for Buddhist nun, it is characterized in that: the synthesis of 4-(6-formamyl-7-methoxy quinoline-4-oxygen base)-2-chloroanilino t-butyl formate,
7-methoxyl group-4-chloroquinoline-6-carboxylic acid amides, (2-chloro-4-hydroxyl-phenyl) t-butyl carbamate and cesium carbonate is added in dimethyl sulfoxide (DMSO); heated and stirred 8-12 hour at 60-98 DEG C; reaction solution is down to room temperature; reaction solution is poured in water; stir 20-60 minute; filter, drying obtains 4-(6-formamyl-7-methoxy quinoline-4-oxygen base)-2-chloroanilino t-butyl formate.
4. a kind of pleasure according to claim 1 cuts down the preparation method for Buddhist nun, it is characterized in that: the synthesis of 4-(4-amino-3-chlorophenoxy)-7-methoxy quinoline-6-carboxamide hydrochloride,
4-(6-formamyl-7-methoxy quinoline-4-oxygen base)-2-chloroanilino t-butyl formate is added in methyl alcohol; appropriate methanol hydrochloride solution; stirring at room temperature 3-8 hour; ether is added in reaction solution; stir 20-60 minute; filter, drying obtains 4-(4-amino-3-chlorophenoxy)-7-methoxy quinoline-6-carboxamide hydrochloride.
5. a kind of pleasure according to claim 1 cuts down the preparation method for Buddhist nun, it is characterized in that:
4-(4-amino-3-chlorophenoxy)-7-methoxy quinoline-6-carboxamide hydrochloride, cyclopropylamine, N is added in methylene dichloride, N-carbonyl dimidazoles and triethylamine, 40-60 DEG C of reflux stirs 3-12 hour, reaction solution washes with water, anhydrous sodium sulfate drying, decompression steams solvent, recrystallizing methanol, obtains happy cutting down for Buddhist nun.
6. a kind of pleasure according to claim 1 cuts down the preparation method for Buddhist nun, it is characterized in that:
4-(4-amino-3-chlorophenoxy)-7-methoxy quinoline-6-carboxamide hydrochloride, cyclopropylamine, N is added in methylene dichloride; N-carbonyl dimidazoles and triethylamine; CO2 protects; 40-60 DEG C of reflux stirs 3-12 hour; reaction solution washes with water, anhydrous sodium sulfate drying, and decompression steams solvent; recrystallizing methanol, obtains happy cutting down for Buddhist nun.
7. pleasure cuts down the tablet for Buddhist nun, it is characterized in that: component is: 10-100g is happy to be cut down for Buddhist nun, 2-10g silicon-dioxide, 10-100g potassium primary phosphate, 2-50g low-substituted hydroxypropyl cellulose, 2-50g Natvosol, 100-300g lactose.
8. a kind of pleasure according to claim 7 cuts down the tablet for Buddhist nun, it is characterized in that: as angiogenesis inhibitors.
9. a kind of pleasure according to claim 7 cuts down the tablet for Buddhist nun, it is characterized in that: as antineoplastic agent.
10. a kind of pleasure according to claim 7 cuts down the tablet for Buddhist nun, it is characterized in that: as c-Kit kinase inhibitor.
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| CN107629001A (en) * | 2017-10-24 | 2018-01-26 | 重庆大学 | A kind of cancer therapy drug pleasure cuts down the synthetic method for Buddhist nun |
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| 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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