CN101899057A - Preparation method of pyrimido-oxazole derivative and use thereof in medicine - Google Patents
Preparation method of pyrimido-oxazole derivative and use thereof in medicine Download PDFInfo
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Abstract
The invention relates to a synthetic method of a pyrimido-oxazole derivative which is related to inhibition of tumor angiogenesis and a medical use thereof. The preparation comprises the steps of taking 2-methyl-4,6-dichloro-5-aminopyrimidine as a starting raw material, and carrying out three-step reaction of N-alkylation condensation, acylation and ring-closing reaction. The method has simple operation, mild reaction conditions, cheap and readily-available raw materials and reaction reagents and high yield in each step. The compound is mainly applied in the inhibition of the tumor angiogenesis.
Description
Technical field
This patent relates to a kind of method for preparing phonetic pyridine and oxazole derivative and its relevant intermediate, with and in medically purposes.
Background technology
The oxazole ring is the stable heterocycle of a class formation, is found in many natural product structures.Because of it has human body low toxicity, superior bioactive such as efficient, and be widely used in SARS drug design, fields such as the synthetic and medicine bioactivity research of medicine.Heterocycle Bing oxazole class formation micromolecular compound is developed in recent years and is applied to a plurality of pharmacological agenies field, as antitumor, and anti-inflammatory, antibiotic etc., have the prospect of good drug development.
2, the Mi Ding Bing oxazole heterocyclic compounds (formula VI) of 7 replacements has been in the news and has been used for the antitumor drug exploitation, it is primarily aimed at target spot is EGF-R ELISA (EGFR), endothelial cell growth factor receptor 2 body network propylhomoserin kinases such as (VEGFR), suppress their excessive Expression of phosphorylated, suppress tumor neogenetic blood vessels and generate, thereby suppress tumor cell proliferation, impel apoptosis of tumor cells.
Mi Ding Bing oxazole has shown superior skeleton activity, but relevant its synthetic report is very few.(Bioorganic ﹠amp; MedicinalChemistry Letters, 14,2004, P
1997-2000) reported the synthetic method of the Mi Ding Bing oxazole heterocyclic compounds of 2,7 replacements.With 4,6-dihydroxyl-5-aminopyrimidine is a raw material, at first carries out acidylate with aroyl chloride; be cyclization Gou Jian oxazole ring under the solvent condition at polyphosphoric acid afterwards; and 7 hydroxyls are carried out chloro with phosphorus oxychloride, and use 7 chlorine of aminocompound nucleophilic substitution at last, obtain end product.This method characteristics are to make up Mi Ding Bing oxazole ring earlier, connect amino substituent at 7 afterwards, and totally 4 steps obtained target product.Shortcoming be the amino nucleophilic substitution reaction of final step difficulty carry out, must be in the DMF solvent 110 degree reactions more than 10 hours, and productive rate is lower; Use the very big reaction reagents of toxicity, corrodibility such as phosphorus oxychloride, polyphosphoric acid in the reaction simultaneously, synthetic cost is also higher, is unfavorable for suitability for industrialized production.
Simultaneously, other heterocycles reported at present and the synthetic method of oxazole compound are more common in the synthetic of pyrrole pyridine and oxazole greatly, and its synthetic committed step is the structure of oxazole ring, and synthetic method is broadly divided into following a few class:
1. (Synthesis, 1,1990, P
64-66) be raw material with 2-chloro-3-aminopyridine, after the acyl chlorides acylation reaction, under trimethyl silicane polyphosphate catalytic condition, be heated to 180 degree, condensation, Gou Jian oxazole ring obtains end product.Temperature of reaction is too high during this method Huan He oxazole ring, and trimethyl silicane polyphosphate price is comparatively expensive, is unfavorable for suitability for industrialized production.
2. (Synthesis, 13,2003, P
2033～2040) use 2-amino-3-bromopyridine to be raw material, after the acidylate, use Huan He oxazole ring under sodium amide/sodium tert-butoxide highly basic condition.Defective is that the highly basic condition is easy to produce by product, and reaction yield is not high.
3. (Tetrahedron Letters, 48,2007, P
2295-2298) use 2-amino-3-pyridone and carboxylic acid under microwave condition, next step direct cyclization of high temperature.Shortened the reaction times, simplified operation, carried out, reaction conditions is had relatively high expectations, and product yield is different widely different because of substrate but be reflected under the microwave.
Summary of the invention
1. the objective of the invention is to research and develop the method for the Mi Ding Bing oxazole analog derivative of 2,7 replacements of a kind of preparation, overcome the severe reaction conditions that exists in the heterocycle Bing oxazole construction process of report before many, reagent costliness, shortcoming such as productive rate is lower.
For overcoming the above problems, provide technological method as follows:
A) formula I compound and formula II compound are dissolved in the reaction solvent, add small amount of acid catalysis, carry out N-hydrocarbonylation condensation reaction, production III compound;
B) under the alkaline condition, formula III compound is dissolved in the reaction solvent, after the stirring fully, slow dropping formula IV compound carries out acidylate and replaces production V compound to system under the 0 degree condition;
C) formula V compound through ring-closure reaction, obtains having the Mi Ding Bing oxazole analog derivative of formula VI under metal and basic ligands catalysis;
R1-R5 is hydrogen, halogen, C1～C10 alkyl, C1～C10 alkoxyl group, nitro, amino, hydroxyl, C1～C10 alkyl acyl, benzoyl, N-phenyl urea groups;
R6-R10 is hydrogen, halogen, C1～C10 alkyl, C1～C10 alkoxyl group, nitro, amino, hydroxyl;
N is 0 or 1 or 2.
Key of the present invention is by formula V compounds accepted way of doing sth VI compound, the i.e. structure of Mi Ding Bing oxazole ring.Design is used under the mineral alkali catalytic condition in synthetic, and the cuprous and nitrogenous basic ligands of halo forms the chelating intermediate, goes to promote that acid amides substrate (formula V compound) shape becomes the catalyzed cyclization of oxazole ring (formula VI compound).Preferred salt of wormwood, cuprous iodide, the N of using, N '-dimethyl-ethylenediamine be as catalysts, formula V compound and salt of wormwood, cuprous iodide, N, and N '-dimethyl-ethylenediamine molar ratio is 1: 2～10: 0.05～0.2: 0.1～0.2.The preferred tetrahydrofuran (THF) of reaction solvent.
The invention provides a kind of method of easy, efficiently synthetic Mi Ding Bing oxazole derivative, compare with existing additive method, this method advantage is as follows:
A) easy and simple to handle, need not special reaction equipment, total overall reaction is all carried out under room temperature or backflow situation, the reaction conditions gentleness.
B) all reaction reagents and reaction solvent are the conventional reagent in laboratory, and economy is easy to get.
C) whole synthetic employing is carried out the amino replacement at 7 earlier, and the method that the Hang oxazole ring of Zai Jin makes up is made up of three-step reaction, and per step yield is all more than 80%.Wherein, the structure of one step of formula V compounds accepted way of doing sth VI compound ， Ji oxazole ring, the ultimate yield of different substrates is all more than 90%.
2. another object of the present invention is in formula VI compound, exploration discovery has the symptom of a trend compound that suppresses the tumor neogenetic blood vessels generation.Pharmacological testing shows, formula VI compound is mostly for the tumor neogenetic blood vessels closely-related VEGF-HUVEC cell (endothelial cell growth factor (ECGF) inductive Human umbilical vein endothelial cells) of growing stronger inhibited proliferation being arranged, thereby stoped the tumor growth that relies on enough vascularities, stoped the formation of metastatic tumor.
Table 1 segment bounds VI compound is to VEGF-HUVEC cell inhibitory effect experimental result
Embodiment
The present invention can further be set forth by the following example, but is not restriction the present invention.
Embodiment 1
A) formula III compound (R
3=Cl, n=0, the preparation of intermediate III-a)
Add 4 successively in reaction flask, 6-two chloro-2-methyl-5-aminopyrimidine 5g, p-Chlorobenzoic acid amide 4.5g, ethanol/water mixing solutions (ethanol: 45ml water=1: 8), room temperature condition slowly drips the 0.5ml concentrated hydrochloric acid down to reaction system, is heated to backflow, stirring reaction 6 hours, stop heating afterwards, stirring at room reaction 1 hour.Separate out a large amount of solids, filter, filter cake washs respectively with sherwood oil and water, and vacuum-drying gets gray solid 6.4g, yield 85%.
B) formula V compound (R
3=Cl, R
8=Cl, n=0, the preparation of intermediate V-a)
In 50ml anhydrous methylene chloride solution, add 2.7g intermediate III-a and 1.2ml anhydrous pyridine, after stirring, under the 0 degree condition, slowly drip the 1.4ml parachlorobenzoyl chloride, room temperature reaction 2 hours.Separate out a large amount of solids, filter.Filter cake methylene dichloride and sherwood oil mixing solutions (methylene dichloride: recrystallization sherwood oil=1: 10).Vacuum-drying gets white solid 3.3g, yield 81%.
C) formula VI compound (R
3=Cl, R
8=Cl, n=0, the preparation of end product VI-a)
In the 15ml tetrahydrofuran solution, add 2.2g intermediate V-a, 2g salt of wormwood, 0.06ml (50mg) N, N '-dimethyl-ethylenediamine, the 60mg cuprous iodide, nitrogen protection is heated to 65 degree reactions 4 hours.Filter while hot, (developping agent is a methylene dichloride to the filtrate column chromatography for separation: sherwood oil=1: 2), get white solid 1.85g, yield 92%.
1H?NMR(CDCl3)δ8.75(s，1H)，8.24(d，2H，J＝6.6Hz)，7.78(d，2H?J＝8.7Hz)，7.52(d，2H，J＝6.6Hz)，7.37(d，2H，J＝8.7Hz)，2.73(s，3H)；EI-MS?370/372(M
+).
Embodiment 2
A) formula III compound (R
3=CH
3, n=0, the preparation of intermediate III-h)
Add 4 successively in reaction flask, 6-two chloro-2-methyl-5-aminopyrimidine 5g, to monomethylaniline 3.7g, ethanol/water mixing solutions (ethanol: 45ml water=1: 8), room temperature condition slowly drips the 0.5ml concentrated hydrochloric acid down to reaction system, is heated to backflow, stirring reaction 6 hours, stop heating afterwards, stirring at room reaction 1 hour.Separate out a large amount of solids, filter, filter cake washs respectively with sherwood oil and water, and vacuum-drying gets gray solid 6.6g, yield 95%.
B) formula V compound (R
3=CH
3, R
8=NO
2, n=0, the preparation of intermediate V-h)
In 50ml anhydrous methylene chloride solution, add 2.5g intermediate III-h and 1.2ml anhydrous pyridine, after stirring, under the 0 degree condition, slowly add the 2.2g paranitrobenzoyl chloride, room temperature reaction 5 hours.Separate out a large amount of solids, filter.Filter cake methylene dichloride and sherwood oil mixing solutions (methylene dichloride: recrystallization sherwood oil=1: 10).Vacuum-drying gets faint yellow solid 3.2g, yield 80%.
C) formula VI compound (R
3=CH
3, R
8=NO
2, n=0, the preparation of end product VI-h)
In the 15ml tetrahydrofuran solution, add 2g intermediate V-h, 2g salt of wormwood, 0.06ml (50mg) N, N '-dimethyl-ethylenediamine, the 60mg cuprous iodide, nitrogen protection is heated to 65 degree reactions 6 hours.Filter while hot, filtrate column chromatography for separation (developping agent is a methylene dichloride) gets faint yellow solid 1.65g, yield 91%.
1H?NMR(CDCl
3)δ8.75(s，1H)，8.40(d，2H?J＝9.0Hz)，8.33(d，2H?J＝9.0Hz)，7.67(d，2H?J＝8.1Hz)，7.24(d，2HJ＝8.1Hz)，2.73(s，3H)，2.39(s，3H)；EI-MS?361(M
+)。
Embodiment 3
A) formula III compound (
N=0, the preparation of intermediate III-k)
Add 4 successively in reaction flask, 6-two chloro-2-methyl-5-aminopyrimidine 5g, 4-N-phenyl urea groups aniline 7.7g, ethanol/water mixing solutions (ethanol: 60ml water=1: 5), room temperature condition slowly drips the 1ml concentrated hydrochloric acid down to reaction system, is heated to backflow, stirring reaction 6 hours, stop heating afterwards, stirring at room reaction 1 hour.Separate out a large amount of solids, filter, filter cake washs respectively with sherwood oil and water, and vacuum-drying gets filbert solid 8.4g, yield 81%.
B) formula V compound (
R
8=OCH
3, n=0, the preparation of intermediate V-k)
In 50ml anhydrous methylene chloride solution, add 3.7g intermediate III-k and 1.2ml anhydrous pyridine, after stirring, under the 0 degree condition, slowly drip the 1.6ml anisoyl chloride, room temperature reaction 2 hours.Separate out a large amount of solids, filter.Filter cake methylene dichloride and sherwood oil mixing solutions (methylene dichloride: recrystallization sherwood oil=1: 10).Vacuum-drying gets faint yellow solid 4.4g, yield 87%.
C) formula VI compound (
R
8=OCH
3, n=0, the preparation of end product VI-k)
In the 25ml tetrahydrofuran solution, add 2.5g intermediate V-k, 1g salt of wormwood, 0.03ml (25mg) N, N '-dimethyl-ethylenediamine, the 30mg cuprous iodide, nitrogen protection is heated to 65 degree reactions 4 hours.Filter while hot, filtrate column chromatography for separation (developping agent is a methylene dichloride) gets faint yellow solid 2.15g, yield 93%.
1H?NMR(DMSO)δ8.67(s，1H)，8.11(d，2H?J＝8.7Hz)，7.80(d，2H?J＝8.7Hz)，7.45(t，4H)，7.30(t，2H)，7.19(d，2H?J＝8.4Hz)，6.98(s，2H)，3.87(s，3H)，2.75(s，3H)；EI-MS?466(M
+)。
Embodiment 4
A) formula III compound (n=1, the preparation of intermediate III-n)
Add 4 successively in reaction flask, 6-two chloro-2-methyl-5-aminopyrimidine 5g, benzylamine 3.9ml, ethanol/water mixing solutions (ethanol: 45ml water=1: 8), room temperature condition slowly drips the 0.5ml concentrated hydrochloric acid down to reaction system, is heated to backflow, stirring reaction 6 hours, stop heating afterwards, stirring at room reaction 1 hour.Separate out a large amount of solids, filter, filter cake washs respectively with sherwood oil and water, and vacuum-drying gets tawny solid 6.5g, yield 93%.
B) formula V compound (R
8=OCH
3, n=1, the preparation of intermediate V-n)
In 50ml anhydrous methylene chloride solution, add 2.5g intermediate III-n and 1.2ml anhydrous pyridine, after stirring, under the 0 degree condition, slowly drip the 1.6ml anisoyl chloride, room temperature reaction 2 hours.Separate out a large amount of solids, filter.Filter cake methylene dichloride and sherwood oil mixing solutions (methylene dichloride: recrystallization sherwood oil=1: 10).Vacuum-drying gets brown solid 3.4g, yield 88%.
C) formula VI compound (R
8=OCH
3, n=1, the preparation of end product VI-n)
In the 15ml tetrahydrofuran solution, add 1.9g intermediate V-n, 2g salt of wormwood, 0.06ml (50mg) N, N '-dimethyl-ethylenediamine, the 60mg cuprous iodide, nitrogen protection is heated to 65 degree reactions 4 hours.Filter while hot, (developping agent is a methylene dichloride to the filtrate column chromatography for separation: sherwood oil=1: 2), get yellowish solid 1.55g, yield 90%.
1H?NMR(CDCl
3)δ8.08(d，2H?J＝8.7Hz)，7.34(m，5H)，7.00(d，2H?J＝8.7Hz)，4.95(s，2H)，4.95(bs，1H)，3.88(s，3H)，2.64(s，3H)；EI-MS?346(M
+)。
Claims (10)
1. method for preparing phonetic pyridine and oxazole derivative, this method comprises:
A) formula I compound and formula II compound are carried out N-hydrocarbonylation condensation reaction, production III compound;
B) under the alkaline condition, formula III compound and formula IV compound carry out acylation reaction, production V compound;
C) formula V compound through ring-closure reaction, obtains having the Mi Ding Bing oxazole analog derivative of formula VI under metal and basic ligands catalysis;
R1-R5 is hydrogen, halogen, C1～C10 alkyl, C1～C10 alkoxyl group, nitro, amino, hydroxyl, C1～C10 alkyl acyl, benzoyl, N-phenyl urea groups;
R6-R10 is hydrogen, halogen, C1～C10 alkyl, C1～C10 alkoxyl group, nitro, amino, hydroxyl;
N is 0 or 1 or 2.
2. according to the preparation method of claim 1, the alkali in the step b) is organic bases.
3. according to the preparation method of claim 2, wherein said organic bases is pyridine, triethylamine, 4-Dimethylamino pyridine, 1-hydroxyl-benzo-triazole or N, the N-diisopropylethylamine.
4. according to the preparation method of claim 3, the preferred pyridine of wherein said organic bases.
5. according to the preparation method of claim 1, the metal in the step c) is a cuprous halide.
6. according to the preparation method of claim 5, the preferred cuprous iodide of wherein said metal.
7. according to the preparation method of claim 1, the basic ligands in the step c) is a containing n-donor ligand.
8. according to the preparation method of claim 7, wherein said containing n-donor ligand is a L-proline(Pro), 1,10-phenanthroline, N, N '-dimethyl-ethylenediamine, oxine.
9. preparation method according to Claim 8, the preferred N of wherein said containing n-donor ligand, N '-dimethyl-ethylenediamine.
10. compound VI in the claim 1 and pharmaceutically acceptable carrier have the purposes in the inhibiting medicine in preparation treatment tumor neogenetic blood vessels generation and to tumor cell proliferation, migration.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104650111A (en) * | 2015-01-14 | 2015-05-27 | 中国药科大学 | Aryl urea and aryl amide substituted oxaole pyrimindine compounds as well as preparation method and application thereof |
| CN111646995A (en) * | 2019-03-04 | 2020-09-11 | 四川大学 | 4-amino-pyrimidoazenitrogen heterocycle-phenylurea derivative and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1509291A (en) * | 2001-05-14 | 2004-06-30 | ��˹��ŵ�� | Oxazolo-and-furopyrimidines and their use in medicaments against tumors |
| US20080269238A1 (en) * | 2004-04-01 | 2008-10-30 | Takeda Pharmaceutical Company Limited | Thiazolopyrimidine Derivative |
-
2010
- 2010-07-21 CN CN 201010232505 patent/CN101899057A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1509291A (en) * | 2001-05-14 | 2004-06-30 | ��˹��ŵ�� | Oxazolo-and-furopyrimidines and their use in medicaments against tumors |
| US20080269238A1 (en) * | 2004-04-01 | 2008-10-30 | Takeda Pharmaceutical Company Limited | Thiazolopyrimidine Derivative |
Non-Patent Citations (1)
| Title |
|---|
| 《Helvetica Chimica Acta》 20041231 Martin-Kohler, Andreas et al. Furo[2,3-d]pyrimidines and oxazolo[5,4-d]pyrimidines as inhibitors of receptor tyrosine kinases (RTK) 956-975 1-10 第87卷, 第4期 2 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104650111A (en) * | 2015-01-14 | 2015-05-27 | 中国药科大学 | Aryl urea and aryl amide substituted oxaole pyrimindine compounds as well as preparation method and application thereof |
| CN111646995A (en) * | 2019-03-04 | 2020-09-11 | 四川大学 | 4-amino-pyrimidoazenitrogen heterocycle-phenylurea derivative and preparation method and application thereof |
| CN111646995B (en) * | 2019-03-04 | 2023-03-21 | 四川大学 | 4-amino-pyrimidoazenitrogen heterocycle-phenylurea derivative and preparation method and application thereof |
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Application publication date: 20101201 |