CN106883192B - The synthetic method of the benzoic acid derivative of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl modification - Google Patents
The synthetic method of the benzoic acid derivative of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl modification Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Abstract
The invention discloses a kind of synthetic methods of the benzoic acid derivative of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl modification, it includes three-step reaction: first, cyanobenzaldehyde class compound and alkamine compound reaction generation intermediate: 4,5- dihydro-oxazole -2- base compound of benzene nitriles, then the intermediate is further oxidized to the compound of benzene nitriles of oxazolyl modification, and the compound of benzene nitriles of last oxazolyl modification is through basic hydrolysis and is acidified to obtain the benzoic acid derivative modified of oxazolyl.Method of the invention does not use metallic catalyst, and reaction condition is mild, and post-processing is simple, and reaction yield and product purity are higher, and reaction is not required to special producing equipment, no high-temperature operation, no strong corrosive material.
Description
Technical field
The present invention relates to a kind of synthetic methods of nitrogenous class heterocyclic antineoplastic pharmaceutical actives, and in particular to a kind of oxazolyl
The synthetic method of the benzoic acid derivative of modification.
Background technique
The benzoic acid derivative of oxazolyl modification can be used as dopamine D 3 receptor anticaking agent class and prostate EP2 receptor is anti-
Agent antipsychotic drug is tied, by taking 4- (oxazole -2- base) benzoic acid as an example, field of medicinal chemistry is widely applied.Firstly, treatment or
In the drug for inhibiting tumour, histone demethylase (KDM1A) is a kind of drug target of potential treatment tumour, and
KDM1A is also believed to, 4- (oxazole -2- base) benzoic acid molecule important skeleton as KDM1A related with some inflammation class diseases
There is important application value (WO2016130952) in above-mentioned field of medicaments.
The method reported at present of synthesis of the benzoic acid derivative of oxazolyl modification is simultaneously few.Known method is: 1)
The synthetic method of patent WO2012149157 and WO2016067043 report.This method is using paracyanobenzoic acid as raw material, and 40 DEG C
Lower through sulphuric acid hydrolysis is to formamide benzene formic acid, then with bromo- 1, the 1- dimethoxy-ethane of 2- 4 hours to be reacted in dioxane
Generate 4- (oxazole -2- base) benzoic acid.This method yield is too low (~3%), generates the solid wastes such as a large amount of silica gel, is not easy to industrialize
Production；2) synthetic method of patent WO2016130952 report.This method is using terephthalic acid monomethyl ester as raw material, and 80 DEG C first
It is lower to use thionyl chloride at acyl chlorides, react 1 small in methylene chloride secondly with 2- amino -1,1- dimethoxy-ethane and triethylamine
When, then at methanesulfonic acid and 140 DEG C of phosphorus pentoxide generate 4- (oxazole -2- base) methyl benzoate, finally with sodium hydroxide water
Solution hydrochloric acid tune acid, obtains 1- (thiazol-2-yl) piperidines -4- alcohol.This method uses thionyl chloride and phosphorus pentoxide, and these are acute
Malicious and seriously polluted material；In addition yield is relatively low (~50%)；3) document Journal of
Organometallic Chemistry,791,266-273；2015 only reported 4- (4,5- dihydro-oxazole -2- base) benzoic acid
Method to use the ruthenium metal of specific customization although this method makes key intermediate have very high yield (~94%)
Catalyst keeps cost very high；4) in addition there are also some documents (such as: Tetrahedron, 69 (32), 6591-6597；
2013), using terephthalonitrile and 2- ethylaminoethanol as raw material, need synthesized using metallic catalyst key intermediate 4- (4,
5- dihydro-oxazole -2- base) cyanophenyl, or reaction process be difficult to control, cause yield uncontrollable.
Summary of the invention
The technical problem to be solved by the present invention is to overcome the defects of the prior art, provide a kind of nitrogenous class heterocyclic antineoplastic medicine
The synthetic method of the benzoic acid derivative of object active matter oxazolyl modification, this method is easy to operate, and reaction yield is higher.
To solve above-mentioned technical proposal, the technical solution adopted by the present invention is that:
A kind of synthetic method of the benzoic acid derivative of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl modification,
The following steps are included:
(1) the anti-of the alkamine compound including the cyanobenzaldehyde class compound indicated of formula I and the expression of formula II is provided
Mixture is answered, reaction mixture generates intermediate: the compound that formula III indicates:
(2) compound that formula III indicates is oxidized to the compound that the formula IV of oxazolyl modification indicates:
(3) compound that formula IV indicates successively obtains the benzene of the oxazolyl modification of the expression of formula VI through hydrolysis and acidification reaction
Formic acid compound:
Wherein, R1-R6It is independently selected from H, methoxyl group, ethyoxyl, C1-C5 alkyl.Preferably, R1-R6Independently
Be selected from H, methoxyl group, C1-C3 alkyl.Most preferably, R1-R6It is H.
Preferably, in step (1): introducing elemental iodine into its reaction mixture.Preferably, the cyano benzene first that formula I indicates
The molar ratio for the alkamine compound that aldehyde compound and formula II indicate is 1:2.0-5.0.Preferably, join in solvent A
Add reaction, solvent A is organic solvent, preferably be selected from one of toluene, the tert-butyl alcohol, methylene chloride, tetrahydrofuran, ethyl acetate or
More than one mixed solution.Further preferred reaction condition are as follows: 25-50 DEG C of reaction temperature, 8-24 hour of reaction time,
Step further includes post-processing step in (1), and preferred post-processing step includes: column chromatography, and column chromatography is preferably to fill out with silica gel
The column of material chromatographs, and elution is also petroleum ether or/and ethyl acetate.
Preferably, in step (2): introducing the DDQ of manganese dioxide and catalytic amount thereto.Preferably, change shown in formula III
The molar ratio of object and manganese dioxide is closed as 1:2.0-10.0, the molar ratio of III compound represented of formula and DDQ are 1:0.05-0.5.
The reaction of step (2) carries out in organic solvent solvent B, preferred solvent B be selected from methylene chloride, tetrahydrofuran, ethyl acetate,
One of acetone, DMF, DMSO, methanol, tert-butyl alcohol or more than one mixture.The reaction condition of step (2) is selected as:
25-50 DEG C of reaction temperature, 8-24 hour of reaction time.Step further includes post-processing step in (2), the post-processing step packet
It includes and is filtered, washed, dries, post-processing step did not included chromatographic column.It is further preferred that filtering is filtered using diatomite, wash
It washs including washing and salt washing.
Preferably, in step (3), inorganic base is introduced into its hydrolysis reaction.Preferably, the compound that formula IV indicates
Molar ratio with inorganic base is 1:2.0-10.0.The preferred inorganic base is selected from sodium carbonate, potassium carbonate, sodium hydroxide, hydrogen-oxygen
Change one of potassium, lithium hydroxide or more than one mixture.It is further preferred that the acidification reaction in step (3) uses
Be concentration be 1-6mol/L hydrochloric acid, and with hydrochloric acid adjust to PH be 1-6.Preferred reaction condition are as follows: reaction temperature 25-50
DEG C, the reaction time is 1-24 hours, more preferably 4 hours.Step further includes post-processing step in (3), the post-processing step packet
It includes and is filtered, washed, dries, do not included chromatographic column.
C1-C5 alkyl of the present invention includes: methyl, ethyl, propyl, isopropyl, normal-butyl, sec-butyl, tert-butyl, positive penta
Base, isopentyl.
In the compound of the present invention structural formulaIndicate the position of connected group on phenyl ring be it is uncertain, such as
Itrile group in the cyanobenzaldehyde class compound that formula I indicates on phenyl ring is with respect to can be contraposition, meta position or ortho position for aldehyde radical
's.
Raw material (compound represented by formula I and formula II) used in the present invention can be by being commercially available, can also be by ability
Method known to domain synthesizes to obtain.Other reagents used in the present invention in addition to raw material are commercially available, and used
Solvent reagent is not necessarily to specially treated, also has no special requirements to its purity.
Advantageous effects of the invention:
Method of the invention does not use metallic catalyst, and reaction condition is mild, and post-processing is simple, and reaction yield and product are pure
Degree is higher, and especially 4- (oxazole -2- base) benzoic acid, total recovery is up to 77%.And reaction is not required to special producing equipment, no height
Temperature operation, no strong corrosive material.
Detailed description of the invention
Fig. 1 is reaction general line figure in embodiment 1.
Specific embodiment
The invention will be further described below in conjunction with the accompanying drawings.Following embodiment is only used for clearly illustrating the present invention
Technical solution, and not intended to limit the protection scope of the present invention.
Embodiment 1
As shown in Figure 1.13.1 grams of 4- cyanobenzaldehydes, 12.2 grams of 2- amino second are added in the reaction flask with blender
Alcohol, 0.25 gram of iodine and 400 milliliters of tert-butyl alcohols, heating are reacted to 40-50 DEG C, react 12 hours.Then reaction mixture is added
Enter 600 milliliters of ethyl acetate and 400 milliliters of water, separate organic phase, then with 300 milliliters of ethyl acetate aqueous phase extracteds, merges organic
Twice with 200 milliliters of saturated common salt washing organic phases, sodium sulphate dries, filters, and filter cake is washed with a small amount of ethyl acetate, organic phase
It is concentrated and does after merging, (pillar filling agent is silica gel to gained crude product, and eluant, eluent is petroleum ether: second by column chromatographic isolation and purification
Acetoacetic ester=1:1 obtains 15.5 grams of cyanophenyl of 4- (4,5- dihydro-oxazole -2- base), yield 90%.
With blender reaction flask in be added 15 grams of 4- (4,5- dihydro-oxazole -2- base) cyanophenyls, 15 grams of manganese dioxide,
1 gram of DDQ and 400 milliliter of methylene chloride reacts at 25 DEG C, reacts 12 hours.Then reaction mixture is passed through into diatomite
Filtering washs filter cake with methylene chloride, and merging filtrate is washed with 200 milliliters, and 200 mL of saline are washed, and sodium sulphate dries, filters,
Filter cake is washed with a small amount of methylene chloride, and organic phase is concentrated after merging and does, and obtains 13.3 grams of cyanophenyl of 4- (oxazole -2- base), yield
90%.
13 grams of 4- (oxazole -2- base) cyanophenyls, 6.2 grams of sodium hydroxides and 100 millis are added in the reaction flask with blender
Water is risen, reacts at 50 DEG C, reacts 4 hours.Then the pH value for adjusting reaction solution with the dilute hydrochloric acid of 1M/L is cooled to 25 to 6
DEG C, filtering, filter cake twice, collects filter cake with 100 milliliters of washings, and it is dry at 50 DEG C, 13.7 grams of white solid are obtained, yield
95%, purity 99.8%.
1HNMR(400MHz,DMSO):13.22(1H,s),8.27(1H,s),8.07(4H,s),7.44(1H,s)。
Embodiment 2
13.1 grams of 4- cyanobenzaldehydes, 30.5 grams of 2- ethylaminoethanols, 0.5 gram of iodine are added in the reaction flask with blender
8 hours are reacted at 25-30 DEG C with 400 milliliters of tert-butyl alcohols.Then by reaction mixture be added 600 milliliters of ethyl acetate and
400 milliliters of water, separate organic phase, then with 300 milliliters of ethyl acetate aqueous phase extracteds, merge organic 200 milliliters of saturated salt solutions
Wash organic phase twice, sodium sulphate dries, filters, and filter cake is washed with a small amount of ethyl acetate, and organic phase is concentrated after merging and does, and gained is thick
Product by column chromatographic isolation and purification (pillar filling agent be silica gel, eluant, eluent is petroleum ether: ethyl acetate=1:1 obtain 4- (4,
5- dihydro-oxazole -2- base) 14.6 grams of cyanophenyl, yield 85%.
10 grams of 4- (4,5- dihydro-oxazole -2- base) cyanophenyls, 25.2 grams of titanium dioxides are added in the reaction flask with blender
Manganese, 6.6 grams of DDQ and 300 milliliter of ethyl acetate react at 25 DEG C, react 8 hours.Then reaction mixture is passed through into silicon
Diatomaceous earth filtering washs filter cake with ethyl acetate, and merging filtrate is washed with 200 milliliters, and 200 mL of saline are washed, and sodium sulphate is dry,
Filtering, filter cake are washed with a small amount of ethyl acetate, and organic phase is concentrated after merging and does, and obtains 8.7 grams of cyanophenyl of 4- (oxazole -2- base), are received
Rate 88%.
5 grams of 4- (oxazole -2- base) cyanophenyls, 7 grams of lithium hydroxides and 50 milliliters of water are added in the reaction flask with blender,
Reaction reacts 1 hour at 50 DEG C.Then the pH value for adjusting reaction solution with the dilute hydrochloric acid of 2M/L is cooled to 25 DEG C, mistake to 4
Filter, filter cake twice, are collected filter cake, dry at 50 DEG C, obtain 5 grams of white solid with 50 milliliters of washings, yield 90%, purity
99.3%.
Embodiment 3
13.1 grams of 4- cyanobenzaldehydes, 18.3 grams of 2- ethylaminoethanols, 0.5 gram of iodine are added in the reaction flask with blender
24 hours are reacted at 30-40 DEG C with 400 milliliters of toluene.Then 600 milliliters of ethyl acetate and 400 are added in reaction mixture
Milliliter water, separates organic phase, then uses 300 milliliters of ethyl acetate aqueous phase extracteds, and merging organic washed with 200 milliliters of saturated common salts has
Mutually twice, sodium sulphate dries, filters machine, and filter cake is washed with a small amount of ethyl acetate, and dry, gained crude product is concentrated in organic phase after merging
By column chromatographic isolation and purification, (pillar filling agent is silica gel, and eluant, eluent is petroleum ether: ethyl acetate=1:10 obtains 4- (4,5-
Dihydro-oxazole -2- base) 15 grams of cyanophenyl, yield 87%.
15 grams of 4- (4,5- dihydro-oxazole -2- base) cyanophenyls, 75.9 grams of titanium dioxides are added in the reaction flask with blender
Manganese, 5.9 grams of DDQ and 300 milliliter of tetrahydrofurans react at 30-40 DEG C, react 8 hours.Then reaction mixture is passed through
Diatomite filtering washs filter cake with ethyl acetate, and merging filtrate is washed with 200 milliliters, and 200 mL of saline are washed, and sodium sulphate is dry
Dry, filtering, filter cake is washed with a small amount of ethyl acetate, and organic phase is concentrated after merging and does, and obtains 4- (oxazole -2- base) cyanophenyl 12.4
Gram, yield 84%.
10 grams of 4- (oxazole -2- base) cyanophenyls of addition, 40.6 grams of potassium carbonate and 100 milliliters in the reaction flask with blender
Water reacts at 40 DEG C, reacts 24 hours.Then the pH value for adjusting reaction solution with the dilute hydrochloric acid of 6M/L is cooled to 25 to 1
DEG C, filtering, filter cake twice, collects filter cake with 100 milliliters of washings, and it is dry at 50 DEG C, 10.3 grams of white solid are obtained, yield
93%, purity 99.1%.
Embodiment 4
26.2 grams of 4- cyanobenzaldehydes, 48.8 grams of 2- ethylaminoethanols, 0.5 gram of iodine are added in the reaction flask with blender
24 hours are reacted at 40-50 DEG C with 600 milliliters of tetrahydrofurans.Then 600 milliliters of ethyl acetate are added in reaction mixture
With 400 milliliters of water, organic phase is separated, then with 600 milliliters of ethyl acetate aqueous phase extracteds, merge organic 200 milliliters of saturated common salts
Wash organic phase twice, sodium sulphate dries, filters, and filter cake is washed with a small amount of ethyl acetate, and dry, gained is concentrated in organic phase after merging
By column chromatographic isolation and purification, (pillar filling agent is silica gel to crude product, and eluant, eluent is petroleum ether: ethyl acetate=1:5 obtains 4-
27.5 grams of cyanophenyl of (4,5- dihydro-oxazole -2- base), yield 80%.
25 grams of 4- (4,5- dihydro-oxazole -2- base) cyanophenyls, 37.9 grams of titanium dioxides are added in the reaction flask with blender
Manganese, 3.3 grams of DDQ and 500 milliliter of ethyl acetate react at 25-30 DEG C, react 24 hours.Then reaction mixture is passed through
Diatomite filtering is crossed, washs filter cake with ethyl acetate, merging filtrate is washed with 200 milliliters, and 200 mL of saline are washed, and sodium sulphate is dry
Dry, filtering, filter cake is washed with a small amount of ethyl acetate, and organic phase is concentrated after merging and does, and obtains 4- (oxazole -2- base) cyanophenyl 21.3
Gram, yield 86%.
20 grams of 4- (oxazole -2- base) cyanophenyls of addition, 99.8 grams of potassium carbonate and 300 milliliters in the reaction flask with blender
Water reacts at 40 DEG C, reacts 16 hours.Then the pH value for adjusting reaction solution with the dilute hydrochloric acid of 4M/L is cooled to 25 to 5
DEG C, filtering, filter cake twice, collects filter cake with 200 milliliters of washings, and it is dry at 50 DEG C, 21.1 grams of white solid are obtained, yield
95%, purity 98.9%.
Embodiment 5
With blender reaction flask in be added 10 grams of 4- cyanobenzaldehydes, 18.6 grams of 2- ethylaminoethanols, 0.5 gram of iodine and
300 milliliters of tert-butyl alcohols react 16 hours at 40-50 DEG C.Then 600 milliliters of ethyl acetate and 400 are added in reaction mixture
Milliliter water, separates organic phase, then uses 600 milliliters of ethyl acetate aqueous phase extracteds, and merging organic washed with 200 milliliters of saturated common salts has
Mutually twice, sodium sulphate dries, filters machine, and filter cake is washed with a small amount of ethyl acetate, and dry, gained crude product is concentrated in organic phase after merging
By column chromatographic isolation and purification, (pillar filling agent is silica gel, and eluant, eluent is petroleum ether: ethyl acetate=1:5 obtains 4- (4,5- bis-
Hydrogen oxazole -2- base) 13.1 grams of cyanophenyl, yield 88%.
12 grams of 4- (4,5- dihydro-oxazole -2- base) cyanophenyls, 30.3 grams of titanium dioxides are added in the reaction flask with blender
Manganese, 3.2 grams of DDQ and 300 milliliter of methylene chloride react at 35-40 DEG C, react 10 hours.Then reaction mixture is passed through
Diatomite filtering is crossed, washs filter cake with methylene chloride, merging filtrate is washed with 200 milliliters, and 200 mL of saline are washed, and sodium sulphate is dry
Dry, filtering, filter cake is washed with a small amount of methylene chloride, and organic phase is concentrated after merging and does, and obtains 4- (oxazole -2- base) cyanophenyl 10.7
Gram, yield 90%.
10.7 grams of 4- (oxazole -2- base) cyanophenyls, 10.6 grams of potassium hydroxide and 100 are added in the reaction flask with blender
Milliliter water, reacts at 30 DEG C, reacts 5 hours.Then the pH value for adjusting reaction solution with the dilute hydrochloric acid of 6M/L is cooled to 3
25 DEG C, filtering, filter cake twice, collects filter cake with 100 milliliters of washings, dry at 50 DEG C, obtains 11.2 grams of white solid, yield
94%, purity 99.9%.
Embodiment 6
The cyanobenzaldehyde class compound indicated in the present embodiment using formula I -1 is instead of the 4- cyano benzene first in embodiment 1
Aldehyde, remaining is same as Example 1, including reagent dosage and process steps.The oxazolyl that the formula VI -1 ultimately generated indicates is repaired
The yield of the benzoic acid derivative of decorations is 58%, purity 99.9%.
Embodiment 7
The cyanobenzaldehyde class compound indicated in the present embodiment using formula I -2 is instead of the 4- cyano benzene first in embodiment 1
Aldehyde, remaining is same as Example 1, including reagent dosage and process steps.The oxazolyl that the formula VI -2 ultimately generated indicates is repaired
The yield of the benzoic acid derivative of decorations is 45%, purity 99.3%.
Embodiment 8
The cyanobenzaldehyde class compound indicated in the present embodiment using formula I -3 is instead of the 4- cyano benzene first in embodiment 1
Aldehyde, remaining is same as Example 1, including reagent dosage and process steps.The oxazolyl that the formula VI -3 ultimately generated indicates is repaired
The yield of the benzoic acid derivative of decorations is 49%, purity 99.6%.
Embodiment 9
The cyanobenzaldehyde class compound indicated in the present embodiment using formula I -4 is instead of the 4- cyano benzene first in embodiment 1
Aldehyde, remaining is same as Example 1, including reagent dosage and process steps.The oxazolyl that the formula VI -4 ultimately generated indicates is repaired
The yield of the benzoic acid derivative of decorations is 53%, purity 99.8%.
Embodiment 10
The cyanobenzaldehyde class compound indicated in the present embodiment using formula I -5 is instead of the 4- cyano benzene first in embodiment 1
Aldehyde, the alkamine compound that formula II -5 indicates replace the 2- ethylaminoethanol in embodiment 1, remaining is same as Example 1, packet
Include reagent dosage and process steps.The yield of the benzoic acid derivative for the oxazolyl modification that the formula VI -5 that ultimately generates indicates is
36%, purity 98.9%.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, without departing from the technical principles of the invention, several improvement and deformations can also be made, these improvement and deformations
Also it should be regarded as protection scope of the present invention.
Claims (8)
1. a kind of synthetic method of the benzoic acid derivative of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl modification, packet
Include following steps:
(1) reaction for providing the alkamine compound including the cyanobenzaldehyde class compound indicated of formula I and the expression of formula II is mixed
Object is closed, reaction mixture generates intermediate: the compound that formula III indicates:
(2) compound that formula III indicates is oxidized to the compound that the formula IV of oxazolyl modification indicates:
(3) compound that formula IV indicates successively obtains the benzoic acid of the oxazolyl modification of the expression of formula VI through hydrolysis and acidification reaction
Class compound:
Wherein, R1-R6It is independently selected from H, methoxyl group, ethyoxyl, C1-C5 alkyl；
Wherein in step (1): the alkamine compound that the cyanobenzaldehyde class compound and formula II that formula I indicates indicate is in solvent
Reaction is participated in A, introduces elemental iodine into its reaction mixture, 25-50 DEG C of reaction temperature, 8-24 hour of reaction time；Its
The molar ratio for the alkamine compound that the cyanobenzaldehyde class compound and formula II that Chinese style I indicates indicate is 1:2.0-5.0, molten
One of agent A toluene, the tert-butyl alcohol, methylene chloride, tetrahydrofuran, ethyl acetate or more than one mixed solution；Post-processing
Step includes: column chromatography, and eluant, eluent is petroleum ether or/and ethyl acetate.
2. a kind of benzoic acids of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl modification according to claim 1
Close the synthetic method of object, which is characterized in that the DDQ of manganese dioxide and catalytic amount is introduced in the reaction of step (2).
3. -2 described in any item a kind of benzene of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl modification according to claim 1
The synthetic method of formic acid compound, which is characterized in that introduce inorganic base in the hydrolysis reaction in step (3).
4. a kind of benzoic acids of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl modification according to claim 2
Close the synthetic method of object, which is characterized in that III compound represented of formula and the molar ratio of manganese dioxide are 1:2.0-10.0, formula III
Compound represented and the molar ratio of DDQ are 1:0.05-0.5.
5. a kind of benzoic acids of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl modification according to claim 3
Close the synthetic method of object, which is characterized in that the molar ratio of compound and inorganic base that formula IV indicates is 1:2.0-10.0.
6. a kind of benzoic acids of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl modification according to claim 3
Close the synthetic method of object, which is characterized in that the inorganic base is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, hydrogen-oxygen
Change one of lithium or more than one mixture.
7. a kind of benzoic acids of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl modification according to claim 3
Close the synthetic method of object, which is characterized in that it is the hydrochloric acid of 1-6mol/L that the acidification in step (3), which uses concentration, and uses salt
It is 1-6 that acid, which is adjusted to PH,.
8. a kind of benzoic acids of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl modification according to claim 2
Close the synthetic method of object, which is characterized in that the alkamine chemical combination that the cyanobenzaldehyde class compound and formula II that formula I indicates indicate
The molar ratio of object is 1:2.0-5.0.
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Non-Patent Citations (2)
| Title |
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| A Powerful Palladium-Catalyzed Multicomponent Process for the Preparation of Oxazolines and Benzoxazoles;Patrick J. Boissarie et al.;《 Org. Lett.》;20110211;第13卷(第23期);第6256-6259页 |
| Direct oxidative conversion of aldehydes and alcohols to 2-imidazolines and 2-oxazolines using molecular iodine;Midori Ishihara et al.;《Tetrahedron》;20061220;第63卷;第1474–1480页 |
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