CN106883192A - 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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- 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
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Abstract
The invention discloses a kind of synthetic method 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：The base compound of benzene nitriles of 4,5 dihydro-oxazole 2, then the intermediate be further oxidized to the compound of benzene nitriles of oxazolyl modification, the compound of benzene nitriles of last oxazolyl modification through basic hydrolysis and be acidified oxazolyl modification benzoic acid derivative.The method of the present invention does not use metallic catalyst, and reaction condition is gentle, and post processing is simple, and reaction yield and product purity are higher, and reaction is not required to special producing equipment, without high-temperature operation, without severe corrosive material.
Description
Technical field
The present invention relates to a kind of synthetic method 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 technology
The benzoic acid derivative of oxazolyl modification can be anti-as dopamine D 3 receptor anticaking agent class and prostate EP2 acceptors
Knot agent antipsychotic drug, by taking 4- (oxazole -2- bases) benzoic acid as an example, it is extensively using medicinal chemistry art.First, treatment or
Suppress in the medicine of tumour, histone demethylase (KDM1A) is a kind of drug target of potential treatment tumour, and
KDM1A be also believed to it is relevant with some inflammation class diseases, 4- (oxazole -2- bases) benzoic acid molecules as KDM1A important skeleton
There is important application value (WO2016130952) in above-mentioned field of medicaments.
The method that the synthesis of the benzoic acid derivative of oxazolyl modification is reported at present is simultaneously few.Known method is：1)
The synthetic method of patent WO2012149157 and WO2016067043 report.The method with paracyanobenzoic acid as raw material, 40 DEG C
Lower is that, to formamide benzene formic acid, then 1,1- dimethoxy-ethanes bromo- with 2- react 4 hours in dioxane through sulphuric acid hydrolysis
Generation 4- (oxazole -2- bases) benzoic acid.The method yield is too low (~3%), produces the solid wastes such as substantial amounts of silica gel, is difficult industrialization
Production；2) synthetic method of patent WO2016130952 reports.The method with terephthalic acid monomethyl ester as raw material, 80 DEG C first
Lower use thionyl chloride into acyl chlorides, secondly with 2- amino -1,1- dimethoxy-ethanes and triethylamine reacted in dichloromethane 1 it is small
When, then with 140 DEG C of methanesulfonic acid and phosphorus pentoxide at generate 4- (oxazole -2- bases) methyl benzoate, finally with NaOH water
Solution uses hydrochloric acid acid adjustment, obtains 1- (thiazol-2-yl) piperidines -4- alcohol.The method uses thionyl chloride and phosphorus pentoxide, and these are acute
Malicious and with serious pollution material；Other yield is relatively low (~50%)；3) document Journal of
Organometallic Chemistry,791,266-273；2015 only reported 4- (4,5- dihydro-oxazole -2- bases) benzoic acid
Method, although the method makes key intermediate have yield (~94%) very high, but to use the ruthenium metal of specific customization
Catalyst, makes cost very high；4) there are some documents (for example in addition：Tetrahedron,69(32),6591-6597；
2013), with terephthalonitrile and 2- ethylaminoethanols as raw material, it is necessary to synthesized using metallic catalyst key intermediate 4- (4,
5- dihydro-oxazole -2- bases) cyanophenyl, or reaction process be difficult control, cause yield uncontrollable.
The content of the invention
The technical problem to be solved in the present invention is the defect for overcoming prior art, there is provided a kind of nitrogenous class heterocyclic antineoplastic medicine
The synthetic method of the benzoic acid derivative of thing active matter oxazolyl modification, the 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：
A kind of synthetic method of the benzoic acid derivative of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl modification, its
Comprise the following steps：
(1) providing includes the anti-of the alkamine compound that the cyanobenzaldehyde class compound and formula II of the expression of formula I are represented
Answer mixture, reactant mixture generation intermediate：The compound that formula III is represented：
(2) compound that formula III is represented is oxidized to the compound that the formula IV of oxazolyl modification is represented：
(3) benzene that the oxazolyl that the compound that formula IV is represented obtains the expression of formula VI through hydrolysis and acidification reaction successively is modified
Formic acid compound：
Wherein, R1-R6It is independently selected from H, methoxyl group, ethyoxyl, C1-C5 alkyl.Preferably, R1-R6Independently
Selected from H, methoxyl group, C1-C3 alkyl.Most preferably, R1-R6It is H.
Preferably, in step (1)：To introducing elemental iodine in its reactant mixture.Preferably, the cyano group benzene first that formula I is represented
The mol ratio of the alkamine compound that aldehyde compound and formula II are represented is 1:2.0-5.0.Preferably, it joins in solvent orange 2 A
Plus reaction, solvent orange 2 A is organic solvent, one kind for preferably being selected from toluene, the tert-butyl alcohol, dichloromethane, tetrahydrofuran, ethyl acetate or
More than one mixed solution.Further preferred reaction condition is：25-50 DEG C of reaction temperature, 8-24 hour of reaction time,
Also include post-processing step in step (1), preferred post-processing step includes：Column chromatography, column chromatography is preferably with silica gel to fill out
The column chromatography of material, wash-out is also petroleum ether or/and ethyl acetate.
Preferably, in step (2)：It is introduced therein to the DDQ of manganese dioxide and catalytic amount.Preferably, the change shown in formula III
Compound is 1 with the mol ratio of manganese dioxide:2.0-10.0, compound and the mol ratio of DDQ shown in formula III are 1:0.05-0.5.
The reaction of step (2) is carried out in organic solvent solvent B, preferred solvent B be selected from dichloromethane, tetrahydrofuran, ethyl acetate,
One or more mixture in acetone, DMF, DMSO, methyl alcohol, the tert-butyl alcohol.The reaction condition of step (2) is elected as：
25-50 DEG C of reaction temperature, 8-24 hour of reaction time.Also include post-processing step, the post-processing step bag in step (2)
Include filtering, washing, dry, post-processing step did not included chromatographic column.It is further preferred that filtering is washed using diatomite filtering
Wash including washing and salt washing.
Preferably, in step (3), to introducing inorganic base in its hydrolysis reaction.Preferably, the compound that formula IV is represented
It is 1 with the mol ratio of inorganic base:2.0-10.0.The preferred inorganic base is selected from sodium carbonate, potassium carbonate, NaOH, hydrogen-oxygen
Change one or more the mixture in potassium, lithium hydroxide.It is further preferred that the acidification reaction in step (3) is used
Be concentration be 1-6mol/L hydrochloric acid, and with hydrochloric acid adjust to PH be 1-6.Preferred reaction condition is：Reaction temperature 25-50
DEG C, the reaction time is 1-24 hours, more preferably 4 hours.Also include post-processing step, the post-processing step bag in step (3)
Include filtering, washing, dry, do not include chromatographic column.
C1-C5 alkyl of the present invention includes：Methyl, ethyl, propyl group, isopropyl, normal-butyl, sec-butyl, the tert-butyl group, positive penta
Base, isopentyl.
In structural formula of compound of the inventionRepresent the position of connected group on phenyl ring be it is uncertain, such as
Itrile group in the cyanobenzaldehyde class compound that formula I is represented on phenyl ring is relative can be for aldehyde radical align, meta or ortho position
's.
Raw material (compound represented by formula I and formula II) used in the present invention can be by being commercially available, also can be by ability
Method synthesis known to domain is obtained.Other reagents in addition to raw material used in the present invention are commercially available and used
Solvent reagent also has no special requirements without specially treated to its purity.
The beneficial effect that the present invention is reached：
The method of the present invention does not use metallic catalyst, and reaction condition is gentle, and post processing is simple, and reaction yield and product are pure
Higher, particularly 4- (oxazole -2- bases) benzoic acid is spent, its total recovery is up to 77%.And reaction is not required to special producing equipment, without height
Temperature operation, without severe corrosive material.
Brief description of the drawings
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 examples are only used for clearly illustrating the present invention
Technical scheme, and can not be limited the scope of the invention with this.
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 bulb with agitator
Alcohol, 0.25 gram of iodine and 400 milliliters of tert-butyl alcohols, heating response react 12 hours to 40-50 DEG C.Then reactant 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, merge organic
Organic phase is washed with 200 milliliters of saturated common salts twice, sodium sulphate is dried, filtering, filter cake is washed with a small amount of ethyl acetate, organic phase
Concentrated after merging and done, (pillar filling agent is silica gel to gained crude product, and eluant, eluent is petroleum ether by column chromatographic isolation and purification：Second
Acetoacetic ester=1：1 obtains 4- (4,5- dihydro-oxazole -2- bases) 15.5 grams of cyanophenyl, yield 90%.
Added in the reaction bulb with agitator 15 grams of 4- (4,5- dihydro-oxazole -2- bases) cyanophenyls, 15 grams of manganese dioxide,
1 gram of DDQ and 400 milliliter of dichloromethane, reacts at 25 DEG C, reacts 12 hours.Then by reactant mixture by diatomite
Filtering, filter cake is washed with dichloromethane, and merging filtrate is washed with 200 milliliters, and 200 mL of saline are washed, and sodium sulphate is dried, filtering,
Filter cake is washed with a small amount of dichloromethane, and concentration is dry after organic phase merges, and obtains 4- (oxazole -2- bases) 13.3 grams of cyanophenyl, yield
90%.
13 grams of 4- (oxazole -2- bases) cyanophenyls, 6.2 grams of NaOH and 100 millis are added in the reaction bulb with agitator
Water is risen, is reacted at 50 DEG C, react 4 hours.Then the pH value of reaction solution is adjusted to 6 with the watery hydrochloric acid of 1M/L, be cooled to 25
DEG C, filtering, 100 milliliters of washings of filter cake twice, collect filter cake, are dried at 50 DEG C, obtain 13.7 grams of white solid, 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 bulb with agitator
With 400 milliliters of tert-butyl alcohols, at 25-30 DEG C, 8 hours are reacted.Then by reactant mixture add 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 with 200 milliliters of saturated aqueous common salts
Wash organic phase twice, sodium sulphate is dried, filtering, filter cake is washed with a small amount of ethyl acetate, concentration is dry after organic phase merges, and gained is thick
By column chromatographic isolation and purification, (pillar filling agent is silica gel to product, and eluant, eluent is petroleum ether：Ethyl acetate=1：1 obtain 4- (4,
5- dihydro-oxazole -2- bases) 14.6 grams of cyanophenyl, yield 85%.
10 grams of 4- (4,5- dihydro-oxazole -2- bases) cyanophenyls, 25.2 grams of titanium dioxides are added in the reaction bulb with agitator
Manganese, 6.6 grams of DDQ and 300 milliliter of ethyl acetate, react at 25 DEG C, react 8 hours.Then by reactant mixture by silicon
Diatomaceous earth is filtered, and filter cake is washed with ethyl acetate, and merging filtrate is washed with 200 milliliters, and 200 mL of saline are washed, and sodium sulphate is dried,
Filtering, filter cake is washed with a small amount of ethyl acetate, and concentration is dry after organic phase merges, and obtains 4- (oxazole -2- bases) 8.7 grams of cyanophenyl, receives
Rate 88%.
5 grams of 4- (oxazole -2- bases) cyanophenyls, 7 grams of lithium hydroxides and 50 milliliters of water are added in the reaction bulb with agitator,
Reaction reacts 1 hour at 50 DEG C.Then the pH value of reaction solution is adjusted to 4 with the watery hydrochloric acid of 2M/L, be cooled to 25 DEG C, mistake
Filter, 50 milliliters of washings of filter cake twice, collect filter cake, are dried at 50 DEG C, obtain 5 grams of white solid, 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 bulb with agitator
With 400 milliliters of toluene, at 30-40 DEG C, 24 hours are reacted.Then reactant mixture is added into 600 milliliters of ethyl acetate and 400
Milliliter water, separates organic phase, then with 300 milliliters of ethyl acetate aqueous phase extracteds, merging organic 200 milliliters of saturated common salts washings has
Mutually twice, sodium sulphate is dried machine, and filtering, filter cake is washed with a small amount of ethyl acetate, and concentration is dry after organic phase merges, gained crude product
By column chromatographic isolation and purification, (pillar filling agent is silica gel, and eluant, eluent is petroleum ether：Ethyl acetate=1:10 obtain 4- (4,5-
Dihydro-oxazole -2- bases) 15 grams of cyanophenyl, yield 87%.
15 grams of 4- (4,5- dihydro-oxazole -2- bases) cyanophenyls, 75.9 grams of titanium dioxides are added in the reaction bulb with agitator
Manganese, 5.9 grams of DDQ and 300 milliliter of tetrahydrofurans, react at 30-40 DEG C, react 8 hours.Then reactant mixture is passed through
Diatomite is filtered, and filter cake is washed with ethyl acetate, and merging filtrate is washed with 200 milliliters, and 200 mL of saline are washed, and sodium sulphate is done
Dry, filtering, filter cake is washed with a small amount of ethyl acetate, and concentration is dry after organic phase merges, and obtains 4- (oxazole -2- bases) cyanophenyl 12.4
Gram, yield 84%.
10 grams of 4- (oxazole -2- bases) cyanophenyls of addition, 40.6 grams of potassium carbonate and 100 milliliters in the reaction bulb with agitator
Water, reacts at 40 DEG C, reacts 24 hours.Then the pH value of reaction solution is adjusted to 1 with the watery hydrochloric acid of 6M/L, be cooled to 25
DEG C, filtering, 100 milliliters of washings of filter cake twice, collect filter cake, are dried at 50 DEG C, obtain 10.3 grams of white solid, 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 bulb with agitator
With 600 milliliters of tetrahydrofurans, at 40-50 DEG C, 24 hours are reacted.Then reactant mixture is added into 600 milliliters of ethyl acetate
With 400 milliliters of water, organic phase is separated, then with 600 milliliters of ethyl acetate aqueous phase extracteds, merge organic with 200 milliliters of saturated common salts
Twice, sodium sulphate is dried washing organic phase, and filtering, filter cake is washed with a small amount of ethyl acetate, and concentration is dry after organic phase merges, gained
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 obtain 4-
(4,5- dihydro-oxazole -2- bases) 27.5 grams of cyanophenyl, yield 80%.
25 grams of 4- (4,5- dihydro-oxazole -2- bases) cyanophenyls, 37.9 grams of titanium dioxides are added in the reaction bulb with agitator
Manganese, 3.3 grams of DDQ and 500 milliliter of ethyl acetate, react at 25-30 DEG C, react 24 hours.Then reactant mixture is passed through
Diatomite filtering is crossed, filter cake is washed with ethyl acetate, merging filtrate is washed with 200 milliliters, and 200 mL of saline are washed, and sodium sulphate is done
Dry, filtering, filter cake is washed with a small amount of ethyl acetate, and concentration is dry after organic phase merges, and obtains 4- (oxazole -2- bases) cyanophenyl 21.3
Gram, yield 86%.
20 grams of 4- (oxazole -2- bases) cyanophenyls of addition, 99.8 grams of potassium carbonate and 300 milliliters in the reaction bulb with agitator
Water, reacts at 40 DEG C, reacts 16 hours.Then the pH value of reaction solution is adjusted to 5 with the watery hydrochloric acid of 4M/L, be cooled to 25
DEG C, filtering, 200 milliliters of washings of filter cake twice, collect filter cake, are dried at 50 DEG C, obtain 21.1 grams of white solid, yield
95%, purity 98.9%.
Embodiment 5
In the reaction bulb with agitator add 10 grams of 4- cyanobenzaldehydes, 18.6 grams of 2- ethylaminoethanols, 0.5 gram of iodine and
300 milliliters of tert-butyl alcohols, at 40-50 DEG C, react 16 hours.Then reactant mixture is added into 600 milliliters of ethyl acetate and 400
Milliliter water, separates organic phase, then with 600 milliliters of ethyl acetate aqueous phase extracteds, merging organic 200 milliliters of saturated common salts washings has
Mutually twice, sodium sulphate is dried machine, and filtering, filter cake is washed with a small amount of ethyl acetate, and concentration is dry after organic phase merges, gained crude product
By column chromatographic isolation and purification, (pillar filling agent is silica gel, and eluant, eluent is petroleum ether：Ethyl acetate=1:5 obtain 4- (4,5- bis-
Hydrogen oxazole -2- bases) 13.1 grams of cyanophenyl, yield 88%.
12 grams of 4- (4,5- dihydro-oxazole -2- bases) cyanophenyls, 30.3 grams of titanium dioxides are added in the reaction bulb with agitator
Manganese, 3.2 grams of DDQ and 300 milliliter of dichloromethane, react at 35-40 DEG C, react 10 hours.Then reactant mixture is passed through
Diatomite filtering is crossed, filter cake is washed with dichloromethane, merging filtrate is washed with 200 milliliters, and 200 mL of saline are washed, and sodium sulphate is done
Dry, filtering, filter cake is washed with a small amount of dichloromethane, and concentration is dry after organic phase merges, and obtains 4- (oxazole -2- bases) cyanophenyl 10.7
Gram, yield 90%.
10.7 grams of 4- (oxazole -2- bases) cyanophenyls, 10.6 grams of potassium hydroxide and 100 are added in the reaction bulb with agitator
Milliliter water, reacts at 30 DEG C, reacts 5 hours.Then the pH value of reaction solution is adjusted to 3 with the watery hydrochloric acid of 6M/L, be cooled to
25 DEG C, filtering, 100 milliliters of washings of filter cake twice, collect filter cake, are dried at 50 DEG C, obtain 11.2 grams of white solid, yield
94%, purity 99.9%.
Embodiment 6
The cyanobenzaldehyde class compound represented using formula I -1 in the present embodiment replaces the 4- cyano group 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 for ultimately generating is represented is repaiied
The yield of the benzoic acid derivative of decorations is 58%, purity 99.9%.
Embodiment 7
The cyanobenzaldehyde class compound represented using formula I -2 in the present embodiment replaces the 4- cyano group 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 for ultimately generating is represented is repaiied
The yield of the benzoic acid derivative of decorations is 45%, purity 99.3%.
Embodiment 8
The cyanobenzaldehyde class compound represented using formula I -3 in the present embodiment replaces the 4- cyano group 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 for ultimately generating is represented is repaiied
The yield of the benzoic acid derivative of decorations is 49%, purity 99.6%.
Embodiment 9
The cyanobenzaldehyde class compound represented using formula I -4 in the present embodiment replaces the 4- cyano group 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 for ultimately generating is represented is repaiied
The yield of the benzoic acid derivative of decorations is 53%, purity 99.8%.
Embodiment 10
The cyanobenzaldehyde class compound represented using formula I -5 in the present embodiment replaces the 4- cyano group benzene first in embodiment 1
Aldehyde, the alkamine compound that formula II -5 is represented replaces the 2- ethylaminoethanols in embodiment 1, and remaining is same as Example 1, bag
Include reagent dosage and process steps.The yield of the benzoic acid derivative of the oxazolyl modification that the formula VI -5 that ultimately generates is represented is
36%, purity 98.9%.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, on the premise of the technology of the present invention principle is not departed from, some improvement and deformation can also be made, these improve and deform
Also should be regarded as protection scope of the present invention.
Claims (10)
1. a kind of synthetic method of the benzoic acid derivative of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl modification, its bag
Include following steps：
(1) providing includes that the reaction of the cyanobenzaldehyde class compound that formula I is represented and the alkamine compound that formula II is represented is mixed
Compound, reactant mixture generation intermediate：The compound that formula III is represented：
(2) compound that formula III is represented is oxidized to the compound that the formula IV of oxazolyl modification is represented：
(3) benzoic acid that the oxazolyl that the compound that formula IV is represented obtains the expression of formula VI through hydrolysis and acidification reaction successively is modified
Class compound：
Wherein, R1-R6It is independently selected from H, methoxyl group, ethyoxyl, C1-C5 alkyl.
2. the benzoic acids that a kind of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl according to claim 1 is modified
The synthetic method of compound, it is characterised in that introduce elemental iodine in the reactant mixture of step (1).
3. the benzoic acids that a kind of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl according to claim 1 is modified
The synthetic method of compound, it is characterised in that the DDQ of manganese dioxide and catalytic amount is introduced in the reaction of step (2).
4. the benzene that a kind of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl according to claim any one of 1-3 is modified
The synthetic method of formic acid compound, it is characterised in that introduce inorganic base in the hydrolysis reaction in step (3).
5. the benzoic acids that a kind of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl according to claim 3 is modified
The synthetic method of compound, it is characterised in that compound and the mol ratio of manganese dioxide shown in formula III are 1:2.0-10.0, formula III
Shown compound is 1 with the mol ratio of DDQ:0.05-0.5.
6. the benzoic acids that a kind of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl according to claim 4 is modified
The synthetic method of compound, it is characterised in that the compound that formula IV is represented is 1 with the mol ratio of inorganic base:2.0-10.0.
7. the benzoic acids that a kind of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl according to claim 4 is modified
The synthetic method of compound, it is characterised in that the inorganic base is selected from sodium carbonate, potassium carbonate, NaOH, potassium hydroxide, hydrogen-oxygen
Change one or more the mixture in lithium.
8. the benzoic acids that a kind of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl according to claim 4 is modified
The synthetic method of compound, it is characterised in that the acidifying in step (3) uses concentration to be the hydrochloric acid of 1-6mol/L, and uses salt
It is 1-6 that PH is arrived in acid regulation.
9. the benzene that a kind of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl according to claim any one of 1-3 is modified
The synthetic method of formic acid compound, it is characterised in that the amino that the cyanobenzaldehyde class compound and formula II that formula I is represented are represented
The mol ratio of alcohol compound is 1:2.0-5.0.
10. the benzoic acids that a kind of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl according to claim 1 is modified
The synthetic method of compound, it is characterised in that the reaction temperature of step (1)-step (3) is 20-50 DEG C.
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| CN110305074A (en) * | 2019-04-02 | 2019-10-08 | 上海克琴科技有限公司 | A kind of green synthesis method of quaternary ammonium salt -73 |
| CN110305074B (en) * | 2019-04-02 | 2021-05-07 | 上海克琴科技有限公司 | Synthesis method of quaternary ammonium salt-73 |
| CN110407763A (en) * | 2019-08-08 | 2019-11-05 | 苏州汉德创宏生化科技有限公司 | A kind of 4-(oxazole -2- base) benzoic acid synthetic method |
| CN110407763B (en) * | 2019-08-08 | 2022-10-14 | 苏州汉德创宏生化科技有限公司 | Synthesis method of 4- (oxazole-2-yl) benzoic acid |
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