CN105601580B - The synthetic method of Yi Zhong oxazole class pharmaceutical intermediate compounds - Google Patents
The synthetic method of Yi Zhong oxazole class pharmaceutical intermediate compounds 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
- C07D263/34—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 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
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Abstract
The present invention relates to a kind of synthetic method for the lower formula (III) oxazole compounds that can be used as pharmaceutical intermediate, methods described includes：Under nitrogen atmosphere, in organic solvent, in the presence of catalyst, organic phosphine compound, organic base and auxiliary agent, lower formula (I) compound and lower formula (II) compound were in 70 90 DEG C of stirring reactions 46 hours, react after terminating through post processing, so as to obtain the formula (III) compoundWherein, R1Selected from H, halogen, C1‑C6Alkyl or C1‑C6Alkoxy；R2For C1‑C6Alkyl.This method is by using catalyst, organic phosphine compound, organic base and auxiliary agent, and the recombination reaction system of organic solvent structure, purpose product is obtained so as to high yield, realize quick, the Efficient Conversion of starting material, the utilization rate of material is substantially increased, there is good application value and productive potentialities.
Description
Technical field
The present invention relates to a kind of synthetic method of nitrogen-containing heterocycle compound, relate more particularly to one kind and can be used as among medicine
The synthetic method of Ti oxazole compounds, belong to organic chemical synthesis especially medicine intermediate synthesis field.
Background technology
It is a kind of very important five member ring heterocyclic compound in medicinal chemistry art , oxazole compounds, it is widely present
Among natural products, active alkaloid, medical compounds, there are a variety of medical actives, for example, it is antimycotic, antibacterial, anticancer, anti-
Virus, treating tuberculosis, hypoglycemic, anticonvulsion, anti-inflammatory analgesic etc..At present, all Han You oxazole rings in a variety of marketed drugs.
Therefore, such important effect of Ji Yu oxazole compounds, Kai Fa oxazole compounds efficiently synthesize technique
Always scientists hot issue of interest.
Up to the present, in the prior art it has been reported that the synthetic method of many You Guan oxazole compounds, such as：
Zhang Jianmin etc. (" Synthesis of 5-Amino-oxazole-4-carboxylates from α-
Chloroglycinates ", Organic Letters, 2010,12,3942-3945) a kind of aluminium base lewis acid is reported to urge
The synthetic method of Hua oxazole compounds, its reaction equation are as follows：
(" the 2-Anilino-4-aryl-1,3-thiazole inhibitors of such as Matthew G.Bursavich
valosin-containing protein(VCP or p97)”,Bioorganic&Medicinal Chemistry
Letters, 2010,20,1677-1679) one kind is reported using α-nitrine ketone as initiation material reaction Bei oxazole compounds processed
Method, its reaction equation is as follows：
As described above, a variety of methods of He Cheng oxazole compounds are disclosed in the prior art, but these methods still suffer from
Some defects, such as the substrate scope of application is not wide enough, reaction yield has much room for improvement etc..
These problems cause existing method to consume substantial amounts of raw material and energy consumption in the industrial production, virtually increase
Production burden and be unfavorable for the long-run development of enterprise.In order to improve technique to agree with sustainable development and green atom economy
Theory, the new and effective synthetic method of Dui Yu oxazole compounds, the necessity for continuing research is still suffered from, this is also the current field
In study hotspot and emphasis.
The content of the invention
In order to overcome many defects as indicated above, present inventor has performed in-depth study and exploration, is paying
After enough creative works, so as to complete the present invention.
Specifically, technical scheme and content are related to a kind of lower formula (III) institute that can be used as pharmaceutical intermediate
The synthetic method of Shi oxazole compounds, methods described include：Under nitrogen atmosphere, in organic solvent, in catalyst, organic
In the presence of phosphine compound, organic base and auxiliary agent, lower formula (I) compound and lower formula (II) compound are in 70-90 DEG C of stirring reaction 4-6
Hour, react through post-processing after terminating, so as to obtain the formula (III) compound,
Wherein, R1Selected from H, halogen, C1-C6Alkyl or C1-C6Alkoxy；
R2For C1-C6Alkyl.
In the synthetic method of the present invention, the halogen is halogen, such as can be F, Cl, Br or I.
In the synthetic method of the present invention, the C1-C6The implication of alkyl refers to the straight chain with 1-6 carbon atom
Or branched alkyl, for example can be methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, uncle in non-limiting manner
Butyl, n-pentyl, isopentyl or n-hexyl etc..
In the synthetic method of the present invention, the C1-C6The implication of alkoxy refers to the C with above-mentioned implication1-C6
The group that alkyl obtains after being connected with oxygen atom.
In the synthetic method of the present invention, the catalyst is AgNTf2(double (trifluoromethane sulfonyl group) acid imides
Silver) and Cu (PPh3)2NO3The mixture of (double (triphenylphosphine) cuprous nitrates), wherein AgNTf2With Cu (PPh3)2NO3Mole
Than for 1:3-4, such as can be 1:3、1:3.5 or 1:4.
In the synthetic method of the present invention, the organic phosphine compound is any one in following formula L1-L2,
Most preferably L1.
In the synthetic method of the present invention, the organic base is N-methylmorpholine, potassium tert-butoxide, dimethylamino naphthyridine
(DMPA), 1,4- diazabicylos [2.2.2] octane (DABCO), triisopropanolamine, 4-methyl-diaminopropane, tetramethylethylenediamine
(TMEDA), any one in DIPEA (DIPEA) or lithium diisopropylamine (LDA), most preferably LDA.
In the synthetic method of the present invention, the auxiliary agent is ammonium ceric nitrate.
In the synthetic method of the present invention, the organic solvent is that volume ratio is 4:1 DMSO (dimethyl sulfoxide (DMSO))
With the mixture of polyethylene glycol 200 (PEG-200).
Wherein, the dosage of the organic solvent does not have strict restriction, and those skilled in the art can be according to actual conditions
Carry out suitably selection and determine, such as its dosage size is no longer carried out detailed herein with facilitating reaction progress and post processing
Thin description.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and formula (II) compound is 1:1-
2, such as can be 1:1、1:1.5 or 1:2.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and catalyst is 1:0.12-0.2,
The mole dosage of i.e. described formula (I) compound and the AgNTf for forming the catalyst2(double (trifluoromethane sulfonyl group) acid imides
Silver) and Cu (PPh3)2NO3The ratio of the total moles dosage of (double (triphenylphosphine) cuprous nitrates) is 1:0.12-0.2, such as can be 1:
0.12、1:0.15、1:0.18 or 1:0.2.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and organic phosphine compound is 1:
0.08-0.14, such as can be 1:0.08、1:0.1、1:0.12 or 1:0.14.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and organic base is 1:0.3-0.5,
Such as can be 1:0.3、1:0.4 or 1:0.5.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and auxiliary agent is 1:0.15-0.22,
Such as can be 1:0.15、1:0.17、1:0.19、1:0.21 or 1:0.22.
In the synthetic method of the present invention, the post processing after reaction terminates can be specific as follows：After the completion of reaction, while hot
Filtering, the pH value for adjusting filtrate are neutrality, and the saturated aqueous sodium carbonate for then adding equivalent filtrate volume is washed, then is added
The saturated aqueous common salt for entering equivalent filtrate volume is washed, and is finally extracted with acetone, separates organic phase, and organic phase is with anhydrous
Magnesium sulfate is dried, and is evaporated under reduced pressure, and silica gel column chromatography is crossed, with volume ratio 1:2 petroleum ether is eluted with chloroform mixed liquor, so as to
Obtain the formula (III) compound.
In summary, should the invention provides a kind of synthetic method that can be used as pharmaceutical intermediate oxazole compounds
Method is by using catalyst, organic phosphine compound, organic base and auxiliary agent, and the recombination reaction system of organic solvent structure,
Purpose product is obtained so as to high yield, quick, the Efficient Conversion of starting material is realized, substantially increases the utilization of material
Rate, there is good application value and productive potentialities.
Embodiment
Below by specific embodiment, the present invention is described in detail, but the purposes of these exemplary embodiments and
Purpose is only used for enumerating the present invention, not forms any type of any restriction to the real protection scope of the present invention, more non-to incite somebody to action
Protection scope of the present invention is confined to this.
Embodiment 1
At room temperature, (it is 4 for volume ratio to appropriate organic solvent:1 DMSO (dimethyl sulfoxide (DMSO)) and polyethylene glycol 200
(PEG-200) mixture) in, add formula (I) compound, the upper formula (II) compounds of 100mmol, 12mmol on 100mmol and urge
Agent (3mmol AgNTf2With 9mmol Cu (PPh3)2NO3Mixture), 8mmol organic phosphine compounds L1,30mmol it is organic
Alkali LDA and 15mmol auxiliary agent ammonium ceric nitrate, then with nitrogen displacement 2-3 times so that reaction atmosphere is nitrogen atmosphere；Stirring heating
To 70 DEG C, and stirring reaction 4 hours at such a temperature；
After the completion of reaction, filter while hot, the pH value for adjusting filtrate is neutrality, then adds the saturated carbon of equivalent filtrate volume
Acid sodium aqueous solution is washed, and the saturated aqueous common salt for adding equivalent filtrate volume is washed, and is finally extracted with acetone,
Organic phase is separated, organic phase is dried with anhydrous magnesium sulfate, is evaporated under reduced pressure, and silica gel column chromatography is crossed, with volume ratio 1:2 petroleum ether with
Chloroform mixed liquor is eluted, so as to obtain upper formula (III) compound, yield 95.7%.
1H NMR(CDCl3,400MHz):δ7.78(s,1H),7.38-7.35(m,1H),7.32-7.29(m,1H),7.23-
7.19 (m, 2H), 4.23 (q, J=7.1Hz, 2H), 2.19 (s, 3H), 1.18ppm (t, J=7.2Hz, 3H).
Embodiment 2
At room temperature, (it is 4 for volume ratio to appropriate organic solvent:1 DMSO (dimethyl sulfoxide (DMSO)) and polyethylene glycol 200
(PEG-200) mixture) in, add formula (I) compound, the upper formula (II) compounds of 150mmol, 16mmol on 100mmol and urge
Agent (3.2mmol AgNTf2With 12.8mmol Cu (PPh3)2NO3Mixture), 11mmol organic phosphine compounds L1,
40mmol organic base LDA and 18mmol auxiliary agent ammonium ceric nitrates, then with nitrogen displacement 2-3 times so that reaction atmosphere is blanket of nitrogen
Enclose；Stirring is warming up to 80 DEG C, and stirring reaction 5 hours at such a temperature；
After the completion of reaction, filter while hot, the pH value for adjusting filtrate is neutrality, then adds the saturated carbon of equivalent filtrate volume
Acid sodium aqueous solution is washed, and the saturated aqueous common salt for adding equivalent filtrate volume is washed, and is finally extracted with acetone,
Organic phase is separated, organic phase is dried with anhydrous magnesium sulfate, is evaporated under reduced pressure, and silica gel column chromatography is crossed, with volume ratio 1:2 petroleum ether with
Chloroform mixed liquor is eluted, so as to obtain upper formula (III) compound, yield 95.5%.
1H NMR(CDCl3,400MHz):δ8.05-8.04(m,2H),7.85(s,1H),6.97-6.95(m,2H),4.38
(q, J=7.2Hz, 2H), 3.83 (s, 3H), 1.39ppm (t, J=7.2Hz, 3H).
Embodiment 3
At room temperature, (it is 4 for volume ratio to appropriate organic solvent:1 DMSO (dimethyl sulfoxide (DMSO)) and polyethylene glycol 200
(PEG-200) mixture) in, add formula (I) compound, the upper formula (II) compounds of 200mmol, 20mmol on 100mmol and urge
Agent (4.5mmol AgNTf2With 15.5mmol Cu (PPh3)2NO3Mixture), 14mmol organic phosphine compounds L1,
50mmol organic base LDA and 22mmol auxiliary agent ammonium ceric nitrates, then with nitrogen displacement 2-3 times so that reaction atmosphere is blanket of nitrogen
Enclose；Stirring is warming up to 90 DEG C, and stirring reaction 4 hours at such a temperature；
After the completion of reaction, filter while hot, the pH value for adjusting filtrate is neutrality, then adds the saturated carbon of equivalent filtrate volume
Acid sodium aqueous solution is washed, and the saturated aqueous common salt for adding equivalent filtrate volume is washed, and is finally extracted with acetone,
Organic phase is separated, organic phase is dried with anhydrous magnesium sulfate, is evaporated under reduced pressure, and silica gel column chromatography is crossed, with volume ratio 1:2 petroleum ether with
Chloroform mixed liquor is eluted, so as to obtain upper formula (III) compound, yield 95.1%.
1H NMR(CDCl3,400MHz):δ8.02(s,1H),7.51-7.49(m,2H),7.45-7.41(m,1H),7.37-
7.33 (m, 1H), 4.28 (q, J=7.1Hz, 2H), 1.22 (t, J=6.8Hz, 3H).
Embodiment 4
At room temperature, (it is 4 for volume ratio to appropriate organic solvent:1 DMSO (dimethyl sulfoxide (DMSO)) and polyethylene glycol 200
(PEG-200) mixture) in, add formula (I) compound, the upper formula (II) compounds of 120mmol, 18mmol on 100mmol and urge
Agent (4.6mmol AgNTf2With 13.4mmol Cu (PPh3)2NO3Mixture), 10mmol organic phosphine compounds L1,
35mmol organic base LDA and 20mmol auxiliary agent ammonium ceric nitrates, then with nitrogen displacement 2-3 times so that reaction atmosphere is blanket of nitrogen
Enclose；Stirring is warming up to 75 DEG C, and stirring reaction 5 hours at such a temperature；
After the completion of reaction, filter while hot, the pH value for adjusting filtrate is neutrality, then adds the saturated carbon of equivalent filtrate volume
Acid sodium aqueous solution is washed, and the saturated aqueous common salt for adding equivalent filtrate volume is washed, and is finally extracted with acetone,
Organic phase is separated, organic phase is dried with anhydrous magnesium sulfate, is evaporated under reduced pressure, and silica gel column chromatography is crossed, with volume ratio 1:2 petroleum ether with
Chloroform mixed liquor is eluted, so as to obtain upper formula (III) compound, yield 95.4%.
1H NMR(CDCl3,400MHz):δ8.22-8.21(m,1H),8.03-8.00(m,1H),7.91(s,1H),7.56-
7.54 (m, 1H), 7.33-7.29 (m, 1H), 4.38 (q, J=7.2Hz, 2H), 1.37ppm (t, J=7.2Hz, 3H).
Embodiment 5-12
Embodiment 5-8：Except by catalyst replace with dosage be the total dosage of original two kinds of components one-component AgNTf2Outside,
Other operations are constant, so as to repeat to implement embodiment 1-4, sequentially obtain embodiment 5-8.
Embodiment 9-12：Except by catalyst replace with dosage be the total dosage of original two kinds of components one-component Cu (PPh3)2NO3Outside, other operations are constant, so as to repeat to implement embodiment 1-4, sequentially obtain embodiment 9-12.
As a result it see the table below 1.
Table 1
As can be seen here, when using one-component as catalyst, yield is significantly reduced.Thus demonstrate only same
When use AgNTf2With Cu (PPh3)2NO3Mixture as catalyst, the unique concerted catalysis effect of competence exertion between the two
Fruit, so as to obtain the superior product yield of the present invention.
Embodiment 13-20
Embodiment 13-16：In addition to organic phosphine compound L1 is replaced with into L2, other operations are constant, so as to repeat to implement
Embodiment 1-4, sequentially obtains embodiment 13-16.
Embodiment 17-20：In addition to organic phosphine compound L1 is omitted, other operations are constant, so as to repeat to implement
Embodiment 1-4, sequentially obtains embodiment 17-20.
As a result 2 be see the table below.
Table 2
As can be seen here, although organic phosphine compound L1 and L2 are highly similar in structure, L1 effect will be significantly better than
L2, and when without using any organic phosphine compound, then yield is reduced and become apparent.
Embodiment 21-52
Embodiment 21-24：In addition to organic base LDA is replaced with into N-methylmorpholine, other operations are constant, real so as to repeat
Embodiment 1-4 has been applied, has sequentially obtained embodiment 21-24.
Embodiment 25-28：In addition to organic base LDA is replaced with into potassium tert-butoxide, other operations are constant, so as to repeat to implement
Embodiment 1-4, sequentially obtains embodiment 25-28.
Embodiment 29-32：In addition to organic base LDA is replaced with into DMPA, other operations are constant, so as to repeat to implement reality
A 1-4 is applied, sequentially obtains embodiment 29-32.
Embodiment 33-36：In addition to organic base LDA is replaced with into DABCO, other operations are constant, so as to repeat to implement
Embodiment 1-4, sequentially obtain embodiment 33-36.
Embodiment 37-40：In addition to organic base LDA is replaced with into triisopropanolamine, other operations are constant, real so as to repeat
Embodiment 1-4 has been applied, has sequentially obtained embodiment 37-40.
Embodiment 41-44：In addition to organic base LDA is replaced with into 4-methyl-diaminopropane, other operations are constant, so as to repeat
Embodiment 1-4 is implemented, sequentially obtains embodiment 41-44.
Embodiment 45-48：In addition to organic base LDA is replaced with into TMEDA, other operations are constant, so as to repeat to implement
Embodiment 1-4, sequentially obtain embodiment 45-48.
Embodiment 49-52：In addition to organic base LDA is replaced with into DIPEA, other operations are constant, so as to repeat to implement
Embodiment 1-4, sequentially obtain embodiment 49-52.
As a result 3 be see the table below.
Table 3
As can be seen here, in all organic bases, LDA has best effect, and it is bright that other organic bases cause yield to have
Aobvious or significant reduction.
Embodiment 53-56
In addition to auxiliary agent ammonium ceric nitrate is omitted, other operations are constant, suitable so as to repeat to implement embodiment 1-4
Secondary to obtain embodiment 53-56, it is 84.3-85.2% as a result to find its products collection efficiency, it can be seen that, the presence of auxiliary agent ammonium ceric nitrate
Products collection efficiency can be significantly improved.
Embodiment 57-64
Embodiment 57-60：In addition to organic solvent is replaced with into one-component DMSO, other operations are constant, so as to repeat
Embodiment 1-4 is implemented, sequentially obtains embodiment 57-60.
Embodiment 61-64：In addition to organic solvent is replaced with into one-component PEG-200, other operations are constant, so as to weight
Embodiment 1-4 is implemented again, sequentially obtains embodiment 61-64.
As a result 4 be see the table below.
Table 4
As can be seen here, when using one-component solvent, its yield will be significantly lower than using DMSO and PEG-200 mixtures
When products collection efficiency, this prove when use the mixture of two kinds of components as organic solvent, can obtain superior technique imitate
Fruit.
In summary, should the invention provides a kind of synthetic method that can be used as pharmaceutical intermediate oxazole compounds
Method is by using catalyst, organic phosphine compound, organic base and auxiliary agent, and the recombination reaction system of organic solvent structure,
Purpose product is obtained so as to high yield, quick, the Efficient Conversion of starting material is realized, substantially increases the utilization of material
Rate, there is good application value and productive potentialities.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to the protection model of the limitation present invention
Enclose.In addition, it should also be understood that, after the technology contents of the present invention have been read, those skilled in the art can make each to the present invention
Kind change, modification and/or variation, all these equivalent form of values equally fall within the guarantor that the application appended claims are limited
Within the scope of shield.
Claims (6)
1. a kind of lower formula (III) shows the synthetic method of oxazole compounds, methods described includes：Under nitrogen atmosphere, having
In solvent, in the presence of catalyst, organic phosphine compound, organic base and auxiliary agent, lower formula (I) compound and lower formula (II) chemical combination
Thing in 70-90 DEG C of stirring reaction 4-6 hour, reaction terminate after through post processing, so as to obtain the formula (III) compound,
Wherein, R1Selected from H, halogen, C1-C6Alkyl or C1-C6Alkoxy；
R2For C1-C6Alkyl；
The catalyst is the mixture of double (trifluoromethane sulfonyl group) acid imide silver and double (triphenylphosphine) cuprous nitrates, wherein
The mol ratio of double (trifluoromethane sulfonyl group) acid imide silver and double (triphenylphosphine) cuprous nitrates is 1:3-4；
The organic phosphine compound is following formula L1,
The organic base is lithium diisopropylamine；
The auxiliary agent is ammonium ceric nitrate；
The organic solvent is that volume ratio is 4:1 dimethyl sulfoxide (DMSO) and the mixture of polyethylene glycol 200.
2. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound is rubbed with formula (II) compound
You are than being 1:1-2.
3. synthetic method as claimed in claim 1, it is characterised in that：The mole dosage of formula (I) compound is with forming institute
Double (trifluoromethane sulfonyl group) acid imides silver and the ratio of the total moles dosage of pair (triphenylphosphine) cuprous nitrates for stating catalyst are
1:0.12-0.2。
4. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound and organic phosphine compound rub
You are than being 1:0.08-0.14.
5. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound and the mol ratio of organic base are
1:0.3-0.5。
6. the synthetic method as described in claim any one of 1-5, it is characterised in that：Formula (I) compound and auxiliary agent rub
You are than being 1:0.15-0.22.
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