CN107235889A - Utilize the method for carbonylation one pot process TNF alpha inhibitors - Google Patents
Utilize the method for carbonylation one pot process TNF alpha inhibitors Download PDFInfo
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- CN107235889A CN107235889A CN201710461370.9A CN201710461370A CN107235889A CN 107235889 A CN107235889 A CN 107235889A CN 201710461370 A CN201710461370 A CN 201710461370A CN 107235889 A CN107235889 A CN 107235889A
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- carbonylation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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Abstract
The method that the present invention relates to the use of carbonylation one pot process TNF alpha inhibitors.This method is with benzaldehyde and 2, and 6 diisopropyl anilines are as reaction raw materials through the condensation of amine aldehyde, oxidation carbonylation, one pot process TNF alpha inhibitors.Reaction condition of the present invention is gentle, and raw material is simple and easy to get, and target product, synthesizing mean novel and unique can be built by carbonylation one kettle way.
Description
Technical field
The present invention relates to the technical field such as medicine, clinic, cell biology, and in particular to one pot of carbonylation of utilization
Method synthesizes the novel synthesis of TNF-α inhibitor.
Background technology
Rheumatoid arthritis (Rheumatoid Arthritis, RA) is a kind of incidence of disease very high LADA disease
Disease, on the disease at present temporarily without effective treatment means.As a pro-inflammatory cellular molecule, TNF-α is in RA pathogenic processes
In played very important effect.Therefore, continuing to develop with biological agent, is clinically controlled using TNF-α inhibitor
RA is treated, increasing application has been obtained.These application characteristics having just because of TNF-α inhibitor so that synthesis
TNF-α inhibitor is in a study hotspot as new drug development field.We utilize carbonylation one pot process one
Plant TNF-α inhibitor to exist, its synthetic route is as follows：
The TNF-α inhibitor that the present invention is synthesized, its structural formula is as follows：
Invention TNF-α inhibitor by carbonylation one pot process, is provided for the structure of such compound
One efficient easily synthesizing mean, the medicament research and development to such compound has actively and far-reaching influence.
The content of the invention
The method that the present invention relates to the use of carbonylation one pot process TNF-α inhibitor.This method with benzaldehyde and
2,6-DIPA is as reaction raw materials through the condensation of amine aldehyde, oxidation carbonylation, one pot process TNF-α inhibitor.
This method has synthesis technique succinct, and raw material is cheap and easy to get, the advantages of reaction condition is gentle.
Technical solution of the present invention is as follows.
Using the method for carbonylation one pot process TNF-α inhibitor, synthetic route is as follows：
Further, the TNF-α inhibitor by compound 1 and compound 2 through the condensation of amine aldehyde, oxidation carbonylation system
；The compound 1 is benzaldehyde；The compound 2 is 2,6- diisopropyl anilines；
Comprise the following steps that：
(1) compound 1 and compound 2 are taken in test tube, catalyst, oxidant and solvent is added, in stirring at 10-60 DEG C
1-48 hours；
(2) take step (1) to react the test tube after terminating, the balloon filled with carbon monoxide and oxygen gas is put, in 40-
Stirred 1-72 hours at 150 DEG C, separating-purifying obtains TNF-α inhibitor；The volume ratio of the carbon monoxide and oxygen is 10:1-
1:10。
Further, the catalyst is palladium salt；The oxidant is oxygen, 1,4-benzoquinone, manganese dioxide, silver carbonate, vinegar
Sour copper, cupric oxide or potassium peroxydisulfate；The solvent is the mixed solvent of toluene (PhMe) and DMF (DMF),
Wherein the mixed volume ratio of toluene (PhMe) and N,N-dimethylformamide (DMF) is 1：100~100：1；The carbonylation
Reaction temperature is 40-150 DEG C.
Further, the mol ratio of the compound 1 and compound 2 is 1：(1~4).
Further, the addition of the catalyst is met：The mol ratio of catalyst and compound 1 is (0.05~0.5):
1；The addition of the oxidant is met：The mol ratio of oxidant and compound 1 is (1~4):1.
Further, the balloon pressure filled with carbon monoxide and oxygen gas is 1~100 atmospheric pressure.
Further, the reaction time of the specific steps (1) is 1-48 hours；During the reaction of the specific steps (2)
Between be 1~72 hour.
Further, product is isolated and purified using column chromatography after carbonylation terminates；The column chromatography eluent is
The mixed solvent of petroleum ether and ethyl acetate, the volume ratio between petroleum ether and ethyl acetate is 1~40:1.
Compared with prior art, advantage of the invention is that：This method provides a kind of height for the synthesis of TNF-α inhibitor
Direct synthesizing mean is imitated, reaction condition is gentle, and raw material is simple and easy to get, can build target by carbonylation one kettle way produces
Thing, synthesizing mean novel and unique.
Brief description of the drawings
Fig. 1 is the proton nmr spectra of the TNF-α inhibitor obtained in embodiment 1；
Fig. 2 is the carbon-13 nmr spectra of the TNF-α inhibitor obtained in embodiment 1.
Embodiment
The invention is further described below by specific embodiment.
Embodiment 1
0.2 mM of benzaldehyde, 0.2 mM of 2,6-DIPA, dichlorodiethyl are added in 25mL test tube
0.01 mM of nitrile palladium, 0.2 mM of cupric oxide adds toluene (PhMe) and DMF (DMF) as mixing
Solvent, volume ratio is 10:1, in stirring 12 hours under normal temperature.Then put containing carbon monoxide and oxygen gas (volume ratio
1:1) balloon is as carbonyl source, in stirring 48 hours under 100 degrees Celsius.TLC (thin-layered chromatography) detection reactions will after terminating
Reaction solution is cooled to room temperature, removes balloon, is slowly vented unreacted carbon monoxide and oxygen.Reacting liquid filtering, filtrate decompression
Revolving removes solvent, then by column chromatographic isolation and purification, obtains target product TNF-α inhibitor, column chromatography eluent used
It is 10 for volume ratio：1 petroleum ether：Ethyl acetate mixed solvent, yield 45%.
The present embodiment structure of title compound is shown according to Fig. 1 and Fig. 2.
Embodiment 2
0.2 mM of benzaldehyde, 0.2 mM of 2,6-DIPA, dichlorodiethyl are added in 25mL test tube
0.01 mM of nitrile palladium, 0.2 mM of cupric oxide adds toluene (PhMe) as solvent, in stirring 12 hours under normal temperature.Then
Put containing carbon monoxide and oxygen gas (volume ratio 1:1) balloon is small in stirring 48 under 100 degrees Celsius as carbonyl source
When.TLC (thin-layered chromatography) tracing detection, does not detect target product.
Embodiment 3
0.2 mM of benzaldehyde, 0.2 mM of 2,6-DIPA, dichlorodiethyl are added in 25mL test tube
0.01 mM of nitrile palladium, 0.2 mM of cupric oxide adds DMF (DMF) as solvent, in stirring under normal temperature
12 hours.Then put containing carbon monoxide and oxygen gas (volume ratio 1:1) balloon is Celsius in 100 as carbonyl source
The lower stirring of degree 48 hours.TLC (thin-layered chromatography) tracing detection, does not detect target product.
Embodiment 4
0.2 mM of benzaldehyde, 0.2 mM of 2,6-DIPA, dichlorodiethyl are added in 25mL test tube
0.01 mM of nitrile palladium, 0.2 mM of cupric oxide adds acetonitrile (CH3CN) as solvent, in stirring 12 hours under normal temperature.So
Contain carbon monoxide and oxygen gas (volume ratio 1 in rear enclosure:1) balloon is as carbonyl source, in stirring 48 under 100 degrees Celsius
Hour.TLC (thin-layered chromatography) tracing detection, does not detect target product.
Embodiment 5
0.2 mM of benzaldehyde, 0.2 mM of 2,6-DIPA, dichlorodiethyl are added in 25mL test tube
0.01 mM of nitrile palladium, 0.2 mM of cupric oxide adds Isosorbide-5-Nitrae-dioxane (dioxane) as solvent, in stirring under normal temperature
12 hours.Then put containing carbon monoxide and oxygen gas (volume ratio 1:1) balloon is Celsius in 100 as carbonyl source
The lower stirring of degree 48 hours.TLC (thin-layered chromatography) tracing detection, does not detect target product.
Embodiment 6
0.2 mM of benzaldehyde, 0.2 mM of 2,6-DIPA, dichlorodiethyl are added in 25mL test tube
0.01 mM of nitrile palladium, 0.2 mM of cupric oxide adds dimethyl sulfoxide (DMSO) (DMSO) as solvent, small in stirring 12 under normal temperature
When.Then put containing carbon monoxide and oxygen gas (volume ratio 1:1) balloon is as carbonyl source, under 100 degrees Celsius
Stirring 48 hours.TLC (thin-layered chromatography) tracing detection, does not detect target product.
Embodiment 7
0.2 mM of benzaldehyde, 0.2 mM of 2,6-DIPA, dichlorodiethyl are added in 25mL test tube
0.01 mM of nitrile palladium, 0.2 mM of cupric oxide adds toluene (PhMe) and DMF (DMF) as mixing
Solvent, volume ratio is 5:1, in stirring 12 hours under normal temperature.Then put containing carbon monoxide and oxygen gas (volume ratio 1:
1) balloon is as carbonyl source, in stirring 48 hours under 100 degrees Celsius.TLC (thin-layered chromatography) detection reactions will be anti-after terminating
Answer liquid to be cooled to room temperature, remove balloon, be slowly vented unreacted carbon monoxide and oxygen.Reacting liquid filtering, filtrate decompression rotation
Boil off except solvent, then by column chromatographic isolation and purification, obtain target product TNF-α inhibitor, column chromatography eluent used is
Volume ratio is 10：1 petroleum ether：Ethyl acetate mixed solvent, yield is reduced to 11%.
Embodiment 8
0.2 mM of benzaldehyde, 0.2 mM of 2,6-DIPA, dichlorodiethyl are added in 25mL test tube
0.01 mM of nitrile palladium, 0.2 mM of cupric oxide adds toluene (PhMe) and DMF (DMF) as mixing
Solvent, volume ratio is 1:1, in stirring 12 hours under normal temperature.Then put containing carbon monoxide and oxygen gas (volume ratio 1:
1) balloon is as carbonyl source, in stirring 48 hours under 100 degrees Celsius.TLC (thin-layered chromatography) tracing detection, is not detected
Target product.
Embodiment 9
0.2 mM of benzaldehyde, 0.2 mM of 2,6-DIPA, dichlorodiethyl are added in 25mL test tube
0.01 mM of nitrile palladium, 0.2 mM of cupric oxide adds toluene (PhMe) and DMF (DMF) as mixing
Solvent, volume ratio is 10:1, in stirring 12 hours under normal temperature.Then put containing carbon monoxide and oxygen gas (volume ratio
1:1) balloon is as carbonyl source, in stirring 48 hours under normal temperature.TLC (thin-layered chromatography) tracing detection, does not detect mesh
Mark product.
Embodiment 10
0.2 mM of benzaldehyde, 0.2 mM of 2,6-DIPA, dichlorodiethyl are added in 25mL test tube
0.01 mM of nitrile palladium, 0.2 mM of cupric oxide adds toluene (PhMe) and DMF (DMF) as mixing
Solvent, volume ratio is 10:1, in stirring 12 hours under normal temperature.Then put containing carbon monoxide and oxygen gas (volume ratio
1:1) balloon is as carbonyl source, in stirring 48 hours under 80 degrees Celsius.TLC (thin-layered chromatography) tracing detection, is not detected
To target product.
Embodiment 11
0.2 mM of benzaldehyde, 0.2 mM of 2,6-DIPA, dichlorodiethyl are added in 25mL test tube
0.01 mM of nitrile palladium, 0.2 mM of cupric oxide adds toluene (PhMe) and DMF (DMF) as mixing
Solvent, volume ratio is 10:1, in stirring 12 hours under normal temperature.Then put containing carbon monoxide and oxygen gas (volume ratio
1:1) balloon is as carbonyl source, in stirring 48 hours under 90 degrees Celsius.TLC (thin-layered chromatography) tracing detection, can only be detected
To the target product of trace.
Embodiment 12
0.2 mM of benzaldehyde, 0.2 mM of 2,6-DIPA, dichlorodiethyl are added in 25mL test tube
0.01 mM of nitrile palladium, 0.2 mM of cupric oxide adds toluene (PhMe) and DMF (DMF) as mixing
Solvent, volume ratio is 10:1, in stirring 12 hours under normal temperature.Then put containing carbon monoxide and oxygen gas (volume ratio
1:1) balloon is as carbonyl source, in stirring 48 hours under 110 degrees Celsius.TLC (thin-layered chromatography) detection reactions will after terminating
Reaction solution is cooled to room temperature, removes balloon, is slowly vented unreacted carbon monoxide and oxygen.Reacting liquid filtering, filtrate decompression
Revolving removes solvent, then by column chromatographic isolation and purification, obtains target product TNF-α inhibitor, column chromatography eluent used
It is 10 for volume ratio：1 petroleum ether：Ethyl acetate mixed solvent, yield 25%.
Embodiment 13
0.2 mM of benzaldehyde, 0.2 mM of 2,6-DIPA, dichlorodiethyl are added in 25mL test tube
0.01 mM of nitrile palladium, 0.2 mM of cupric oxide adds toluene (PhMe) and DMF (DMF) as mixing
Solvent, volume ratio is 10:1, in stirring 12 hours under normal temperature.Then put containing carbon monoxide and oxygen gas (volume ratio
1:1) balloon is as carbonyl source, in stirring 48 hours under 120 degrees Celsius.TLC (thin-layered chromatography) detection reactions will after terminating
Reaction solution is cooled to room temperature, removes balloon, is slowly vented unreacted carbon monoxide and oxygen.Reacting liquid filtering, filtrate decompression
Revolving removes solvent, then by column chromatographic isolation and purification, obtains target product TNF-α inhibitor, column chromatography eluent used
It is 10 for volume ratio：1 petroleum ether：Ethyl acetate mixed solvent, yield 9%.
Test result in above-described embodiment is shown in Tables 1 and 2.
Table 1
Table 2
| T/ DEG C (temperature) | Yield (%) |
| Normal temperature | It is reactionless |
| 80 | 0 |
| 90 | Trace |
| 100 | 45 |
| 110 | 25 |
| 120 | 9 |
Solvent and the temperature parameter setting of the present invention can significantly improve reaction yield.Conjunction on such compound at present
Use single solvent as reaction dissolvent into majority, but it is of the invention when using single solvent as reaction dissolvent, all detect not
To target product, when only using toluene (PhMe) and DMF (DMF) instead as mixed solvent, reaction could be sent out
It is raw.And the proportioning of solvent also has a significant impact to reaction yield, only solvent ratios are PhMe/DMF (10:1) when, reaction
Effect is only best；In addition, temperature parameter of the invention setting can also significantly improve reaction yield.
Claims (8)
1. utilize the method for carbonylation one pot process TNF-α inhibitor, it is characterised in that synthetic route is as follows：
2. the method for carbonylation one pot process TNF-α inhibitor is utilized according to claim 1, it is characterised in that
The TNF-α inhibitor is made by compound 1 with compound 2 through the condensation of amine aldehyde, oxidation carbonylation；The compound 1 is
Benzaldehyde；The compound 2 is 2,6- diisopropyl anilines；
Comprise the following steps that：
(1) compound 1 and compound 2 are taken in test tube, catalyst, oxidant and solvent is added, in stirring 1-48 at 10-60 DEG C
Hour；
(2) take step (1) to react the test tube after terminating, the balloon filled with carbon monoxide and oxygen gas is put, in 40-150 DEG C
Lower stirring 1-72 hours, separating-purifying obtains TNF-α inhibitor；The volume ratio of the carbon monoxide and oxygen is 10:1-1:10.
3. the method for carbonylation one pot process TNF-α inhibitor is utilized according to claim 2, it is characterised in that：
The catalyst is palladium salt；The oxidant is oxygen, 1,4-benzoquinone, manganese dioxide, silver carbonate, copper acetate, cupric oxide or over cure
Sour potassium；The solvent is the mixed solvent of toluene (PhMe) and DMF (DMF), wherein toluene (PhMe) and N,
The mixed volume ratio of dinethylformamide (DMF) is 1：100~100：1；The reaction temperatures for carbonylation is 40-150 DEG C.
4. the method for carbonylation one pot process TNF-α inhibitor is utilized according to claim 2, it is characterised in that：
The mol ratio of the compound 1 and compound 2 is 1：(1~4).
5. the method for carbonylation one pot process TNF-α inhibitor is utilized according to claim 2, it is characterised in that：
The addition of the catalyst is met：The mol ratio of catalyst and compound 1 is (0.05~0.5):1；The oxidant plus
Enter amount satisfaction：The mol ratio of oxidant and compound 1 is (1~4):1.
6. the method for carbonylation one pot process TNF-α inhibitor is utilized according to claim 2, it is characterised in that：
The balloon pressure filled with carbon monoxide and oxygen gas is 1~100 atmospheric pressure.
7. the method for carbonylation one pot process TNF-α inhibitor is utilized according to claim 2, it is characterised in that：
The reaction time of the specific steps (1) is 1-48 hours；The reaction time of the specific steps (2) is 1~72 hour.
8. the method for carbonylation one pot process TNF-α inhibitor is utilized according to claim 1, it is characterised in that：
Carbonylation is isolated and purified product using column chromatography after terminating；The column chromatography eluent is petroleum ether and ethyl acetate
Mixed solvent, the volume ratio between petroleum ether and ethyl acetate is 1~40:1.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014096732A1 (en) * | 2012-12-21 | 2014-06-26 | Centre National De La Recherche Scientifique (Cnrs) | Metal nano-catalysts in glycerol and applications in organic synthesis |
| CN104926711A (en) * | 2015-06-01 | 2015-09-23 | 华南理工大学 | Method for synthesizing TRPA1-like modifier precursor by use of carbonylation one-pot reaction |
| CN105130874A (en) * | 2015-07-25 | 2015-12-09 | 华南理工大学 | One-pot method for synthesizing N-substituted phthalimide through carbonylation |
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2017
- 2017-06-18 CN CN201710461370.9A patent/CN107235889A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014096732A1 (en) * | 2012-12-21 | 2014-06-26 | Centre National De La Recherche Scientifique (Cnrs) | Metal nano-catalysts in glycerol and applications in organic synthesis |
| CN104926711A (en) * | 2015-06-01 | 2015-09-23 | 华南理工大学 | Method for synthesizing TRPA1-like modifier precursor by use of carbonylation one-pot reaction |
| CN105130874A (en) * | 2015-07-25 | 2015-12-09 | 华南理工大学 | One-pot method for synthesizing N-substituted phthalimide through carbonylation |
Non-Patent Citations (2)
| Title |
|---|
| JOE W. WRIGGLESWORTH ET AL.: "New Heteroannulation Reactions of N-Alkoxybenzamides by Pd(II) Catalyzed C-H Activation", 《ORG. LETT.》 * |
| MAYUR V. KHEDKARA ET AL.: "Immobilized palladium metal containing ionic liquid catalyzedone step synthesis of isoindole-1,3-diones by carbonylativecyclization reaction", 《JOURNAL OF MOLECULAR CATALYSIS A: CHEMICAL》 * |
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Application publication date: 20171010 |