CN110066259A - A kind of synthetic method of N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide - Google Patents
A kind of synthetic method of N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide Download PDFInfo
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- CN110066259A CN110066259A CN201910429132.9A CN201910429132A CN110066259A CN 110066259 A CN110066259 A CN 110066259A CN 201910429132 A CN201910429132 A CN 201910429132A CN 110066259 A CN110066259 A CN 110066259A
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- thiomorpholine
- dioxo
- cyclopenta
- formamide
- synthetic method
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
Abstract
The invention discloses a kind of N- cyclopenta -1, the synthetic method of 1- dioxo -4- thiomorpholine formamide, the following steps are included: by 1,1- dioxo -4- thiomorpholine formyl chloride is dissolved in solvent, -15 DEG C ~ 5 DEG C are cooled to, acid binding agent is added, cyclopentamine is added after stirring into uniform solution, N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide is prepared after being stirred to react 10 ~ 20h.A kind of synthetic method of N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide of the invention, raw material is cheap and easy to get, small toxicity; synthetic method is simple, and reaction condition is mild, and yield can reach 84.5%; suitable for large-scale production N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide.
Description
Technical field
The present invention relates to a kind of synthetic methods of N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide, belong to medicine
Intermediate preparation technical field.
Background technique
Histon deacetylase (HDAC) (histone deacetylase, HDAC) is a kind of from relying on chromatin histone
Histidine residue removes the protease of acetyl group, plays an important role in the structural modification and gene expression regulation of chromosome.
HDAC6 is a member of HDAC family, and the research and development of HDAC6 inhibitor are in cancer, inflammation, autoimmune disease and neurological
There is important application in the research of property disease.N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide (I) is that synthesis is a kind of
The important intermediate of HDAC6 inhibitor, therefore wide market.
The synthesis technology of N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide (I) report is as follows, cyclopenta isocyanide
Acid esters (II) and thiomorpholine 1, the reaction of 1- dioxide, obtain I.
In the technique, raw material cyclopenta isocyanates (II) has offensive odour, and irritation is larger.The stabilization of II
Property it is poor, be easy and amine, water, alcohol, acid and alkali reaction, and it is heated be easy to decompose, be unsuitable for largely storing and transport.It is a large amount of to use
When, II is usually required by cyclopentamine and phosgene or triphosgene reaction preparation.Therefore, which is unsuitable for large scale preparation I.
N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide (I) be synthesize one kind HDAC6 inhibitor it is important in
Mesosome, wide market.Therefore, exploitation one is easy to operate, and route is short, high income, synthesis side suitable for scale production
Method is of great significance.
Summary of the invention
The technical problem to be solved by the present invention is to overcome the deficiencies of existing technologies, a kind of N- cyclopenta -1,1- bis- is provided
The synthetic method of oxo -4- thiomorpholine formamide, raw material is cheap and easy to get, small toxicity, and synthetic method is simple, is suitable for scale metaplasia
Produce N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide.
Above-mentioned technical purpose of the invention has the technical scheme that
A kind of synthetic method of N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide, comprising the following steps:
1,1- dioxo -4- thiomorpholine formyl chloride is dissolved in solvent, is cooled to -15 DEG C~5 DEG C, acid binding agent is added,
Cyclopentamine is added after stirring into uniform solution, N- cyclopenta -1,1- dioxo -4- sulphur is prepared after being stirred to react 10~20h
For morpholine formamide；
Reaction process are as follows:
By using above-mentioned technical proposal, use is cheap and easy to get, N- is prepared by single step reaction in small toxicity raw material
Cyclopenta -1,1- dioxo -4- thiomorpholine formamide.
Preferably, the solvent be methylene chloride, chloroform, tetrahydrofuran, ether, acetonitrile, Isosorbide-5-Nitrae-dioxane, toluene,
One of ethyl acetate or acetone or several mixtures.
By using above-mentioned technical proposal, by using the small solvent of cheap and easy to get, pollution, so that compound is in solvent
In react.
Preferably, the molar ratio of 1, the 1- dioxo -4- thiomorpholine formyl chloride and cyclopentamine be 1.0:0.2~
1.0:10.0。
Preferably, the molar ratio of 1, the 1- dioxo -4- thiomorpholine formyl chloride and cyclopentamine be 1.0:0.8~
1.0:2.5。
By using above-mentioned technical proposal, using 1, the 1- dioxo -4- thiomorpholine formyl chloride and ring of certain mol proportion
Amylamine is reacted, and is conducive to the progress and post-processing of reaction, and yield is high.
Preferably, the acid binding agent is at least one of cyclopentamine, triethylamine or n,N-diisopropylethylamine.
It, can be with the by-product that is generated in compound reaction process using above-mentioned acid binding agent by using above-mentioned technical proposal
Hydrochloric acid is combined, and is produced ammonium salt, is avoided hydrochloric acid in conjunction with target product, yield is caused to decline.
Preferably, the molar ratio of 1, the 1- dioxo -4- thiomorpholine formyl chloride and acid binding agent be 1.0:0.2~
1.0:10.0。
Preferably, the molar ratio of 1, the 1- dioxo -4- thiomorpholine formyl chloride and acid binding agent be 1.0:0.8~
1.0:1.5。
By using above-mentioned technical proposal, using 1, the 1- dioxo -4- thiomorpholine formyl within the scope of certain mol proportion
Chlorine and acid binding agent are conducive to improve yield.
Preferably, the reaction temperature is -20 DEG C to 180 DEG C.
Preferably, the reaction temperature is 10 DEG C to 30 DEG C.
By using above-mentioned technical proposal, cyclopenta -1 N- that yield is high, by-product is few is obtained in certain temperature range,
1- dioxo -4- thiomorpholine formamide, and reaction speed is fast.
In conclusion the invention has the following advantages:
(1) a kind of synthetic method of N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide of the invention, raw material are honest and clean
Valence is easy to get, small toxicity, and synthetic method is simple, is suitable for large-scale production N- cyclopenta -1,1- dioxo -4- thiomorpholine formyl
Amine；
(2) synthetic method of a kind of N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide of the invention, passes through one
N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide is prepared in footwork, and reaction condition is mild, and yield can reach
84.5%, it is suitable for large-scale production N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide；
(3) synthetic method of a kind of N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide of the invention, is prepared into
N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide of the high yield arrived can be used for producing HDAC6 inhibitor, have very
High medical and medical value.
Detailed description of the invention
Fig. 1 is N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide of the invention1HNMR figure.
Specific embodiment
The invention will be further described below.Following embodiment is only used for clearly illustrating technical side of the invention
Case, and not intended to limit the protection scope of the present invention.
Such as Fig. 1, the present invention a kind of N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide being prepared1H
NMR figure, synthetic method, comprising the following steps:
1,1- dioxo -4- thiomorpholine formyl chloride is dissolved in solvent, is cooled to -15 DEG C~5 DEG C, acid binding agent is added,
Cyclopentamine is added after stirring into uniform solution, N- cyclopenta -1,1- dioxo -4- sulphur is prepared after being stirred to react 10~20h
For morpholine formamide；
Reaction process are as follows:
Embodiment 1
1,1- dioxo -4- thiomorpholine formyl chloride (15.00g, 0.0759mol, 1.0equiv.) is dissolved in 150mL bis-
In chloromethanes, -15 DEG C are cooled to, is added triethylamine (8.43g, 0.0835 mol, 1.1equiv.), 1h is stirred, is formed uniform molten
It after liquid, is added dropwise cyclopentamine (7.10g, 0.0835mol, 1.1equiv.), is reacted 16 hours after being added dropwise to complete in 15 DEG C, washing,
0.1 N HCl washing, anhydrous sodium sulfate dry, filter, and white solid 15.20g, yield: 81.2% is concentrated under reduced pressure to obtain.
1H NMR (400M Hz, CDCl3) δ (ppm) 4.62-4.60 (d, J=6.8Hz, 1H), 4.15-4.10 (m, 1H),
3.88-3.85 (m, 4H), 3.05-3.02 (m, 4H) 2.05-1.97 (m, 2H), 1.70-158 (m, 4H), 1.39-1.31 (m,
2H)。
Reaction process are as follows:
Embodiment 2
1,1- dioxo -4- thiomorpholine formyl chloride (10.00g, 0.0506mol, 1.0equiv.) is dissolved in 100mL first
Benzene, ice-water bath are down to 0 DEG C, are added dropwise cyclopentamine (10.77g, 0.126mol, 2.5equiv.), after being added dropwise to complete, react in 30 DEG C
10 hours, washing, 0.1N HCl was washed, and anhydrous sodium sulfate dries, filters, and white solid 10.53g was concentrated under reduced pressure to obtain, yield:
84.5%.
1H NMR (400M Hz, CDCl3) δ (ppm) 4.62-4.60 (d, J=6.8Hz, 1H), 4.15-4.10 (m, 1H),
3.88-3.85 (m, 4H), 3.03 (m, 4H) 2.05-1.97 (m, 2H), 1.70-158 (m, 4H), 1.39-1.31 (m, 2H).
Reaction process are as follows:
Embodiment 3
1,1- dioxo -4- thiomorpholine formyl chloride (10.00g, 0.0506mol, 1.0equiv.) is dissolved in 100mL tetra-
In hydrogen furans, -7 DEG C are cooled to, n,N-diisopropylethylamine (9.809 g, 0.0759mol, 1.5equiv.) is added and stirs 1h,
It after forming uniform solution, is added dropwise cyclopentamine (10.77g, 0.126mol, 2.5equiv.), after being added dropwise to complete, reacts 16 in 0 DEG C
Hour, washing, 0.1N HCl is washed, and anhydrous sodium sulfate dries, filters, white solid 10.02g is concentrated under reduced pressure to obtain, yield:
80.5%.
1H NMR (400M Hz, CDCl3) δ (ppm) 4.62-4.60 (d, J=6.8Hz, 1H), 4.15-4.10 (m, 1H),
3.88-3.85 (m, 4H), 3.03 (m, 4H) 2.05-1.97 (m, 2H), 1.70-158 (m, 4H), 1.39-1.31 (m, 2H).
Reaction process are as follows:
The above is only a preferred embodiment of the present invention, protection scope of the present invention is not limited merely to above-mentioned implementation
Example, all technical solutions belonged under thinking of the present invention all belong to the scope of protection of the present invention.It should be pointed out that for the art
Those of ordinary skill for, several improvements and modifications without departing from the principles of the present invention, these improvements and modifications
It should be regarded as protection scope of the present invention.
Claims (9)
1. a kind of synthetic method of N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide, characterized in that including following step
It is rapid:
1,1- dioxo -4- thiomorpholine formyl chloride is dissolved in solvent, is cooled to -15 DEG C ~ 5 DEG C, acid binding agent is added, stirs into
Cyclopentamine is added after uniform solution, N- cyclopenta -1,1- dioxo -4- thiomorpholine first is prepared after being stirred to react 10 ~ 20h
Amide；
Reaction process are as follows:
。
2. a kind of synthetic method of N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide according to claim 1,
It is characterized in that the solvent is methylene chloride, chloroform, tetrahydrofuran, ether, acetonitrile, Isosorbide-5-Nitrae-dioxane, toluene, acetic acid second
One of ester or acetone or several mixtures.
3. a kind of synthetic method of N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide according to claim 1,
It is characterized in that the molar ratio of 1, the 1- dioxo -4- thiomorpholine formyl chloride and cyclopentamine is 1.0:0.2 ~ 1.0:10.0.
4. a kind of synthetic method of N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide according to claim 3,
It is characterized in that the molar ratio of 1, the 1- dioxo -4- thiomorpholine formyl chloride and cyclopentamine is 1.0:0.8 ~ 1.0:2.5.
5. a kind of synthetic method of N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide according to claim 1,
It is characterized in that the acid binding agent be cyclopentamine, triethylamine orN,NAt least one of diisopropylethylamine.
6. a kind of synthesis side of N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide according to claim 1 or 5
Method, characterized in that the molar ratio of 1, the 1- dioxo -4- thiomorpholine formyl chloride and acid binding agent is 1.0:0.2 ~ 1.0:
10.0。
7. a kind of synthetic method of N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide according to claim 6,
It is characterized in that the molar ratio of 1, the 1- dioxo -4- thiomorpholine formyl chloride and acid binding agent is 1.0:0.8 ~ 1.0:1.5.
8. a kind of synthetic method of N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide according to claim 1,
It is characterized in that the reaction temperature is -20 DEG C to 180 DEG C.
9. a kind of synthetic method of N- cyclopenta -1,1- dioxo -4- thiomorpholine formamide according to claim 8,
It is characterized in that the reaction temperature is 10 DEG C to 30 DEG C.
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| US20100009964A1 (en) * | 2006-11-21 | 2010-01-14 | Boehringer Ingelheim International Gmbh | Compounds Which Modulate The CB2 Receptor |
| CN102050802A (en) * | 2010-11-10 | 2011-05-11 | 许景峰 | N-(2-ethoxyl)ferulamide nitrate derivative with anoxia resisting pharmaceutical activity and preparation method thereof |
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| WO2015084998A1 (en) * | 2013-12-05 | 2015-06-11 | Pharmacyclics, Inc. | Inhibitors of bruton's tyrosine kinase |
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Application publication date: 20190730 |