CN106543040A - A kind of synthetic method of medicine intermediate carbamate compounds - Google Patents
A kind of synthetic method of medicine intermediate carbamate compounds Download PDFInfo
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- CN106543040A CN106543040A CN201611010725.4A CN201611010725A CN106543040A CN 106543040 A CN106543040 A CN 106543040A CN 201611010725 A CN201611010725 A CN 201611010725A CN 106543040 A CN106543040 A CN 106543040A
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- carbamate compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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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
- C07D295/205—Radicals derived from carbonic acid
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a kind of synthetic method of carbamate compounds, formula (I) compound and formula (II) compound react in organic solvent, in the presence of catalyst and part, obtain carbamate compounds, the synthesis in high yield of carbamate compounds is realized, is had a good application prospect.
Description
Technical field
The present invention relates to a kind of synthetic method of pharmaceutical intermediate compound, relates more particularly to a kind of urethane
The synthetic method of compound, belongs to medical compoundss synthesis field.
Background technology
Carbamate structures are very important class active groups in organic chemical synthesis, are present in various biological living
In property molecule, it is one of important framing structure of many pharmaceutical active compounds.Carbamate compounds are used as pharmaceutical synthesis
Intermediate, can carry out the expansion and modification of group by various reactions, and so as to obtain bioactive compound, which is organic
There is in chemosynthesis consequence.
In recent years, the synthetic method for developing carbamate compounds is increasingly taken seriously, and what which had been carried out is a large amount of
Research, obtains some new synthetic routes and method.So far, it has been reported that various relevant amino first in prior art
The synthetic method of ester compound.
However, existing these methods but there are still some defects, such as products collection efficiency is relatively low, environmental pollution, operation
It is complicated, with high costs etc., have a strong impact on the large-scale production and utilization of such compound.
In order to overcome, the above-mentioned yield that carbamate compounds synthetic method in prior art is present is relatively low, environment is dirty
The defect such as dye, complex operation, with high costs, the present inventor are conducted in-depth research to the preparation method of such compound, from
And obtain a kind of novel synthesis of carbamate compounds.
The content of the invention
The invention provides a kind of synthetic method of carbamate compounds, comprises the following steps：In Raney nickel and
In the presence of part, formula (I) compound and formula (II) compound react in organic solvent, obtain the carbamic acid of formula (III)
Ester compounds.
Wherein, R1Selected from H, halogen, C1-C6Alkyl or C1-C6Alkoxyl；
R2And R3It is each independently selected from C1-C6Alkyl, or R2And R3Ring structure is formed together with the nitrogen-atoms being bonded with them；
The C1-C6Alkyl selected from 1-6 carbon atom straight or branched alkyl, in non-limiting manner for example can be methyl,
Ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl or n-hexyl etc..
The C1-C6Alkoxyl is selected from the C with above-mentioned implication1-C6The group that alkyl is obtained after being connected with oxygen atom.
The Raney nickel is two (triphenylphosphine) Nickel dichloride. (NiCl2(PPh3)2), nickel acetate, Nickel dichloride., two (three hexamethylenes
Base phosphine) Nickel dichloride. (NiCl2(PCy3)2) in any one, preferably two (triphenylphosphine) Nickel dichloride. (NiCl2(PPh3)2)。
In the synthetic method, compound of the part for formula L1。
The synthetic method of above-mentioned carbamate compounds, comprises the following steps：In the presence of Raney nickel and part,
Formula (I) compound and formula (II) compound react in organic solvent, and 0.5-12 hours are reacted at 30-100 DEG C, and reaction is completed
Afterwards, all volatile matters are removed in vacuum, product is extracted with ethyl acetate, organic faciess remove solvent, by gained residue Jing 300-400
Mesh silica gel column chromatography is separated, and obtains the carbamate compounds of formula (III).Reaction temperature is preferred 50-60 DEG C, and the response time is excellent
Select 0.5-1.5 hours.
In the synthetic method of the present invention, the organic solvent is DMF, dimethyl sulfoxide, first
Any one in benzene, benzene or acetonitrile or arbitrarily various mixture, most preferably volume ratio 2:1 N,N-dimethylformamide
With the mixture of acetonitrile.
Wherein, the consumption of the organic solvent does not have strict restriction, and those skilled in the art can be according to practical situation
Carry out suitable selection and determine, to facilitate reaction to carry out and post processing, here is no longer carried out in detail such as its consumption size
It is thin to describe.
In the synthetic method of the present invention, formula (I) compound is 1 with the mol ratio of formula (II) compound:1-
2, can for example be 1:1.1、1:1.5 or 1:1.8.
In the synthetic method of the present invention, formula (I) compound is 1 with the mol ratio of Raney nickel:0.1-
0.2, can for example be 1:0.2、1:0.16 or 1:0.18.
In the synthetic method of the present invention, formula (I) compound is 1 with the mol ratio of part:0.1-0.5, example
Can such as be 1:0.12、1:0.16 or 1:0.2.
In the synthetic method of the present invention, the above-mentioned all materials for using can be purchased by various commercial channel
Can buy, then this is no longer described in detail.
In sum, the invention provides a kind of synthetic method of carbamate compounds, methods described is by starting
The selection of material, special catalystic converter system are comprehensively cooperateed with and are mutually promoted, it is achieved thereby that carbamate compounds
Synthesize in high yield, have a good application prospect.
Specific 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 constitutes 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
100 ml volume ratios 2 are added in the reactor:1 DMF and the mixed organic solvents of acetonitrile, successively
It is added thereto to formula (II) compound on formula (I) compound on 10 mmol, 12 mmol, 1.2 mmol catalyst, two (triphenyl
Phosphine) Nickel dichloride. (NiCl2(PPh3)2), 2.0 mmol ligand Ls 1, be heated to 50 DEG C while stirring, and stir at such a temperature
Reaction 1 hour.After the completion of reaction, all volatile matters are removed in vacuum, product is extracted with ethyl acetate, organic faciess remove solvent, will
Gained residue Jing 300-400 mesh silica gel column chromatography is separated, and eluting solvent is volume ratio 2:8 ethyl acetate and the mixing of hexane
Thing, obtains final product above-mentioned formula (III) compound, and yield is 94.7%.
1H NMR (CDCl3, 400 MHz): δ 10.19 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H),
7.62 (t, J = 7.6 Hz, 1H), 7.21-7.35 (m, 2H), 3.34-3.55 (m, 4H), 1.20−1.34 (m,
6H) ppm.
Embodiment 2
100 ml volume ratios 2 are added in the reactor:1 DMF and the mixed organic solvents of acetonitrile, successively
It is added thereto to formula (II) compound on formula (I) compound on 10 mmol, 12 mmol, 1.6 mmol catalyst, two (triphenyl
Phosphine) Nickel dichloride. (NiCl2(PPh3)2), 2.0 mmol ligand Ls 1, be heated to 50 DEG C while stirring, and stir at such a temperature
Reaction 1 hour.After the completion of reaction, all volatile matters are removed in vacuum, product is extracted with ethyl acetate, organic faciess remove solvent, will
Gained residue Jing 300-400 mesh silica gel column chromatography is separated, and obtains final product above-mentioned formula (III) compound, and yield is 90.7%.1H NMR
(d 6-DMSO, 400 MHz): δ 10.14 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.69 (d, J =
8.0 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 3.41-3.58 (m, 4H), 1.19-1.38 (m, 6H)
ppm。
Embodiment 3
100 ml volume ratios 2 are added in the reactor:1 DMF and the mixed organic solvents of acetonitrile, successively
It is added thereto to formula (II) compound on formula (I) compound on 10 mmol, 12 mmol, 1.2 mmol catalyst, two (triphenyl
Phosphine) Nickel dichloride. (NiCl2(PPh3)2), 2.0 mmol ligand Ls 1, be heated to 50 DEG C while stirring, and stir at such a temperature
Reaction 1 hour.After the completion of reaction, all volatile matters are removed in vacuum, product is extracted with ethyl acetate, organic faciess remove solvent, will
Gained residue Jing 300-400 mesh silica gel column chromatography is separated, and obtains final product above-mentioned formula (III) compound, and yield is 95.7%.1H NMR
(CDCl3, 400 MHz): δ10.04 (s, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.73-7.88 (m,
2H), 3.88(s, 3H), 3.68 (br m, 2H), 3.53 (br m, 2H), 1.66 (br 6H) ppm。
Embodiment 4-12
The Raney nickel in embodiment 1-3 is replaced with into nickel acetate respectively, other operation all sames, so as to sequentially obtain embodiment
4-6。
The Raney nickel in embodiment 1-3 is replaced with into Nickel dichloride. respectively, other operation all sames, so as to sequentially obtain reality
Apply a 7-9.
The Raney nickel in embodiment 1-3 is replaced with into two (tricyclohexyl phosphine) Nickel dichloride. respectively, other operation all sames,
So as to sequentially obtain embodiment 10-12.
As a result see the table below 1：
Table 1
Embodiment 13-15
Ligand L 1 in embodiment 1-3 is omitted into (other steps are constant), operation again respectively obtains embodiment 13-15, finds
Its yield has significantly reduction compared to embodiment 1-3, and the presence of ligand L 1 can improve the catalytic effect of catalyst, promote
The carrying out of reaction, so as to obtain higher yields.See the table below 2：
Table 2
In sum, the invention provides a kind of synthetic method of carbamate compounds, methods described is by starting material
Selection, special catalystic converter system comprehensively cooperate with and mutually promote, it is achieved thereby that the high receipts of carbamate compounds
Rate synthesizes, and has a good application prospect.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limit the protection model of the present invention
Enclose.Additionally, it will also be appreciated that after the technology contents for having read the present invention, those skilled in the art can make each to the present invention
Plant and change, change and/or modification, all these equivalent form of value equally falls within the guarantor limited by the application appended claims
Within the scope of shield.
Claims (10)
1. a kind of synthetic method of carbamate compounds shown in formula (III), comprises the following steps：In Raney nickel and part
In the presence of, formula (I) compound and formula (II) compound react in organic solvent, obtain the urethane of formula (III)
Compound,
Wherein, R1Selected from H, halogen, C1-C6Alkyl or C1-C6Alkoxyl；
R2And R3It is each independently selected from C1-C6Alkyl, or R2And R3Ring structure is formed together with the nitrogen-atoms being bonded with them；
Compound of the part for formula L1。
2. synthetic method as claimed in claim 1, it is characterised in that：The Raney nickel be two (triphenylphosphine) Nickel dichloride.,
Any one in nickel acetate, Nickel dichloride., two (tricyclohexyl phosphine) Nickel dichloride., preferably two (triphenylphosphine) Nickel dichloride..
3. synthetic method as claimed in claim 1 or 2, it is characterised in that：Formula (I) compound and formula (II) compound
Mol ratio is 1:1-2.
4. synthetic method as claimed in claim 1 or 2, it is characterised in that：The organic solvent be N,N-dimethylformamide,
Any one in dimethyl sulfoxide, toluene, benzene or acetonitrile or arbitrarily various mixture, most preferably volume ratio 2:1 N,
The mixture of dinethylformamide and acetonitrile.
5. synthetic method as claimed in claim 1 or 2, it is characterised in that：Formula (I) compound and Raney nickel mole
Than for 1:0.1-0.2.
6. synthetic method as claimed in claim 1 or 2, it is characterised in that：Formula (I) compound with the mol ratio of part is
1:0.1-0.5。
7. synthetic method as claimed in claim 1 or 2, it is characterised in that：R1Selected from H, chlorine or methoxyl group；R2 and R3 are each only
Ethyl is on the spot selected from, or piperidines group is formed together with the nitrogen-atoms that are bonded with them of R2 and R3.
8. the synthetic method as described in claim 1-7 any one, it is characterised in that：In the presence of Raney nickel and part
Under, formula (I) compound and formula (II) compound react in organic solvent, react 0.5-12 hours, reacted at 30-100 DEG C
Cheng Hou, is removed in vacuum all volatile matters, and product is extracted with ethyl acetate, and organic faciess remove solvent, by gained residue Jing 300-
400 mesh silica gel column chromatographies are separated, and obtain the carbamate compounds of formula (III).
9. synthetic method as claimed in claim 8, it is characterised in that：Reaction temperature is 50-60 DEG C.
10. synthetic method as claimed in claim 8, it is characterised in that：Response time is 0.5-1.5 hours.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112481319A (en) * | 2020-12-10 | 2021-03-12 | 中国科学院青岛生物能源与过程研究所 | Green synthesis method of carbamate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101863800A (en) * | 2009-04-14 | 2010-10-20 | 拜耳材料科技(中国)有限公司 | Method for synthesizing carbamate, catalyst applicable to method and preparation method and use thereof |
-
2016
- 2016-11-17 CN CN201611010725.4A patent/CN106543040B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101863800A (en) * | 2009-04-14 | 2010-10-20 | 拜耳材料科技(中国)有限公司 | Method for synthesizing carbamate, catalyst applicable to method and preparation method and use thereof |
Non-Patent Citations (2)
| Title |
|---|
| BALAJI D. BRAVE ET AL.: "Copper-Catalyzed Oxidative Coupling of Formamides with Salicylaldehydes: Synthesis of Carbamates in the Presence of a Sensitive Aldehyde Group", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
| TARUN KANTI PRADHAN ET AL.: "Application of directed metalation in synthesis. Part 6：A novel anionic rearrangement under directed metalation conditions leading to heteroannulation", 《TETRAHEDRON》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112481319A (en) * | 2020-12-10 | 2021-03-12 | 中国科学院青岛生物能源与过程研究所 | Green synthesis method of carbamate |
| CN112481319B (en) * | 2020-12-10 | 2022-06-28 | 中国科学院青岛生物能源与过程研究所 | Green synthesis method of carbamate |
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Effective date of registration: 20200907 Address after: Room 303, 3 / F, building 8, hi tech city, No. 5, Lushan South Road, hi tech Zone, Liaocheng City, Shandong Province Patentee after: Liaocheng high tech Zone quantum Biomedical Industry Development Co., Ltd Address before: 266000 East Road, high tech Zone, Shandong, Qingdao, 826-38 Patentee before: QINGDAO ZHONGKEQINGHUAN BIOTECHNOLOGY Co.,Ltd. |