CN104193722A - Preparation method of N-tert-butyloxycarbonyl-3-methylaminothiophene - Google Patents
Preparation method of N-tert-butyloxycarbonyl-3-methylaminothiophene Download PDFInfo
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- CN104193722A CN104193722A CN201410425783.8A CN201410425783A CN104193722A CN 104193722 A CN104193722 A CN 104193722A CN 201410425783 A CN201410425783 A CN 201410425783A CN 104193722 A CN104193722 A CN 104193722A
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- reaction
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- xylol
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- tertbutyloxycarbonyl
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- IXXCPUJNVGXNGT-UHFFFAOYSA-N CC(C)(C)OC(NCc1c[s]cc1)=O Chemical compound CC(C)(C)OC(NCc1c[s]cc1)=O IXXCPUJNVGXNGT-UHFFFAOYSA-N 0.000 description 1
- 0 FC(CC*1=CCNC=C1)(F)F Chemical compound FC(CC*1=CCNC=C1)(F)F 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
Abstract
The invention discloses a preparation method of N-tert-butyloxycarbonyl-3-methylaminothiophene, which comprises the following steps: by using 3-thienylformaldehyde as an initial raw material, carrying out reduction, bromination, amination and tert-butyloxycarbonyl protection to obtain the target product. The compound is an important medicine intermediate.
Description
Technical field
The present invention relates to a kind of novel preparation method of medicine intermediate, particularly a kind of preparation method of a kind of preparation method of N-tertbutyloxycarbonyl-3-methylamine thiophene.
Technical background
Compound N-tertbutyloxycarbonyl-3-methylamine thiophene, structural formula is:
This compound N-tertbutyloxycarbonyl-3-methylamine thiophene and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.N-tertbutyloxycarbonyl-3-methylamine thiophene is synthetic comparatively difficult at present.Therefore, need to develop a raw material and be easy to get, easy to operate, reaction is easy to control, the synthetic method that overall yield is suitable.
Summary of the invention
The invention discloses a kind of method of the N-of preparation tertbutyloxycarbonyl-3-methylamine thiophene, take 3-thiophenecarboxaldehyde as starting raw material, through reduction, bromo, amination, tertbutyloxycarbonyl protection, obtain target product 5, synthetic route as shown in Figure 1.Synthesis step is as follows:
(1) 3-thiophenecarboxaldehyde is starting raw material, through reduction reaction, obtains 2;
(2) 2, carry out bromo-reaction, obtain 3;
(3) 3, carry out amination reaction and obtain 4;
(3) 4, carry out tertbutyloxycarbonyl protective reaction and obtain target product 5,
One preferred embodiment in, described reduction reaction is prepared compound 2 reagent used and is selected from sodium borohydride; Described bromo-reaction is prepared compound 3 reagent used and is selected from Hydrogen bromide; Described amination reaction is prepared compound 4 reductive agent used used and is selected from ammoniacal liquor; Described tertbutyloxycarbonyl protective reaction is prepared compound 5 reagent used and is selected from tert-Butyl dicarbonate.
One preferred embodiment in, described reduction reaction is prepared compound 2 solvent used and is selected from methyl alcohol; Described bromo-reaction is prepared compound 3 solvent used and is selected from water; Described amination reaction is prepared compound 4 solvent used and is selected from DMF; Described tertbutyloxycarbonyl protective reaction is prepared compound 5 solvent used and is selected from methylene dichloride.
One preferred embodiment in, it is room temperature that described reduction reaction is prepared compound 2 temperature of reaction used; It is the reflux temperature of solvent that described bromo-reaction is prepared compound 3 temperature used; It is 150 ℃ that described amination reaction is prepared compound 4 temperature used; Described tertbutyloxycarbonyl protective reaction prepare compound 5 used be room temperature.
The preparation method who the present invention relates to a kind of N-tertbutyloxycarbonyl-3-methylamine thiophene, does not have other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of compound N-tertbutyloxycarbonyl-3-methylamine thiophene.
The present invention is further described by the following embodiment, and these descriptions are not that content of the present invention is further limited.One skilled in the art will understand that the replacement that is equal to that technical characterictic of the present invention is done, or improve accordingly, within still belonging to protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) 3-thiophen(e)alcohol is synthetic
50g 3-thiophenecarboxaldehyde is joined in 800ml methyl alcohol, slowly add 27g sodium borohydride, stirring at room 5 hours, concentrate and remove most of methyl alcohol, drip saturated aqueous ammonium chloride, then add ethyl acetate, separatory, dry, concentrated, the separation of residuum upper prop obtains 39g 3-thiophen(e)alcohol.
(2) 3-bromomethyl thiophene is synthetic
35g 3-thiophen(e)alcohol is joined in 200ml water, add in 200ml Hydrogen bromide, reheating refluxes spends the night, and is cooled to room temperature, concentrated, then add water and methylene dichloride, extraction separatory, collect organic phase, separatory, dry, concentrated, the separated 36g 3-bromomethyl thiophene that obtains of silicagel column on residuum.
(3) 3-aminomethyl thiophene is synthetic
30g 3-bromomethyl thiophene is joined in 150ml DMF, then add 200ml ammoniacal liquor, tube sealing to be heated to 150 ℃ of stirrings 18 hours, add ethyl acetate, filter, extraction separatory, obtains 19g 3-aminomethyl thiophene.
(4) N-tertbutyloxycarbonyl-3-methylamine thiophene is synthetic
15g 3-aminomethyl thiophene is joined in 400ml methylene dichloride, add 31g tert-Butyl dicarbonate in batches, stirring at room 24 hours, concentrated, the separated 18g N-tertbutyloxycarbonyl-3-methylamine thiophene that obtains of silicagel column on residuum.
Claims (6)
1. prepare a method for N-tertbutyloxycarbonyl-3-methylamine thiophene, take 3-thiophenecarboxaldehyde as starting raw material, through reduction, bromo, amination, tertbutyloxycarbonyl protection, obtain target product 5, synthetic route is as follows.
2. according to the method for claim 1,4 steps described in it is characterized by are reacted and are,
(1) 3-thiophenecarboxaldehyde is starting raw material, through reduction reaction, obtains 2;
(2) 2, carry out bromo-reaction, obtain 3;
(3) 3, carry out amination reaction and obtain 4;
(3) 4, carry out tertbutyloxycarbonyl protective reaction and obtain target product 5,
3. according to the method for claim 1-2, it is characterized in that, described reduction reaction is prepared compound 2 reagent used and is selected from one or more the mixture in sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, sodium cyanoborohydride, lithium aluminium hydride, borine; Described bromo-reaction is prepared compound 3 reagent used and is selected from one or more the mixture in bromine, Hydrogen bromide, phosphorus tribromide, tribromo oxygen phosphorus; Described amination reaction is prepared compound 4 reagent used and is selected from ammoniacal liquor; Described tertbutyloxycarbonyl protective reaction is prepared compound 5 reagent used and is selected from tert-Butyl dicarbonate.
4. according to the method for claim 1-2, it is characterized in that, described reduction reaction is prepared compound 2 solvent used and is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide; Described bromo-reaction is prepared compound 3 solvent used and is selected from methylene dichloride, trichloromethane, ethyl acetate, tetrahydrofuran (THF), toluene, tetrahydrofuran (THF), toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, water; Described aminating reaction is prepared compound 4 solvent used and is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, water; Described tertbutyloxycarbonyl protective reaction is prepared compound 5 solvent used and is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, trichloromethane, ethyl acetate, toluene, o-Xylol, p-Xylol, m-xylene, N; the mixture of one or more in dinethylformamide, N,N-dimethylacetamide.
5. according to the method for claim 1-2, it is characterized in that, it is the reflux temperature of 0 ℃～solvent that described reduction reaction is prepared compound 2 temperature of reaction used; It is the reflux temperature of 0 ℃～solvent that described bromo-reaction is prepared compound 3 temperature used; It is room temperature～200 ℃ that described aminating reaction is prepared compound 4 temperature used; Described tertbutyloxycarbonyl protective reaction prepare compound 5 used be 0 ℃～room temperature.
6. according to the method for claim 1-2, it is characterized in that, it is room temperature that described acylation reaction is prepared compound 2 temperature of reaction used; It is the reflux temperature of solvent that described bromo-reaction is prepared compound 3 temperature used; It is 150 ℃ that described aminating reaction is prepared compound 4 temperature used; Described tertbutyloxycarbonyl protective reaction prepare compound 5 used be room temperature.
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| CN201410425783.8A CN104193722A (en) | 2014-08-27 | 2014-08-27 | Preparation method of N-tert-butyloxycarbonyl-3-methylaminothiophene |
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| CN201410425783.8A CN104193722A (en) | 2014-08-27 | 2014-08-27 | Preparation method of N-tert-butyloxycarbonyl-3-methylaminothiophene |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1526131A1 (en) * | 2003-10-22 | 2005-04-27 | Graffinity Pharmaceuticals Aktiengesellschaft | Aminoalkyl-pyrazinones and -pyridones as thrombin inhibitors |
| CN101939313A (en) * | 2008-02-08 | 2011-01-05 | 善利亚新药工业股份有限公司 | 3,8-diamino tetrahydroquinoline derivative |
| CN102762575A (en) * | 2009-12-04 | 2012-10-31 | 桑诺维恩药品公司 | Multicyclic compounds and methods of use thereof |
| CN103189369A (en) * | 2010-09-01 | 2013-07-03 | 吉利德康涅狄格有限公司 | Pyridinones/pyrazinones, method of making, and method of use thereof |
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2014
- 2014-08-27 CN CN201410425783.8A patent/CN104193722A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1526131A1 (en) * | 2003-10-22 | 2005-04-27 | Graffinity Pharmaceuticals Aktiengesellschaft | Aminoalkyl-pyrazinones and -pyridones as thrombin inhibitors |
| CN101939313A (en) * | 2008-02-08 | 2011-01-05 | 善利亚新药工业股份有限公司 | 3,8-diamino tetrahydroquinoline derivative |
| CN102762575A (en) * | 2009-12-04 | 2012-10-31 | 桑诺维恩药品公司 | Multicyclic compounds and methods of use thereof |
| CN103189369A (en) * | 2010-09-01 | 2013-07-03 | 吉利德康涅狄格有限公司 | Pyridinones/pyrazinones, method of making, and method of use thereof |
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Application publication date: 20141210 |