CN104086460A - Synthesis method of tert-butyl 2-(methylamino)ethylcarbamate - Google Patents
Synthesis method of tert-butyl 2-(methylamino)ethylcarbamate Download PDFInfo
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- CN104086460A CN104086460A CN201410301872.1A CN201410301872A CN104086460A CN 104086460 A CN104086460 A CN 104086460A CN 201410301872 A CN201410301872 A CN 201410301872A CN 104086460 A CN104086460 A CN 104086460A
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- methylamino
- butyl ester
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Abstract
The invention provides a synthesis method of tert-butyl 2-(methylamino)ethylcarbamate, which is characterized by comprising the following steps: (a) carrying out reduction reaction on N-tert-butyloxycarbonyl-1,2-ethylenediamine and polyformaldehyde in an organic solvent in the presence of acid at reflux temperature to obtain 2-(N-isobutoxyformamido)ethylisocyanide; and (b) carrying out reduction reaction on the 2-(N-isobutoxyformamido)ethylisocyanide and sodium borohydride in an aprotic solvent at 20-30 DEG C to obtain the tert-butyl 2-(methylamino)ethylcarbamate. The method has the advantages of higher two-step reaction yield, lower cost and less generated waste liquor, and is convenient for industrial production. The structural formula is disclosed in the specification.
Description
Technical field
the present invention relates to medicine intermediate, relate more specifically to a kind of 2-(methylamino) synthetic method of the ethyl carbamic acid tert-butyl ester.
Background technology
methyl ethylenediamine is important fine chemistry industry and medicine intermediate, can be used for preparing rifamycin antibiotic flat (rifampicin), anti-equal medicine Pefloxacin (pefloxacin), difloxacin (difloxacin) etc., owing to easily there is oxidation and substitution reaction causes generating the mixture of primary amino and secondary amino group in exposed amino, in order to make molecule can carry out monoamine glycosylation reaction, need to carry out selective protection to amino, 2-(methylamino) the ethyl carbamic acid tert-butyl ester is exactly the product of Boc protecting group selective protection primary amine groups, use 2-(methylamino) the ethyl carbamic acid tert-butyl ester replaces N-methyl ethylenediamine and reacts, can effectively improve the directive property of anti-methyl N alkyl-alkyl, avoid the exposed N atom of N-methyl ethylenediamine to participate in N alkylation and introduce monoalkyl and dialkyl group by product, and then raising reaction yield and product purity.
at present, 2-(methylamino) synthetic route of the ethyl carbamic acid tert-butyl ester mainly contains following several:
(1) thanomin is that raw material reacts with tert-Butyl dicarbonate and obtains N-BOC-thanomin, and N-BOC-thanomin reacts the product obtaining and reacts with methylamine and obtain 2-(methylamino) the ethyl carbamic acid tert-butyl ester (Patent:Purkayastha Subhasish with Methanesulfonyl chloride; Dey, Subhakar, Sewell Street, North Billerica, WO2008/105896 A2).But second step reaction preference is poor in the method, a large amount of dialkyl group by products is produced in reaction simultaneously, by recrystallization, is purified and is difficult to obtain sterling, and concrete route is as follows:
(2) take N-methyl ethylenediamine as raw material and 2-(tert-Butoxycarbonyloxyimino)-2-benzyl cyanide reaction obtains 2-(methylamino) the ethyl carbamic acid tert-butyl ester (Federico Corellia, Maurizio Bottaa, Andrea Lossanib, Serena Pasquinia, Silvio Spadarib, Federico Focherb, F. Corelli et al./IL FARMACO 59 (2004) 987 – 992), two cost of material in the method are all higher, especially N-methyl ethylenediamine price is higher, Financial cost is higher, be not suitable for amplifying and produce, concrete route is as follows:
(3) with 2-bromine ethylamine hydrobromide, tert-Butyl dicarbonate is that raw material reaction obtains N-Boc-bromine ethamine, and N-Boc-bromine ethamine reacts with methylamine and obtains 2-(methylamino) the ethyl carbamic acid tert-butyl ester.（Meng?An?Hao，Li?Ping?Wang，Wu?Liang，Kai?Chen.?Preparation?of?mono-Boc-protected?unsymmetrical?diamines?[J].?Organic?Preparations?and?Procedures?International，2009，41(4)，301-307）。The shortcoming of the method and method (1) are similar, and second step reaction preference is poor, and a large amount of dialkyl group by products are produced in reaction simultaneously, and by recrystallization, being difficult to purify obtains sterling, and concrete route is as follows:
(4) take N-Boc-quadrol as raw material by with phenyl aldehyde, iodomethane reaction, Pd (OH)
2
/ C debenzylation obtains 2-(methylamino) the ethyl carbamic acid tert-butyl ester (Patent; Jenkins, Thomas E.; Husfeld, Craig O.; Seroogy, Julie D.; Wray, Jonathan W; US2011/26235 5).The method route is longer, and overall yield is lower, and noble metal catalyst cost is higher, is unfavorable for suitability for industrialized production, and concrete route is as follows:
。
Summary of the invention
in order to overcome the problems referred to above of the prior art, the invention provides a kind of 2-(methylamino) synthetic method of the ethyl carbamic acid tert-butyl ester, the method yield is high, cost is low, be applicable to suitability for industrialized production.
the technical solution used in the present invention is: a kind of 2-(methylamino) synthetic method of the ethyl carbamic acid tert-butyl ester, comprises the following steps:
(a) formula (1) compound N-tertbutyloxycarbonyl-1,2-quadrol and paraformaldehyde are in organic solvent, under the condition existing in acid, at reflux temperature, issue raw reduction reaction, obtain formula (II) compound 2-(N-isobutoxy formamido-) ethyl group isocyanide, this organic solvent is toluene or benzene;
(b) formula (II) the compound 2-(N-isobutoxy formamido-obtaining in step (a)) ethyl group isocyanide and sodium borohydride are in aprotic solvent, at 20 ℃ ~ 30 ℃, issue raw reduction reaction, obtain formula (III) compound 2-(methylamino) the ethyl carbamic acid tert-butyl ester;
the reaction formula of the method is as follows:
further, in step (a), acid is acetic acid or tosic acid.In this step, paraformaldehyde depolymerization under acidic conditions obtains formaldehyde, and formaldehyde participates in reaction.
preferably, the consumption of acetic acid or tosic acid is catalytic amount, be in particular paraformaldehyde quality 0.5% ~ 2%.More preferably, be 1% of the quality of paraformaldehyde.
further, in step (b), aprotic solvent is selected from one or both in tetrahydrofuran (THF), dimethyl formamide.
further, in step (a), the time of reduction amination is 4 ~ 6 hours.
further, in step (b), the time of reduction reaction is 3 ~ 5 hours.
compared with prior art, the present invention has the following advantages: at 2-(methylamino of the present invention) in the synthetic method of the ethyl carbamic acid tert-butyl ester, the raw material using is N-Boc-quadrol, paraformaldehyde, sodium borohydride, wherein paraformaldehyde replaces formaldehyde both can reduce the energy consumption of dehydration, can greatly reduce wastewater treatment capacity again, and take toluene or benzene as solvent can with water azeotropic layering, easily the water in reaction process is separated, and sodium borohydride reduction 2-(N-isobutoxy formamido-) ethyl group isocyanide, technique is simple, and yield is higher.The two-step reaction yield of the method for the present invention is relatively all higher, and cost is lower, and the waste liquid of generation is less, is convenient to suitability for industrialized production.
Embodiment
below in conjunction with specific embodiment, the present invention is described in further detail, so that those skilled in the art can understand the present invention better, thereby protection scope of the present invention is made to more explicit defining.
embodiment 1
preparation 2-(N-isobutoxy formamido-) ethyl group isocyanide, concrete steps are as follows:
in the there-necked flask (band water trap) of 1000ml, N-Boc-quadrol (160g, 1mol) and paraformaldehyde (31.5 g, 0.35mol) are dissolved in toluene (500ml), drip acetic acid (0.3 g), reflux 5 hours is branched away to no longer including water in water trap.Then, concentration of reaction solution, with except desolventizing, is dissolved in residue in ethyl acetate (500ml), and water (300ml) is washed successively, saturated aqueous sodium carbonate (300ml) is washed and saturated aqueous common salt (300ml) is washed, dry organic phase, concentrated product 108 g oily liquids, the yield 62% of obtaining.
embodiment 2
preparation 2-(N-isobutoxy formamido-) ethyl group isocyanide, concrete steps are as follows:
in the there-necked flask (band water trap) of 1000ml, N-Boc-quadrol (160g, 1mol) and paraformaldehyde (31.5 g, 0.35mol) are dissolved in benzene (500ml), drip tosic acid (0.45g), reflux 5.5 hours is branched away to no longer including water in water trap.Then, concentration of reaction solution, with except desolventizing, is dissolved in residue in ethyl acetate (500ml), and water (300ml) is washed successively, saturated aqueous sodium carbonate (300ml) is washed and saturated aqueous common salt (300ml) is washed, dry organic phase, concentrated product 113 g oily liquids, the yield 65% of obtaining.
embodiment 1,2 can repeat according to actual needs, obtains more 2-(N-isobutoxy formamido-s) ethyl group isocyanide, is used for subsequent embodiment.
embodiment 3
preparation 2-(methylamino) the ethyl carbamic acid tert-butyl ester, concrete steps are as follows:
in the there-necked flask of 1000ml, 2-(N-isobutoxy formamido-) ethyl group isocyanide (172 g, 1mol) be dissolved in tetrahydrofuran (THF) (600ml), in room temperature (at about 20 ℃ ~ 30 ℃), add sodium borohydride (74 g in batches, 2mol), reinforced complete, at room temperature stir 4 hours, add the unreacted sodium borohydride of acetic acid cancellation, the concentrated tetrahydrofuran (THF) of removing, add water (500ml), ethyl acetate (500ml * 2) extraction, merge organic phase and wash (500ml) with saturated common salt, organic phase is dry, concentrated, obtain oily crude product, with oil pump underpressure distillation crude product, obtain colorless oil 148 g, yield 85%.
embodiment 4
preparation 2-(methylamino) the ethyl carbamic acid tert-butyl ester, concrete steps are as follows:
in the there-necked flask of 1000ml, 2-(N-isobutoxy formamido-) ethyl group isocyanide (172 g, 1mol) be dissolved in dimethyl formamide (DMF, 600ml), in room temperature (at about 20 ℃ ~ 30 ℃), add sodium borohydride (74 g in batches, 2mol), reinforced complete, at room temperature stir 5 hours, add the unreacted sodium borohydride of acetic acid cancellation, the concentrated THF that removes, add water (500ml), ethyl acetate (500ml * 2) extraction, merge organic phase and wash (500ml) with saturated common salt, organic phase is dry, concentrated, obtain oily crude product, with oil pump underpressure distillation crude product, obtain colorless oil 146 g, yield 84%.
in sum, the method for synthetic 2-(methylamino) the ethyl carbamic acid tert-butyl ester of the present invention has advantages of that synthetic route is brief, easy and simple to handle, productive rate is high, the low suitability for industrialized production that is easy to of cost.
above specific embodiment of the present invention is illustrated; but protection content of the present invention is not only limited to above embodiment; under of the present invention, in technical field, the common knowledge of a GPRS just can be carried out diversified change within the scope of its technology main idea.
Claims (7)
1. 2-(methylamino) synthetic method for the ethyl carbamic acid tert-butyl ester, is characterized in that, comprises the following steps:
(a) formula (1) compound N-tertbutyloxycarbonyl-1,2-quadrol and paraformaldehyde are in organic solvent, under the condition existing in acid, at reflux temperature, issue raw reduction reaction, obtain formula (II) compound 2-(N-isobutoxy formamido-) ethyl group isocyanide, described organic solvent is toluene or benzene;
(b) formula (II) the compound 2-(N-isobutoxy formamido-obtaining in step (a)) ethyl group isocyanide and sodium borohydride are in aprotic solvent, at 20 ℃ ~ 30 ℃, issue raw reduction reaction, obtain formula (III) compound 2-(methylamino) the ethyl carbamic acid tert-butyl ester;
The reaction formula route of the method is as follows:
。
2. 2-(methylamino according to claim 1) synthetic method of the ethyl carbamic acid tert-butyl ester, is characterized in that: in step (a), described acid is acetic acid or tosic acid.
3. 2-(methylamino according to claim 2) synthetic method of the ethyl carbamic acid tert-butyl ester, is characterized in that: 0.5% ~ 2% of the quality that the consumption of described acetic acid or tosic acid is paraformaldehyde.
4. 2-(methylamino according to claim 3) synthetic method of the ethyl carbamic acid tert-butyl ester, is characterized in that: 1% of the quality that the consumption of described acetic acid or tosic acid is paraformaldehyde.
5. 2-(methylamino according to claim 1) synthetic method of the ethyl carbamic acid tert-butyl ester, is characterized in that: in step (b), described aprotic solvent is selected from one or both in tetrahydrofuran (THF), dimethyl formamide.
6. 2-(methylamino according to claim 1) synthetic method of the ethyl carbamic acid tert-butyl ester, is characterized in that: in step (a), the time of described reduction reaction is 4 ~ 6 hours.
7. 2-(methylamino according to claim 1) synthetic method of the ethyl carbamic acid tert-butyl ester, is characterized in that: in step (b), the time of described reduction reaction is 3 ~ 5 hours.
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Citations (1)
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| CN102731316A (en) * | 2012-05-21 | 2012-10-17 | 南通市华峰化工有限责任公司 | Production method for 1,2-N,N'dimethylcyclohexanediamine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102731316A (en) * | 2012-05-21 | 2012-10-17 | 南通市华峰化工有限责任公司 | Production method for 1,2-N,N'dimethylcyclohexanediamine |
Non-Patent Citations (2)
| Title |
|---|
| RENATO A. DA SILVA,ET AL: "Reductive methylation of primary and secondary amines and amino acids by aqueous formaldehyde and zinc", 《TETRAHEDRON LETTERS》, vol. 48, 31 August 2007 (2007-08-31), pages 1 - 1 * |
| SUKANTA BHATTACHARYYA,ET AL: "Use of Zinc Borohydride in Reductive Amination: An Efficient and Mild Method for N-Methylation of Amines", 《J.CHEM.SOC.PERKIN TRANS.1》, 1 January 1994 (1994-01-01), pages 1 - 1 * |
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