CN104086460B - Synthesis method of tert-butyl 2-(methylamino)ethylcarbamate - Google Patents
Synthesis method of tert-butyl 2-(methylamino)ethylcarbamate Download PDFInfo
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- CN104086460B CN104086460B CN201410301872.1A CN201410301872A CN104086460B CN 104086460 B CN104086460 B CN 104086460B CN 201410301872 A CN201410301872 A CN 201410301872A CN 104086460 B CN104086460 B CN 104086460B
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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 ethylcarbamate.
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., easily occur to be oxidized due to exposed amino and substitution reaction causes generation primary amino and the mixture of secondary amino group, monoamine glycosylation reaction is carried out in order to enable molecule, need to carry out selective protection to amino, 2-(methylamino) ethylcarbamate is exactly the product of Boc protecting group selective protection primary amine groups, use 2-(methylamino) ethylcarbamate replaces N-methyl ethylenediamine and reacts, effectively can improve the directive property of anti-methyl N alkyl-alkyl, avoid the exposed atom N of N-methyl ethylenediamine to participate in N alkylation and introduce monoalkyl and dialkyl group by product, and then improve reaction yield and product purity.
at present, 2-(methylamino) synthetic route of ethylcarbamate mainly contains following several:
(1) thanomin is that raw material and tert-Butyl dicarbonate are obtained by reacting N-BOC-thanomin, and the product that N-BOC-thanomin and Methanesulfonyl chloride are obtained by reacting and methylamine are obtained by reacting 2-(methylamino) ethylcarbamate (Patent:Purkayastha Subhasish; Dey, Subhakar, Sewell Street, North Billerica, WO2008/105896 A2).But second step reaction preference is poor in the method, a large amount of di by products is produced in reaction simultaneously, and being purified by recrystallization is difficult to obtain sterling, and concrete route is as follows:
(2) with N-methyl ethylenediamine for raw material and 2-(tert-Butoxycarbonyloxyimino)-2-benzyl cyanide is obtained by reacting 2-(methylamino) ethylcarbamate (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 and methylamine are obtained by reacting 2-(methylamino) ethylcarbamate.（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) similar, second step reaction preference is poor, reaction produce a large amount of di by product simultaneously, be difficult to purification by recrystallization and obtain sterling, concrete route is as follows:
(4) with N-Boc-quadrol for raw material by with phenyl aldehyde, iodomethane reaction, Pd (OH)
2
/ C debenzylation obtains 2-(methylamino) ethylcarbamate (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 ethylcarbamate, 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 ethylcarbamate, comprise the following steps:
(a) formula (1) compound N-tertbutyloxycarbonyl-1,2-quadrol and paraformaldehyde are in organic solvent, reduction reaction is there is at a reflux temperature under sour existent condition, obtain formula (II) compound 2-(N-isobutoxy formamido-) ethyl group isocyanide, this organic solvent is toluene or benzene;
formula (II) the compound 2-(N-isobutoxy formamido-obtained in (b) step (a)) ethyl group isocyanide and sodium borohydride be in aprotic solvent, issue raw reduction reaction at 20 DEG C ~ 30 DEG C, obtain formula (III) compound 2-(methylamino) ethylcarbamate;
the reaction formula of the method is as follows:
。
further, in step (a)., acid is acetic acid or tosic acid.In this step, paraformaldehyde in acid condition depolymerization obtains formaldehyde, and formaldehyde participates in reaction.
preferably, the consumption of acetic acid or tosic acid is catalytic amount, is in particular 0.5% ~ 2% of the quality of paraformaldehyde.More preferably, for paraformaldehyde quality 1%.
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 ethylcarbamate, the raw material used is N-Boc-quadrol, paraformaldehyde, sodium borohydride, wherein paraformaldehyde replaces formaldehyde both can reduce the energy consumption of dehydration, wastewater treatment capacity can be greatly reduced again, and with toluene or benzene for solvent can with water azeotropic and 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, thus more explicit defining is made to protection scope of the present invention.
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), (0.3 g), and the little water that no longer includes in water trap of reflux 5 is branched away to drip acetic acid.Then, residue, with except desolventizing, is dissolved in ethyl acetate (500ml) by concentration of reaction solution, uses that water (300ml) is washed, saturated aqueous sodium carbonate (300ml) is washed and washed with saturated aqueous common salt (300ml) successively, dry organic phase, concentratedly obtain product 108 g oily liquids, yield 62%.
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), the little water that no longer includes in water trap of reflux 5.5 is branched away.Then, residue, with except desolventizing, is dissolved in ethyl acetate (500ml) by concentration of reaction solution, uses that water (300ml) is washed, saturated aqueous sodium carbonate (300ml) is washed and washed with saturated aqueous common salt (300ml) successively, dry organic phase, concentratedly obtain product 113 g oily liquids, yield 65%.
embodiment 1,2 can repeat according to actual needs, obtains more 2-(N-isobutoxy formamido-s) ethyl group isocyanide, use for subsequent embodiment.
embodiment 3
preparation 2-(methylamino) ethylcarbamate, 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), add sodium borohydride (74 g in room temperature (at about 20 DEG C ~ 30 DEG C) in batches, 2mol), reinforced complete, at room temperature stir 4 hours, add the unreacted sodium borohydride of acetic acid cancellation, concentrated removal tetrahydrofuran (THF), add water (500ml), ethyl acetate (500ml × 2) extracts, merge organic phase and wash (500ml) with saturated common salt, organic phase is dry, concentrated, obtain crude oil, colorless oil 148 g is obtained with oil pump underpressure distillation crude product, yield 85%.
embodiment 4
preparation 2-(methylamino) ethylcarbamate, 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), add sodium borohydride (74 g in room temperature (at about 20 DEG C ~ 30 DEG C) in batches, 2mol), reinforced complete, at room temperature stir 5 hours, add the unreacted sodium borohydride of acetic acid cancellation, concentrated removal THF, add water (500ml), ethyl acetate (500ml × 2) extracts, merge organic phase and wash (500ml) with saturated common salt, organic phase is dry, concentrated, obtain crude oil, colorless oil 146 g is obtained with oil pump underpressure distillation crude product, yield 84%.
in sum, the method that the present invention synthesizes 2-(methylamino) ethylcarbamate has that synthetic route is brief, easy and simple to handle, productive rate is high, the low advantage being easy to suitability for industrialized production 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; in art of the present invention, the usual knowledge of a GPRS, just can carry out diversified change within the scope of its technology main idea.
Claims (6)
1. 2-(methylamino) synthetic method of ethylcarbamate, it is characterized in that, comprise the following steps:
(a) formula (1) compound N-tertbutyloxycarbonyl-1,2-quadrol and paraformaldehyde are in organic solvent, reduction reaction is there is at a reflux temperature under sour existent condition, obtain formula (II) compound 2-(N-isobutoxy formamido-) ethyl group isocyanide, described organic solvent is toluene or benzene, and described acid is acetic acid or tosic acid;
Formula (II) the compound 2-(N-isobutoxy formamido-obtained in (b) step (a)) ethyl group isocyanide and sodium borohydride be in aprotic solvent, issue raw reduction reaction at 20 DEG C ~ 30 DEG C, obtain formula (III) compound 2-(methylamino) ethylcarbamate;
The reaction process route of the method is as follows:
。
2. 2-(methylamino according to claim 1) synthetic method of ethylcarbamate, it is characterized in that: the consumption of described acetic acid or tosic acid is 0.5% ~ 2% of the quality of paraformaldehyde.
3. 2-(methylamino according to claim 2) synthetic method of ethylcarbamate, it is characterized in that: the consumption of described acetic acid or tosic acid is 1% of the quality of paraformaldehyde.
4. 2-(methylamino according to claim 1) synthetic method of ethylcarbamate, it is characterized in that: in step (b), described aprotic solvent be selected from tetrahydrofuran (THF), dimethyl formamide one or both.
5. 2-(methylamino according to claim 1) synthetic method of ethylcarbamate, it is characterized in that: in step (a)., the time of described reduction reaction is 4 ~ 6 hours.
6. 2-(methylamino according to claim 1) synthetic method of ethylcarbamate, it is characterized in that: in step (b), the time of described reduction reaction is 3 ~ 5 hours.
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