CN85104078A - The preparation of 1-substituted azetidine-3-alcohol derivate - Google Patents
The preparation of 1-substituted azetidine-3-alcohol derivate Download PDFInfo
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- CN85104078A CN85104078A CN85104078.0A CN85104078A CN85104078A CN 85104078 A CN85104078 A CN 85104078A CN 85104078 A CN85104078 A CN 85104078A CN 85104078 A CN85104078 A CN 85104078A
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Abstract
The method of preparation formula II-substituted azetidine-3-alcohol derivate,
R wherein
1Represent an aromatic base, R
2Expression hydrogen atom or alkyl, aryl or aralkyl and its moieties contains 8 carbon atoms of as many as, its method is with the amino alcohol shown in the formula II, wherein Hal
The expression halogen atom, R
1And R
2Define as above, cyclization in triethylamine solution, the purposes of this analog derivative is the intermediate as preparation azetidine-3-carboxylic acid derivative.
Description
The present invention relates to a kind of intermediate of bioactive compounds, the preparation process of 1-substituted azetidine-3-alcohol derivate.
For example, from organic chemistry magazine 37,3953(1972) known 1-dibenzo-p-methyl-aza-cyclobutane-3-alcohol can be reacted in methyl alcohol by benzhydryl amine and epichlorohydrin and prepare.Yet concerning a practical economically synthetic route, it is very inconvenient introducing diphenyl-methyl, because the size of this group has greatly increased the volume of the material that will react and had only when its defencive function no longer needs and just can remove.Be sought after with a kind of volume protecting group little from saying economically than diphenyl-methyl, but before delivered some attempt epichlorohydrin and a primary amine such as benzylamine are reacted the azetidine product of the needed cyclization that all can not obtain certain productive rate.
The applicant finds, uses a kind of aqueous reaction medium, might as benzylamine, obtain the 1-substituted azetidine, and productive rate be also good from epoxy halogenide and the less amine of volume.This process has constituted the theme of No. 8312104, United Kingdom pending application application.The test narrated in that part application for patent explanation, when during as reaction medium, can not forming azetidine as acetonitrile, methyl alcohol, butanols and ethylene glycol with organic solvent, but when using water-containing reacting medium, cyclization becomes azetidine just can realize.The applicant is surprised to find that now, though realize that with organic solvent cyclization is to have failed in the work in the past, but as when replacing water-containing reacting medium as solvent, can not only generate the azetidine ， And of cyclization and the productive rate of product and also can considerably promote with triethylamine.In addition, it seems that triethylamine has beyond thought peculiar property making to promote on the productive rate; Can not generate any azetidine product with other alkyl amine.And triethylamine promoting that on the ring-closure reaction clearly be unique, also is very easily on commerce not only, because its boiling point (89 ℃) is very convenient to back flow reaction.Further, triethylamine can be removed the hydrogen halide that produces effectively when ring-closure reaction, become amine halogenation hydrogen salt precipitation, and this precipitation can also be taken the unnecessary by product that generates sometimes, the i.e. polymkeric substance of any non-cyclization out of in ring-closure reaction.
By this, the invention provides preparation method suc as formula the 1-substituted azetidine-3-alcohol derivate of I:
R wherein
1Represent an arylmethyl, R
2Represent a hydrogen atom or an alkyl, aryl or aralkyl wherein moieties contains 8 carbon atoms of as many as, and method is the amino alcohol with the formula II, wherein
Hal represents a halogen atom, cyclization in triethylamine solution.
R preferably
1Group is represented a single arylmethyl, and suitable is benzyl; R
2Represent a hydrogen atom; Hal represents a chlorine atom.
The cyclization of amino alcohol II becomes the azetidine I to suit to carry out at elevated temperatures, and for example from 50 ° to 150 ℃, preferably the boiling point at reaction mixture refluxes.Find that also ring-closure reaction can be accelerated effectively when containing phase-transfer catalyst and particularly contain the phase-transfer catalyst of iodide ion.Suitable phase-transfer catalyst comprises tetraalkylammonium halide, and iodide particularly are just as the TBuA iodide.Catalyzer De Liang And is nonessential; Lower bound is common 0.1 mol %(0.1mole%) can increase speed of reaction effectively; High limit normally determined by the solution degree in the triethylamine reaction medium, is generally about percent 1.6 mol.
The initial amino alcohol of formula II can be easily by the preparation of being narrated in the pending application 8312104, that is, and and will be suc as formula the epoxy halogenide of IV, with the primary amine reaction suc as formula IV, wherein R
1,
R
1-NH
2Ⅳ
Hal and R
2Definition as above.Reaction can be that reactant is mixed in organic solvent, for example the hydrocarbons solvent as hexanaphthene in, carry out.Suitable temperature of reaction is from 10 ℃ to 50 ℃, and the suitable reaction times is from 12 to 36 hours.The amino alcohol of formula II can be received from reaction mixture with usual method; And and as need, can be refining earlier before cyclization, for example use the method for recrystallization.
As mentioned above, the derivative of 1-substituted azetidine-3-alcohol (formula I) is a useful as intermediates.Like this, they can use known program, for example, through corresponding 3-cyanogen azetidine derivatives, are transformed into azetidine-3-carboxylic acid derivative; It shows the character of plant-growth regulator, particularly makes the unseeded character of male plant part.
Thus, the present invention includes with 1-substituted azetidine-3-alcohol derivate, as the intermediate of preparation azetidine-3-carboxylic acid derivative by method preparation of the present invention.
The present invention illustrates with the following example.
The preparation of embodiment 1 1-benzyl aza-cyclobutane-3-alcohol
N-benzyl-3-amino-1-chlorine propan-2-ol (333 gram) is dissolved in the triethylamine (1665 milliliters), adds TBuA iodide (10 gram).Reaction mixture stirring and refluxing 13 hours, postcooling removes by filter the precipitation of hydrogen chloride salt, and precipitation is washed twice with triethylamine.Merging filtrate evaporates to such an extent that 252 grams are oily, and it gets 180.8 gram white crystals from toluene (250 milliliters) and hexane (150 milliliters) recrystallization, and fusing point 66-67 ℃, productive rate is that 66.5%(is by aminopropanol).
Embodiment 2 uses 1-benzyl aza-cyclobutane-3-alcohol and prepares azetidinyl-3-carboxylic acid
(a) 1-benzyl aza-cyclobutane-3-alcohol (5.0 gram), methylsulfonyl chloride (3.52 gram) and triethylamine (6 milliliters) stirred 18 hours in methylene dichloride (40 milliliters).Mixture filters, and solution decompression is removed.Residue is refining with silica gel chromatography, makes eluent with the solution of Virahol in methylene dichloride, gets methylsulfonyl thing 4.25 grams of 1-benzyl aza-cyclobutane-3-alcohol.
(b) the methylsulfonyl thing of 1-benzyl aza-cyclobutane-3-alcohol (1.7 grams are by the preparation of (a) method), sodium cyanide (1.2 gram) in water (1 milliliter) and dimethyl formamide (20 milliliters), at 60 ℃, stirred 16 hours together.Solution decompression is removed, and residue is refining with silica gel chromatography to be eluent with the solution of Virahol in methylene dichloride, gets 1-benzyl-3-cyano group azetidine, 0.5 gram.
(c) 1-benzyl-3-cyano group azetidine (0.5 gram is by method preparation in (b)) is in saturated barium hydroxide solution (10 milliliters), reflux 30 hours.After the reaction mixture cooling, saturated with carbon dioxide, filter.Decompression is removed solution to such an extent that 1-benzyl azetidine-3-carboxylic acid productive rate is 80% from filtrate down.
(d) 1-benzyl azetidine-3-carboxylic acid (0.5 gram is by (c) method preparation) is in methyl alcohol (15 milliliters), in the presence of 5% palladium-carbon catalyst, and room temperature hydrogenation.Elimination catalyzer, solution from filtrate, reduce pressure remove azetidine-3-carboxylic acid, productive rate is 90%.
Embodiment 3
Undertaken by embodiment 1 similar program, but remove the TBuA iodide, but replace above-mentioned phase transfer reagent with bromide and sodium iodide.Can both obtain product in all cases, productive rate also similar (about 65%) is though need the long reaction times.
Comparison test
Repeat the program of embodiment 1, just the triethylamine in (b) step replaces with Tributylamine, tripropyl amine, diisopropylethylamine, tetramethyleneimine, pyridine or 2.6-lutidine.Do not have an example reaction can produce any a certain amount of azetidine, this has confirmed the unexpected peculiar property of triethylamine in promoting the azetidine productive rate very clearly.
Claims (10)
1, the preparation method of azepine fourth lopps compound is characterized in that this compound is the 1-substituted azetidine-3-alcohol derivate shown in formula I
R wherein
1Represent an arylmethyl, R
2Expression hydrogen atom or alkyl, aryl or aralkyl and its moieties contains 8 carbon atoms of as many as, its preparation method is with the amino alcohol suc as formula II, wherein
Hal represents halogen atom, R
1And R
2Definition as above, cyclization in triethylamine solution.
2, method according to claim 1 is characterized in that wherein R
1The expression benzyl; R
2Expression hydrogen atom and Hal represent the chlorine atom.
3, method according to claim 1 is characterized in that wherein cyclization carries out in the presence of phase-transfer catalyst.
4, method according to claim 2 is characterized in that cyclization carries out in the presence of phase-transfer catalyst.
5, method according to claim 3 is characterized in that used phase-transfer catalyst is a tetraalkylammonium halide.
6, method according to claim 4 is characterized in that used phase-transfer catalyst is a tetraalkylammonium halide.
7, according to any described method in the aforesaid right requirement, it is characterized in that cyclization is in Heating temperature realization from 50 ° to 150 ℃.
8, method according to claim 7 is characterized in that cyclization carries out under refluxing.
9, the substituted azetidine of the 1-shown in the formula I-3-alcohol derivate is characterized in that what this compound was prepared by any described method in the claim 1 to 8.
10, by the purposes of the formula I 1-substituted azetidine-3-alcohol derivate of any described method preparation of claim 1-8, it is characterized in that this compound is the intermediate as preparation azetidine-3-carboxylic acid derivative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 85104078 CN1013110B (en) | 1984-05-18 | 1985-05-28 | The preparation of 1-benzyl aza-cyclobutane-3-alcohol |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB848412814A GB8412814D0 (en) | 1984-05-18 | 1984-05-18 | 1-substituted azetidine-3-ol derivatives |
| CN 85104078 CN1013110B (en) | 1984-05-18 | 1985-05-28 | The preparation of 1-benzyl aza-cyclobutane-3-alcohol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN85104078A true CN85104078A (en) | 1986-11-26 |
| CN1013110B CN1013110B (en) | 1991-07-10 |
Family
ID=25741698
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 85104078 Expired CN1013110B (en) | 1984-05-18 | 1985-05-28 | The preparation of 1-benzyl aza-cyclobutane-3-alcohol |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1013110B (en) |
-
1985
- 1985-05-28 CN CN 85104078 patent/CN1013110B/en not_active Expired
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| Publication number | Publication date |
|---|---|
| CN1013110B (en) | 1991-07-10 |
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