CN100582094C - Process for preparing 3,4,5-trihydroxy piperidine alkaloid - Google Patents
Process for preparing 3,4,5-trihydroxy piperidine alkaloid Download PDFInfo
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Abstract
The present invention relates to compound synthesis, and is especially process of preparing 3, 4, 5-trihydroxy piperidine alkaloid. The compound 3, 4, 5-trihydroxy piperidine alkaloid is prepared with optically pure 2, 3-dihydroxy-gamma-butyrolactone as the initial material and through a universal flexible and simple synthesis path.
Description
Technical field
The present invention relates to a kind of synthetic method of compound, especially relate to a kind of 3,4, the preparation method of 5-trihydroxy-pyridine alkaloid.
Background technology
3,4,5-trihydroxy-piperidines (1,2,3,4) is that a class is separated the polyhydroxylated alkaloid that obtains from plant, and the structural formula of compound is as follows:
The plant Eupatorium Fortunei TURZ that wherein produces compound 1,3 and 4 among the peoplely is being used for diuresis, is bringing down a fever, stimulates the menstrual flow and the treatment of anti-diabetic etc.Physiologically active experiment shows 3,4, and 5-trihydroxy-piperidines all has glucoside inhibiting activity, wherein with the strongest (IC of activity of compound 1
50=3.18 μ M).Therefore, 3,4,5-trihydroxy-piperidines has the potential use of some disease of treatment such as diabetes, cancer and acquired immune deficiency syndrome (AIDS).In addition, this class Polycarboxy-heterocyclic compound can also be as the intermediate of chemosynthesis and the drug effect unit of new drug development.Therefore, 3,4, the practicality of 5-trihydroxy-piperidines is synthetic to have the potential using value.
That is reported at present synthesizes 3,4, and the method for 5-trihydroxy-piperidines mainly is synthesizing from carbohydrate, represent synthetic route as from D-glucose and D-ribose synthetic compound 1 (N.T.Patil et al, Bioorg.Med.Chem., 2002,10,2155.; D.K.Kim et al, J.Chem.Soc., Perkin Trans.1., 1996,803.), by D-seminose and D-pectinose set out synthetic compound 2 (Y.Suhara et al., Heterocycles, 2004,62,423.; G.Legler et al, Carbohydr.Res., 1995,272,17.) etc.These methods respectively have weak point, as route is long, raw material is difficult to obtain and reaction conditions than harshness etc.
Summary of the invention
Purpose of the present invention is intended at existing synthetic 3,4, the deficiency that exists in the method for 5-trihydroxy-piperidines, optical purity 2 conveniently to be easy to get is provided, 3-dihydroxyl-gamma-butyrolactone (5A or 5B) is a starting raw material, and synthetic route is general, flexible, simple and direct, and can reach 100% stereochemistry optionally 3 for having optically active compound 2 and compound 4,4, the preparation method of 5-trihydroxy-pyridine alkaloid.
Reaction equation of the present invention is as follows, and wherein P is hydroxy-protective group, especially acetonylidene commonly used, and benzyl or tertiary butyl dimethyl are silica-based; R is the alkyl of C1～C4, perfluoroalkyl or the aryl of C1～C4.
Its concrete reactions steps is as follows:
1) preparation (R, R)-and (S, R)-2,3-dihydroxyl-lactol (6A and 6B)
According to literature method (N.Cohen et al, J.Am.Chem.Soc., 1983; 105; 3661.), with hydroxyl protection (R, R)-or (S; R)-2; 3-dihydroxyl-gamma-butyrolactone (5A or 5B) with diisobutyl aluminium hydride (DIBAL-H) in-78 ℃ of reduction make (R, R)-or (S, R)-2; 3-dihydroxyl-lactol (6A) or (6B), productive rate is 80%～92%.
2) preparation (R, S)-and (S, S)-enol (7A and 7B)
Reference literature method (A.Gypser et al, Liebigs Ann.Chem., 1994,775.) general (R, R)-or (S, R)-2,3-dihydroxyl-lactol (6A or 6B) is used by Ph
3P
+CH
3Br
-With the Wittig reagent react that t-BuOK forms, obtain accordingly (R, S)-or (S, S)-enol (7A or 7B), productive rate is 75%～87%.
3) preparation (R, S)-and (S, S)-sulphonate (8A and 8B)
With (R; S)-or (S; S)-enol (7A or 7B) is dissolved in the methylene dichloride; make 0.1～0.5 mol; the solution of 0.2～0.3 mol preferably; after the ice-water bath cooling; stir to add down and be equivalent to (7A or 7B) 1.0～1.5 times of molar weights; the sulfonylation agent of 1.2～1.3 times of molar weights and be equivalent to (7A or 7B) 1.0～2.0 times of molar weights preferably, the triethylamine of 1.1～1.4 times of molar weights preferably, it is complete that mixture is stirred to feedstock conversion; obtain (R after the conventional aftertreatment; S)-or (S, S)-sulphonate (8A or 8B), productive rate is 85%～95%.Described sulfonylation agent is selected from a kind of in alkyl sulfonyl chloride, aryl sulfonyl chloride and the perfluorinated sulfonic acid acid anhydride of C1～C4, alkyl sulfonyl chloride, the aryl sulfonyl chloride of preferred C1～C2.
4) preparation epoxide (9A α, 9A β and 9B α, 9B β)
With (R; S)-sulphonate (8A) or (S; S)-sulphonate (8B) is dissolved in the methylene dichloride; make 0.1～0.3 mol; the solution of 0.2～0.25 mol preferably; add and be equivalent to 1.0～1.3 times of molar weights of compound (8A or 8B); the m-chloro-benzoic acid peroxide of 1.1～1.2 times of molar weights (mCPBA) preferably. it is complete that reaction mixture is stirred to raw material reaction at 0 ℃～20 ℃, conventional aftertreatment with obtain (R, R after silica gel column chromatography separates; S)-and (R; R, R)-epoxide (9A α and 9A β) or (S, R; S)-and (S; R, R)-epoxide (9B α and 9B β), according to the difference of blocking group; the productive rate of 9A α is 20%～60%, and the productive rate of 9A β is 70%～30%.
The productive rate of epoxide (9B α and 9B β) is the same.
5) preparation 3,4,5-trihydroxy-piperidine derivative (10A α, 10A β and 10B α, 10B β)
(9A α) is dissolved in the acetonitrile with epoxide, makes 0.1～0.4 mol, and preferably the solution of 0.2～0.3 mol adds 1.0～1.5 moles of multiples that molar weight is equivalent to (9A α), preferably the benzylamine of 1.1～1.3 moles of multiples.Reaction mixture is at 50～90 ℃, preferably reacts complete to raw material reaction under 70～85 ℃, pressure reducing and steaming solvent then, and thick product gets 3,4 through purification by silica gel column chromatography, 5-trihydroxy-piperidine derivative (10A α), productive rate is 60%～85%.
Epoxide (9A β, 9B α or 9B β) is reacted according to above-mentioned condition, obtain corresponding 3,4,5-trihydroxy-piperidine derivative (10A β, 10B α or 10B β), productive rate is suitable with 10A α.
6) preparation 3,4,5-trihydroxy-piperidines (1～4) hydrochloride
With 3,4,5-trihydroxy-piperidine derivative (10A α) is dissolved in the methyl alcohol, make 0.1～0.5 mol, preferably the solution of 0.2～0.3 mol adds and is equivalent to compound (10A α) 1.5～5.0 moles of multiples, preferably concentrated hydrochloric acids of 2.0～3.5 moles of multiples, with 0.5%～10% mole, 1.0%～4.5% mole 10%Pd/C catalyzer preferably, the air in the reaction mixture with hydrogen exchange after, complete in stirring at room to raw material reaction under nitrogen atmosphere, remove by filter catalyzer, behind the pressure reducing and steaming solvent, obtain 3,4, the hydrochloride of 5-trihydroxy-piperidines (2), productive rate is 85%～98%.
By 3,4, it is corresponding 3,4 that 5-trihydroxy-piperidine derivative (10A β, 10B α or 10B β) obtains according to aforesaid method, the hydrochloride of 5-trihydroxy-piperidines (1,3 or 4), and productive rate is suitable with (2).
Raw material of the present invention is easy to get, route is simple and direct flexibly, has better practicability.Wherein has optically active compound (2) and compound (4) can reach 100% stereochemistry selectivity for synthetic.Product 3,4,5-trihydroxy-piperidines are the useful chemosynthesis intermediates of a class, can be used for the exploitation of chemical new drug.
Embodiment
The invention will be further described below by embodiment.
Embodiment 1
1) preparation (R, R)-2,3-dihydroxyl-lactol (6A)
Reference literature method (N.Cohen et al, J.Am.Chem.Soc., 1983,105,3661.) with acetonylidene protection (R, R)-2,3-dihydroxyl-gamma-butyrolactone (5A, P=CMe
2) with diisobutyl aluminium hydride in-78 ℃ down reduction obtain corresponding (R, R)-2,3-dihydroxyl-lactol (6A, P=CMe
2), productive rate 90%.
2) preparation (R, S)-enol (7A)
Referring again to literature method (A.Gypser et al, Liebigs Ann.Chem., 1994,775.) uses (6A) by Ph
3 P+ CH
3Br
-With the formed Wittig reagent react of t-BuOK, obtain (R, S)-enol (7A, P=CMe
2), productive rate 80%.
3) preparation (R, S)-sulphonate (8A)
Will (R, S)-enol (7A, P=CMe
2) be dissolved in the methylene dichloride, make the solution of 0.2 mol, after the ice-water bath cooling, stir to add down and be equivalent to the methylsulfonyl chloride of (7A) 1.2 times of mole multiples and the triethylamine of 1.3 times of mole multiples, it is complete that mixture is stirred to feedstock conversion, obtain after the aftertreatment (R, S)-sulphonate (8A, P=CMe
2, R=CH
3), productive rate 91%.
4) preparation epoxide (9A α and 9A β)
Will (R, S)-sulphonate (8A, P=CMe
2, R=CH
3) be dissolved in the methylene dichloride, make the solution of 0.15 mol, add the m-chloro-benzoic acid peroxide that is equivalent to 1.2 times of molar weights of compound (8A), it is complete that reaction mixture is stirred to raw material reaction at 20 ℃, aftertreatment with obtain (R after silica gel column chromatography separates, R, S)-epoxide (9A α, P=CMe
2, R=CH
3) and (R, R, R)-epoxide (9A β, P=CMe
2, R=CH
3), overall yield 72%.
5) preparation 3,4,5-trihydroxy-piperidine derivative (10A α, P=CMe
2)
With epoxide (9A α, P=CMe
2) be dissolved in the acetonitrile, make the solution of 0.2 mol, the adding molar weight is equivalent to the benzylamine of 1.3 moles of multiples of (9A α), it is complete to feedstock conversion that reaction mixture reacts under 85 ℃, pressure reducing and steaming solvent then, thick product gets 3,4 through purification by silica gel column chromatography, 5-trihydroxy-piperidine derivative (10A α, P=CMe
2), productive rate 80%.
6) preparation 3,4,5-trihydroxy-piperidines (2) hydrochloride
With 3,4,5-trihydroxy-piperidine derivative (10A α, P=CMe
2) be dissolved in the methyl alcohol, make the solution of 0.2 mol, add and be equivalent to the concentrated hydrochloric acid of 2.5 moles of multiples of compound (10A α) and 3.5% mole 10%Pd/C catalyzer, air in the reaction mixture with hydrogen exchange after, complete in stirring at room under nitrogen atmosphere to raw material reaction, remove by filter catalyzer, behind the pressure reducing and steaming solvent, obtain 3,4, the hydrochloride of 5-trihydroxy-piperidines (2), productive rate 86%.
7) preparation 3,4, the hydrochloride of 5-trihydroxy-piperidines (1)
From step 5, with step 4 obtain (R, R, R)-epoxide (9A β, P=CMe
2, R=CH
3) substitute 9A α, with same reaction conditions, through 3,4,5-trihydroxy-piperidine derivative (10A β, P=CMe
2), obtain 3,4, the hydrochloride of 5-trihydroxy-piperidines (1), productive rate 89%.
Embodiment 2
1) similar to Example 1; its difference is to be used for (R; R)-2, the hydroxy-protective group of 3-dihydroxyl-gamma-butyrolactone is two-tertiary butyl dimethyl silica-based (TBS), is used for preparation (R; S)-sulphonate (8A; P=TBS) SULPHURYL CHLORIDE is a Tosyl chloride, resulting (R, S)-sulphonate (8A; P=TBS, R=p-Tol) productive rate 92%.
2) preparation epoxide (9A α and 9A β, P=TBS, R=p-Tol)
Will (R, S)-sulphonate (8A, P=TBS, R=p-Tol) be dissolved in the methylene dichloride, make the solution of 0.2 mol, add the m-chloro-benzoic acid peroxide that is equivalent to 1.2 times of molar weights of compound (8A), it is complete that reaction mixture is stirred to raw material reaction at 20 ℃, aftertreatment with obtain (R, R after silica gel column chromatography separates, S)-and epoxide (9A α, P=TBS is R=p-Tol) with (R, R, R)-epoxide (9A β, P=TBS, R=p-Tol), overall yield 68%.
3) preparation 3,4,5-trihydroxy-piperidine derivative (10A α)
With epoxide (9A α, P=TBS, R=p-Tol) being dissolved in the acetonitrile, making the solution of 0.1 mol, add the benzylamine that molar weight is equivalent to 1.5 moles of multiples of (9A α). reaction mixture reacts complete to feedstock conversion under 75 ℃, pressure reducing and steaming solvent then, thick product gets 3,4 through purification by silica gel column chromatography, 5-trihydroxy-piperidine derivative (10A α, P=TBS), productive rate 82%.
4) preparation 3,4,5-trihydroxy-piperidines (2) hydrochloride
With 3,4,5-trihydroxy-piperidine derivative (10A α, P=TBS) be dissolved in the methyl alcohol, make the solution of 0.2 mol, add the concentrated hydrochloric acid that is equivalent to 5.0 moles of multiples of compound (10A α), with 5.0% mole 10%Pd/C catalyzer, the air in the reaction mixture with hydrogen exchange after, complete in stirring at room to raw material reaction under nitrogen atmosphere, remove by filter catalyzer, behind the pressure reducing and steaming solvent, obtain 3,4, the hydrochloride of 5-trihydroxy-piperidines (2), productive rate 92%.
Similarly, with (R, R, R)-(9A β, P=TBS are intermediate R=p-Tol) to epoxide, and through 3,4, (10A β P=TBS), obtains 3,4 to 5-trihydroxy-piperidine derivative, the hydrochloride of 5-trihydroxy-piperidines (1), productive rate 94%.
Embodiment 3
1) similar to Example 1; its difference be to be used for (R, R)-2, the hydroxy-protective group of 3-dihydroxyl-gamma-butyrolactone is two benzyls (P=Bn); be used for preparation (R; S)-and sulphonate (8A, SULPHURYL CHLORIDE P=Bn) is a methylsulfonyl chloride, obtains (R; S)-sulphonate (8A; P=Bn, R=Me), productive rate 94%.
2) preparation epoxide (9A α and 9A β, P=Bn, R=Me)
Will (R, R)-sulphonate (8A, P=Bn, R=Me) be dissolved in the methylene dichloride, make the solution of 0.2 mol, add the m-chloro-benzoic acid peroxide that is equivalent to 1.2 times of molar weights of compound (8A), it is complete that reaction mixture is stirred to raw material reaction at 20 ℃, aftertreatment with obtain (R, R after silica gel column chromatography separates, S)-and epoxide (9A α, P=Bn is R=Me) with (R, R, R)-epoxide (9A β, P=Bn, R=Me), productive rate 70%.
3) preparation 3,4,5-trihydroxy-piperidine derivative (10A α)
With epoxide (9A α, P=Bn, R=Me) being dissolved in the acetonitrile, making the solution of 0.1 mol, add the benzylamine that molar weight is equivalent to 1.5 moles of multiples of (9A α). reaction mixture reacts complete to feedstock conversion under 75 ℃, pressure reducing and steaming solvent then, thick product gets 3,4 through purification by silica gel column chromatography, 5-trihydroxy-piperidine derivative (10A α, P=Bn), productive rate 84%.
4) preparation 3,4,5-trihydroxy-piperidines (2) hydrochloride
With 3,4,5-trihydroxy-piperidine derivative (10A α, P=Bn) be dissolved in the methyl alcohol, make the solution of 0.2 mol, add the concentrated hydrochloric acid that is equivalent to 5.0 moles of multiples of compound (10A α), with 5.0% mole 10%Pd/C catalyzer, the air in the reaction mixture with hydrogen exchange after, complete in stirring at room to raw material reaction under nitrogen atmosphere, remove by filter catalyzer, behind the pressure reducing and steaming solvent, obtain 3,4, the hydrochloride of 5-trihydroxy-piperidines (2), productive rate 95%.
Similarly, with (R, R, S)-(9A β, P=Bn are intermediate R=Me) to epoxide, and through 3,4, (10A β P=Bn), obtains 3,4 to 5-trihydroxy-piperidine derivative, the hydrochloride of 5-trihydroxy-piperidines (1), productive rate 94%.
Embodiment 4
1) similar to Example 1; its difference is that starting raw material is the (R of the two-dimethyl tertiary butyl silica-based (TBS) protection; S)-2, and 3-dihydroxyl-gamma-butyrolactone (5B, P=TBS); butyrolactone (5B; P=TBS) reference literature method, with diisobutyl aluminium hydride in-78 ℃ down reduction obtain corresponding (R, S)-2; 3-dihydroxyl-lactol (6B, P=TBS).Refer again to literature method with (6B P=TBS) uses by Ph
3P
+CH
3Br
-With the formed Wittig reagent react of t-BuOK, obtain (S, S)-enol (7B, P=TBS), productive rate 82%.
2) preparation (S, S)-sulphonate (8B)
With (S, S)-(7B P=TBS) is dissolved in the methylene dichloride enol, makes the solution of 0.2 mol, after the ice-water bath cooling, stir and to add down and be equivalent to (7B, it is complete that the P=TBS) triethylamine of the methylsulfonyl chloride of 1.2 times of mole multiples and 1.3 times of mole multiples, mixture are stirred to feedstock conversion, obtain (S after the aftertreatment, S)-sulphonate (8B, P=TBS, R=CH
3), productive rate 89%.
3) preparation epoxide (9B α and 9B β)
Will (S, S)-sulphonate (8B, P=TBS, R=CH
3) be dissolved in the methylene dichloride, make the solution of 0.15 mol, add the m-chloro-benzoic acid peroxide that is equivalent to 1.2 times of molar weights of compound (8B), it is complete that reaction mixture is stirred to raw material reaction at 20 ℃, aftertreatment with obtain after silica gel column chromatography separates (S, R, S)-epoxide (9B α, P=TBS, R=CH
3) and (S, R, R)-epoxide (9B β, P=TBS, R=CH
3), overall yield 64%.
4) preparation 3,4, and 5-trihydroxy-piperidine derivative (10B α, P=TBS)
With epoxide (9B α, P=TBS) be dissolved in the acetonitrile, make the solution of 0.2 mol, adding molar weight and be equivalent to the benzylamine of 1.3 moles of multiples of (9B α). reaction mixture reacts complete to feedstock conversion under 85 ℃, pressure reducing and steaming solvent then, thick product gets 3 through purification by silica gel column chromatography, 4,5-trihydroxy-piperidine derivative (10B α, P=TBS), productive rate 77%.
5) preparation 3,4,5-trihydroxy-piperidines (3) hydrochloride
With 3,4,5-trihydroxy-piperidine derivative (10B α, P=TBS) be dissolved in the methyl alcohol, make the solution of 0.2 mol, add the concentrated hydrochloric acid that is equivalent to 5.0 moles of multiples of compound (10B α), with 3.5% mole 10%Pd/C catalyzer, the air in the reaction mixture with hydrogen exchange after, complete in stirring at room to raw material reaction under nitrogen atmosphere, remove by filter catalyzer, behind the pressure reducing and steaming solvent, obtain 3,4, the hydrochloride of 5-trihydroxy-piperidines (3), productive rate 90%.
Similarly, with (S, R, R)-epoxide (9B β, P=TBS, R=CH
3) be intermediate, through 3,4, (10B β P=TBS), obtains 3,4 to 5-trihydroxy-piperidine derivative, the hydrochloride of 5-trihydroxy-piperidines (4), productive rate 92%.
Embodiment 5
1) similar to Example 4; its difference is that starting raw material is the (R of two benzyl (Bn) protections; S)-2, and 3-dihydroxyl-gamma-butyrolactone (5B, P=Bn); butyrolactone (5B; P=Bn) reference literature method, with diisobutyl aluminium hydride in-78 ℃ down reduction obtain corresponding (R, S)-2; 3-dihydroxyl-lactol (6B, P=Bn).Refer again to literature method with (6B P=Bn) uses by Ph
3P
+CH
3Br
-With the formed Wittig reagent react of t-BuOK, obtain (S, S)-enol (7B, P=Bn), productive rate 81%.
2) preparation (S, S)-sulphonate (8B)
With (S, S)-enol (7B, P=Bn) be dissolved in the methylene dichloride, make the solution of 0.2 mol, after the ice-water bath cooling, stir to add down and be equivalent to the methylsulfonyl chloride of (7B) 1.2 times of mole multiples and the triethylamine of 1.3 times of mole multiples, it is complete that mixture is stirred to feedstock conversion, obtain after the aftertreatment (S, S)-sulphonate (8B, P=Bn, R=CH
3), productive rate 86%.
3) preparation epoxide (9B α and 9B β)
Will (S, S)-sulphonate (8B, P=Bn, R=CH
3) be dissolved in the methylene dichloride, make the solution of 0.15 mol, add the m-chloro-benzoic acid peroxide that is equivalent to 1.2 times of molar weights of compound (8B), it is complete that reaction mixture is stirred to raw material reaction at 20 ℃, aftertreatment with obtain after silica gel column chromatography separates (S, R, S)-epoxide (9B α, P=Bn, R=CH
3) and (S, R, R)-epoxide (9B β, P=Bn, R=CH
3), overall yield 65%.
4) preparation 3,4, and 5-trihydroxy-piperidine derivative (10B α, P=Bn)
With epoxide (9B α, P=TBS) be dissolved in the acetonitrile, make the solution of 0.2 mol, add the benzylamine that molar weight is equivalent to 1.3 moles of multiples of (9B α), it is complete to feedstock conversion that reaction mixture reacts under 85 ℃, pressure reducing and steaming solvent then, thick product gets 3,4 through purification by silica gel column chromatography, 5-trihydroxy-piperidine derivative (10B α, P=Bn), productive rate 78%.
5) preparation 3,4,5-trihydroxy-piperidines (3) hydrochloride
With 3,4,5-trihydroxy-piperidine derivative (10B α, P=Bn) be dissolved in the methyl alcohol, make the solution of 0.2 mol, add the concentrated hydrochloric acid that is equivalent to 5.0 moles of multiples of compound (10B α), with 3.5% mole 10%Pd/C catalyzer, the air in the reaction mixture with hydrogen exchange after, complete in stirring at room to raw material reaction under nitrogen atmosphere, remove by filter catalyzer, behind the pressure reducing and steaming solvent, obtain 3,4, the hydrochloride of 5-trihydroxy-piperidines (3), productive rate 98%.
Similarly, with (S, R, S)-epoxide (9B β, P=TBS, R=CH
3) be intermediate, through 3,4, (10B β P=TBS), obtains 3,4 to 5-trihydroxy-piperidine derivative, the hydrochloride of 5-trihydroxy-piperidines (4), productive rate 96%.
Claims (9)
1.3,4, the preparation method of the hydrochloride of 5-trihydroxy-piperidines, with optical purity 2,3-dihydroxyl-gamma-butyrolactone (5A or 5B) is a starting raw material, it is characterized in that reaction equation is as follows:
Wherein P is the hydroxy-protective group acetonylidene, and benzyl or tertiary butyl dimethyl are silica-based; R is the alkyl of C1～C4, and the perfluoroalkyl of C1～C4 or aryl, mCPBA are m-chloro-benzoic acid peroxide.
2. as claimed in claim 13,4, the preparation method of the hydrochloride of 5-trihydroxy-piperidines is characterized in that its concrete reactions steps is as follows:
1) preparation (R, R)-and (R, S)-2,3-dihydroxyl-lactol
With hydroxyl protection (R, R)-2,3-dihydroxyl-gamma-butyrolactone or (R, S)-2,3-dihydroxyl-gamma-butyrolactone is dissolved in the methylene dichloride, makes the solution of 0.25～0.35 mol, adds the diisobutyl aluminium hydride of 1.0～1.2 times of molar weights that are equivalent to compound, in-78 ℃ of reduction, make (R, R)-2,3-dihydroxyl-lactol or (R, S)-2,3-dihydroxyl-lactol;
2) preparation (R, S)-and (S, S)-enol
With (R, R)-dihydroxyl-lactol or (R, S)-2,3-dihydroxyl-lactol is dissolved in the anhydrous tetrahydro furan, make the solution of 0.4～0.6 mol, add be equivalent to compound (R, R)-dihydroxyl-lactol or (R, S)-2,1.1～1.3 times of molar weights of 3-dihydroxyl-lactol uses by Ph
3P
+CH
3Br
-The Wittig reagent that forms with t-BuOK, in-78 ℃ to 30 ℃ reactions, obtain corresponding (R, S)-enol and (S, S)-enol;
3) preparation (R, S)-and (S, S)-sulphonate
With (R, S)-or (S, S)-enol is dissolved in the methylene dichloride, make 0.1～0.5 mol, after the ice-water bath cooling, stir to add down and be equivalent to (R, S)-or (S, S)-sulfonylation agent of 1.0～1.5 times of molar weights of enol and be equivalent to (R, S)-or (S, S)-triethylamine of 1.0～2.0 times of molar weights of enol, it is complete that mixture is stirred to feedstock conversion, obtain after the conventional aftertreatment (R, S)-or (S, S)-and sulphonate, described sulfonylation agent is selected from a kind of in alkyl sulfonyl chloride, aryl sulfonyl chloride and C1～C4 perfluoroalkyl SULPHURYL CHLORIDE of C1～C4;
4) preparation epoxide
Will (R, S)-sulphonate or (S, S)-sulphonate is dissolved in the methylene dichloride, make the solution of 0.1～0.3 mol, add be equivalent to compound (R, S)-sulphonate or (S, S)-metachloroperbenzoic acid of 1.0～1.3 times of molar weights of sulphonate, it is complete that reaction mixture is stirred to raw material reaction at 0～20 ℃, conventional aftertreatment with obtain (R after silica gel column chromatography separates, R, S)-and (R, R, R)-epoxide or (S, R, S)-and (S, R, R)-epoxide;
5) preparation 3,4,5-trihydroxy-piperidine derivative
Epoxide is dissolved in the acetonitrile, make the solution of 0.1～0.4 mol, the adding molar weight is equivalent to the benzylamine of 1.0～1.5 moles of multiples of epoxide, it is complete to raw material reaction that reaction mixture reacts under 50～90 ℃, pressure reducing and steaming solvent then, thick product gets 3,4 through purification by silica gel column chromatography, 5-trihydroxy-piperidine derivative;
6) preparation 3,4,5-trihydroxy-piperidine hydrochlorate
With 3,4,5-trihydroxy-piperidine derivative is dissolved in the methyl alcohol, make the solution of 0.1～0.5 mol, add and be equivalent to 3,4, the concentrated hydrochloric acid of 1.5～5.0 moles of multiples of 5-trihydroxy-piperidine derivative and 0.5%～10% mole 10%Pd/C catalyzer, the air in the reaction mixture with hydrogen exchange after, complete in stirring at room to raw material reaction under nitrogen atmosphere, remove by filter catalyzer, behind the pressure reducing and steaming solvent, obtain 3,4, the hydrochloride of 5-trihydroxy-piperidines.
3. as claimed in claim 23,4, the preparation method of the hydrochloride of 5-trihydroxy-piperidines, it is characterized in that in the step 3 will (R, S)-or (S, S)-enol is dissolved in the solution of making 0.2～0.3 mol in the methylene dichloride; The add-on of sulfonylation agent be equivalent to (R, S)-or (S, S)-1.2～1.3 times of molar weights of enol; The add-on of triethylamine be equivalent to (R, S)-or (S, S)-1.1～1.4 times of molar weights of enol.
4. as claim 2 or 3 described 3,4, the preparation method of the hydrochloride of 5-trihydroxy-piperidines is characterized in that the sulfonylation agent described in the step 3 is alkyl sulfonyl chloride or the aryl sulfonyl chloride of C1～C2.
5. as claimed in claim 23,4, the preparation method of the hydrochloride of 5-trihydroxy-piperidines, it is characterized in that in the step 4 will (R, S)-sulphonate or (S, S)-sulphonate is dissolved in the solution of making 0.2～0.25 mol in the methylene dichloride; The add-on of m-chloro-benzoic acid peroxide for be equivalent to compound (R, S)-sulphonate or (S, S)-1.1～1.2 times of molar weights of sulphonate.
6. as claimed in claim 23,4, the preparation method of the hydrochloride of 5-trihydroxy-piperidines, the acetonitrile solution concentration that it is characterized in that epoxide in the step 5 is 0.2～0.3 mol; The add-on of benzylamine is equivalent to 1.1～1.3 moles of multiples of epoxide.
7. as claimed in claim 23,4, the preparation method of the hydrochloride of 5-trihydroxy-piperidines is characterized in that reaction mixture is 70～85 ℃ of reactions down in the step 5.
8. as claimed in claim 23,4, the preparation method of the hydrochloride of 5-trihydroxy-piperidines is characterized in that in the step 63,4, and the content of 5-trihydroxy-piperidine derivative in methanol solution is 0.2～0.3 mol; The add-on of concentrated hydrochloric acid is equivalent to compound 3,4,2.0～3.5 moles of multiples of 5-trihydroxy-piperidine derivative.
9. as claimed in claim 23,4, the preparation method of the hydrochloride of 5-trihydroxy-piperidines is characterized in that adding in the step 6 and is equivalent to compound 3,4,1.0%～4.5% mole 10%Pd/C catalyzer of 5-trihydroxy-piperidine derivative.
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| 1-aza-sugars from D-glucose. preparationof 1-deoxy-5-dehydroxymethyl-nojirimycin,its analoguesand evaluation of glycosidase inhibitory activity. Nitin T.Patil,et al.Bioorganic & Medicinal Chemistry,Vol.10. 2002 * |
| D-erythronolactone and 2, 3-O-isopropylidene-L-erythroseas C4 building units: an efficient synthesis of both enantiomersof endo-brevicomin and its 7-vinyl analogues.. Andreas Gypser, et al.Liebigs Ann. Chem.. 1994 |
| D-erythronolactone and 2,3-O-isopropylidene-L-erythroseas C4 building units: an efficient synthesis of both enantiomersof endo-brevicomin and its 7-vinyl analogues. Andreas Gypser,et al.Liebigs Ann.Chem. 1994 * |
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