CN101037457A - Branched polyhydroxy pyrrole derivatives and preparation method and application - Google Patents
Branched polyhydroxy pyrrole derivatives and preparation method and application Download PDFInfo
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Abstract
The invention discloses a branched pyrrolidine polyol derivate and the producing method and application thereof. The provided branched pyrrolidine polyol derivate has a structural formula as formula I, wherein R1 is hydroxymethyl and etc., R2 and R3 are hydrogen and etc., R4 is C1-C20 alkyl and etc., R5 is hydrogenand etc., R6 is hydrogen and etc., R7 is hydroxy and etc. The pyrrolidine polyol is the most important component for the natural imide glucose. The invention provides a general method for synthesizing the branched pyrrolidine polyol compound which comprises an additon reaction of glycosyl aldoxime and nucleophilic reagent to get the hydroxylamine, oxidating it to get substituted aldoxime, and getting a poly-substituted hydroxylamine after another additon reaction, repeating such, getting the highly branched polyol nitrogen heterocyclic pyrrolidine compound. The inventive method has a gentle reacting condition, a high yield, a high solid selectivity and is a feasible synthesis method for the new 2,5-poly-substituted polyol pyrrolidine compound.
Description
Technical field
The present invention relates to branched polyhydroxy pyrrole derivatives and preparation method thereof and application.
Background technology
Branched polyhydroxy pyrrole derivatives is meant 2 of pyrrole ring, contains a plurality of substituent polyhydroxy pyrrole compounds on the 5-position.The polyhydroxy pyrrole compounds since with the similar of furanose, contain a plurality of hydroxyls, only the Sauerstoffatom on the sugar ring is replaced by nitrogen-atoms, is a topmost compounds in the imines sugar.The imido saccharide compound is well-known Glycosylase and glycosyl transferase inhibitor, for example, 1, the two deoxidations-1 of 4-, 4-imido-D-pectinose and 1, the two deoxidations-1 of 4-, 4-imido-D-ribose is naturally occurring imido sugar, has good Glycosylase inhibition.Basen wherein, the such imido sugar of Miglitol have become the medicine of treatment diabetes.In view of very significant biological activity of these compounds and potential pharmaceutical use, people have given very big effort aspect this compounds synthetic.Polyhydric proline(Pro) since with the polyhydroxy pyrrole similar that contains methylol, and be the analogue of α-proline(Pro), the same with imido sugar, they also have inhibition to Glycosylase.In addition, the poly-hydroxy proline(Pro) is also the same with common amino acid to be directed in the synthetic field of polypeptide, discovers that the poly-hydroxy proline(Pro) has tangible influence to the secondary conformation of polypeptide.A plurality of polypeptide drugs that contain the oxyproline of oxyproline or replacement have developed and have been applied to clinical.
Compare with naturally occurring imido saccharide compound, the analogue of synthetic often has higher biological activity.For example, polyhydric tetramethyleneimine 1-deoxy-L-fuconojirimycin (DFJ) is the most effective known glycosidase inhibitor.It has been recognized that now between medicine and the protein acceptor that on, the interaction between the hydrophobic group occupies crucial status.Act in order to improve between medicine and the protein acceptor, people need introduce lipophilic group in drug molecule, thereby how Stereoselective is introduced the hydrophobic group at pharmacophoric group just becomes one of emphasis of people's research.
Yet the synthetic method of polysubstituted polyhydroxy pyrrole but is very limited.People such as J ger calendar year 2001 proposed synthetic this compounds method (Eur.J.Org.Chem.2001,2547-2558), but this method only limits to the polyhydroxy pyrrole that synthesizing methyl replaces, and can not synthesize other substituent analogue; People such as B.G.Davis have proposed in 2002 that imines and Grignard reagent addition reaction prepare 2 in a kind of glycosyl ring, the method for the polyhydroxy pyrrole that 5-replaces, but productive rate lower (B.G.Davis, et al, Org.Lett., 2002,4,103-106.).
Summary of the invention
The purpose of this invention is to provide a kind of branched polyhydroxy pyrrole derivatives and preparation method thereof and application.
Branched polyhydroxy pyrrole derivatives provided by the present invention, structural formula be suc as formula I,
(formula I)
Wherein, R
1Be methylol, alkoxyl-methyl, fragrant methoxyl methyl, triphen methoxyl methyl, benzyloxymethyl, trialkyl silica methyl, carboxyl or ester group;
R
2And R
3Be hydrogen, C
1-C
20-alkyl, C
3-C
8-cycloalkyl, C
6-C
10The benzyl of-aryl, replacement, methoxyl methyl, ethoxymethyl, front three are silica-based, uncle's fourth oxygen silicon base, isopropylidene, cyclohexylidene base, benzal base or cyclopropyl methylene fork base;
R
4Be C
1-C
20-alkyl, C
3-C
8-cycloalkyl, C
6-C
10-aryl, C
6-C
10-arylmethyl, vinyl, allyl group, alkynyl, propargyl, 2-furyl or cyano group;
R
5Be hydrogen, C
1-C
20-alkyl, C
3-C
8-cycloalkyl, C
6-C
10-aryl, C
6-C
10-arylmethyl, vinyl, allyl group, alkynyl, propargyl, 2-furyl or cyano group;
R
6Be hydrogen, C
1-C
20-alkyl, C
3-C
8-cycloalkyl, C
6-C
10-aryl, C
6-C
10-arylmethyl, vinyl, allyl group, alkynyl, propargyl, 2-furyl or cyano group;
R
7Be hydroxyl, hydrogen, acetoxyl group, benzyloxy, tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or 9-fluorenylmethoxycarbonyl;
And, work as R
1When being not carboxyl or ester group, R
5And R
6Be not hydrogen simultaneously.
The synthetic of The compounds of this invention can be divided into the following different stage:
One, R among the synthesis type I
7Be hydroxyl, R
5And R
6In have one to be the branched polyhydroxy pyrrole derivatives of hydrogen
1) azanol with the formula III structure carries out oxidizing reaction, obtains the nitrone suc as formula IV/a or formula IV/b structure,
(formula III) (formula IV/a) (formula IV/b)
Used oxygenant is general inorganic or organic oxidizing agent, and as Manganse Dioxide, oxidation such as red precipitate, hydrogen peroxide, Oxone, benzoquinones etc. well should reactions.Being reflected at general organic solvent or organic solvent and aqueous phase carries out.
2) with gained nitrone and organometallic reagent R
5MX[or (R
5)
2M] react, obtain the pyrrolidin derivatives of formula II/a or formula II/b structure;
(formula II/a) (formula II/b)
Wherein, R
1, R
2, R
3, R
4, R
5Definition cotype I,
M is magnesium, lithium, zinc, copper, manganese or its mixture;
X is chlorine, bromine, iodine.
Organometallic reagent is meant organomagnesium reagent, organic zinc reagent, organolithium reagent, organic copper reagent, organosilicon reagent etc.Be reflected at anhydrous aprotic solvent such as ether, tetrahydrofuran (THF), dioxane carries out in the methylene dichloride, and temperature of reaction is generally-80 ℃ to room temperature.
Two, R among the synthesis type I
7Be hydrogen, R
5And R
6In have one to be the branched polyhydroxy pyrrole derivatives of hydrogen
The pyrrolidin derivatives of formula II/a or formula II/b structure is carried out reduction reaction, obtain the pyrrolidin derivatives of formula II/c or formula II/d structure.
(formula II/c) (formula II/d)
Reductive agent can use metal simple-substance such as zinc powder, indium, and samarium or its sub-compound, as samarium diodide, or zinc-copper idol, also can use transition metal such as palladium, nickel, the catalytic hydrogenation of cobalt and salt thereof.
Three, R among the synthesis type I
2, R
3, R
7Be hydrogen, R
1Be CH
2OH, R
5And R
6In have one to be the branched polyhydroxy pyrrole derivatives of hydrogen
The pyrrolidin derivatives of formula II/a or formula II/b structure is carried out reduction reaction under acidic conditions, perhaps, the pyrrolidin derivatives of formula II/c or formula II/d structure is handled with acid, obtain the pyrrolidin derivatives of formula II/e or formula II/f structure.
(formula II/e) (formula II/f)
The general acid of using is meant mineral acid commonly used and organic acid, example hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, acetate, formic acid etc.
Four, R among the synthesis type I
7Be not hydrogen or hydroxyl, R
5And R
6In have one to be the branched polyhydroxy pyrrole derivatives of hydrogen
The pyrrolidin derivatives and the amino protecting group reagent of formula II/c or formula II/d structure are reacted, obtain the pyrrolidin derivatives of formula II/g or formula II/h structure;
(formula II/g) (formula II/h)
Wherein, R
7Be ethanoyl, benzoyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or 9-fluorenylmethoxycarbonyl.
Amido protecting agent commonly used has diacetyl oxide, benzoyl oxide, Boc acid anhydrides, benzyloxy dicarbonyl chloride, carbalkoxy class protecting group such as 9-fluorenes methoxy dicarbonyl chloride and Benzoyl chloride, benzene sulfonyl chloride etc.
Five, R among the synthesis type I
7Be not hydrogen or hydroxyl, R
1Be CH
2OH, R
5And R
6In have one to be the branched polyhydroxy pyrrole derivatives of hydrogen
The pyrrolidin derivatives of formula II/g or formula II/h structure is removed R under acidic conditions
1In hydroxy-protective group, obtain the pyrrolidin derivatives of formula II/i or formula II/j structure;
(formula II/i) (formula II/j)
Wherein, R
7Be ethanoyl, benzoyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or 9-fluorenylmethoxycarbonyl.
The general acid of using is meant mineral acid commonly used and organic acid, example hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, acetate, formic acid etc.
Six, R among the synthesis type I
7Be not hydrogen or hydroxyl, R
1Be COOR
8, R
5And R
6In have one to be the branched polyhydroxy pyrrole derivatives of hydrogen
The pyrrolidin derivatives of formula II/i or formula II/j structure is carried out oxidizing reaction, obtain the pyrrolidin derivatives of formula II/k or formula II/l structure;
(formula II/k) (formula II/l)
Wherein, R
7Be ethanoyl, benzoyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or 9-fluorenylmethoxycarbonyl; R
8Be hydrogen, alkyl or benzyl.
Oxidising agent has the catalytic sodium periodate of metal ruthenium compound (ruthenium trichloride, maintenance ruthenium), or at first is oxidized to behind the corresponding aldehyde again with method for oxidation such as Textone or iodo-methyl alcohol with Swern reagent or IBX reagent oxidation method, or directly uses hypochlorite oxidation.
Seven, R among the synthesis type I
7Branched polyhydroxy pyrrole derivatives for hydroxyl
1) azanol with formula II/a or formula II/b structure carries out oxidizing reaction, obtains the nitrone suc as formula V/a or formula V/b structure,
(formula V/a) (formula V/b)
Used oxygenant is general inorganic or organic oxidizing agent, and as Manganse Dioxide, oxidation such as red precipitate, hydrogen peroxide, potassium hydrogen persulfate, benzoquinones etc. well should reactions.Being reflected at general organic solvent or organic solvent and aqueous phase carries out.
2) with gained nitrone and organometallic reagent R
6MX reacts, and obtains the pyrrolidin derivatives of formula II/m or formula II/n structure;
(formula II/m) (formula II/n)
Organometallic reagent is meant organomagnesium reagent, organic zinc reagent, organolithium reagent, organic copper reagent, organosilicon reagent etc.Be reflected at anhydrous aprotic solvent such as ether, tetrahydrofuran (THF), dioxane carries out in the methylene dichloride, and temperature of reaction is generally-80 ℃ to room temperature.
Method according to one to six can progressively be converted into corresponding amine, carboxylic acid or ester etc. with the pyrrolidin derivatives of formula II/m or formula II/n structure equally.
The compounds of this invention be the compound with the formula III structure to be that starting raw material is synthetic obtain, this compound can select the sugar of suitable configuration to obtain (Synlett.2003,35 by chemosynthesis with known method; J.Org.Chem.2005,70,1459).
Another object of the present invention provides the purposes of branched polyhydroxy pyrrole derivatives of the present invention.
Branched polyhydroxy pyrrole derivatives of the present invention is the key intermediate of the imines sugar of the poly-hydroxy proline(Pro) of synthetic cladodification and cladodification.
According to method of the present invention, will be with following formula II/a, II/b, II/m, when the compound of II/n representative can be sloughed hydroxyl protecting group under acidic conditions, can obtain the imines sugar of cladodification with catalytic hydrogenation reduction azanol, also can the step-by-step reduction azanol and the dehydroxylation protecting group obtain the imines sugar of cladodification; The compound of formula II/c-II/f representative can directly be sloughed the imines sugar that hydroxyl protecting group obtains cladodification under acidic conditions; The compound of formula II/g-II/j representative also can be with suitable method deaminize, and hydroxyl protecting group obtains the imines sugar of cladodification.2; the synthetic of the polysubstituted poly-hydroxy proline(Pro) of 5-is according to above-mentioned stage one to six stepwise synthesis; just at first suitable azanol feed oxygen is turned to nitrone IV/a; IV/b or V/a; V/b; obtain azanol II/a with the nucleophilic reagent addition then; II/b or II/m; II/n; again the azanol reduction is obtained amine II/c or II/d, amino with after the suitable protecting group protection, the protecting group that optionally removes methylol under acidic conditions obtains primary alconol II/j or II/k; primary alconol can obtain 2 with the appropriate means oxidation, the polysubstituted poly-hydroxy proline(Pro) of 5-.If the R among II/g and the II/h
4, R
5In have one for thiazolinyl, alkynyl, during unsaturated groups such as phenyl, can direct oxidation and obtain 2, the polysubstituted poly-hydroxy proline(Pro) of 5-.
Polyhydric tetramethyleneimine is the main composition that constitutes naturally occurring imines sugar, the invention provides a kind of Synthetic 2, the universal method of the polysubstituted polyhydroxy pyrrole compounds of 5-, this method is the nitrone of getting back and replacing by the azanol oxidation that glycosyl nitrone and nucleophilic reagent addition obtain, addition obtains polysubstituted azanol again, so repeatedly, can obtain 2, the polysubstituted poly-hydroxy azepine of 5-pyrrolidines.The inventive method has the reaction conditions gentleness, the productive rate height, the stereoselectivity advantages of higher, be the preparation this class novel 2, the practicable synthetic method of the polysubstituted polyhydroxy pyrrole compounds of 5-.
Description of drawings
Fig. 1 and Fig. 2 are the synthetic route synoptic diagram of The compounds of this invention;
Fig. 3 is the single crystal structure figure of embodiment 9 compounds.
Embodiment
Below in conjunction with route map illustrated in figures 1 and 2 the The compounds of this invention synthetic method is described.
Synthetic route shown in Figure 1 is with (2S, 3S, 4R, 5S)-and N-hydroxyl-2-benzyl-3,4-O-isopropylidene-5-triphen methoxyl methyl tetramethyleneimine (1) is a raw material, oxidation obtains nitrone (2), nitrone (2) and the addition of methyl magnesium iodide obtain azanol (3), productive rate 84%.Azanol (2) obtains corresponding secondary amine (4), productive rate 74% with zinc powder reduction under the catalysis of venus crystals in acetic acid water solution.The amino of secondary amine (4) obtains compound (5), productive rate 73% with the CbzCl protection.Trityl-protecting group in the following compound of hydrochloric acid-methanol system (5) removes and obtains primary alconol (6), productive rate 57%; Primary alconol (6) can directly be used RuCl
3-NaIO
4Oxidation obtains polysubstituted proline(Pro) (7), productive rate 76%; Also can remove amino and hydroxyl protecting group obtains free imines sugar (8), productive rate 100% in catalytic hydrogenation under the acidic conditions.Azanol (2) can direct oxidation obtain polysubstituted nitrone (9), productive rate 94.5%.Nitrone (9) can be further and the Grignard reagent addition, as allyl group bromination magnesium generation addition reaction.In order to determine the structure of product, unsettled N-hydroxyl is protected with diacetyl oxide, obtain compound (10), productive rate 79%.
Reaction conditions represented among Fig. 1 is as follows:
i：MnO
2，CH
2Cl
2；ii：MeMgBr，THF，-78-0℃；iii：Zn-Cu(OAc)
2，HOAc-H
2O；iv：CbzCl，NaHCO
3，EtOH-H
2O；v：HCl(c)-MeOH；vi：RuCl
3-NaIO
4，CCl
4-MeCN-H
2O(1∶1∶1.5)；vii：Pd-C，H
2，HCl，MeOH；viii：MnO
2，CH
2Cl
2；ix：(a)CH
2＝CH
2MgBr，Et
2O；(b)Ac
2O，Pyridine.
Synthetic route shown in Figure 2 is with (2S, 3S, 4R, 5S)-and N-hydroxy-2-methyl-3,4-O-isopropylidene-5-triphen methoxyl methyl tetramethyleneimine (11) is a raw material, oxidation obtains nitrone (12) productive rate 77%, nitrone (12) and the addition of benzyl magnesium bromide obtain azanol (13), productive rate 82%.Azanol (13) obtains corresponding secondary amine (14) with zinc powder reduction under the catalysis of venus crystals in acetic acid water solution.The amino of hydroxyl secondary amine (14) obtains compound (15), productive rate 78% with the CbzCl protection.Trityl-protecting group in the following compound of hydrochloric acid-methanol system (15) removes and obtains primary alconol (16), productive rate 61%; Primary alconol (16) can directly be used RuCl
3-NaIO
4Oxidation obtains polysubstituted pair of oxyproline (17), productive rate 76%; Azanol (13) catalytic hydrogenation reduction azanol under acidic conditions removes hydroxyl protecting group simultaneously, can obtain free imines sugar (18).
Reaction conditions represented among Fig. 2 is as follows:
i：Oxone，EtOAc，Me
2O；ii：BnMgI，THF，-78-0℃；iii：Zn-Cu(OAc)
2，HOAc-H
2O；iv：CbzCl，NaHCO
3，EtOH-H
2O；v：HCO
2H-MeCN；vi：RuCl
3-NaIO
4，CCl
4-MeCN-H
2O(1∶1∶1.5)；vii：Pd-C，H
2，HCl，MeOH.
The present invention is described by the following examples, it should be understood that these embodiment only are used for explanation, do not limit the scope of the invention.
Embodiment 1: synthetic (3R, 4S, 5R)-and 2-triphen methoxyl methyl-3,4-O-isopropylidene-5-benzyl-1-pyrroline-N-oxide compound (nitrone (2))
With (2S, 3S, 4R, 5S)-and N-hydroxyl-2-benzyl-3,4-O-isopropylidene-5-triphen methoxyl methyl tetramethyleneimine (1) (2.20 gram 4.22 mmoles) is dissolved in 20 milliliters the methylene dichloride, is cooled to 0 ℃, add Manganse Dioxide (3.7 grams, 42.2 mmoles), stirring is spent the night.TLC shows that raw material reaction is complete, the solids removed by filtration residue, and the pressure reducing and steaming solvent, column chromatography for separation obtains product 2.1 grams, productive rate: 95%.
Spectroscopic data:
1H?NMR(CDCl
3)δ(ppm)：1.33(s，6H，CH
3)，3.12(dd，J＝14.1，4.2Hz，1H，PhCH
2)，3.17(dd，J＝14.4，6.3Hz，1H，PhCH
2)，4.03(dt，J＝15.0，1.5Hz，1H，TrOCH
2)，4.18(d，J＝15.0Hz，1H，TrOCH
2)，4.31(t，J＝1.5Hz，1H，H-5)，4.52(d，J＝6.3Hz，1H，H-4)，4.63(dd，J＝6.0，0.6Hz，1H，H-3)，7.10-7.45(m，20H，ArH).
FT-Ms?Calcd.for?C
34H
34NO
3[M+H]
+：504.2533，found：520.2858.
Embodiment 2: synthetic (2S, 3R, 4S, 5S)-and N-hydroxy-2-methyl-2-triphen methoxyl methyl-3,4-O-isopropylidene-5-benzyl-pyrrole alkane (azanol (3))
Nitrone (2) (1.34 grams, 2.58 mmoles) is dissolved in the anhydrous tetrahydro furan, drips methyl iodate magnesium solution (1.0M, 6.5 milliliters), react between room temperature, handle with ordinary method after reaction is finished at-78 ℃.Obtain product 1.2 grams.Productive rate: 84%.
Spectroscopic data:
1H?NMR(CDCl
3)δ(ppm)：1.17(s，3H)，1.19(s，3H)，1.74(s，3H)，2.80(dd，J＝14.1，8.7Hz，1H)，3.06-3.11(m，1H，)，3.27(dd，J＝14.1，3.6Hz，1H)，3.46(t，J＝10.2Hz，2H)，4.25(d，J＝6.3Hz，1H)，4.27(d，J＝7.5Hz，1H)，6.69(s，1H)，7.23-7.40(m，15H)，7.55-7.60(m，5H).
FT-Ms?Calcd.for?C
35H
38NO
4[M+H]
+：536.2801，found：536.2797.
Embodiment 3: synthetic (2S, 3R, 4S, 5S)-and 2-methyl-2-triphen methoxyl methyl-3,4-O-isopropylidene-5-benzyl-pyrrole alkane (secondary amine (4))
Azanol (3) (0.42 gram, 0.78 mmole) is dissolved in the methylene dichloride, splashes in the acetic acid aqueous solution of the zinc powder that is suspended with 0.51 gram (7.8 mmole), add the venus crystals of catalytic amount, stirring at room shows that to TLC raw material reaction is complete.The ordinary method aftertreatment obtains 300 milligrams of products.Productive rate: 73.7%.
Spectroscopic data:
1H?NMR(CDCl
3)δ(ppm)：1.22(s，3H)，1.33(s，3H)，1.54(s，3H)，2.03(brs，1H)，2.70(dd，J＝13.8，7.2Hz，1H)，2.89(dd，J＝13.5，5.7Hz，1H)，3.07(s，2H)，3.46(dd，J＝12.0，5.4Hz，1H)，4.33(dd，J＝6.9Hz，4.8Hz，1H)，4.45(d，J＝6.9Hz，1H)，7.22-7.45(m，20H).
FT-Ms?Calcd.for?C
35H
38NO
3[M+H]
+：520.2852，found：520.2858.
Embodiment 4, synthetic (2S, 3R, 4S, 5S)-N-carbobenzoxy-(Cbz)-2-methyl-2-triphen methoxyl methyl-3,4-O-isopropylidene-5-benzyl-pyrrole alkane (compound (5))
Secondary amine (4) (1.80 grams, 3.46 mmoles) is dissolved in the dichloromethane solution, joins and be dissolved with NaHCO
3The EtOH/H of (420 milligrams, 5.0 mmoles)
2In the O solution, stir and drip Cbz-Cl (0.60 milliliter, 4.15 mmoles) down, stirring at room is to reacting completely, and the ordinary method aftertreatment obtains product 1.65 grams, productive rate: 73%.
Spectroscopic data:
1H?NMR(CDCl
3)δ(ppm)：1.08(s，1H)，1.37(s，1H)，1.42(s，4H)，2.74(t，J＝12.0Hz，0.4H)，2.93(q，J＝13.5Hz，0.6H)，3.15(d，J＝13.2Hz，0.6H).3.30(d，J＝12.9Hz，0.4H)，3.58(d，J＝6.6Hz，0.4H)，3.68(d，J＝7.2Hz，0.6H)，3.81(d，J＝6.6Hz，0.4H)，4.15-4.32(m，1.6H)，4.66(brs，1.4H)，4.74(brs，0.6H)，4.96-5.20(m，2H)，7.10-7.66(m，25H).
FT-ICMS：calcd.for?C
43H
43NNaO
5[M+H]
+：676.3039，found：676.3023.
Embodiment 5: synthetic (2S, 3R, 4S, 5S)-and N-carbobenzoxy-(Cbz)-2-methyl-2-methylol-3,4-O-isopropylidene-5-benzyl-pyrrole alkane (primary alconol (6))
In the dichloromethane solution that is dissolved with 0.89 gram (1.36 mmole) compound (5), add hydrochloric acid-methyl alcohol HCl/MeOH mixing solutions, stirring reaction is to reacting completely, add proper amount of sodium hydroxide solution cancellation reaction, aftertreatment obtains product 0.32 gram, productive rate: 57.1%.Colourless bulk crystals, mp.125 ℃.
Spectroscopic data:
1H?NMR(CDCl
3)δ(ppm)：1.23(s，3H)，1.32(s，3H)，1.512(s，3H)，2.67(t，J＝12.7Hz，1H，H-6)，3.17(d，J＝13.4Hz，1H)，3.92(t，J＝12.3Hz，1H)，4.10(dd，J＝12.4，3.3Hz，1H)，4.30(d，J＝10.5Hz，1H)，4.47(dd，J＝9.6，3.2Hz，1H)，4.52(d，J＝5.7Hz，1H)，4.61(d，J＝5.6Hz，1H)，5.25(q，J＝11.7Hz，2H)，7.12(d，J＝6.0Hz，2H)，7.32(brm，3H)，7.40-7.48(m，5H).
FT-IRMS：calcd.For?C
24H
30NO
5[M+H]
+，412.2124，found：412.2119.
Embodiment 6: synthetic (2R, 3R, 4S, 5S)-and N-carbobenzoxy-(Cbz)-2-methyl-2-methylol-3,4-O-isopropylidene-5-benzyl proline(Pro) (proline(Pro) (7))
The RuCl of catalytic amount
3Join the primary alconol (6) and the 0.64 gram NaIO that are dissolved with 0.27 milligram
4MeCN/CCl
4/ H
2In the mixing solutions of O (1: 1: 1.5).Be stirred to reaction under the room temperature and finish, aftertreatment obtains product 0.21 gram, productive rate: 76%.
Spectroscopic data:
1H?NMR(CDCl
3)δ(ppm)：1.20(s，2H)，1.42(s，3H)，1.59(s，1H)，2.17(s，3H)，2.65(dd，J＝13.6，10.2Hz，0.6H)，2.79(dd，J＝13.2，9.9Hz，0.4H)，3.08(dd，J＝13.5，2.7Hz，0.6H)，3.22(dd，J＝13.8，2.7Hz，0.4H)，4.39(d，J＝6.0Hz，0.4H)，4.45(d，J＝5.7Hz，0.8H)，4.49(d，J＝2.7Hz，0.3H)，4.56-4.64(m，1.5H)，5.04(d，J＝12.3Hz，0.4H)，5.10(d，J＝11.7Hz，0.6H)，5.22(d，J＝11.7Hz，.0.6H)，5.24(d，J＝12.3Hz，0.4H)，7.02-7.42(m，10H)，12.5(brs，1H).
N-SIMS：calcd.For?C
24H
26NO
6[M-H]
-：424.1760；found：424.1768.
Embodiment 7: synthetic (2S, 3R, 4S, 5S)-and 2-methyl-2-methylol-3, the two hydroxyls of 4--5-benzyl-pyrrole heptane hydrochloride salt (imines sugar (8))
Primary alconol (6) (260 milligrams) is dissolved in the amount of methanol, adds palladium carbon and several concentrated hydrochloric acids of catalytic amount, stirring reaction spends the night under hydrogen atmosphere.The pressure reducing and steaming solvent obtains product 0.17 gram, productive rate: 100%.
FT-MS：calcd.for?C
13H
20NO
3，[M+H]
+：238.1443；found：238.1431.
Embodiment 8: synthetic (3S, 4R, 5S)-and 2-benzyl-3,4-O-isopropylidene-5-methyl-5-triphen methoxyl methyl pyrroline-N-oxide compound (nitrone (9))
Raw material azanol (3) (0.76 gram) is dissolved in an amount of methylene dichloride, and stirring is spent the night.Remove by filter MnO
2, aftertreatment gets product 0.72 gram, productive rate: 94.5%.
FT-Ms?Calcd.for?C
35H
36NO
4[M+H]
+：534.2639，found：534.2632.
Embodiment 9: synthetic (2S, 3R, 4S, 5R)-and N-acetoxyl group-2-triphen methoxyl methyl-2-methyl-3,4-O-isopropylidene-5-benzyl-5-allyl group tetramethyleneimine (compound (10))
Raw material nitrone (9) (0.12 gram) is dissolved in the ether, and the ice-water bath cooling adds allyl group bromination magnesium solution (1M, 0.5 milliliter), after reacting completely, and saturated ammonium chloride solution cancellation reaction.The ordinary method aftertreatment obtains product 0.11 gram.Productive rate: 79%.
Spectroscopic data:
1H?NMR(CDCl
3)δ(ppm)：1.35(s，3H)，1.46(s，3H)，1.54(s，3H)，1.63(s，3H)，2.26(brs，1H，CH
2)，2.47(brs，1H)，2.73(d，J＝13.5Hz，1H)，2.80(brs，1H)，3.24(brd，J＝12.9Hz，1H)，3.70(d，J＝8.4Hz，1H，CH
2)，4.50(d，J＝6.0Hz，1H)，4.62(brs，1H)，5.01(d，J＝16.8Hz，1H)，5.07(t，J＝9.6Hz，1H)，5.88(brs，1H)，7.16-7.40(m，15H)，7.48-7.60(brm，5H).
Embodiment 10: synthetic (3R, 4S, 5R)-and 2-triphen methoxyl methyl-3,4-O-isopropylidene-5-crassitude (nitrone (12))
Raw material azanol (11) (7.0 grams, 15.7 mmoles) is dissolved in an amount of ethyl acetate, adds an amount of sodium bicarbonate, acetone, water adds the Oxone aqueous solution (14 gram) again, reacts separatory after 10 minutes, and the ordinary method aftertreatment obtains product, productive rate 77%.
Spectroscopic data:
1H?NMR(CDCl
3)δ(ppm)：1.38(d，J＝7.2Hz，3H)，1.43(s，3H)，1.54(s，3H)，4.03(q，J＝6.9Hz，1H)，4.24(tdd，J＝17.1，3.6，1.5Hz，2H)，4.45(dd，J＝5.1，0.9Hz，1H)，5.39(dd，J＝6.3，0.9Hz，1H)，7.24-7.33(m，9H)，7.48(dt，J＝6.9，0.9Hz，6H).
Embodiment 11: synthetic (2S, 3R, 4S, 5S)-and N-hydroxy-2-methyl-3,4-O-isopropylidene-5-benzyl-5-triphen methoxyl methyl tetramethyleneimine (azanol (13))
Nitrone (12) (4.27 gram) is dissolved in the anhydrous diethyl ether, is cooled to-70 ℃, drip benzyl bromination magnesium solution (2.0M, 10 milliliters) and react completely.The ordinary method aftertreatment obtains product, productive rate 82%.
Spectroscopic data:
13C?NMR(CDCl
3)δ(ppm)：17.28，24.33，25.59，40.00，63.82，67.45，79.61，81.00，88.01，112.79，125.95，126.26，126.63，127.36，127.63，127.94，128.07，128.43，128.52，128.66，129.03，129.56，130.97，137.24，143.24.
Embodiment 12: synthetic (2S, 3R, 4S, 5S)-and N-carbobenzoxy-(Cbz)-2-triphen methoxyl methyl-3,4-O-isopropylidene-5-crassitude (compound (15))
Azanol is dissolved in the dichloromethane solution for (13) 0.60 milligrams, adds an amount of acetic acid aqueous solution, zinc powder, venus crystals, at room temperature high degree of agitation is to reacting completely.Solids removed by filtration impurity, the ordinary method aftertreatment obtains product.Then the amine (14) that obtains is dissolved in the methylene dichloride, adds EtOH/H with volume
2O solution stirs and to drip CbzCl after adding an amount of sodium bicarbonate down, stirs 2 hours, adds the reaction of going out of coming together of 20 milliliters of saturated sodium bicarbonate solutions.The usual method aftertreatment gets product, productive rate 78%.
Spectroscopic data:
1H?NMR(CDCl
3)δ(ppm)：0.65(brs，1.8H)，0.91(brs，1.2H)，1.27(s，3H)，1.42(s，3H)，2.95(brd，J＝10.8Hz，1H)，3.50(brd，J＝10.8Hz，1H)，3.80(dd，J＝5.9，2.9Hz，1H)，3.92(brs，1H)，4.70(brs，1H，)，4.72(brd，J＝6.0Hz，1H)，4.87(brs，1H)，5.04(d，J＝11.9Hz，1H)，5.19(s，1H)，5.24(brs，1H)，7.12(brs，2H)，7.23(t，J＝2.8Hz，3H)，7.34-7.44(m，25H).
Embodiment 13: synthetic (2S, 3R, 4S, 5S)-and N-carbobenzoxy-(Cbz)-2-triphen methoxyl methyl-3,4-O-isopropylidene-5-crassitude (compound (16))
Digest and add 3 milliliters of formic acid in the acetonitrile solution of compound (15) to being dissolved with 0.54, stirring reaction 2 hours adds an amount of sodium hydrogen carbonate solution cancellation and reacts, and aftertreatment obtains product, productive rate 61%.
Spectroscopic data:
1H?NMR(CDCl
3)δ(ppm)(300MHz)：0.61(brs，3H，CH
3)，1.12(s，3H，OCH
3)，1.27(s，3H，OCH
3)，3.06(s，2H)，3.71(brs，3H)，3.94(brd，J＝11.8Hz，1H)，4.06(brs，1H)，4.53(brs，1H)，4.96(t，J＝12.3Hz，1H)，5.12(d，J＝11.8Hz，1H)，7.06(s，5H)，7.31(s，5H).
Embodiment 14: synthetic (2R, 3R, 4S, 5S)-and N-carbobenzoxy-(Cbz)-2-benzyl-3,4-O-isopropylidene-5-methylproline (proline(Pro) (17))
Raw material is dissolved in an amount of MeCN/H for (16) 110 milligrams
2O/CCl
4/ Me
2In the mixed solvent of CO, stir the hydration ruthenium chloride that adds solid sodium periodate and catalytic amount down, stirring at room is after 30 minutes, the Virahol collection that the drips 3ml reaction of going out, the solids removed by filtration residue, ethyl acetate is washed, column chromatography for separation obtains product after boiling off solvent, productive rate 76%.
Spectroscopic data:
IR：v(cm
-1)：2600-3400(br)，3060(w)，3032(m)，2981(m)，2940(m)，1702(vs)，1496(m)，1455(m)，1403(s)，1381(m)，1351(m)，1275(m)，1213(m)，1159(m)，1064(s)，1011(m)，911(m)，866(m)，732(m)，703(m).
N-SIMS：calcd.For?C
24H
26NO
6[M-H]
-：424.1760；found：424.1761.
Embodiment 15: synthetic (2S, 3R, 4S, 5S)-and 2-benzyl-2-methylol-3, the two hydroxy-5-methyl base pyrroles hydrochlorides (polysubstituted imines sugar (18)) of 4-
Raw material is dissolved in the HCl-MeOH solution for (13) 50 milligrams, at room temperature stirred 2 hours, behind the pressure reducing and steaming solvent, obtain 21 milligrams of products, productive rate 84%.
Spectroscopic data:
IR：v(cm
-1)：3485(m)，3362(brs)，3296(brs)，2980(s)，2577(w)，2495(m)，2453(m)，2236(w)，1593(m)，1494(m)，1455(s)，1423(m)，1336(m)，1252(m)，1216(m)，1119(s)，1072(s)，1035(m)，969(w)，830(w)，766(w)，707(m)，652(m)，560(w).
FT-IRMS?calcd.For?C
13H
20NO
3[M+H]
+：238.1443，found：238.1434.
Claims (15)
1, the branched polyhydroxy pyrrole derivatives of formula I structure,
Wherein, R
1Be methylol, alkoxyl-methyl, fragrant methoxyl methyl, triphen methoxyl methyl, benzyloxymethyl, trialkyl silica methyl, carboxyl or ester group;
R
2And R
3Be hydrogen, C
1-C
20-alkyl, C
3-C
8-cycloalkyl, C
6-C
10The benzyl of-aryl, replacement, methoxyl methyl, ethoxymethyl, front three are silica-based, uncle's fourth oxygen silicon base, isopropylidene, cyclohexylidene base, benzal base or cyclopropyl methylene fork base;
R
4Be C
1-C
20-alkyl, C
3-C
8-cycloalkyl, C
6-C
10-aryl, C
6-C
10-arylmethyl, vinyl, allyl group, alkynyl, propargyl, 2-furyl or cyano group;
R
5Be hydrogen, C
1-C
20-alkyl, C
3-C
8-cycloalkyl, C
6-C
10-aryl, C
6-C
10-arylmethyl, vinyl, allyl group, alkynyl, propargyl, 2-furyl or cyano group;
R
6Be hydrogen, C
1-C
20-alkyl, C
3-C
8-cycloalkyl, C
6-C
10-aryl, C
6-C
10-arylmethyl, vinyl, allyl group, alkynyl, propargyl, 2-furyl or cyano group;
R
7Be hydroxyl, hydrogen, acetoxyl group, benzyloxy, tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or 9-fluorenylmethoxycarbonyl;
And, work as R
1When being not carboxyl or ester group, R
5And R
6Be not hydrogen simultaneously.
2, R among the formula I
7Be hydroxyl, R
5And R
6In a preparation method for the branched polyhydroxy pyrrole derivatives of hydrogen is arranged, comprise the steps:
1) azanol with the formula III structure carries out oxidizing reaction, obtains the nitrone suc as formula IV/a or formula IV/b structure,
(formula III) (formula IV/a) (formula IV/b)
2) with gained nitrone and organometallic reagent R
5MX or (R
5)
2M reacts, and obtains the pyrrolidin derivatives of formula II/a or formula II/b structure;
(formula II/a) (formula II/b)
Wherein, R
1Be methylol, alkoxyl-methyl, fragrant methoxyl methyl, triphen methoxyl methyl, benzyloxymethyl, trialkyl silica methyl, carboxyl or ester group;
R
2And R
3Be hydrogen, C
1-C
20-alkyl, C
3-C
8-cycloalkyl, C
6-C
10The benzyl of-aryl, replacement, methoxyl methyl, ethoxymethyl, front three are silica-based, uncle's fourth oxygen silicon base, isopropylidene, cyclohexylidene base, benzal base or cyclopropyl methylene fork base;
R
4Be C
1-C
20-alkyl, C
3-C
8-cycloalkyl, C
6-C
10-aryl, C
6-C
10-arylmethyl, vinyl, allyl group, alkynyl, propargyl, 2-furyl or cyano group;
R
5Be hydrogen, C
1-C
20-alkyl, C
3-C
8-cycloalkyl, C
6-C
10-aryl, C
6-C
10-arylmethyl, vinyl, allyl group, alkynyl, propargyl, 2-furyl or cyano group;
M is magnesium, lithium, zinc, copper, manganese or its mixture;
X is chlorine, bromine, iodine.
3, preparation method according to claim 2 is characterized in that: the oxygenant of the described oxidizing reaction of step 1) is Manganse Dioxide, red precipitate, hydrogen peroxide, Oxone or benzophenone; Step 2) described organometallic reagent is organomagnesium reagent, organic zinc reagent, organolithium reagent, organic copper reagent or organosilicon reagent.
4, R among the formula I
7Be hydrogen, R
5And R
6In a preparation method for the branched polyhydroxy pyrrole derivatives of hydrogen is arranged, be that the pyrrolidin derivatives with formula II/a or formula II/b structure carries out reduction reaction, obtain the pyrrolidin derivatives of formula II/c or formula II/d structure.
(formula II/c) (formula II/d)
5, preparation method according to claim 4 is characterized in that: the reductive agent of described reduction reaction is a metal simple-substance, samarium, low price samarium compound, the hydrogenation that zinc-copper is occasionally transition metal-catalyzed.
6, R among the formula I
2, R
3, R
7Be hydrogen, R
1Be CH
2OH, R
5And R
6In a preparation method for the branched polyhydroxy pyrrole derivatives of hydrogen is arranged, be that pyrrolidin derivatives with formula II/a or formula II/b structure carries out reduction reaction under acidic conditions, perhaps, the pyrrolidin derivatives of formula II/c or formula II/d structure is handled with acid, obtained the pyrrolidin derivatives of formula II/e or formula II/f structure.
(formula II/e) (formula II/f)
7, preparation method according to claim 6 is characterized in that: described acid is hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, acetate or formic acid.
8, R among the formula I
7Be not hydrogen or hydroxyl, R
5And R
6In a preparation method for the branched polyhydroxy pyrrole derivatives of hydrogen is arranged, be that pyrrolidin derivatives and the amido protecting agent with formula II/c or formula II/d structure reacts, obtain the pyrrolidin derivatives of formula II/g or formula II/h structure;
(formula II/g) (formula II/h)
Wherein, R
7Be ethanoyl, benzoyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or 9-fluorenylmethoxycarbonyl.
9, preparation method according to claim 8, it is characterized in that: amido protecting agent is selected from diacetyl oxide, benzoyl oxide, Boc acid anhydrides, benzyloxy dicarbonyl chloride, 9-fluorenes methoxy dicarbonyl chloride, Benzoyl chloride or benzene sulfonyl chloride etc.
10, R among the formula I
7Be not hydrogen or hydroxyl, R
1Be CH
2OH, R
5And R
6In a preparation method for the branched polyhydroxy pyrrole derivatives of hydrogen is arranged, be that the pyrrolidin derivatives with formula II/g or formula II/h structure removes R under acidic conditions
1In hydroxy-protective group, obtain the pyrrolidin derivatives of formula II/i or formula II/j structure;
(formula II/i) (formula II/h)
Wherein, R
7Be ethanoyl, benzoyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or 9-fluorenylmethoxycarbonyl.
11, preparation method according to claim 10 is characterized in that: described acid is hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, acetate or formic acid.
12, R among the formula I
7Be not hydrogen or hydroxyl, R
1Be COOR
8, R
5And R
6In a preparation method for the branched polyhydroxy pyrrole derivatives of hydrogen is arranged, be that the pyrrolidin derivatives with formula II/i or formula II/j structure carries out oxidizing reaction, obtain the pyrrolidin derivatives of formula II/k or formula II/l structure;
(formula II/k) (formula II/l)
Wherein, R
7Be ethanoyl, benzoyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or 9-fluorenylmethoxycarbonyl; R
8Be hydrogen, alkyl or benzyl.
13, preparation method according to claim 12, it is characterized in that: described oxygenant is the catalytic sodium periodate of metal ruthenium compound, clorox, or at first be oxidized to behind the corresponding aldehyde again with Textone or iodo-methanol oxidation with Swern reagent or IBX reagent oxidation method.
14, R among the formula I
7Preparation method for the branched polyhydroxy pyrrole derivatives of hydroxyl comprises the steps:
1) azanol with formula II/a or formula II/b structure carries out oxidizing reaction, obtains the nitrone suc as formula V/a or formula V/b structure,
(formula V/a) (formula V/b)
2) with gained nitrone and organometallic reagent R
6MX reacts, and obtains the pyrrolidin derivatives of formula II/m or formula II/n structure;
(formula II/m) (formula II/n)
Wherein, R
6Be hydrogen, C
1-C
20-alkyl, C
3-C
8-cycloalkyl, C
6-C
10-aryl, C
6-C
10-arylmethyl, vinyl, allyl group, alkynyl, propargyl, 2-furyl or cyano group;
M is magnesium, lithium, zinc, copper, manganese or its mixture;
X is chlorine, bromine, iodine.
15, the described branched polyhydroxy pyrrole derivatives of claim 1 is in preparation 2, the polysubstituted poly-hydroxy proline(Pro) of 5-and 2, the application in the polysubstituted imines sugar of 5-.
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| CN103772233A (en) * | 2014-01-06 | 2014-05-07 | 华东师范大学 | Multi-halothane five-member cyclic nitrone derivative and preparation method thereof |
| CN106966943A (en) * | 2017-03-24 | 2017-07-21 | 中国科学院化学研究所 | Polyhydroxy pyrrole class compound of C4 cladodification and its preparation method and application |
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| CN103772233A (en) * | 2014-01-06 | 2014-05-07 | 华东师范大学 | Multi-halothane five-member cyclic nitrone derivative and preparation method thereof |
| CN103772233B (en) * | 2014-01-06 | 2015-06-10 | 华东师范大学 | Multi-halothane five-member cyclic nitrone derivative and preparation method thereof |
| CN106966943A (en) * | 2017-03-24 | 2017-07-21 | 中国科学院化学研究所 | Polyhydroxy pyrrole class compound of C4 cladodification and its preparation method and application |
| CN106966943B (en) * | 2017-03-24 | 2020-09-18 | 中国科学院化学研究所 | C4 branched polyhydroxy pyrrolidine compound and preparation method and application thereof |
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