CN102702079A - Novel methods for preparing 1-DNJ (1-deoxynojirinmycin) and precursor of 1-deoxynojirinmycin - Google Patents
Novel methods for preparing 1-DNJ (1-deoxynojirinmycin) and precursor of 1-deoxynojirinmycin Download PDFInfo
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- 0 *C([C@](CN[C@@]1COCc2ccccc2)OCc2ccccc2)[C@@]1OCc1ccccc1 Chemical compound *C([C@](CN[C@@]1COCc2ccccc2)OCc2ccccc2)[C@@]1OCc1ccccc1 0.000 description 3
- ZTJQTIBBDAWOAC-YYWHXJBOSA-N C[C@@H](C[C@@H](COCc1ccccc1)[O]=C1)[C@H]1OCc1ccccc1 Chemical compound C[C@@H](C[C@@H](COCc1ccccc1)[O]=C1)[C@H]1OCc1ccccc1 ZTJQTIBBDAWOAC-YYWHXJBOSA-N 0.000 description 1
- YVBOTXRDJJAUQO-NJTBCWBZSA-N C[C@@H]([C@@H](C(COCc1ccccc1)=O)OCc1ccccc1)[C@H](C(N)=O)OCc1ccccc1 Chemical compound C[C@@H]([C@@H](C(COCc1ccccc1)=O)OCc1ccccc1)[C@H](C(N)=O)OCc1ccccc1 YVBOTXRDJJAUQO-NJTBCWBZSA-N 0.000 description 1
- FKADCTWKCIXILH-FMPXFOGJSA-N O=C([C@@H](/C1=[O]\Cc2ccccc2)OCc2ccccc2)N[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1 Chemical compound O=C([C@@H](/C1=[O]\Cc2ccccc2)OCc2ccccc2)N[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1 FKADCTWKCIXILH-FMPXFOGJSA-N 0.000 description 1
- SQXIVZOCLRZWCM-QBESDBSVSA-N O=C([C@@H]([C@H]1OCc2ccccc2)OCc2ccccc2)OC(C2)(C2OCc2ccccc2)[C@H]1OCc1ccccc1 Chemical compound O=C([C@@H]([C@H]1OCc2ccccc2)OCc2ccccc2)OC(C2)(C2OCc2ccccc2)[C@H]1OCc1ccccc1 SQXIVZOCLRZWCM-QBESDBSVSA-N 0.000 description 1
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Abstract
The invention provides a method for preparing 1-DNJ (1-deoxynojirinmycin). The method comprises the following steps: providing a precursor of the 1-DNJ (1-deoxynojirinmycin), wherein the precursor is 3, 4, 5-tris (benzyloxy)-2-benzyl-oxygen-methyl-piperidine, and carrying out hydrogenation on the precursor to obtain the 1-DNJ (1-deoxynojirinmycin). The invention also provides a preparation method of the precursor of the 1-DNJ (1-deoxynojirinmycin).
Description
Technical field
The invention belongs to pharmaceutical-chemical intermediate and relevant technical field of chemistry thereof, relate to a kind of 1-DNJ (the wild buttocks poison of 1-deoxidation) and precursor 3,4 thereof, the preparation method of 5-three benzyloxies-2-benzyloxymethyl piperidines.
Background technology
1-DNJ is a kind of pyridine alkaloid, and chemical name is: 3,4, and the 5-trihydroxy-, 2-methylol tetrahydropyridine is the abbreviation of 1-deoxynojirimycin.Structure is shown below:
1-DNJ (the wild buttocks poison of 1-deoxidation) structural formula
1-DNJ can suppress alpha-glucosidase efficiently, thus the rising that postprandial plasma glucose level is lowered in the absorption of the digestion of reduction glucide and glucose.1-DNJ can be used for treating mellitus, diabetic complication, virus infection, obesity and correlation function disorder etc.
Reported the method for a kind of synthetic 1-DNJ (1-deoxidation wild buttocks poison) at document J.Med.Chem. (medical chemistry magazine) 2010,53,689 – 698, its shortcoming is that the raw material of using is difficult to obtain, and raw material is expensive, and reaction conditions is strict, is not suitable for suitability for industrialized production.
At document J.Org.Chem. (organic chemistry magazine) 2007,72,1088-1097 has reported the midbody method of a kind of synthetic 1-DNJ (the wild buttocks poison of 1-deoxidation); Its shortcoming is raw materials used dangerous, as using lithium aluminum hydride, very easily catches fire; Severe reaction conditions like its used DMSO 99.8MIN. and oxalyl chloride oxidation, used-70 ° of following temperature of C; Its dialdehyde midbody is extremely unstable, and its technology will be not suitable for suitability for industrialized production with being operation such as post.
In sum, this area lacks the preparation technology of a kind of 1-DNJ (1-deoxidation wild buttocks poison) and midbody thereof, and this method route is short, the raw material cheapness that is easy to get, and reaction conditions is gentle, and product purification is simple, and product purity is high, is fit to suitability for industrialized production.
Therefore, this area presses for the preparation technology of a kind of 1-DNJ of exploitation (1-deoxidation wild buttocks poison) and midbody thereof, and this method route is short, the raw material cheapness that is easy to get, and reaction conditions is gentle, and product purification is simple, and product purity is high, is fit to suitability for industrialized production.
Summary of the invention
First purpose of the present invention is to obtain the preparation technology of 1-DNJ (the wild buttocks poison of 1-deoxidation), and this method route is short, the raw material cheapness that is easy to get, and reaction conditions is gentle, and product purification is simple, and product purity is high, is fit to suitability for industrialized production.
Second purpose of the present invention is to obtain the preparation technology of 1-DNJ (the wild buttocks poison of 1-deoxidation) and midbody thereof, and this method route is short, the raw material cheapness that is easy to get, and reaction conditions is gentle, and product purification is simple, and product purity is high, is fit to suitability for industrialized production.
The 3rd purpose of the present invention is to obtain a kind of with 3,4, and 5-three benzyloxies-2-benzyloxymethyl piperidines is as the purposes of the precursor of preparation 1-DNJ (the wild buttocks poison of 1-deoxidation).
In first aspect of the present invention, a kind of 1-DNJ is provided the preparation method of (the wild buttocks poison of 1-deoxidation), it comprises the steps:
1-DNJ is provided the precursor of (the wild buttocks poison of 1-deoxidation), and said precursor is 3,4,5-three benzyloxies-2-benzyloxymethyl piperidines;
Said precursor carries out hydrogenation, obtains said 1-DNJ (the wild buttocks poison of 1-deoxidation).
In an embodiment of the present invention, the preparation method of said 1-DNJ (the wild buttocks poison of 1-deoxidation) comprises the steps:
(a) provide suc as formula 2,3,4 shown in (I), 6-four-benzyl-β-D-glucopyranose (2,3,4,6-tetra-O-benzyl-β-D-glucopyranose),
(b) 2 shown in the said formula (I); 3; 4; 6-four-benzyl-β-D-glucopyranose is through synthetic route as follows, comprises that the ammonia of oxidation, the step (2) of step (1) is separated, the oxidation of step (3), the reduction amination of step (4), the reduction of step (5) and the hydrogenation of step (6), obtains said precursor suc as formula the 1-DNJ shown in (VI) (the wild buttocks poison of 1-deoxidation);
(c) saidly carry out hydrogenation, obtain suc as formula the 1-DNJ shown in (VII) (the wild buttocks poison of 1-deoxidation) suc as formula the precursor shown in (VI).
In an embodiment of the present invention, in the oxidation of said step (1), with suc as formula 2,3 shown in (I); 4,6-four-benzyl-β-D-glucopyranose (2,3,4; 6-tetra-O-benzyl-β-D-glucopyranose) is a raw material, having under solvent or the solvent-free situation, with 2 of the said formula of oxygenant oxidation (I); 3,4,6-four-benzyl-β-D-glucopyranose obtains suc as formula the compound shown in (II):
Said oxidizing reaction is Swern oxidation style or hypochlorite oxidation method, and said oxygenant is the oxygenant that is applicable to the Swern oxidation style; Or the oxygenant of hypochlorite oxidation method; Temperature of reaction is controlled between-80 ° of C～60 ° C.
In an embodiment, said oxygenant comprises DMSO 99.8MIN. and acetic anhydride, methyl-sulphoxide and oxalyl chloride, pyridine sulphur trioxide, 2,2,6,6-tetramethyl piperidine oxide compound, Youxiaolin, Textone or its combination.
In an embodiment, said oxygenant is DMSO 99.8MIN. and acetic anhydride, and raw material I and DMSO 99.8MIN. mol ratio are 1:1～1:30 in the step (1), and raw material formula (I) compound and acetic anhydride mol ratio are 1:1～1:20.
In an embodiment, solvent is a methylene dichloride in the step (1), ethylene dichloride, and THF, 1, single or mixed solvents such as 4-dioxane, perhaps solvent-free.Be preferably solvent-free.
In an embodiment, be preferably solvent-freely, oxygenant is preferably DMSO 99.8MIN. and acetic anhydride, and temperature of reaction is preferably between 10 ° of C～30 ° C.
In an embodiment of the present invention, during the ammonia of said step (2) is separated,
Formula (II) compound is dissolved in the organic solvent logical ammonia to carry out ammonia and separates the formula of obtaining (III) compound,
Temperature of reaction is controlled between-20 ° of C～60 ° C.
In a preferred implementation of the present invention, said organic solvent is alcoholic solvent or ether solvent.Said alcoholic solvent for example is a methyl alcohol, ethanol, Virahol, various types of butanols.Said ether solvent for example is a THF, ether, single or mixed solvent such as MTBE.
In a preferred implementation of the present invention, solvent is preferably methyl alcohol in the step (2), and temperature of reaction is preferably between 10 ° of C～30 ° C.
In a preferred implementation of the present invention, the mol ratio of raw material formula (II) compound and ammonia is 1:1～1:10 in the step (2).
In an embodiment of the present invention, in the oxidation of said step (3),
Having under solvent or the solvent-free situation, obtaining formula (IV) compound with oxygenant oxidation formula (III) compound,
Said oxidizing reaction is Swern oxidation style or hypochlorite oxidation method; Said oxygenant is the oxygenant that is applicable to the Swern oxidation style; Or the oxygenant of hypochlorite oxidation method; Temperature of reaction is controlled between-20 ° of C～60 ° C.
In an embodiment, said oxygenant comprises DMSO 99.8MIN. and acetic anhydride, methyl-sulphoxide and oxalyl chloride, pyridine sulphur trioxide, 2,2,6,6-tetramethyl piperidine oxide compound, Youxiaolin, Textone or its combination
In an embodiment, said solvent is generally organic solvent.When adopting solvent, said solvent is a methylene dichloride, ethylene dichloride, THF, 1, single or mixed solvents such as 4-dioxane.
In a preferred embodiment, the middle solvent of step (3) is preferably solvent-free, and oxygenant is preferably DMSO 99.8MIN. and acetic anhydride, and temperature of reaction is preferably between 10 ° of C～30 ° C.
In a preferred embodiment, oxygenant is DMSO 99.8MIN. and acetic anhydride described in the step (3), and said raw material formula (III) compound and DMSO 99.8MIN. mol ratio are 1:1～1:30, and raw material formula (I) compound and acetic anhydride mol ratio are 1:1～1:20.
In an embodiment of the present invention, in the reduction amination of said step (4),
Said formula (IV) compound is dissolved in the organic solvent, in the presence of reductive agent, obtains the formula V compound in acidic conditions reduction amination formula (IV) compound:
Temperature of reaction is controlled between-20 ° of C～120 ° C.
In an embodiment, said organic solvent comprises acetonitrile, alcoholic solvent or ether solvent, concrete for example methyl alcohol, ethanol, Virahol, various types of butanols, THF, ether, single or mixed solvent such as MTBE.
In an embodiment, said acid is organic acid, more specifically comprises formic acid, acetate, trifluoroacetic acid or its combination.
In an embodiment, reductive agent comprises Peng Qinghuana, sodium triacetoxy borohydride, sodium cyanoborohydride.
In an embodiment, solvent is preferably acetonitrile in the step (4), and acid is preferably formic acid, and reductive agent is preferably sodium cyanoborohydride, and temperature of reaction is preferably between 70 ° of C～100 ° C.
In an embodiment, adopt sodium cyanoborohydride as reductive agent in the step (4), raw material (IV) compound and sodium cyanoborohydride mol ratio are 1:1～1:5, raw material (IV) compound is 1:1～1:50 with the mol ratio of acid.
In an embodiment of the present invention, in the reduction of the step of said synthetic route (5),
The formula V compound is dissolved in the organic solvent, reduces said formula V compound down and obtains formula (VI) compound in the reductive agent existence:
Temperature of reaction is controlled between-20 ° of C～120 ° C.
In a preferred implementation, solvent is an ether solvent, like THF, and ether, glycol dimethyl ether, single or mixed solvent such as MTBE.
In a preferred implementation, reductive agent comprises lithium aluminum hydride, the THF of borine or dimethyl sulphide solution, or boron trifluoride and Peng Qinghuana original position resultant.In a preferred implementation, solvent is preferably THF in the step (5), and reductive agent is preferably the original position resultant of boron trifluoride and Peng Qinghuana, and temperature of reaction is preferably between 70 ° of C～100 ° C.
In a preferred implementation, the reductive agent that step (5) adopts is boron trifluoride and Peng Qinghuana original position resultant, and the mol ratio of raw material (V) compound and boron trifluoride is 1:1～1:5, and the mol ratio of boron trifluoride and Peng Qinghuana is 3:4.
In an embodiment of the present invention, in the hydrogenation of the step of said synthetic route (6),
The formula V compound is dissolved in the organic solvent, and hydrogenation formula V compound obtains formula (VI) compound in the presence of catalyzer:
Temperature of reaction is controlled between-20 ° of C～120 ° C.
In a preferred implementation, said organic solvent is an alcoholic solvent, like methyl alcohol, and ethanol, propyl alcohol, Virahol, butanols, 1-butanols, single or mixed solvents such as 2-butanols.
In a preferred implementation, catalyzer comprises Pd/C, Pd (OH)
2/ C, Raney-Ni, PtO
2Deng.In a preferred implementation, solvent is preferably methyl alcohol in the step (6), and catalyzer is Pd/C, and temperature of reaction is preferably between 20 ° of C～80 ° C.
In a preferred implementation, raw material (V) is 1:0.001～1:0.1 with the mass ratio of catalyzer in the step (6).
In a preferred implementation, reaction pressure is 1～3 normal atmosphere in the step (6).
In an embodiment, comprise the steps:
(1) with 2,3,4,6-tetra-O-benzyl-β-D-glucopyranose (I) is a raw material, is having under solvent or the solvent-free situation; With oxygenant oxidation 2,3,4,6-tetra-O-benzyl-β-D-glucopyranose (I) obtains II, and oxygenant comprises DMSO 99.8MIN. and acetic anhydride; Methyl-sulphoxide and oxalyl chloride, pyridine sulphur trioxide, 2,2,6; 6-tetramethyl piperidine oxide compound, Youxiaolin, Textone etc., temperature of reaction is controlled between-80 ° of C～60 ° C.Solvent is a methylene dichloride, ethylene dichloride, THF, 1, single or mixed solvents such as 4-dioxane.
(2) II is dissolved in the organic solvent, like alcoholic solvent or ether solvent, methyl alcohol, ethanol; Virahol, various types of butanols, THF, ether; Single or mixed solvent such as MTBE, logical ammonia carry out ammonia to be separated and obtains II I, and temperature of reaction is controlled between-20 ° of C～60 ° C.
(3) having under solvent or the solvent-free situation, III obtains IV with the oxygenant oxidation, and oxygenant comprises DMSO 99.8MIN. and acetic anhydride; Methyl-sulphoxide and oxalyl chloride, pyridine sulphur trioxide, 2; 2,6,6-tetramethyl piperidine oxide compound; Youxiaolin, Textone etc., temperature of reaction is controlled between-20 ° of C～60 ° C.Solvent is a methylene dichloride, ethylene dichloride, THF, 1, single or mixed solvents such as 4-dioxane.
(4) IV is dissolved in the organic solvent, adds acid, adds reductive agent, and reduction amination IV becomes V.Solvent comprises acetonitrile, alcoholic solvent or ether solvent, methyl alcohol, ethanol; Virahol, various types of butanols, THF, ether; Single or mixed solvent such as MTBE, acid comprises formic acid, acetate, trifluoroacetic acid etc.; Reductive agent comprises Peng Qinghuana, sodium triacetoxy borohydride, sodium cyanoborohydride.Temperature of reaction is controlled between-20 ° of C～120 ° C.
(5) V is dissolved in the organic solvent, adds reductive agent, and reduction V obtains VI.Solvent is an ether solvent, like THF, and ether, glycol dimethyl ether, single or mixed solvent such as MTBE.Reductive agent comprises, lithium aluminum hydride, the THF of borine or dimethyl sulphide solution, or boron trifluoride and Peng Qinghuana original position resultant.Temperature of reaction is controlled between-20 ° of C～120 ° C.
(6) VI is dissolved in the organic solvent, adds catalyzer, and reduction VI obtains VII.Solvent is an alcoholic solvent, like methyl alcohol, and ethanol, propyl alcohol, Virahol, butanols, 1-butanols, single or mixed solvents such as 2-butanols.Catalyzer comprises Pd/C, Pd (OH)
2/ C, Raney-Ni, PtO
2Deng.Temperature of reaction is controlled between-20 ° of C～120 ° C.Reaction pressure is controlled at 1～3 normal atmosphere.
Second aspect of the present invention provides the preparation method of the precursor of a kind of 1-DNJ (the wild buttocks poison of 1-deoxidation), and it comprises the steps:
(A) provide suc as formula 2,3,4 shown in (I), 6-four-benzyl-β-D-glucopyranose (2,3,4,6-tetra-O-benzyl-β-D-glucopyranose),
(B) 2 shown in the said formula (I); 3; 4; The ammonia that 6-four-benzyl-β-D-glucopyranose carries out oxidation, the step (2) of step (1) through synthetic route as follows is separated, the oxidation of step (3), the reduction amination of step (4), the reduction of step (5), obtains said precursor as shown in the formula the 1-DNJ shown in (VI) (the wild buttocks poison of 1-deoxidation):
It is a kind of with 3,4 that the third aspect of the invention provides, and 5-three benzyloxies-2-benzyloxymethyl piperidines is as the purposes of the precursor of preparation 1-DNJ (the wild buttocks poison of 1-deoxidation).
Embodiment
The inventor through improving preparation technology, provides a kind of 3 through extensive and deep research; 4, the preparation technology of 5-three benzyloxies-2-benzyloxymethyl piperidines and 1-DNJ (the wild buttocks poison of 1-deoxidation), this method route is short; The raw material cheapness that is easy to get, reaction conditions is gentle, and product purification is simple; Product purity is high, is fit to suitability for industrialized production.Accomplished the present invention on this basis.
Among the present invention, term " contains " or the various compositions of " comprising " expression can be applied in mixture of the present invention or the compsn together.Therefore, term " mainly by ... form " be included in " by ... composition " that term " contains " or in " comprising ".
Below detail to various aspects of the present invention:
The preparation method of 1-DNJ (the wild buttocks poison of 1-deoxidation)
The present invention provides a kind of 1-DNJ the preparation method of (the wild buttocks poison of 1-deoxidation), and it comprises the steps:
1-DNJ is provided the precursor of (the wild buttocks poison of 1-deoxidation), and said precursor is 3,4,5-three benzyloxies-2-benzyloxymethyl piperidines;
Said precursor carries out hydrogenation, obtains said 1-DNJ (the wild buttocks poison of 1-deoxidation).
More specifically, comprise the steps:
(a) provide suc as formula 2,3,4 shown in (I), 6-four-benzyl-β-D-glucopyranose (2,3,4,6-tetra-O-benzyl-β-D-glucopyranose),
(b) 2 shown in the said formula (I); 3; 4; 6-four-benzyl-β-D-glucopyranose is through synthetic route as follows, comprises that the ammonia of oxidation, the step (2) of step (1) is separated, the oxidation of step (3), the reduction amination of step (4), the reduction of step (5) and the hydrogenation of step (6), obtains said precursor suc as formula the 1-DNJ shown in (VI) (the wild buttocks poison of 1-deoxidation);
(c) saidly carry out hydrogenation, obtain suc as formula the 1-DNJ shown in (VII) (the wild buttocks poison of 1-deoxidation) suc as formula the precursor shown in (VI).
The inventor finds that adopt said synthesis route can reach following effect: route is short, the raw material cheapness that is easy to get, and reaction conditions is gentle, and product purification is simple, and product purity is high, is fit to suitability for industrialized production.
And said precursor can commercially availablely obtain, and further improved the short effect of route of the present invention.
The oxidation of step (1)
In the oxidation of said step (1), with suc as formula 2,3,4 shown in (I); 6-four-benzyl-β-D-glucopyranose (2,3,4; 6-tetra-O-benzyl-β-D-glucopyranose) is a raw material, having under solvent or the solvent-free situation, with 2 of the said formula of oxygenant oxidation (I); 3,4,6-four-benzyl-β-D-glucopyranose obtains suc as formula the compound shown in (II):
Said oxidizing reaction is Swern oxidation style or hypochlorite oxidation method, and said oxygenant is the oxygenant that is applicable to the Swern oxidation style; Or the oxygenant of hypochlorite oxidation method; Temperature of reaction is controlled between-80 ° of C～60 ° C.
Said Swern oxidation style or hypochlorite oxidation method are the known synthetic routes of art technology, do not do at this and give unnecessary details.For example be found in Tetrahedron Letters; Vol.34; Nb.15; (1993); P.2527 – 2528.
In an embodiment, said oxygenant comprises DMSO 99.8MIN. and acetic anhydride, methyl-sulphoxide and oxalyl chloride, pyridine sulphur trioxide, 2,2,6,6-tetramethyl piperidine oxide compound, Youxiaolin, Textone or its combination.
Said organic solvent makes formula (I) compound dissolution and oxidizing reaction constitute not being hindered get final product.
In an embodiment, solvent is a methylene dichloride in the step (1), ethylene dichloride, THF; 1, single or mixed solvents such as 4-dioxane, perhaps solvent-free; Be preferably solvent-freely, oxygenant is preferably DMSO 99.8MIN. and acetic anhydride, and temperature of reaction is preferably between 10 ° of C～30 ° C.
In an embodiment, said oxygenant is DMSO 99.8MIN. and acetic anhydride, and raw material I and DMSO 99.8MIN. mol ratio are 1:1～1:30 in the step (1), and raw material formula (I) compound and acetic anhydride mol ratio are 1:1～1:20.
The ammonia of step (2) is separated
During the ammonia of said step (2) is separated,
Formula (II) compound is dissolved in the organic solvent logical ammonia to carry out ammonia and separates the formula of obtaining (III) compound,
Temperature of reaction is controlled between-20 ° of C～60 ° C.
Said organic solvent makes formula (II) compound dissolution and ammonolysis reaction constitute not being hindered get final product.
In a preferred implementation of the present invention, said organic solvent is alcoholic solvent or ether solvent.Said alcoholic solvent for example is a methyl alcohol, ethanol, Virahol, various types of butanols.Said ether solvent for example is a THF, ether, single or mixed solvent such as MTBE.
In a preferred implementation of the present invention, solvent is preferably methyl alcohol in the step (2), and temperature of reaction is preferably between 10 ° of C～30 ° C.
In a preferred implementation of the present invention, the mol ratio of raw material formula (II) compound and ammonia is 1:1～1:10 in the step (2).
The oxidation of step (3)
In the oxidation of said step (3),
Having under solvent or the solvent-free situation, obtaining formula (IV) compound with oxygenant oxidation formula (III) compound,
Said oxidizing reaction is Swern oxidation style or hypochlorite oxidation method; Said oxygenant is the oxygenant that is applicable to the Swern oxidation style; Or the oxygenant of hypochlorite oxidation method; Temperature of reaction is controlled between-20 ° of C～60 ° C.
In an embodiment, said oxygenant comprises DMSO 99.8MIN. and acetic anhydride, methyl-sulphoxide and oxalyl chloride, pyridine sulphur trioxide, 2,2,6,6-tetramethyl piperidine oxide compound, Youxiaolin, Textone or its combination
In an embodiment, when adopting solvent, said organic solvent makes formula (III) compound dissolution and oxidizing reaction is not constituted to hinder and get final product.
In an embodiment, when adopting solvent, said solvent is a methylene dichloride, ethylene dichloride, THF, 1, single or mixed solvents such as 4-dioxane.
In a preferred embodiment, the middle solvent of step (3) is preferably solvent-free, and oxygenant is preferably DMSO 99.8MIN. and acetic anhydride, and temperature of reaction is preferably between 10 ° of C～30 ° C.
In a preferred embodiment, oxygenant is DMSO 99.8MIN. and acetic anhydride described in the step (3), and said raw material formula (III) compound and DMSO 99.8MIN. mol ratio are 1:1～1:30, and raw material formula (I) compound and acetic anhydride mol ratio are 1:1～1:20.
The reduction amination of step (4)
In the reduction amination of said step (4),
Said formula (IV) compound is dissolved in the organic solvent, in the presence of reductive agent, obtains the formula V compound in acidic conditions reduction amination formula (IV) compound:
Temperature of reaction is controlled between-20 ° of C～120 ° C.
Said organic solvent makes formula (IV) compound dissolution and reductive amination process constitute not being hindered get final product.
In an embodiment, said organic solvent comprises acetonitrile, alcoholic solvent or ether solvent, concrete for example methyl alcohol, ethanol, Virahol, various types of butanols, THF, ether, single or mixed solvent such as MTBE.
In an embodiment, said acid is organic acid, more specifically comprises formic acid, acetate, trifluoroacetic acid or its combination.
In an embodiment, reductive agent comprises Peng Qinghuana, sodium triacetoxy borohydride, sodium cyanoborohydride.
In an embodiment, solvent is preferably acetonitrile in the step (4), and acid is preferably formic acid, and reductive agent is preferably sodium cyanoborohydride, and temperature of reaction is preferably between 70 ° of C～100 ° C.
In an embodiment, adopt sodium cyanoborohydride as reductive agent in the step (4), raw material (IV) compound and sodium cyanoborohydride mol ratio are 1:1～1:5, raw material (IV) compound is 1:1～1:50 with the mol ratio of acid.
The reduction of step (5)
In the reduction of the step of said synthetic route (5),
The formula V compound is dissolved in the organic solvent, reduces said formula V compound down and obtains formula (VI) compound in the reductive agent existence:
Temperature of reaction is controlled between-20 ° of C～120 ° C.
Said organic solvent makes formula V compound dissolution and reduction reaction constitute not being hindered get final product.
In a preferred implementation, solvent is an ether solvent, like THF, and ether, glycol dimethyl ether, single or mixed solvent such as MTBE.
In a preferred implementation, reductive agent comprises lithium aluminum hydride, the THF of borine or dimethyl sulphide solution, or boron trifluoride and Peng Qinghuana original position resultant.In a preferred implementation, solvent is preferably THF in the step (5), and reductive agent is preferably the original position resultant of boron trifluoride and Peng Qinghuana, and temperature of reaction is preferably between 70 ° of C～100 ° C.
In a preferred implementation, the reductive agent that step (5) adopts is boron trifluoride and Peng Qinghuana original position resultant, and the mol ratio of raw material (V) compound and boron trifluoride is 1:1～1:5, and the mol ratio of boron trifluoride and Peng Qinghuana is 3:4.
The hydrogenation of step (6)
In the hydrogenation of the step of said synthetic route (6),
The formula V compound is dissolved in the organic solvent, and hydrogenation formula V compound obtains formula (VI) compound in the presence of catalyzer:
Temperature of reaction is controlled between-20 ° of C～120 ° C.
Said organic solvent makes formula V compound dissolution and hydrogenation constitute not being hindered get final product.
In a preferred implementation, said organic solvent is an alcoholic solvent, like methyl alcohol, and ethanol, propyl alcohol, Virahol, butanols, 1-butanols, single or mixed solvents such as 2-butanols.
In a preferred implementation, catalyzer comprises Pd/C, Pd (OH)
2/ C, Raney-Ni, PtO
2Deng.In a preferred implementation, solvent is preferably methyl alcohol in the step (6), and catalyzer is Pd/C, and temperature of reaction is preferably between 20 ° of C～80 ° C.
In a preferred implementation, raw material (V) is 1:0.001～1:0.1 with the mass ratio of catalyzer in the step (6).
In a preferred implementation, reaction pressure is 1～3 normal atmosphere in the step (6).
In an embodiment, comprise the steps:
(1) with 2,3,4,6-tetra-O-benzyl-β-D-glucopyranose (I) is a raw material, is having under solvent or the solvent-free situation; With oxygenant oxidation 2,3,4,6-tetra-O-benzyl-β-D-glucopyranose (I) obtains II, and oxygenant comprises DMSO 99.8MIN. and acetic anhydride; Methyl-sulphoxide and oxalyl chloride, pyridine sulphur trioxide, 2,2,6; 6-tetramethyl piperidine oxide compound, Youxiaolin, Textone etc., temperature of reaction is controlled between-80 ° of C～60 ° C.Solvent is a methylene dichloride, ethylene dichloride, THF, 1, single or mixed solvents such as 4-dioxane.
(2) II is dissolved in the organic solvent, like alcoholic solvent or ether solvent, methyl alcohol, ethanol; Virahol, various types of butanols, THF, ether; Single or mixed solvent such as MTBE, logical ammonia carry out ammonia to be separated and obtains III, and temperature of reaction is controlled between-20 ° of C～60 ° C.
(3) having under solvent or the solvent-free situation, III obtains IV with the oxygenant oxidation, and oxygenant comprises DMSO 99.8MIN. and acetic anhydride; Methyl-sulphoxide and oxalyl chloride, pyridine sulphur trioxide, 2; 2,6,6-tetramethyl piperidine oxide compound; Youxiaolin, Textone etc., temperature of reaction is controlled between-20 ° of C～60 ° C.Solvent is a methylene dichloride, ethylene dichloride, THF, 1, single or mixed solvents such as 4-dioxane.
(4) IV is dissolved in the organic solvent, adds acid, adds reductive agent, and reduction amination IV becomes V.Solvent comprises acetonitrile, alcoholic solvent or ether solvent, methyl alcohol, ethanol; Virahol, various types of butanols, THF, ether; Single or mixed solvent such as MTBE, acid comprises formic acid, acetate, trifluoroacetic acid etc.; Reductive agent comprises Peng Qinghuana, sodium triacetoxy borohydride, sodium cyanoborohydride.Temperature of reaction is controlled between-20 ° of C～120 ° C.
(5) V is dissolved in the organic solvent, adds reductive agent, and reduction V obtains VI.Solvent is an ether solvent, like THF, and ether, glycol dimethyl ether, single or mixed solvent such as MTBE.Reductive agent comprises, lithium aluminum hydride, the THF of borine or dimethyl sulphide solution, or boron trifluoride and Peng Qinghuana original position resultant.Temperature of reaction is controlled between-20 ° of C～120 ° C.
(6) VI is dissolved in the organic solvent, adds catalyzer, and reduction VI obtains VII.Solvent is an alcoholic solvent, like methyl alcohol, and ethanol, propyl alcohol, Virahol, butanols, 1-butanols, single or mixed solvents such as 2-butanols.Catalyzer comprises Pd/C, Pd (OH)
2/ C, Raney-Ni, PtO
2Deng.Temperature of reaction is controlled between-20 ° of C～120 ° C.Reaction pressure is controlled at 1～3 normal atmosphere.
The preparation method of the precursor of 1-DNJ (the wild buttocks poison of 1-deoxidation)
The present invention provides the preparation method of the precursor of a kind of 1-DNJ (the wild buttocks poison of 1-deoxidation), and it comprises the steps:
(A) provide suc as formula 2,3,4 shown in (I), 6-four-benzyl-β-D-glucopyranose (2,3,4,6-tetra-O-benzyl-β-D-glucopyranose),
(B) 2 shown in the said formula (I); 3; 4; The ammonia that 6-four-benzyl-β-D-glucopyranose carries out oxidation, the step (2) of step (1) through synthetic route as follows is separated, the oxidation of step (3), the reduction amination of step (4), the reduction of step (5), obtains said precursor as shown in the formula the 1-DNJ shown in (VI) (the wild buttocks poison of 1-deoxidation):
Said precursor can also obtain by the known technology through this area except can making through aforesaid method, organic chemistry periodical J.Org.Chem for example, and Vol.72, No.4,20071088～1097 reported method obtain.
Purposes
The present invention also provides 3,4, and 5-three benzyloxies-2-benzyloxymethyl piperidines is as the purposes of the precursor of preparation 1-DNJ (the wild buttocks poison of 1-deoxidation).
Specify like nothing, various raw materials of the present invention all can obtain through commercially available; Or prepare according to the ordinary method of this area.Only if definition or explanation are arranged in addition, the same meaning that all specialties used herein and scientific words and those skilled in the art are familiar with.Any in addition with the institute similar content of putting down in writing or the equalization method and material all can be applicable in the inventive method.
With 2,3,4,6-tetra-O-benzyl-β-D-glucopyranose (I) is a raw material, and through peroxo-, ammonia is separated, oxidation, and also amination is former,, reduction step obtains 3,4,5-three benzyloxies-2-benzyloxymethyl piperidines, and synthetic route is following:
The technical scheme that is adopted is following:
(1) raw material 2,3,4, and 6-tetra-O-benzyl-β-D-glucopyranose (I) is that those of ordinary skills are total to the source of knowing and buy and obtain.
(2) midbody (II) is with oxidation raw material 2,3,4, and 6-tetra-O-benzyl-β-D-glucopyranose (I) obtains, and this area has several different methods can carry out this kinds of oxidation reaction.Under the situation of raw material I and oxide compound coexistence, there are solvent or solvent-free reaction to carry out.With cost and the convenient consideration of industriallization, be preferably solvent-free reaction, oxygenant is DMSO 99.8MIN. and acetic anhydride earlier.Raw material (I) is 1:1～1:30 with the DMSO 99.8MIN. mol ratio, and raw material (I) is 1:1～1:20 with the acetic anhydride mol ratio.Temperature is good to keep room temperature, and preferred temperature is between 10 ° of C～30 ° C.
(3) midbody (III) just carries out with midbody (II) that ammonolysis reaction obtains.Be reflected in all kinds of SOLVENTS and all can carry out.The present invention selects for use methyl alcohol as solvent.The quality of used methyl alcohol is more than three times of midbody (II) quality.
(4) midbody (IV) just carries out with midbody (III) that oxidizing reaction obtains, with cost and industriallization is convenient considers that be preferably solvent-free reaction, oxygenant is DMSO 99.8MIN. and acetic anhydride earlier.Raw material I and DMSO 99.8MIN. mol ratio are 1:1～1:30, and raw material I and acetic anhydride mol ratio are 1:1～1:20.Temperature is good to keep room temperature, and preferred temperature is between 10 ° of C～30 ° C.
(5) midbody (V) just carries out with midbody (IV) that condensating reductive reaction obtains.Generally select for use alcoholic solvent as reaction solvent, the present invention selects for use acetonitrile and formic acid as solvent, selects for use sodium cyanoborohydride as reductive agent.Select for use other reductive agent such as solvent also can obtain product.
(6) midbody (VI) is that midbody (V) reduction obtains.In this area, there is several different methods to carry out this reduction.But for industriallization considers that the present invention selects for use boron trifluoride ether solution and Peng Qinghuana as reductive agent.
(7) product (VII) is that midbody (VI) hydrogenation obtains.In this area, there is several different methods to carry out this reaction.Generally select alcoholic solvent for use, the present invention preferentially selects for use methyl alcohol as solvent, selects for use Pd/C as catalyzer, selects for use other catalyzer and solvent also can obtain product.
Of the present invention 3,4, the preparation method of 5-three benzyloxies-2-benzyloxymethyl piperidines and 1-DNJ (the wild buttocks poison of 1-deoxidation), reactions step is few; Cost of material is cheap, and reaction conditions is gentle, environmental friendliness, the major safety risks in having avoided producing; The products obtained therefrom yield is high, and purity is high, and steady quality meets the specification of quality as pharmaceutical intermediate fully; Be 3,4, the industrial production of 5-three benzyloxies-2-benzyloxymethyl piperidines and 1-DNJ (the wild buttocks poison of 1-deoxidation) provides favourable condition.
Above-mentioned compound method is the synthetic route of part of compounds of the present invention; According to above-mentioned example; Those skilled in the art can synthesize other compounds of the present invention through the adjustment diverse ways, and perhaps, those skilled in the art can synthesize compound of the present invention according to existing known technology.The synthetic compound can further be further purified through modes such as column chromatography, HPLC or crystallizations.
Synthetic chemistry is transformed, protection functional group methodology (protect or go and protect) is helpful to synthetic application compound; And be technology commonly known in the art; Like R.Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, the third edition, John Wiley and Sons (1999); L.Fieser and M.Fieser, Fieser and Fieser ' s Reagents for Organic Synthesis, John Wileyand Sons (1994); And L.Paquette, ed., Encyclopedia of Reagents for Organic Synthesis has open among the John Wiley and Sons (1995).
Other aspects of the present invention are because the disclosure of this paper is conspicuous to those skilled in the art.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in the restriction scope of the present invention.The experimental technique of unreceipted actual conditions in the following example is measured according to national standard usually.If there is not a corresponding national standards, then carry out according to general international standard, normal condition or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise all umbers are weight part, and all per-cents are weight percentage, and described polymericular weight is a number-average molecular weight.
Only if definition or explanation are arranged in addition, the same meaning that all specialties used herein and scientific words and those skilled in the art are familiar with.Any in addition with the institute similar content of putting down in writing or the equalization method and material all can be applicable in the inventive method.
Embodiment
Raw material I described in the embodiment promptly refers to following formula (I) compound, and the rest may be inferred by analogy for it.All steps are all passed through the reference material comparison and are carried out qualitative to midbody.
Embodiment 1
The preparation of intermediate II
Reaction unit adds 200 gram raw material I and 600 gram exsiccant DMSO 99.8MIN.s formation homogeneous phase solutions under nitrogen protection, at room temperature in this solution, add 113 gram acetic anhydride, and this solution system at room temperature stirring reaction to raw material disappears; In this reaction solution, add the aqueous sodium carbonate of 1400 grams 10% then, stirred 30 minutes, standing demix, product become oily to separate out; Tell the oily product, water is given a baby a bath on the third day after its birth time then, and each water 200 grams, product dissolve with 200 milliliters methylene dichloride then; Water is given a baby a bath on the third day after its birth time again, each water 200 grams, and organic phase merges to concentrate and obtains product 202 grams; Flaxen oil, content 98.6%, yield 99.9%
The preparation of intermediate III
The intermediate II of 50 grams is dissolved with 300 milliliters of anhydrous methanols, at room temperature feeds ammonia to intermediate II and disappears, and reaction solution concentrating under reduced pressure then obtains 100 yellow oilies that restrain, leaves standstill after fixing.This solid adds 300 milliliters of acetic acid ethyl dissolutions, adds 900 milliliters normal hexane, stirred crystallization.Stir 2 hours after-filtration, obtain white solid product 71 grams, dry back 47 grams, content 98.2%, yield 91.1%.
The preparation of intermediate compound IV
Reaction unit adds 197 gram raw material II I and 985 gram exsiccant DMSO 99.8MIN.s formation homogeneous phase solutions under nitrogen protection, at room temperature in this solution, add 290 gram acetic anhydride, and this solution system at room temperature stirring reaction to raw material disappears; In this reaction solution, add 2000 grams, 20% aqueous sodium carbonate then, stirred 30 minutes, standing demix, product become oily to separate out; Tell the oily product, product is used washing twice then with 200 milliliters methylene dichloride dissolving, each water 200 grams, and product solution is washed once with 20% sodium carbonate solution; Again once with washing, water 200 grams, this solution filters the back concentrating under reduced pressure with 30 gram anhydrous sodium sulfate dryings then; Obtain product 220 grams, add 180 milliliters of acetic acid ethyl dissolutions, add 500 ml n-hexane stirred crystallization, filter; Obtain 132 gram product IV after the drying, content 93.5%, yield 67.2%
The preparation of midbody V
Reaction unit is under nitrogen protection, and intermediate compound IV 225 grams dissolve with 1650 milliliters of anhydrous acetonitriles, and adds 535 milliliters 98% formic acid, stirs clarification; Add the sodium cyanoborohydride of 38.4 grams then, be warmed up to backflow, the raw material disappearance after 2 hours that refluxes, reaction solution cools to room temperature; Be added to reaction solution in 2700 milliliters 20% the wet chemical and go, stir and tell organic layer after 15 minutes, organic layer stirring at room 24 hours; There is solid to separate out, filters drying; Obtain 175.6 gram white solid product V, content 96.1%, yield 80.4%
The preparation of midbody VI
Reaction unit is under nitrogen protection; Add midbody V 150 gram and 1500 milliliters of glycol dimethyl ethers, stir clarification, add Peng Qinghuana 15.9 grams; Reaction system cools to negative 5 degree; Drip 79.2 gram boron trifluoride ether solutions then, be warmed up to room temperature reaction after being added dropwise to complete, slowly drip 60 gram methyl alcohol cancellation reactions after raw material disappears.30% hydrochloric acid of 68 grams is added dropwise to complete the back and stirred 12 hours then, and reaction solution is transferred pH to 9 with 20% sodium carbonate solution then; Standing demix, water layer is finally got with 600 milliliters of ETHYLE ACETATE, merges organic layer; Dry back concentrating under reduced pressure obtains 156 gram water white oils; Leave standstill after fixing, content 90.1%, yield 96.2%.
The preparation of product VII
Reaction unit adds midbody VI 200 gram and 3000 ml methanol under nitrogen protection, stir clarification, adds 20 gram 5%Pd/C, nitrogen replacement three times, and hydrogen exchange three times, reaction system is warmed up to 40 degree.1 normal atmosphere reacted 8 hours down.Stopped reaction filters.Filter cake is with twice of 80g methanol wash.Concentrate filtrating merging and obtain bullion.Bullion obtains product VII 43.6g with recrystallizing methanol, content 99%, yield 70.1%.
Embodiment 2～6
Preparing method of the present invention is shown in embodiment 1, and difference is that the oxidation reaction condition of step (1) is different:
Embodiment 7～14
Preparing method of the present invention is shown in embodiment 1, and difference is that the ammonolysis reaction condition of step (2) is different:
Embodiment 15～19
Preparing method of the present invention is shown in embodiment 1, and difference is that the oxidation reaction condition of step (3) is different:
Embodiment 20～28
Preparing method of the present invention is shown in embodiment 1, and difference is that the reductive amination process condition of step (4) is different:
Embodiment 29～33
Preparing method of the present invention is shown in embodiment 1, and difference is that the reduction reaction conditions of step (5) is different:
Embodiment 34～38
Preparing method of the present invention is shown in embodiment 1, and difference is that the hydrogenation condition of step (6) is different:
The above is merely preferred embodiment of the present invention; Be not in order to limit essence technology contents scope of the present invention; Essence technology contents of the present invention is broadly to be defined in the claim scope of application, and if any technological entity or method that other people accomplish are defined identical with the claim scope of application; Also or a kind of change of equivalence, all will be regarded as and be covered by among this claim scope.
All documents in that the present invention mentions are all quoted as a reference in this application, are just quoted such as a reference separately as each piece document.Should be understood that in addition that after having read foregoing of the present invention those skilled in the art can do various changes or modification to the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (10)
1. the preparation method of a 1-DNJ (the wild buttocks poison of 1-deoxidation) is characterized in that, comprises the steps:
1-DNJ is provided the precursor of (the wild buttocks poison of 1-deoxidation), and said precursor is 3,4,5-three benzyloxies-2-benzyloxymethyl piperidines;
Said precursor carries out hydrogenation, obtains said 1-DNJ (the wild buttocks poison of 1-deoxidation).
2. the method for claim 1 is characterized in that, comprises the steps:
(a) provide suc as formula 2,3,4 shown in (I), 6-four-benzyl-β-D-glucopyranose (2,3,4,6-tetra-O-benzyl-β-D-glucopyranose),
(b) 2 shown in the said formula (I); 3; 4; 6-four-benzyl-β-D-glucopyranose is through synthetic route as implied above, comprises that the ammonia of oxidation, the step (2) of step (1) is separated, the oxidation of step (3), the reduction amination of step (4), the reduction of step (5) and the hydrogenation of step (6), obtains said precursor suc as formula the 1-DNJ shown in (VI) (the wild buttocks poison of 1-deoxidation);
(c) saidly carry out hydrogenation, obtain suc as formula the 1-DNJ shown in (VII) (the wild buttocks poison of 1-deoxidation) suc as formula the precursor shown in (VI).
3. method as claimed in claim 2 is characterized in that,
In the oxidation of said step (1), with suc as formula 2,3,4 shown in (I); 6-four-benzyl-β-D-glucopyranose (2,3,4; 6-tetra-O-benzyl-β-D-glucopyranose) is a raw material, having under solvent or the solvent-free situation, with 2 of the said formula of oxygenant oxidation (I); 3,4,6-four-benzyl-β-D-glucopyranose obtains suc as formula the compound shown in (II):
Said oxidizing reaction is Swern oxidation style or hypochlorite oxidation method, and said oxygenant is the oxygenant that is applicable to the Swern oxidation style; Or said oxygenant is the oxygenant of hypochlorite oxidation method; Temperature of reaction is controlled between-80 ° of C～60 ° C.
4. method as claimed in claim 2 is characterized in that, during the ammonia of said step (2) was separated, formula (II) compound is dissolved in the organic solvent logical ammonia to carry out ammonia and separate the formula of obtaining (III) compound,
Temperature of reaction is controlled between-20 ° of C～60 ° C.
5. method as claimed in claim 2 is characterized in that, in the oxidation of said step (3), is having under solvent or the solvent-free situation, obtains formula (IV) compound with oxygenant oxidation formula (III) compound,
Said oxidizing reaction is Swern oxidation style or hypochlorite oxidation method; Said oxygenant is the oxygenant that is applicable to the Swern oxidation style; Or said oxygenant is the oxygenant of hypochlorite oxidation method; Temperature of reaction is controlled between-20 ° of C～60 ° C.
6. method as claimed in claim 2 is characterized in that, in the reduction amination of said step (4),
Said formula (IV) compound is dissolved in the organic solvent, in the presence of reductive agent, obtains the formula V compound in acidic conditions reduction amination formula (IV) compound:
Temperature of reaction is controlled between-20 ° of C～120 ° C.
7. method as claimed in claim 2 is characterized in that, in the reduction of the step of said synthetic route (5),
The formula V compound is dissolved in the organic solvent, reduces said formula V compound down and obtains formula (VI) compound in the reductive agent existence:
Temperature of reaction is controlled between-20 ° of C～120 ° C.
8. method as claimed in claim 2 is characterized in that, in the hydrogenation of the step of said synthetic route (6),
The formula V compound is dissolved in the organic solvent, and hydrogenation formula V compound obtains formula (VI) compound in the presence of catalyzer:
Temperature of reaction is controlled between-20 ° of C～120 ° C.
9. the preparation method of the precursor of a 1-DNJ (the wild buttocks poison of 1-deoxidation) is characterized in that, comprises the steps:
(A) provide suc as formula 2,3,4 shown in (I), 6-four-benzyl-β-D-glucopyranose (2,3,4,6-tetra-O-benzyl-β-D-glucopyranose),
(B) 2 shown in the said formula (I); 3; 4; The ammonia that 6-four-benzyl-β-D-glucopyranose carries out oxidation, the step (2) of step (1) through synthetic route as follows is separated, the oxidation of step (3), the reduction amination of step (4), the reduction of step (5), obtains said precursor as shown in the formula the 1-DNJ shown in (VI) (the wild buttocks poison of 1-deoxidation):
10. one kind with 3,4, and 5-three benzyloxies-2-benzyloxymethyl piperidines is as the purposes of the precursor of preparation 1-DNJ (the wild buttocks poison of 1-deoxidation).
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| CN109293564A (en) * | 2018-12-06 | 2019-02-01 | 江西农业大学 | 1-DNJ-hydroxy-methyl cinnamate heterozygote derivative and its preparation method and application |
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