CN109111366B - Novel synthesis method of valienamine - Google Patents

Novel synthesis method of valienamine Download PDF

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CN109111366B
CN109111366B CN201811276990.6A CN201811276990A CN109111366B CN 109111366 B CN109111366 B CN 109111366B CN 201811276990 A CN201811276990 A CN 201811276990A CN 109111366 B CN109111366 B CN 109111366B
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valienamine
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刘向群
李强
陈宣福
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Changzhou Bohaiwei Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/36—Compounds containing oxirane rings with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

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Abstract

The invention provides a novel synthesis method of valienamine. Specifically, an intermediate II is obtained from an intermediate I through double bond epoxidation reaction, an intermediate III, namely valienamine with an amino protecting group, is obtained from the intermediate II through rearrangement reaction, and the protecting group of the intermediate II is removed to obtain valienamine (Violinamine).

Description

Novel synthesis method of valienamine
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing valienamine.
Background
The chemical name of Voglibose (Voglibose) is: (+) -1-L- [1(OH),2,45/3] -5- [ 2-hydroxy-1- (hydroxymethyl) ethyl ] amino-1-carbon- (hydroxymethyl) -1, 2, 3, 4-cyclohexanetetraol. The structural formula is as follows:
Figure BDA0001847219830000011
is an alpha-glycosidase inhibitor developed by the Japanese Wutian pharmacy, controls postprandial blood sugar, has obvious curative effect which is 190-fold stronger than the acarbose of the similar product and has no influence on digestive tract amylase. On the other hand, the voglibose has low side effect, generally does not have hypoglycemia, and has no report on the influence on anhydride and renal function, and the side effect is abdominal distension and increased exhaust, so that the tolerance of patients is good.
The voglibose glycogen research plant and the mainstream pharmaceutical imitation plants at home and abroad are currently synthesized by taking valienamine as a starting material, and the valienamine are purchased by customers when the customers purchaseN-benzyloxycarbonyl valienamine (R)1Benzyl) which is determined by the manufacturer's declaration of the process, and the purchased raw materials cannot be changed freely.
Figure BDA0001847219830000012
The valienamine is prepared by fermenting or chemically degrading validamycin and also by chemically degrading acarbose, the acarbose is expensive, and the degradation yield is only about 10 percent, so that the valienamine is not produced by using the acarbose in the prior production. Validamycin is fermented to produce valienamine and also to produce valienamine, which: valienamine ═ (0.6-0.8): 1, the validamycin fermentation unit concentration is low, and the yield is low, so that the production cost of valienamine is high.
In view of the above, there is an urgent need in the art to develop a novel method for synthesizing valienamine with low production cost.
Disclosure of Invention
The invention aims to provide a novel method for synthesizing valienamine with low production cost.
In a first aspect of the present invention, there is provided a method for synthesizing valienamine, the method comprising the steps of:
(1)
Figure BDA0001847219830000021
carrying out double bond epoxidation reaction on the intermediate I and peroxide in a first solvent to obtain an intermediate II;
(2)
Figure BDA0001847219830000022
in a second solvent, in the presence of a catalyst, carrying out an epoxy rearrangement reaction on the intermediate II to obtain an intermediate III; and
(3)
Figure BDA0001847219830000023
in a third solvent, removing R from the intermediate III2And optionally R1To thereby obtain amino-protected valienamine (shown as IV), or valienamine;
wherein the content of the first and second substances,
R1is benzyl, p-nitrobenzyl or tert-butyl;
R2each independently selected from the group consisting of: tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, acetyl, or benzoyl.
In another preferred example, in step (1), the peroxide is hydrogen peroxide, a peroxy acid, or a combination thereof.
In another preferred example, in step (1), the peroxyacid is peroxyacetic acid, m-chloroperoxybenzoic acid, or a combination thereof.
In another preferred embodiment, in step (1), the peroxide is selected from the group consisting of: hydrogen peroxide, m-chloroperoxybenzoic acid, peroxyacetic acid, or combinations thereof.
In another preferred example, in the step (1), the first solvent is a halogenated hydrocarbon solvent.
In another preferred example, in the step (1), the molar ratio of the intermediate I to the peroxide is 1:1 to 1: 4.
In another preferred embodiment, in the step (1), the reaction time of the double bond epoxidation reaction is 5 to 20 hours.
In another preferred embodiment, in the step (1), the reaction temperature of the double bond epoxidation reaction of the intermediate I is 20-80 ℃.
In another preferred embodiment, in step (1), the first solvent is selected from the group consisting of: dichloromethane, chloroform, 1, 2-dichloroethane, or combinations thereof.
In another preferred embodiment, in step (2), the catalyst is selected from the group consisting of: aluminum triisopropoxide, trimethylsilyl trifluoromethanesulfonate, 2,6-Lutidine, 1, 8-diazabicycloundecen-7-ene (DBU), 2,6, 6-tetramethylpiperidindimethylaluminum (TMP-AlMe)2) An ammonium salt, or a combination thereof.
In another preferred embodiment, the ammonium salt is selected from the group consisting of: ammonium acetate, ammonium chloride, ammonium nitrate, or combinations thereof; preferably, the ammonium salt is ammonium nitrate.
In another preferred example, in step (2), the catalyst is aluminum triisopropoxide, trimethylsilyl trifluoromethanesulfonate in combination with 2, 6-lutidine, trimethylsilyl trifluoromethanesulfonate in combination with 1, 8-diazabicycloundec-7-ene, 2,6, 6-tetramethylpiperidindimethylaluminum, or an ammonium salt.
In another preferred example, in the step (2), the molar ratio of trimethylsilyl trifluoromethanesulfonate to 2, 6-dimethylpyridine in the catalyst is 1 (1-2).
In another preferred example, in the step (2), the molar ratio of trimethylsilyl trifluoromethanesulfonate to 1, 8-diazabicycloundecen-7-ene in the catalyst is 1 (1-2).
In another preferred embodiment, in step (2), the second solvent is selected from the group consisting of: an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, or a combination thereof.
In another preferred embodiment, the aromatic hydrocarbon solvent is selected from: benzene, toluene, xylene, or combinations thereof.
In another preferred embodiment, the halogenated hydrocarbon solvent is selected from: dichloromethane, chloroform, 1, 2-dichloroethane, 1,1, 1-trichloroethane, 1,1, 2-trichloroethane, or combinations thereof.
In another preferred embodiment, in step (2), the catalyst is selected from: aluminum triisopropoxide, trimethylsilyl trifluoromethanesulfonate, 2, 6-lutidine, 1, 8-diazabicycloundecen-7-ene (DBU), 2,6, 6-tetramethylpiperidindimethylaluminum (TMP-AlMe)2) Or combinations thereof, the second solvent is an aromatic hydrocarbon solvent.
In another preferred embodiment, in the step (2), when the catalyst is an ammonium salt, the second solvent is a halogenated hydrocarbon solvent.
In another preferred example, in the step (2), when the catalyst is aluminum triisopropoxide, the reaction temperature of the epoxy rearrangement reaction is 80 to 150 ℃, preferably 100 to 150 ℃.
In another preferred example, when the catalyst is aluminum triisopropoxide in the step (2), the time is 2 to 8 hours; preferably, it is 3 to 5 hours.
In another preferred example, in the step (2), when the catalyst is aluminum triisopropoxide, the second solvent is an aromatic hydrocarbon solvent; preferably, toluene, xylene, or a combination thereof.
In another preferred example, in the step (2), when the catalyst is aluminum triisopropoxide, the molar ratio of the intermediate II to the catalyst is 1 (1-3).
In another preferred example, in the step (2), when the catalyst is the combination of trimethylsilyl trifluoromethanesulfonate and 2, 6-dimethylpyridine or the combination of trimethylsilyl fluoromethanesulfonate and 1, 8-diazabicycloundec-7-ene, the cosolvent is an aromatic hydrocarbon solvent; preferably, it is toluene.
In another preferred example, in the step (2), when the catalyst is the combination of trimethylsilyl trifluoromethanesulfonate and 2, 6-dimethylpyridine or the combination of trimethylsilyl fluoromethanesulfonate and 1, 8-diazabicycloundec-7-ene, the molar ratio of the intermediate II to the catalyst (calculated as trimethylsilyl trifluoromethanesulfonate) is 1 (0.9-1.1).
In another preferred example, in the step (2), when the catalyst is a combination of trimethylsilyl trifluoromethanesulfonate and 2, 6-dimethylpyridine or a combination of trimethylsilyl fluoromethanesulfonate and 1, 8-diazabicycloundec-7-ene, the reaction time of the epoxy rearrangement reaction is 10-20 hours.
In another preferred example, in the step (2), when the catalyst is the combination of trimethylsilyl trifluoromethanesulfonate and 2, 6-dimethylpyridine, the reaction temperature of the epoxy rearrangement reaction is less than 0 ℃; preferably-100 ℃ to-30 ℃.
In another preferred example, in the step (2), when the catalyst is the combination of trimethylsilyl trifluoromethanesulfonate and 1, 8-diazabicycloundec-7-ene, the reaction temperature of the epoxy rearrangement reaction is 0 ℃ to 50 ℃; preferably, it is 20 to 40 ℃;
in another preferred example, in the step (2), when the catalyst is 2,2,6, 6-tetramethylpiperidindimethylaluminum, the cosolvent is an aromatic hydrocarbon solvent.
In another preferred example, in the step (2), when the catalyst is 2,2,6, 6-tetramethylpiperidindimethylaluminum, the reaction temperature of the epoxy rearrangement reaction is-20 to 20 ℃, preferably-10 to 5 ℃.
In another preferred example, in the step (2), when the catalyst is 2,2,6, 6-tetramethylpiperidindimethylaluminum, the reaction time of the epoxy rearrangement reaction is 1 to 4 hours.
In another preferred example, in the step (2), when the catalyst is 2,2,6, 6-tetramethylpiperidindimethylaluminum, the molar ratio of the intermediate II to the catalyst is 1 (1-5).
In another preferred embodiment, in the step (2), when the catalyst is an ammonium salt, the cosolvent is a halogenated hydrocarbon solvent.
In another preferred example, in the step (2), when the catalyst is an ammonium salt, the reaction temperature of the epoxy rearrangement reaction is 50 to 80 ℃.
In another preferred example, in the step (2), when the catalyst is an ammonium salt, the reaction temperature of the epoxy rearrangement reaction is a reflux temperature.
In another preferred example, in the step (2), when the catalyst is an ammonium salt, the reaction time of the epoxy rearrangement reaction is 2 to 8 hours; preferably, it is 3 to 5 hours.
In another preferred example, in the step (2), when the catalyst is an ammonium salt, the molar ratio of the intermediate II to the catalyst is 1 (0.03-0.3).
In another preferred embodiment, when R is2When each is independently acetyl or benzoyl, step (3) is
(3a)
Figure BDA0001847219830000061
And (3) carrying out a hydrolysis reaction on the intermediate III in a third solvent in the presence of a base to obtain the valienamine.
In another preferred embodiment, when R is2When each is independently t-butyldimethylsilyl group, t-butyldiphenylsilyl group or triethylsilyl group, step (3) comprises the steps of:
Figure BDA0001847219830000062
(3.1b) DeR of intermediate III2Thereby obtaining amino-protected valienamine as shown in IV; and
and optionally (3.2b) subjecting the amino-protected valienamine to a hydrolysis reaction in a third solvent in the presence of a base, thereby obtaining valienamine.
In another preferred embodiment, the base is selected from: sodium hydroxide, potassium hydroxide, barium hydroxide, or a combination thereof.
In another preferred embodiment, the third solvent is selected from: water, methanol, ethanol, tetrahydrofuran, acetone, or combinations thereof.
In another preferred example, in the step (3a), the third solvent is water, methanol, ethanol, a mixed solution of water and methanol, a mixed solution of water and ethanol, a mixed solution of water and tetrahydrofuran, or a mixed solution of water and acetone, and the like. Temperature of
In another preferred example, in the step (3a), the reaction temperature of the hydrolysis reaction is 20-100 ℃; preferably, it is 60 to 80 ℃.
In another preferred embodiment, in step (3.1b), R of intermediate III is removed in the presence of hydrochloric acid, methanol, pyridine hydrofluoric acid, triethylamine hydrofluoric acid and/or tetrabutylammonium fluoride2Thereby obtaining amino-protected valienamine as shown in IV.
In another preferred example, in the step (3.2b), the reaction temperature of the hydrolysis reaction is 20-100 ℃; preferably, it is 60 to 80 ℃.
A second aspect of the present invention provides an intermediate for synthesizing valienamine, which is represented by formula II:
Figure BDA0001847219830000071
wherein the content of the first and second substances,
R1is benzyl, p-nitrobenzyl or tert-butyl;
R2each independently selected from the group consisting of: tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, acetyl, or benzoyl.
A third aspect of the present invention provides a use of the intermediate as described in the second aspect for synthesizing amino-protected valienamine, or valienamine.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The present inventors have made extensive and intensive studies and, as a result, have first developed a method for synthesizing valienamine from valienamine, which is a useless byproduct generated when valienamine is produced by fermentation of validamycin, and have completed the present invention based on the same.
Validamine
When the valienamine is separated from the fermentation liquid, the valienamine with the amount of 60-80% of that of the valienamine is generated, so that the valienamine is effectively converted into the valienamine, which has important significance, namely, the discharge of waste is reduced, and the cost of the valienamine can be reduced.
A study of the route reported by Cabohydrate Research 1985, V140, 185p.
Figure BDA0001847219830000081
The key Intermediate (IV) in the route, namely the starting material intermediate I in the invention, generates an enol structure through double bond epoxidation and rearrangement of epoxy bonds, so that valienamine is synthesized, the production cost of the valienamine is reduced, and the production cost of voglibose is reduced.
Synthetic method of valienamine
The invention provides a method for synthesizing a starting material of voglibose. The method can prepare the valienamine which is a waste generated in the fermentation into the commercial valienamine and the N-benzyloxycarbonyl valienamine through the intermediate (I).
Specifically, the method comprises the steps of carrying out double bond epoxidation reaction on an intermediate I to generate an intermediate II, and carrying out rearrangement reaction on the intermediate II to generate a protecting group (R)1And R2) And removing all or part of the protecting group from the valienamine intermediate III to valienamine (Violinamine) or valienamine with an amino protecting group (such as N-benzyloxycarbonyl valienamine).
Typically, the synthesis method of the present invention comprises the steps of: (I) synthesizing an intermediate III from the intermediate I, and (II) synthesizing amino-protected valienamine or valienamine from the intermediate III.
(I) Synthesis of intermediate III from intermediate I, comprising the steps of:
step 1, reacting the intermediate I with a peroxide to obtain an intermediate II
Figure BDA0001847219830000091
Step 2, in the presence of a catalyst, enabling the intermediate II to perform an epoxy rearrangement reaction so as to obtain an intermediate III;
Figure BDA0001847219830000092
in the above-mentioned steps, the first step,
R1is benzyl, p-nitrobenzyl or tert-butylA group;
R2are each independently selected from the group consisting of: tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, acetyl, or benzoyl.
(II) synthesizing valienamine from the intermediate III, comprising the steps of:
and 3, performing alkaline hydrolysis on the intermediate III to obtain a valienamine product.
Figure BDA0001847219830000093
Wherein R is1As defined above, R2Each independently is acetyl or benzoyl; or
And 3, carrying out deprotection and hydrolysis on the intermediate (III) to obtain a valienamine product.
Figure BDA0001847219830000094
Wherein R is1As defined above; r2Each independently is tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triethylsilyl.
In step 1, intermediate I reacts with peroxide to produce intermediate II. Preferably, the peroxide is selected from hydrogen peroxide, m-chloroperoxybenzoic acid and other peroxy acids such as peroxyacetic acid and the like. The reaction of step 1 is preferably carried out in a halogenated hydrocarbon solvent such as dichloromethane, chloroform, 1, 2-dichloroethane, etc., preferably dichloromethane. Preferably, the molar ratio of the intermediate (I) to the peroxide is 1: 1-1: 4. Preferably, the reaction temperature is from 20 ℃ to 80 ℃. The reaction time is 5-20 hours.
In the step 2, the intermediate II is subjected to rearrangement reaction under the action of a catalyst to obtain an intermediate III. Preferably, the catalyst is selected from the group consisting of aluminum triisopropoxide, trimethylsilyl trifluoromethanesulfonate with 2, 6-lutidine, trimethylsilyl trifluoromethanesulfonate with 1, 8-diazabicycloundecen-7-ene (DBU), 2,6, 6-tetramethylpiperidindimethylaluminum (TMP-AlMe2), or ammonium salts (including ammonium acetate, ammonium chloride, ammonium nitrate, etc.).
Preferably, in step 2, when the catalyst is aluminum triisopropoxide, the reaction solvent is selected from aromatic hydrocarbon solvents: benzene, toluene, xylene, and the like. Toluene and xylene are preferred. The reaction temperature is at reflux conditions for the selected solvent.
Preferably, in step 2, when the catalyst is trimethylsilyl trifluoromethanesulfonate and 2, 6-dimethylpyridine or trimethylsilyl trifluoromethanesulfonate and 1, 8-diazabicycloundec-7-ene (DBU), the reaction solvent is selected from aromatic solvents: benzene, toluene, xylene, etc., preferably toluene.
Preferably, in step 2, when the catalyst is trimethylsilyl trifluoromethanesulfonate and 2, 6-lutidine, the reaction temperature is selected to be below 0 ℃, preferably-100 ℃ to-30 ℃.
Preferably, in step 2, when the catalyst is trimethylsilyl trifluoromethanesulfonate and DBU (1, 8-diazabicycloundec-7-ene), the reaction temperature is selected to be 0 ℃ to 50 ℃, preferably 20 ℃ to 40 ℃.
Preferably, in step 2, when 2,2,6, 6-tetramethylpiperidine dimethylaluminum (TMP-AlMe2) is selected as the catalyst, the reaction solvent is selected from aromatic hydrocarbon solvents: benzene, toluene, xylene, and the like. The reaction temperature is selected from-20 to 20 ℃. Preferably-10 deg.C-5 deg.C.
Preferably, in step 2, when an ammonium salt (such as ammonium acetate, ammonium chloride, ammonium nitrate, etc.) is used as the catalyst, the solvent is selected from halogenated hydrocarbon solvents (such as dichloromethane, chloroform, 1, 2-dichloroethane, 1,1, 1-trichloroethane, 1,1, 2-trichloroethane, etc.). The reaction temperature is the reflux temperature of the selected solvent.
In step 3, when R is2When the protecting group is acetyl or benzoyl, R can be removed simultaneously under the action of alkali1,R2The protecting group and the base can be selected from sodium hydroxide, potassium hydroxide and barium hydroxide. The reaction solvent can be selected from water, methanol, ethanol, a mixed solution of water and methanol, a mixed solution of water and ethanol, a mixed solution of water and tetrahydrofuran, a mixed solution of water and acetone, and the like. The temperature is 20-100 deg.C, preferably 60-80 deg.C.
In step 3, when R is2Each independently is tertiaryWhen the butyl dimethyl silicon base, the triethyl silicon base or the tert-butyl diphenyl silicon base is used, the amino-protected valienamine (shown as IV) is obtained by removing the silane protecting group, namely the N-protected valienamine, and the conventional dealkylation method is adopted for removing the silane protecting group: methanol hydrochloride, pyridine hydrofluoric acid, triethylamine hydrofluoric acid, tetrabutylammonium fluoride and the like.
In step 3, when R is2When the groups are respectively tert-butyl dimethyl silicon base, triethyl silicon base or tert-butyl diphenyl silicon base, the valienamine with protected amino group obtained by removing the silane protecting group can be directly used for synthesizing valiolamine, or R is removed under the alkaline condition1The protecting group is used to obtain validamycin enamine.
Intermediate for synthesis of valienamine
The invention provides an intermediate shown as a formula II, which is used for synthesizing valienamine.
Figure BDA0001847219830000111
Wherein the content of the first and second substances,
wherein R is1Is benzyl, p-nitrobenzyl or tert-butyl; r2Each independently selected from the group consisting of: tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, acetyl, or benzoyl.
The invention also provides an intermediate shown as the formula III, and the intermediate is used for synthesizing valienamine.
Figure BDA0001847219830000112
Wherein R is1Is benzyl, p-nitrobenzyl or tert-butyl; r2Each independently selected from the group consisting of: tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, acetyl, or benzoyl.
The invention also provides an intermediate shown as a formula IV, which is used for synthesizing valienamine:
Figure BDA0001847219830000113
wherein R is1Is benzyl, p-nitrobenzyl or tert-butyl; r2Each independently selected from the group consisting of: tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, acetyl, or benzoyl.
The main advantages of the invention include
The raw material of the invention can be prepared from useless byproducts generated in the valienamine fermentation production by validamycin, and the production cost of the valienamine can be greatly reduced.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
The synthesis of intermediate I can be carried out according to Cabohydrate Research 1985, V140, 185p.
Example 1
Preparation of intermediate II Compound, R1Is benzyl, R2Is acetyl
Intermediate I (32.8g) was dissolved in 750ml chloroform and 33.3g anhydrous Na was added2HPO4Dissolving m-chloroperoxybenzoic acid (19.4g, 85%) in chloroform (400ml), dripping the chloroform solution of m-chloroperbenzoic acid at 20-25 ℃ into the chloroform solution of (I), finishing dripping for 30 minutes, heating to reflux after dripping, refluxing for 6-8 hours, finishing reaction, stopping stirring, cooling to room temperature, stirring for 2 hours at 0 ℃, filtering, washing insoluble substances with chloroform, washing with 20% sodium thiosulfate in sequence, washing with saturated sodium bicarbonate, washing with saturated saline, drying with anhydrous magnesium sulfate, concentrating, passing residues through a silica gel column, and carrying out toluene: the column was washed with ethyl acetate (2:1) to give product 30.7g, yield 90.2%.
Example 2
Preparation of intermediate II Compound, R1Is benzyl, R2Is tert-butyl dimethyl silicon base
Intermediate I (24.8g) was dissolved in 350ml chloroform and 17.0g anhydrous Na was added2HPO4Dissolving m-chloroperoxybenzoic acid (10.0g, 85%) in chloroform (200ml), dripping the chloroform solution of m-chloroperbenzoic acid at 20-25 ℃ into the chloroform solution of (I), heating to reflux after dripping for 30 minutes, refluxing for 6-8 hours, stopping stirring after the reaction is finished, cooling to room temperature, stirring for 2 hours at 0 ℃, filtering, washing insoluble substances with chloroform, washing with 20% sodium thiosulfate sequentially, washing with saturated sodium bicarbonate, washing with saturated saline, drying with anhydrous magnesium sulfate, concentrating, passing the residue through a silica gel column (500ml), collecting the product, concentrating to obtain colorless oily substance 23.4g, and obtaining the yield of 92%.
Example 3
Preparation of intermediate II Compound, R1Is tert-butyl, R2Is acetyl
Intermediate I (15.4g) was dissolved in 350ml chloroform and 17.0g anhydrous Na was added2HPO4Dissolving m-chloroperoxybenzoic acid (10.0g, 85%) in chloroform (200ml), dripping the chloroform solution of m-chloroperbenzoic acid at 20-25 ℃ into the chloroform solution of (I), heating to reflux after dripping for 30 minutes, refluxing for 6-8 hours, stopping stirring after the reaction is finished, cooling to room temperature, stirring for 2 hours at 0 ℃, filtering, washing insoluble substances with chloroform, washing with 20% sodium thiosulfate sequentially, washing with saturated sodium bicarbonate, washing with saturated saline, drying with anhydrous magnesium sulfate, concentrating, passing the residue through a silica gel column (500ml), collecting the product, concentrating to obtain colorless oily substance 13.8g, and obtaining the yield of 86.2%.
Example 4
Preparation of intermediate III, R1Is benzyl, R2Is acetyl
Intermediate II (8.7g) was dissolved in 170ml of dry xylene, aluminum triisopropoxide (4.5g) was added, heated to reflux, reacted for 4 hours, cooled to room temperature, neutralized with aluminum isopropoxide with glacial acetic acid, concentrated, and the residue was passed through a silica gel column (100ml), toluene: eluting with ethyl acetate (1:1), collecting the product, and concentrating to obtain solid 7.1. The yield thereof was found to be 81.6%.
Example 5
Preparation of intermediate III, R1Is benzyl, R2Is acetyl
Trimethylsiliconate triflate (4.3g) was dissolved in 100ml of toluene under nitrogen protection at 20-30 ℃ and 20ml of a toluene solution of intermediate II (8.7g) and DBU (3.8ml) was added dropwise thereto, and after stirring overnight at room temperature, the mixture was concentrated, dissolved in ethyl acetate, washed with 1M hydrochloric acid, the aqueous layer was stripped with ethyl acetate, the organic layers were combined, washed with saturated sodium bicarbonate, washed with saturated brine, concentrated, and the residue was passed through a silica gel column (100ml) to give 7.6g of a product in 87.4% yield.
Example 6
Preparation of intermediate III, R1Is benzyl, R2Is acetyl
Intermediate II (8.7g) was dissolved in 170ml of dry chloroform, ammonium nitrate (0.32g) was added, heated to reflux, reacted for 4 hours, cooled to room temperature, washed with water, concentrated, the residue was passed through a silica gel column (100ml), toluene: the product was collected by elution with ethyl acetate (1:1) and concentrated to dryness to give 6.7g of a solid. The yield thereof was found to be 77.0%.
Example 7
Preparation of intermediate III, R1Is benzyl, R2Is acetyl
Dissolving the intermediate II (8.7g) in 100ml of dry toluene, cooling to 0 ℃, dropwise adding a toluene solution of 2,2,6,6, -tetramethylpiperidyldimethyl aluminum (0.08mol) and stirring at 0 ℃ for 2 hours, dropwise adding glacial acetic acid to quench the reaction, adding 100ml of ethyl acetate, washing with 1M hydrochloric acid, washing with saturated sodium bicarbonate and washing with saturated saline. Concentration and passage of the residue through a silica gel column (100ml) gave 8.1g of the product in 93.1% yield.
Example 8
Preparation of intermediate III, R1Is benzyl, R2Is tert-butyl dimethyl silicon base
Dissolving the intermediate II (13.0g) in 100ml of dry toluene, cooling to 0 ℃, dropwise adding a toluene solution of 2,2,6,6, -tetramethylpiperidyldimethyl aluminum (0.1mol), stirring at 0 ℃ for 2 hours, dropwise adding glacial acetic acid to quench the reaction, adding 100ml of ethyl acetate, washing with saturated ammonium chloride, washing with saturated sodium bicarbonate and washing with saturated common salt water. Concentration and passage of the residue through a silica gel column (100ml) gave 11.7g of the product in 94.3% yield.
Example 9
Preparation of intermediate IV, R1Is benzyl
Intermediate III (R)2Tert-butyldimethylsilyl) (63.7g) was dissolved in 637ml of methanol, 100ml of 2M hydrochloric acid was added thereto under cooling in ice, and then the mixture was stirred at room temperature, after completion of silane removal, the pH was adjusted to 5-5.5 with saturated sodium bicarbonate under cooling in ice, the mixture was concentrated, 100ml of water was added to the residue, 50ml of toluene was added thereto, stirring was carried out for 2 hours under cooling in ice at 0 ℃ and then the mixture was filtered, washed with a small amount of ice to obtain 26.6g of a white solid, and CG50 (H) was added to the aqueous layer of the mother liquor+50ml) was washed with water, the product was collected and concentrated to dryness to give 0.4g of solid, 3.0g was combined, yield 95.7%.
Example 10
Preparation of valienamine
Intermediate III (R)1Is benzyl, R2Acetyl) (43.5g) is added into a reaction bottle, 870ml of water is added, 126.2g of barium hydroxide is added, the temperature is raised to 70-80 ℃, after 3 hours, the mixture is cooled to room temperature, carbon dioxide gas is introduced to the mixture to be passed through the mixture to the PH7-8, the mixture is filtered, a filter cake is washed by water, the mixture is washed by aqueous ethyl acetate, a water layer passes through a CG-50(NH4+,800ml) column and is washed by water, a product is washed by 0.5M ammonia water, the concentration is carried out to about 100ml, the product passes through a DOWEX1X2(OH-,800ml) column and is washed by water, a product part is collected and concentrated to dryness, and ethanol is carried to dryness to obtain white crystals.
Example 11
Preparation of valienamine
Intermediate IV (R)1Benzyl) (30.9g) is dissolved in 450ml of water, 94.6g of barium hydroxide is added, the temperature is raised to 70-80 ℃, after 3 hours, the mixture is cooled to room temperature, carbon dioxide gas is introduced to the mixture to achieve the PH7-8, the mixture is filtered, a filter cake is washed by water, the water solution is washed by ethyl acetate, the water layer passes through a CG-50(NH4+,800ml) column, the product is washed by water and 0.5M ammonia water, the concentration is carried out until the concentration is about 100ml, the product passes through a DOWEX1X2(OH-,800ml) column, the product is washed by water, the product part is collected, concentrated and dried, ethanol is carried to dryness, 16.6g of white crystals are obtained.7％。
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (21)

1. A method for synthesizing valienamine, comprising the steps of:
(1)
Figure FDA0002930340610000011
carrying out double bond epoxidation reaction on the intermediate I and peroxide in a first solvent to obtain an intermediate II; wherein the peroxide is selected from the group consisting of: hydrogen peroxide, m-chloroperoxybenzoic acid, peroxyacetic acid, or combinations thereof;
(2)
Figure FDA0002930340610000012
in a second solvent, in the presence of a catalyst, carrying out an epoxy rearrangement reaction on the intermediate II to obtain an intermediate III; wherein the catalyst is aluminum triisopropoxide, a combination of trimethylsilyl trifluoromethanesulfonate and 2, 6-dimethylpyridine, a combination of trimethylsilyl trifluoromethanesulfonate and 1, 8-diazabicycloundec-7-ene, 2,6, 6-tetramethylpiperidindimethylaluminum, or an ammonium salt; and
(3)
Figure FDA0002930340610000013
in a third solvent, removing R from the intermediate III2And optionallyR1Thereby obtaining valienamine having protected amino groups as shown in IV, or valienamine;
wherein the content of the first and second substances,
R1is benzyl, p-nitrobenzyl or tert-butyl;
R2each independently selected from the group consisting of: tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, acetyl, or benzoyl.
2. The method of claim 1, wherein in step (1), the peroxide is selected from the group consisting of: m-chloroperoxybenzoic acid; and is
R1 is benzyl.
3. The method of claim 1, wherein in step (1), the method has one or more of the following characteristics:
a. the first solvent is a halogenated hydrocarbon solvent;
b. the molar ratio of the intermediate I to the peroxide is 1: 1-1: 4;
c. the reaction time of the double bond epoxidation reaction is 5 to 20 hours; and/or
d. The reaction temperature of the double bond epoxidation reaction of the intermediate I is 20-80 ℃.
4. The method of claim 1, wherein in step (1), the first solvent is selected from the group consisting of: dichloromethane, chloroform, 1, 2-dichloroethane, or combinations thereof.
5. The method of claim 2, wherein in step (2), the catalyst is aluminum triisopropoxide, a combination of trimethylsilyl trifluoromethanesulfonate and 1, 8-diazabicycloundec-7-ene, 2,6, 6-tetramethylpiperidindimethylaluminum, or ammonium nitrate.
6. The method of claim 2, wherein in step (2), the catalyst is 2,2,6, 6-tetramethylpiperidindimethylaluminum.
7. The method of claim 1, wherein in step (2), the second solvent is selected from the group consisting of: an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, or a combination thereof.
8. The process of claim 1, wherein in step (2), when the catalyst is aluminum triisopropoxide, the process has one or more of the following characteristics:
the reaction temperature of the epoxy rearrangement reaction is 80-150 ℃;
the second solvent is an aromatic hydrocarbon solvent; and/or
The molar ratio of the intermediate II to the catalyst is 1 (1-3).
9. The method of claim 1, wherein in step (2), the catalyst is trimethylsilyl trifluoromethanesulfonate in combination with 2, 6-lutidine, or trimethylsilyl fluoromethanesulfonate in combination with 1, 8-diazabicycloundecen-7-ene, wherein the method has one or more of the following characteristics:
the reaction time of the epoxy rearrangement reaction is 10-20 hours;
the solvent is aromatic hydrocarbon solvent; and/or
The molar ratio of the intermediate II to the catalyst is 1 (0.9-1.1), wherein the molar weight of the catalyst is calculated by trimethylsilyl trifluoromethanesulfonate.
10. The process of claim 1, wherein in step (2), when the catalyst is 2,2,6, 6-tetramethylpiperidindimethylaluminum, the process has one or more of the following characteristics:
the solvent is aromatic hydrocarbon solvent;
the reaction temperature of the epoxy rearrangement reaction is-20 ℃;
the reaction time of the epoxy rearrangement reaction is 1-4 hours; and/or
The molar ratio of the intermediate II to the catalyst is 1 (1-5).
11. The process of claim 1, wherein in step (2), when the catalyst is an ammonium salt, the process has one or more of the following characteristics:
the solvent is halogenated hydrocarbon solvent;
the reaction temperature of the epoxy rearrangement reaction is 50-80 ℃;
the reaction time of the epoxy rearrangement reaction is 2-8 hours; and/or
The molar ratio of the intermediate II to the catalyst is 1 (0.03-0.3).
12. The method of claim 1, wherein when R is2When each is independently acetyl or benzoyl, step (3) is
(3a)
Figure FDA0002930340610000031
And (3) carrying out a hydrolysis reaction on the intermediate III in a third solvent in the presence of a base to obtain the valienamine.
13. The method according to claim 12, wherein in the step (3a), the third solvent is water, methanol, ethanol, a mixed solution of water and methanol, a mixed solution of water and ethanol, a mixed solution of water and tetrahydrofuran, or a mixed solution of water and acetone.
14. The method of claim 12, wherein in step (3a), the hydrolysis reaction is carried out at a reaction temperature of 20 to 100 ℃.
15. The method of claim 12, wherein in step (3a), the hydrolysis reaction is carried out at a reaction temperature of 60 to 80 ℃.
16. The method of claim 1Process, characterized in that when R is2When each is independently t-butyldimethylsilyl group, t-butyldiphenylsilyl group or triethylsilyl group, step (3) comprises the steps of:
Figure FDA0002930340610000041
(3.1b) DeR of intermediate III2Thereby obtaining amino-protected valienamine as shown in IV; and
and optionally (3.2b) subjecting the amino-protected valienamine to a hydrolysis reaction in a third solvent in the presence of a base, thereby obtaining valienamine.
17. The method of claim 16, wherein step (3.1b) is performed by removing R from intermediate III in the presence of hydrochloric acid, methanol, pyridine hydrofluoric acid, triethylamine hydrofluoric acid and/or tetrabutylammonium fluoride2Thereby obtaining amino-protected valienamine as shown in IV.
18. The method of claim 12 or 16, wherein the base is selected from the group consisting of: sodium hydroxide, potassium hydroxide, barium hydroxide, or a combination thereof.
19. The method of claim 1, wherein the third solvent is selected from the group consisting of: water, methanol, ethanol, tetrahydrofuran, acetone, or combinations thereof.
20. An intermediate for synthesizing valienamine, which is characterized in that the intermediate is shown as a formula II;
Figure FDA0002930340610000042
wherein the content of the first and second substances,
R1is benzyl, p-nitrobenzyl or tert-butyl;
R2each independently selected from the group consisting of: tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, acetyl, or benzoyl.
21. The use of the intermediate as set forth in claim 20 for synthesizing amino-protected valienamine or valienamine.
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