CN1263753C - Method for synthetizing orixine and RU-19110 intermediate - Google Patents
Method for synthetizing orixine and RU-19110 intermediate Download PDFInfo
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- CN1263753C CN1263753C CN 200410045471 CN200410045471A CN1263753C CN 1263753 C CN1263753 C CN 1263753C CN 200410045471 CN200410045471 CN 200410045471 CN 200410045471 A CN200410045471 A CN 200410045471A CN 1263753 C CN1263753 C CN 1263753C
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Abstract
The present invention discloses a method for synthesizing dichroine and an RU-19110 intermediate body, which relates to a method for synthesizing dichroine and (2R, 3S)-1-benzyloxy carboxyl-2-allyl-3-alkoxy piperidine as the RU-19110 intermediate body. The method comprises the following steps: reacting a compound 4 on a protective agent in a halogenated hydrocarbon or ether solvent to obtain a compound 5; reacting on allyl azoviolet in the halogenated hydrocarbon or ether solvent to obtain a compound 6; reacting on lewis acid and silane in a halogenated hydrocarbon solvent to obtain a compound 7; reacting on ammonium ceric nitrate in a mixed solvent of nitrile and water to obtain a compound 8; reacting on lithium aluminum hydride in an ether solvent to obtain a protective compound (2R, 3S)-9; reacting on m-Chloroperoxybenzoic acid in the halogenated hydrocarbon or ether solvent to obtain a compound 10. Imide 4 with low cost and easy acquisition is used as raw material to synthesize the compound (2R, 3S)-9 in high yield and high selectivity, and the dichroine and the RU-19110 intermediate body are synthesized by the compound (2R, 3S)-9. The present invention has simple steps, high productive rate, short route and high total yield, and a reagent used by the method is cheap and is easy to acquire.
Description
Technical field
The present invention relates to a kind of heterogeneous ring compound, especially contain six-membered ring, do not condense with other ring, with a nitrogen-atoms as unique heterocyclic atom, especially a kind of synthetic febrifugin(e) and RU-19110 intermediate (2R, 3S)-method of 1-benzyloxy carboxyl 2-allyl group-3-alkoxyl group piperidines.
Background technology
Malaria is one of the most serious typicalness parasitosis, and except pulmonary tuberculosis, it is the maximum a kind of case of number that causes death in the transmissible disease.Many medicines, for example: Changshan, chloroquine, quinoline are all effective in cure to malaria.Changshan (Dichroa febrifugelour) is a kind of Chinese medicine commonly used, is mainly used in the treatment malaria, and wherein antimalarial effective constituent is febrifugin(e) and NSC 290495.The anti-malarial activity of febrifugin(e) is that quinine is drug-fast more than 100 times, the anti-malarial activity of NSC 290495 is suitable in quinic resistance, though febrifugin(e) and NSC 290495 be all because side effect such as vomiting fails to be promoted application,, to do not stop to synthesize of its structure of modification and analogue always.Treatment scleroderma, the anti-fiber chemical drug RU-19110 of the research and development of France Roussel-Uclaf company have entered the II clinical trial phase.Febrifugin(e), NSC 290495 and RU-19110 are pyridine alkaloids, also can belong to be quinoline azole alkaloid, and febrifugin(e) is that China scientist isolated first in nineteen fifty, and its absolute configuration was just finally determined by asymmetric synthesis in 1999.At present, the intermediate of the most critical of synthetic febrifugin(e), NSC 290495 and Ru-19110 mostly is (3S) 9-benzyloxy carboxyl-2-allyl group-3-hydroxy piperidine extremely greatly, the allyl group configuration of two replacements can be R, also can be S, then respectively through synthetic febrifugin(e) of different routes and NSC 290495.The structural formula of febrifugin(e), NSC 290495 and RU-19110 is:
NSC 290495 febrifugin(e) RU-19110
At present, the relevant synthetic the most successful feasible method of febrifugin(e) is that (he has mainly obtained (2S, 3S)-9 (P=H) key intermediate by the biological enzyme reduction to Japanese Takeuchi Y. for Chemical Communication2000,1643-1644) report.Main synthetic route is:
(2S, 3S)-9 NSC 290495 febrifugin(e)
This method is through 11 steps, and total recovery is 5.88%, but synthetic (2S, initial feed price 3S)-9 is higher relatively, and committed step will be reduced by enzyme, productive rate not ideal (40%～60%).The same year, Japanese Ogasawara K (OrganicLetter 2000,3193) seminar adopt synthetic method made key intermediate (2R, 3S)-9, synthetic route is as follows:
Though this method has been carried out asymmetric synthesis to febrifugin(e), route will be through 20 multisteps, and according to the productive rate of he or she's report, from the synthetic intermediate, total recovery is 11%, and still, general line is very long, and part reagent (such as RCM, PtO
2Deng) costliness, and used OsO very easily distillation, severe toxicity
4Reagent, operation is inconvenience very, brings very big pollution to environment simultaneously.This route is difficult to carry out suitability for industrialized production.
In addition, (J.Organic Chemistry 1,999 6833 for Japanese Kobayashi Shu in 1999; TetrahehedronLetter 1999,2175) seminar also to (2R, 3S)-1 the equivalent synthon of enantiomorph has carried out asymmetric synthesis:
Utilize this method, two place's committed step selectivity in the route are undesirable, and total recovery is also lower.KobayashiShu people such as (J.American Chemical, Society, 2001,123,12510) has done improvement on synthetic method in addition.Our seminar also reported in 2003 (Synlett, 2003, be chiral source 1663-1667) with L-L-glutamic acid, the method for febrifugin(e) being carried out asymmetric synthesis.Synthetic route is as follows:
Though above-mentioned synthetic method route is shorter, the selectivity of committed step is not ideal, total recovery lower (3.6%).
Summary of the invention
It is raw material with the synthetic six membered ring imide of natural compounds L-L-glutamic acid cheap and easy to get that purpose of the present invention aims to provide a kind of, set up synthetic febrifugin(e) of highly selective and RU-19110 intermediate (2R, 3S)-method of 1-benzyloxy carboxyl-2-allyl group-3-alkoxyl group piperidines.
Concrete synthetic route of the present invention is as follows, and in the statement hereinafter, specific synthetic product is according to the numbering in the structural formula, represents with Arabic numerals.R or S represent compound ground absolute configuration, and Cbz represents carbobenzoxy-(Cbz), and PMB represents that to methoxy-benzyl TBS represents that tertiary butyl dimethyl is silica-based, Bn represent benzyl (P=H, TBS, Bn).
Step of the present invention is:
Step 1: compound 4 in a kind of halohydrocarbon or ether solvent with the reaction of a kind of protective material, through concentrating, obtaining compound 5 (P=TBS) behind the silica gel column chromatography.Said protective material is selected from a kind of organosilane and a kind of alkali, perhaps another kind of halohydrocarbon, and said organosilane is selected from TERT-BUTYL DIMETHYL CHLORO SILANE or tert-butyl diphenyl chlorosilane; Said halohydrocarbon is selected from C
1～C
4Halohydrocarbon, be selected from methylene dichloride or trichloromethane especially; Said ether is selected from C
2～C
4Aliphatic ether or alicyclic ether, particularly ether or tetrahydrofuran (THF); Said alkali is tertiary amine, imidazoles or pyridine, the preferred triethylamine of said tertiary amine; Said another kind of halohydrocarbon is selected from the halogenation benzyl, is selected from cylite or Benzyl Chloride especially.
Step 2: compound 5 in a kind of halohydrocarbon or ether solvent with allyl group azoviolet reaction, through extraction, dry, concentrate, obtain compound 6 behind the silica gel column chromatography.Said halohydrocarbon is selected from C
1～C
4Halohydrocarbon, particularly methylene dichloride or trichloromethane; Said ether is selected from C
2～C
4Aliphatic ether or alicyclic ether, particularly ether or tetrahydrofuran (THF).
Step 3: compound 6 in a kind of halogenated hydrocarbon solvent with a kind of Lewis acid and a kind of silane reaction, through extraction, dry, concentrate, obtain compound 7 behind the silica gel column chromatography.Said halohydrocarbon is selected from C
1～C
4Halohydrocarbon, particularly methylene dichloride or trichloromethane; Said Lewis acid is selected from tin tetrachloride or boron trifluoride diethyl etherate, and said silane is selected from triethyl silicane especially.
Step 4: compound 7 in the mixed solvent of a kind of nitrile and water with ceric ammonium nitrate reaction, through extraction, dry, concentrate, obtain compound 8 behind the silica gel column chromatography.Said nitrile is selected from acetonitrile.
Step 5: compound 8 reacts with lithium aluminium hydride in a kind of ether solvent, through after filtration, concentrating again with chloroformic acid benzyl ester in a kind of halogenated hydrocarbon solvent and under the condition that exists of a kind of alkali, room temperature reaction, through extraction, concentrate, the silicagel column purifying obtains compound 9.Said ether is selected from C
2～C
4Aliphatic ether or alicyclic ether, particularly ether or tetrahydrofuran (THF); Said halohydrocarbon is selected from C
1～C
4Halohydrocarbon, particularly methylene dichloride or trichloromethane; Said alkali is tertiary amine, pyridine or carbonate, and said alkali is selected from triethylamine, and said carbonate is selected from salt of wormwood.
Step 6: compound 9 in a kind of halohydrocarbon or ether solvent with metachloroperbenzoic acid reaction, through extraction, dry, concentrate, obtain compound 10 behind the silica gel column chromatography.Said halohydrocarbon is selected from C
1～C
4Halohydrocarbon, particularly methylene dichloride or trichloromethane; Said ether is selected from C
2～C
4Aliphatic ether or alicyclic ether, particularly ether or tetrahydrofuran (THF).
The present invention is a raw material with imide cheap and easy to get 4 (synthetic method is seen Chinese patent ZL02143833.1), high yield, highly selective have synthesized compound (2R, 3S)-9, and from (2R 3S)-9 sets out and can synthesize febrifugin(e) and RU-19110, each step operation of the present invention separates simple, productive rate is higher, and used reagent is common agents, and is cheap and easy to get, route short (final medicine is totally 9 steps), total recovery higher (total recovery 8.43%).
Embodiment
The invention will be further described for following examples.
Embodiment 1
Step 1 is synthesized (S)-3-tertiary butyl dimethyl Si base-1-(4-methoxy-benzyl)-2,6-dioxopiperidine 5
Under nitrogen protection, add the dichloromethane solution (20mL) of TERT-BUTYL DIMETHYL CHLORO SILANE (17.61mmol) in compound 4 (17.61mmol) and imidazoles (35.21mmol) dichloromethane solution.Stirring at room 6h adds entry, separatory, and water dichloromethane extraction 3 times, organic layer is washed 3 times with saturated aqueous common salt (10mL * 3), and anhydrous sodium sulfate drying concentrates.Thick product gets colorless solid 5 (83%) with the silicagel column column purification.
Step 2 is synthesized (S)-1-(4-methoxybenzyl)-5-(tertiary butyl dimethyl Si base)-6-allyl group-6-hydroxyl-2-piperidone 6
Under nitrogen protection, in the methylene dichloride of dissolved compound 5 (2.8mmol), in the time of-78 ℃, slowly add the diethyl ether solution of AllyMgBr (8.4mmol), stir 3h.Add 10mL NH
4The saturated NaCl cancellation of Cl and 10mL.With anhydrous diethyl ether extraction (20mL * 3) 3 times.Organic phase is used saturated NaCl (10mL * 3) washing 3 times again.Anhydrous Na
2SO
4Drying concentrates, and thick product gets white solid 6 (82%) with silica gel (EtOAc/PE) post column purification, and regioselectivity is 12/88.
Step 3 is synthesized (S)-1-(4-methoxybenzyl)-5-(tertiary butyl dimethyl Si base)-6-allyl group-2-piperidone 7
Under nitrogen protection, (0.71mmol) is dissolved in CH with compound 6
2Cl
2(15mL), be cooled to-78 ℃, add Et
3SiH (7.1mmoL) and SnCl
4(2.13mmoL).Naturally stir and rise to room temperature reaction 8h.Use saturated NaHCO
3The cancellation reaction, separatory, water CH
2Cl
2Extraction (10mL * 3) 3 times, organic phase is with saturated sodium chloride washing 3 times, through Na
2SO
4After the drying, concentrate, thick product purification by silica gel column chromatography obtains colourless liquid 7 (65%).
Step 4 synthetic (5S, 6R)-3-(tertiary butyl dimethyl Si base)-6-allyl group piperidone 8
Compound 7 (2.06mmol) is dissolved in acetonitrile (75mmL) and the water (25mL), adds ceric ammonium nitrate (8.24mmoL), stirring at room 30min.Water (20mL) cancellation reaction, separatory, water ethyl acetate extraction (50mL * 3) 3 times, organic phase is with saturated sodium bicarbonate washing 3 times, through Na
2SO
4After the drying, concentrate, thick product purification by silica gel column chromatography obtains clear crystal 8 (63%).
Step 5 synthetic (2R, 3S)-1-carbobenzoxy-(Cbz)-3-hydroxyl-2-allyl group piperidone 9
Under nitrogen protection, slowly join in the tetrahydrofuran solution of lithium aluminium hydride during with 0 ℃ of tetrahydrofuran (THF) (6mL) solution of dissolved compound 8 (2.13mmol), rise to 60 ℃ and stir 5h.With sal glauberi cancellation reaction, filter, after concentrating; the DMAP that adds methylene dichloride (15mL) and catalytic amount; slowly add chloroformic acid benzyl ester (4mmol) and triethylamine (4mmol) under the nitrogen protection, stirred overnight at room temperature is with the reaction of going out of saturated sodium bicarbonate and saturated sodium-chloride collection.Separatory, water dichloromethane extraction 3 times, organic phase is washed 3 times with saturated sodium bicarbonate and sodium-chlor successively, through Na
2SO
4After the drying, concentrate, thick product purification by silica gel column chromatography obtains 3-hydroxyl-9.Under nitrogen protection, add uncle in the DMF solution of resulting 3-hydroxyl-9 (1.45mmol) and imidazoles (3mmol) and dissolve the DMF solution (3mL) of TERT-BUTYL DIMETHYL CHLORO SILANE (1.74mmol).Stirring at room 20h adds entry, extraction, and separatory, water dichloromethane extraction 3 times, organic layer is washed 3 times with saturated common salt, anhydrous Na
2SO
4Drying concentrates.Thick product gets 3-OTBS-9 (59%) with the silicagel column column purification.
Step 6 synthetic (2R, 3S)-1-carbobenzoxy-(Cbz)-3-tertiary butyl dimethyl Si base-2-ring supports propyl group piperidone 10
CH toward dissolved compound 3-OTBS-9 (200mg)
2Cl
2In in the time of-0 ℃, add MCPBA (266mg), stirring at room 6h.Add 20% Na
2S2O
3Solution dichloromethane extraction 3 times.Organic phase is washed 3 times with saturated sodium bicarbonate and sodium-chlor.Na
2SO
4Drying concentrates, and thick product gets colourless liquid 10 (productive rate 75%) with silica gel (EtOAc/PE) post column purification.
Embodiment 2
Step 1 is synthesized (S)-3-tertiary butyl dimethyl Si base-1-(4-methoxy-benzyl)-2,6-dioxopiperidine 5
The operation of compound 5 is identical with the operation among the embodiment 1, and the solvent of reaction changes tetrahydrofuran (THF) into, and stirring at room 12h, yield are 89%.
Step 2 is synthesized (S)-1-(4-methoxybenzyl)-5-(tertiary butyl dimethyl Si base)-6-allyl group-6-hydroxyl-2-piperidone 6
Under nitrogen protection, in the time of-78 ℃, slowly add the diethyl ether solution of rare propyl group magnesium bromide in the tetrahydrofuran (THF) of dissolved compound 5 (300mg), stir 5h.Use saturated NH
4The Cl cancellation.With anhydrous diethyl ether extraction 3 times.Na
2SO
4Drying concentrates, and thick product makes 6 productive rates 76% with silica gel (EtOAc/PE) post column purification, and regioselectivity is 20/80.
Step 3 is synthesized (S)-1-(4-methoxybenzyl)-5-(tertiary butyl dimethyl Si base)-6-allyl group-2-piperidone 7
Under the nitrogen protection, compound 6 is dissolved in CH
2Cl
2In, be cooled to-78 ℃, add Et
3SiH and boron trifluoride diethyl etherate.Naturally stir and rise to room temperature reaction 10h.Use saturated NaHCO
3The cancellation reaction, separatory, water CH
2Cl
2Extract 3 times, organic phase is with saturated sodium chloride washing 3 times, through Na
2SO
4After the drying, concentrate, thick product purification by silica gel column chromatography obtains compound 7 (69%).
Step 4 synthetic (5S, 6R)-3-(tertiary butyl dimethyl Si base)-6-allyl group piperidone 8
The operation of compound 8 is identical with the operation among the embodiment 1, and 0～25 ℃ is stirred 4h, and yield is 38%.
Step 5 synthetic (2R, 3S)-1-carbobenzoxy-(Cbz)-3-hydroxyl-2-allyl group piperidone 9
Under the nitrogen protection, the tetrahydrofuran solution of dissolved compound 8 is slowly joined in the tetrahydrofuran solution of lithium aluminium hydride, rise to 60 ℃ and stir 2h.With ten current acid sodium cancellation reaction, filter, after concentrating, add methylene dichloride, slowly add chloroformic acid benzyl ester and triethylamine under the nitrogen protection, stirring is spent the night, with the reaction of going out of coming together of saturated sodium bicarbonate and saturated sodium-chloride.Separatory, water dichloromethane extraction 3 times, organic phase is washed 3 times with saturated sodium bicarbonate and sodium-chlor successively, through Na
2SO
4After the drying, concentrate, thick product purification by silica gel column chromatography obtains colourless liquid, and under nitrogen protection, the adding uncle is dissolved TERT-BUTYL DIMETHYL CHLORO SILANE in the tetrahydrofuran solution of resulting colourless liquid and imidazoles.Stirring at room 60h with the anhydrous diethyl ether extraction, uses the saturated common salt water washing, anhydrous Na
2SO
4Drying concentrates.Thick product gets colourless liquid 9 productive rates 28% with the silicagel column column purification.
Step 6 synthetic (2R, 3S)-1-carbobenzoxy-(Cbz)-3-tertiary butyl dimethyl Si base-2-ring supports propyl group piperidone 10
CH toward dissolved compound 9
2Cl
2In adding MCPBA, stirring at room 18h.Add dichloromethane extraction 3 times of 20% hypo solution.Organic phase is washed 3 times with saturated sodium bicarbonate and sodium-chlor.Na
2SO
4Drying concentrates, and thick product gets colourless liquid 10 productive rates 53% with silica gel (EtOAc/PE) column purification.
Embodiment 3
Step 1 is synthesized (S)-3-tertiary butyl dimethyl Si base-1-(4-methoxy-benzyl)-2,6-dioxopiperidine 5
The operation of compound 5 is identical with the operation among the embodiment 1, and the solvent of reaction changes N ' dinethylformamide into, and used alkali is triethylamine, and stirring at room 15h, yield are 55%.
Step 2 is synthesized (S)-1-(4-methoxybenzyl)-5-(tertiary butyl dimethyl Si base)-6-allyl group-6-hydroxyl-2-piperidone 6
Compound 6 is according to step 2 preparation of embodiment 1.
Step 3 is synthesized (S)-1-(4-methoxybenzyl)-5-(tertiary butyl dimethyl Si base)-6-allyl group-2-piperidone 7
Under the nitrogen protection, compound 6 is dissolved in the methylene dichloride, is cooled to-78 ℃, add triethyl silicane and tin tetrachloride.Naturally stir and rise to room temperature reaction 16h.Use saturated NaHCO
3The cancellation reaction, separatory, water CH
2Cl
2Extract 3 times, organic phase is with saturated sodium chloride washing 3 times, through Na
2SO
4After the drying, concentrate, thick product purification by silica gel column chromatography obtains compound 7 (34%).
Step 4 synthetic (5S, 6R)-3-(tertiary butyl dimethyl Si base)-6-allyl group piperidone 8
The operation of compound 8 is identical with the operation among the embodiment 1, and 0 ℃ is stirred 1h, and yield is 44%.
Step 5 synthetic (2R, 3S)-1-carbobenzoxy-(Cbz)-3-hydroxyl-2-allyl group piperidone 9
Compound 9 prepares according to the step among the embodiment 1.
Step 6 synthetic (2R, 3S)-1-carbobenzoxy-(Cbz)-3-tertiary butyl dimethyl Si base-2-ring supports propyl group piperidone 10
CH toward dissolved compound 9
2Cl
2In adding MCPBA and sodium bicarbonate solid, stirring at room 2.5h.Add 20%Na
2S
2O
3Solution dichloromethane extraction 3 times.Organic phase is washed 3 times with saturated sodium bicarbonate and sodium-chlor.Na
2SO
4Drying concentrates, and thick product gets colourless liquid 11 productive rates 46% with silica gel (EtOAc/PE) post column purification.
Embodiment 4
Step 1 is synthesized (S)-3-benzyloxy-1-(4-methoxy-benzyl)-2,6-dioxopiperidine 5
Compound 4 is dissolved in the diethyl ether solution, adds the cylite of 3 normal silver suboxides and 3 molar weights, room temperature reaction 5 days filters, and concentrates, and column purification obtains compound 5, and yield is 51%.
Step 2 is synthesized (S)-1-(4-methoxybenzyl)-5-(benzyloxy)-6-allyl group-6-hydroxyl-2-piperidone 6
Nitrogen protection slowly adds down the diethyl ether solution of rare propyl group magnesium bromide, stirring 4h in the methylene dichloride of dissolved compound 5 in the time of-78 ℃.Use saturated NH
4The Cl cancellation.With anhydrous diethyl ether extraction 3 times.Na
2SO
4Drying concentrates, and thick product makes 6 productive rates 48% with the silicagel column column purification, and regioselectivity is 11/89.
Step 3 is synthesized (S)-1-(4-methoxybenzyl)-5-(benzyloxy)-6-allyl group-2-piperidone 7
Under the nitrogen protection, compound 6 is dissolved in CH
2Cl
2In, be cooled to-78 ℃, add Et
3SiH and boron trifluoride diethyl etherate.Naturally stir and rise to room temperature reaction 14h.Use saturated NaHCO
3The cancellation reaction, separatory, water CH
2Cl
2Extract 3 times, organic phase is with saturated sodium chloride washing 3 times, through Na
2SO
4After the drying, concentrate, thick product purification by silica gel column chromatography obtains compound 7 (84%).
Step 4 synthetic (5S, 6R)-3-(benzyloxy)-6-allyl group piperidone 8
The operation of compound 8 is identical with the operation among the embodiment 1, and 0～25 ℃ is stirred 4h, and yield is 26%.
Step 5 synthetic (2R, 3S)-1-carbobenzoxy-(Cbz)-3-benzyloxy-2-allyl group piperidone 9
Under the nitrogen protection, the tetrahydrofuran solution of dissolved compound 8 is slowly joined in the tetrahydrofuran solution of lithium aluminium hydride, rise to 60 ℃ and stir 7h.With ten current acid sodium cancellation reaction, filter, after concentrating, add methylene dichloride, slowly add chloroformic acid benzyl ester and triethylamine under the nitrogen protection, stirring is spent the night, with the reaction of going out of coming together of saturated sodium bicarbonate and saturated sodium-chloride.Separatory, water dichloromethane extraction 3 times, organic phase is washed 3 times with saturated sodium bicarbonate and sodium-chlor successively, through Na
2SO
4After the drying, concentrate, thick product purification by silica gel column chromatography obtains colourless liquid 9, productive rate 71%.
Claims (7)
1, the method for a kind of synthetic febrifugin(e) and RU-19110 intermediate is characterized in that synthetic route is as follows:
The steps include:
Step 1: compound 4 in a kind of halohydrocarbon or ether solvent with the reaction of a kind of protective material, through concentrating, obtaining compound 5 behind the silica gel column chromatography; Said protective material is selected from a kind of organosilane and a kind of alkali, perhaps another kind of halohydrocarbon, and said halohydrocarbon is selected from C
1～C
4Halohydrocarbon, said ether is selected from C
2～C
4Aliphatic ether or alicyclic ether, said organosilane is selected from TERT-BUTYL DIMETHYL CHLORO SILANE or tert-butyl diphenyl chlorosilane, said alkali is tertiary amine, said another kind of halohydrocarbon is selected from the halogenation benzyl;
Step 2: compound 5 in a kind of halohydrocarbon or ether solvent with allyl group azoviolet reaction, through extraction, dry, concentrate, obtain compound 6 behind the silica gel column chromatography, said halohydrocarbon is selected from C
1～C
4Halohydrocarbon, said ether is selected from C
2～C
4Aliphatic ether or alicyclic ether;
Step 3: compound 6 in a kind of halogenated hydrocarbon solvent with a kind of Lewis acid and a kind of silane reaction, through extraction, dry, concentrate, obtain compound 7 behind the silica gel column chromatography, said halohydrocarbon is selected from C
1～C
4Halohydrocarbon, said Lewis acid is selected from tin tetrachloride or boron trifluoride diethyl etherate, said silane is selected from triethyl silicane;
Step 4: compound 7 in the mixed solvent of a kind of nitrile and water with ceric ammonium nitrate reaction, through extraction, dry, concentrate, obtain compound 8 behind the silica gel column chromatography, said nitrile is selected from acetonitrile;
Step 5: compound 8 reacts with lithium aluminium hydride in a kind of ether solvent, through after filtration, concentrating again with chloroformic acid benzyl ester in a kind of halogenated hydrocarbon solvent and under the condition that exists of a kind of alkali, room temperature reaction, through extraction, concentrate, the silicagel column purifying obtains compound 9, said ether is selected from C
2～C
4Aliphatic ether or alicyclic ether, said halohydrocarbon is selected from C
1～C
4Halohydrocarbon, said alkali is tertiary amine, pyridine or carbonate;
Step 6: compound 9 in a kind of halohydrocarbon or ether solvent with metachloroperbenzoic acid reaction, through extraction, dry, concentrate, obtain compound 10 behind the silica gel column chromatography, said halohydrocarbon is selected from C
1～C
4Halohydrocarbon, said ether is selected from C
2～C
4Aliphatic ether or alicyclic ether.
2, the method for a kind of synthetic febrifugin(e) as claimed in claim 1 and RU-19110 intermediate is characterized in that said another kind of halohydrocarbon is selected from cylite or Benzyl Chloride in step 1.
3, the method for a kind of synthetic febrifugin(e) as claimed in claim 1 and RU-19110 intermediate is characterized in that said tertiary amine is selected from triethylamine in step 1.
4, the method for a kind of synthetic febrifugin(e) as claimed in claim 1 and RU-19110 intermediate is characterized in that said halohydrocarbon is selected from methylene dichloride or trichloromethane in step 1, step 2, step 3, step 5 and step 6.
5, the method for a kind of synthetic febrifugin(e) as claimed in claim 1 and RU-19110 intermediate is characterized in that said ether is selected from ether or tetrahydrofuran (THF) in step 1, step 2, step 5 and step 6.
6, the method for a kind of synthetic febrifugin(e) as claimed in claim 1 and RU-19110 intermediate is characterized in that said alkali is selected from triethylamine in step 5.
7, the method for a kind of synthetic febrifugin(e) as claimed in claim 1 and RU-19110 intermediate is characterized in that said carbonate is selected from salt of wormwood in step 5.
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| US8569492B2 (en) | 2009-09-21 | 2013-10-29 | Xiaoqi WANG | Method for preparing halofuginone derivative |
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| CN101463074B (en) * | 2009-01-22 | 2011-06-29 | 厦门大学 | Method for synthesizing cell toxic alkaloid and epimer thereof |
| EP2802572B1 (en) | 2012-01-13 | 2018-11-07 | President and Fellows of Harvard College | Halofuginol derivatives and their use in cosmetic and pharmaceutical compositions |
| CN102603615B (en) * | 2012-02-22 | 2013-11-13 | 中国海洋大学 | Intermediates of 2-acetonyl-3-methoxy piperidine and preparation method of 2-acetonyl-3-methoxy piperidine |
| CN103467449B (en) * | 2013-08-16 | 2015-06-03 | 浙江工业大学 | Piperidine derivative, and preparation method and application thereof in preparation of halofuginone |
| CN103980251B (en) * | 2014-04-24 | 2017-01-18 | 广东工业大学 | Orixine derivative and application of orixine derivative in preparation of medicine for resisting drug-fast bacteria |
| CN107954923B (en) * | 2016-10-14 | 2021-07-02 | 复旦大学 | Preparation method of key chiral piperidine intermediate of dichroine and halofuginone |
| CN109836451B (en) * | 2017-11-28 | 2021-09-07 | 复旦大学 | Preparation method of 3-hydroxy 2-piperidineamide skeleton dichroine or dichroone intermediate |
| CN109956966B (en) * | 2017-12-22 | 2021-05-04 | 复旦大学 | Method for synthesizing key chiral intermediate of dichroine |
| WO2019237125A1 (en) | 2018-06-08 | 2019-12-12 | The General Hospital Corporation | Inhibitors of prolyl-trna-synthetase |
| EP3904340B1 (en) * | 2018-12-28 | 2023-07-05 | Launch-Pharma Technologies, Ltd. | Synthesis method for halofuginone and intermediate thereof |
-
2004
- 2004-05-21 CN CN 200410045471 patent/CN1263753C/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8569492B2 (en) | 2009-09-21 | 2013-10-29 | Xiaoqi WANG | Method for preparing halofuginone derivative |
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| CN1583729A (en) | 2005-02-23 |
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