CN101066977A - Process of synthesizing (2R, 3S)-3-alkyl siloxy-2-allyl-1-alkoxy carbonyl-pyridine - Google Patents
Process of synthesizing (2R, 3S)-3-alkyl siloxy-2-allyl-1-alkoxy carbonyl-pyridine Download PDFInfo
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Abstract
The present invention provides process of synthesizing (2R, 3S)-3-alkyl siloxy-2-allyl-1-alkoxy carbonyl-pyridine as one key intermediate for synthesizing antimalarial febrifugin and RU-19110. The present invention synthesizes (2R, 3S)-3-alkyl siloxy-2-allyl-1-alkoxy carbonyl-pyridine with cheap facile material (L)-glutamic acid as main material and common reagent as assistant. The synthesizing process is convenient and short, and has high selectivity, high yield and low cost.
Description
Technical field
The invention belongs to chemical field, relate to a kind of asymmetric synthesis of piperidines, relate in particular to a kind of piperidines (2R, 3S)-synthetic method of 3 alkyl siloxies-2-allyl group-1-alkoxy carbonyl-piperidines.
Background technology
(2R, 3S)-3 hydroxyls-2-allyl group piperidines is that preparation has China's medicinal plant febrifugin(e) of antimalarial active and the clinical key intermediate that is used for the treatment of scleroderma, anti-fiber chemical drug RU-19110 of the II phase that enters of French Roussel-Uclaf company research and development.So far promoted application because resistance is the febrifugin(e) of 100 times of quinines because of side effects such as its clinical vomitings, wait the structural modification of side effects not stop always but it is reduced vomiting.Though febrifugin(e) is separated by the Shanghai medicine in eighties of last century the fifties, just determined by the method for asymmetric synthesis by the Japanization scholar up to its structure in 1999.Febrifugin(e) and Roussel-Uclaf key intermediate (2R, 3S)-3 hydroxyls-2-allyl group (substituting group of equal value) piperidines, over past ten years, very active to its research both at home and abroad.
At present, relevant (2R, 3S)-one of the most successful synthetic easy method of 3 hydroxyls-2-allyl group (substituting group of equal value) piperidines is Japanese Takeuchi Y. (Chemical Communication 2000, report 1643-1644) (its synthetic route is as follows), the core technology of this route is for obtaining key intermediate (2S by the biological enzyme reduction, 3S)-9, but synthetic (2S, initial feed price 3S)-9 is higher relatively, by enzyme reductive committed step productive rate not high (only being 40～60%).
The same year, Japanese chemical investigator Ogasawara K (Organic Letter 2000,3193) seminar through synthetic method made key intermediate (2R, 3S)-9, synthetic route is as follows:
This method synthetic (2R, 3S)-3 hydroxyls-2-allyl group (substituting group of equal value) piperidines intermediate, through 20 multisteps, complex process; Simultaneously in building-up process, used such as RCM PtO
2Used hypertoxic OsO in the novel agent, particularly route Deng costliness
4, if a large amount of preparation can cause very big environmental pollution.
(J.Org.Chemistry 1,999 6833 for Japanese chemical investigator Kobayashi Shu in 1999; Tetrahehedron Letter 1999,2175) seminar also to (2R, 3S)-1 the equivalent synthon of enantiomorph has carried out asymmetric synthesis:
Because this method route is longer, selectivity is relatively poor, and practical application is little, but the development of this route just, has just determined the stereochemistry of febrifugin(e) completely.But this seminar in ensuing detailed again in two years research other synthetic method Kobayashi Shu (J.American Chemical, Society, 2001,123,12510).
The Huang Peiqiang of China taught in 2003 and also reported (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:
This seminar is used for (2S, asymmetric synthesis 3S)-1, and with this method application national inventing patent (patent No.: CN1583729) in next year to the method for reduction allylation
But the selectivity of two synthetic routes of this seminar is all undesirable.
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 highly selective synthesized (2R, 3S)-method of 3-alkyl siloxy-2-allyl group-1-alkoxy carbonyl-piperidines.
The present invention synthetic (2R, 3S)-the concrete synthesis step of 3-alkyl siloxy-2-allyl group-1-alkoxy carbonyl-piperidines comprises:
(1): synthetic compound 2---(S)-2-amino-5-(benzyloxy) carboxyl-valeric acid
With the concentrated acid is solvent, makes compound 1---(L)-L-glutamic acid and alcohols with 1: 1～1: 3 mol ratio 0～100 ℃ of following successive reaction 2～10 hours, through extraction, concentrate, dry compound 2.Wherein concentrated acid is the vitriol oil; Alcohols is C
1～C
7Alcohol, particularly methyl alcohol, ethanol, Virahol and benzylalcohol.
(2): synthetic compound 3---(S)-2-hydroxyl-5-(benzyloxy) carboxyl-valeric acid
With the organic acid is solvent, with compound 2 and inorganic salt with 1: 1～1: 3 mol ratio successive reaction 2～10 hours under 0 ℃～rt., filter, concentrate compound 3.Wherein organic acid is C
1～C
3Acid, particularly formic acid, acetate and propyl alcohol; Inorganic salt are sodium salt, particularly Sodium Nitrite.
(3): synthetic compound 4---(S)-2-hydroxyl-5-(benzyloxy) carboxyl-methyl valerate
In organic solvent, under the alkaline condition, compound 3 and halohydrocarbon were reacted 20～60 hours under continuously stirring with 1: 1～1: 2 mol ratio, through obtaining compound 4 behind extraction, drying, the si-enriched plastic column chromatography.Wherein organic solvent is N, dinethylformamide (DMF) or dimethyl sulfoxide (DMSO) (DMSO); Halohydrocarbon is the methylating reagent methyl iodide; Described alkaline condition is a yellow soda ash, sodium bicarbonate, the alkaline condition of salt of wormwood or saleratus.
(4): synthetic compound 5---(S)-2-tertiary butyl dimethyl Si base-5-(benzyloxy) carboxyl-methyl valerate
In organic solvent, under the alkaline condition, compound 4 and organic silica-based halides were reacted under continuously stirring 5～20 hours with 1: 1～1: 2 mol ratio, through extraction, dry, concentrate, the silicagel column purifying gets compound 5.Wherein organic silica-based halides is TERT-BUTYL DIMETHYL CHLORO SILANE, tert-butyl diphenyl chlorosilane or methyl SULPHURYL CHLORIDE; Organic solvent is for containing N solvent: N, dinethylformamide (DMF) or dimethyl sulfoxide (DMSO) (DMSO); Described alkaline condition is the condition that imidazoles, pyridine or triethylamine exist.
(5): synthetic compound 6---(S)-4-tertiary butyl dimethyl Si base-5-(methoxyl group) carboxyl-valeric acid
In organic solvent, under the effect of palladium carbon, make compound 5 and hydrogen complete reaction at room temperature, filter, concentrate compound 6.Described organic solvent is alcoholic solvent or ether solvent, and wherein alcoholic solvent is C
1～C
3Alcohol, particularly methyl alcohol, ethanol or the trimethyl carbinol; Ether solvent is alicyclic ether, particularly tetrahydrofuran (THF); Wherein the amount of palladium carbon is 5%～10% of compound 5 molar weights.
(6): synthetic compound 7---(S)-4-tertiary butyl dimethyl Si base-5-(methoxyl group) carboxyl-amylalcohol
In ether solvent, make compound 6 and reductive agent with 1: 0.5～1: 2 mol ratio successive reaction 5～20 hours under 0 ℃～rt., through filtration, concentrate compound 7.Wherein ether solvent is C
2～C
4Aliphatic ether, alicyclic ether, particularly ether and tetrahydrofuran (THF); Described reductive agent is boracic class organic reagent, particularly borine tetrahydrofuran (THF) and borine dimethyl sulphide.
(7): synthetic compound 8---synthetic (S)-2-tertiary butyl dimethyl Si base-5-(p-toluenesulfonyl) oxygen base-methyl valerate
In halogenated hydrocarbon solvent, under the katalysis (its amount is 5%～10% of compound 7 molar weights) of pyridine base, make compound 7 and acyl chlorides and tertiary amine with 1: 1: 1～1: 2: 2 mol ratio successive reaction 20～60 hours under 0 ℃～rt., through extraction, dry, concentrate, behind the silica gel column chromatography and compound 8.Wherein halohydrocarbon is meant C
1～C
4Halohydrocarbon, particularly methylene dichloride, trichloromethane; Described acyl chlorides is SULPHURYL CHLORIDE, particularly benzene sulfonyl chloride or Tosyl chloride; Described tertiary amine is imidazoles and triethylamine; Described pyridine base catalyzer is the 4-methylamino pyridine.
(8): synthetic compound 9---(S)-2-tertiary butyl dimethyl Si base-5-azido--methyl valerate
In basic solvent, make compound 8 and sodiumazide with 1: 0.1～1: 2 mol ratio successive reaction 20～60 hours under 0 ℃～rt., through extraction, dry, concentrate compound 9.Wherein basic solvent is for containing N solvent, particularly N, dinethylformamide or N, N-diethylformamide.
(9): synthetic compound 10---synthetic (S)-3-tertiary butyl dimethyl Si base-2-piperidone
In alcoholic solvent or ether solvent, under the effect of palladium carbon, make compound 9 and hydrogen complete reaction at room temperature, filter, concentrate and compound 10.Wherein alcoholic solvent is C
1～C
3Alcohol, particularly methyl alcohol, ethanol and the trimethyl carbinol; Ether solvent is for referring to alicyclic ether, particularly tetrahydrofuran (THF); Wherein the amount of palladium carbon is 5%～10% of compound 9 molar weights.
(10): synthetic compound 11---(S)-3-tertiary butyl dimethyl Si base-1-benzyloxycarbonyl-2-piperidone
In ether solvent or halogenated hydrocarbon solvent, under alkaline condition, make compound 10 and alkoxy compound with 1: 1～1: 5 mol ratio in-78～0 ℃ of reaction 10～60 minutes, through extraction, concentrate, the silicagel column purifying gets compound 11.Wherein ether solvent is alicyclic ether, particularly tetrahydrofuran (THF); Halohydrocarbon is C
1～C
4Halohydrocarbon, particularly methylene dichloride, trichloromethane; Described alkaline condition is the condition of pyridine, N-picoline, triethylamine or n-Butyl Lithium; Described alkoxy compound is a kind of carbonyl oxycompound, particularly Carbobenzoxy Chloride (Cbz-Cl) and tertbutyloxycarbonyl acid anhydrides ((Boc)
2O).
(11): synthetic compound 12---Synthetic 2-hydroxyl-3-tertiary butyl dimethyl Si base-1-benzyloxycarbonyl-piperidines
In alcoholic solvent or halohydrocarbon, make compound 11 and reductive agent with 1: 1～1: 5 mol ratio-78～0 ℃ of reaction 2～10 hours down, through extraction, concentrate, the silicagel column purifying gets compound 12.Wherein pure alcoholic solvent is C
1～C
3Fatty Alcohol(C12-C14 and C12-C18), particularly methyl alcohol, ethanol, Virahol; Described halohydrocarbon is C
1～C
4Halohydrocarbon, particularly methylene dichloride, trichloromethane; Described reductive agent is sodium borohydride or diisobutyl aluminium hydride (DIBAl-H).
(12): synthetic compound 13---Synthetic 2-acetoxy-3-tertiary butyl dimethyl Si base-1-benzyloxycarbonyl-piperidines
In halogenated hydrocarbon solvent, under alkaline condition, with compound 12 and acyl chlorides or acid anhydrides with 1: 1～1: 5 mol ratio successive reaction 2～8 hours under 0 ℃～rt., through extraction, concentrate, the silicagel column purifying gets compound 13.Wherein halohydrocarbon is C
1～C
4Halohydrocarbon, particularly methylene dichloride, trichloromethane; Condition, particularly pyridine, triethylamine that described alkaline condition exists for amine alkali; Described acyl chlorides is phenylsulfinyl chlorine or Acetyl Chloride 98Min.; Said acid anhydrides is a diacetyl oxide.
(13): synthetic target product compound 14---(2R, 3S)-3-tertiary butyl dimethyl Si base-2-allyl group-1-benzyloxycarbonyl-piperidines
In halogenated hydrocarbon solvent, under the Lewis acid effect, make compound 13 and organosilicon reagent with 1: 1～1: 3 mol ratio in-78～0 ℃ of following successive reaction 2～10 hours, through extraction, dry, concentrate, silica gel column chromatography gets compound 14.Wherein halohydrocarbon is C
1～C
4Hydrochloric ether, particularly methylene dichloride, trichloromethane; Described organosilicon reagent is trimethylammonium allyl silicane or dimethyl tertiary butyl allyl silicane; Described Lewis acid is tin tetrachloride or boron trifluoride diethyl etherate; Wherein lewis acidic amount is 5%～10% of compound 13 molar weights.
Synthetic route of the present invention is as follows: wherein 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 Boc represents tertiary butyl oxygen carbonyl, and TBS represents that tertiary butyl dimethyl is silica-based, and the TBDPS tert-butyl diphenyl is silica-based, and Ts represents Tosyl chloride.
Wherein P=Boc or Cbz etc.
The present invention compares in prior art and has the following advantages:
1, the present invention is a raw material with L-L-glutamic acid cheap and easy to get, is auxiliary agent with the common agents, low cost, high yield, highly selective synthesized crucial midbody compound (2R, 3S)-14, its total recovery higher (total recovery is 11.35%).
2, route of the present invention is short, and each step operation separates simple, and each step productive rate is higher, and synthetic cost is low.
Embodiment
Further specify the present invention with embodiment below.
Embodiment 1
1: compound 2---(S)-2-amino-5-(benzyloxy) carboxyl-valeric acid synthetic
Under nitrogen protection, with compound 1---L-L-glutamic acid (33.8mmol) is dissolved in the vitriol oil (150mL), adds benzylalcohol (33.8mmol), 0～100 ℃ of following successive reaction 2～10 hours, through extraction, dry, concentrate, behind the silica gel column chromatography and get.The reaction system thin up, with ethyl acetate extraction three times, organic layer is given a baby a bath on the third day after its birth time with saturated aqueous common salt, anhydrous Na
2SO
4Drying, concentrate and compound 2 (yield 50.0%).
2: compound 3---(S)-2-hydroxyl-5-(benzyloxy) carboxyl-valeric acid synthetic
Compound 2 (20.7mmol) is dissolved in the 150mL anhydrous acetic acid, adds Sodium Nitrite (24.8mmol), successive reaction is 2～10 hours under 0 ℃～rt., concentrate the back thin up, with ethyl acetate extraction three times, organic layer is given a baby a bath on the third day after its birth time with saturated aqueous common salt, anhydrous Na
2SO
4Drying, concentrate and compound 3 (yield 80.0%).
3, compound 4---(S)-and 2-hydroxyl-5-(benzyloxy) carboxyl-methyl valerate synthetic
Under the nitrogen protection, compound 3 (5.38mmol) is dissolved among the DMF (50mL), under room temperature, adds NaHCO
3(5.91mmoL), continuously stirring makes reaction 20～60 hours.The reaction system thin up, with ethyl acetate extraction three times, organic layer is given a baby a bath on the third day after its birth time with saturated aqueous common salt, anhydrous Na
2SO
4Drying concentrates, and thick product obtains compound 4 (yield 87.0%) through purification by silica gel column chromatography.
4, compound 5---(S)-and 2-tertiary butyl dimethyl Si base-5-(benzyloxy) carboxyl-methyl valerate synthetic
Compound 4 (3.76mmol) is dissolved among the DMF (50mL), and rt. adds TERT-BUTYL DIMETHYL CHLORO SILANE (5.64mmol), continuously stirring 5～20 hours down.Thin up, separatory, ethyl acetate extraction, organic phase is with saturated sodium carbonate washing three times, through Na
2SO
4After the drying, concentrate, thick product purification by silica gel column chromatography obtains compound 5 (yield 90.0%).
5, compound 6---(S)-and 4-tertiary butyl dimethyl Si base-5-(methoxyl group) carboxyl-valeric acid synthetic
Compound 5 (3.13mmol) is dissolved among the MeOH (50mL), adds 100mg 10%Pd/C, feed the hydrogen continuously stirring under the room temperature until reacting completely.Filter, filtrate concentrates, and thick product promptly gets compound 6 (yield 95.0%) without being further purified.
6, compound 7---(S)-and 4-tertiary butyl dimethyl Si base-5-(methoxyl group) carboxyl-amylalcohol synthetic
Under the nitrogen protection, compound 6 (5.38mmol) is dissolved among the THF (50mL),, adds BH in 0 ℃
3-Me
2S (8.07mmol), continuously stirring makes reaction 5～20 hours under the rt..Use saturated NaHCO
3The cancellation reaction, separatory, water CH
2Cl
2Extract three times, organic phase is with saturated sodium chloride solution washing three times, through Na
2SO
4After the drying, concentrate, thick product obtains compound 7 (yield 88%) through purification by silica gel column chromatography.
7, compound 8---(S)-and 2-tertiary butyl dimethyl Si base-5-(p-toluenesulfonyl) oxygen base-methyl valerate synthetic
Compound 7 (1.86mmol) is dissolved in CH
2Cl
2(30mL), 0 ℃ adds Tosyl chloride (2.05mmol), Et down
3N (3.72mmol) and DMAP (0.19mmol) slowly rise to room temperature, and continuously stirring 20～60 hours is with frozen water cancellation reaction, separatory, water CH
2Cl
2Extract three times, organic phase is with saturated sodium chloride washing three times, through Na
2SO
4After the drying, concentrate, thick product purification by silica gel column chromatography obtains compound 8 (yield 79.0%).
8, compound 9---(S)-and 2-tertiary butyl dimethyl Si base-5-azido--methyl valerate synthetic
Under the nitrogen protection, compound 8 (3.76mmol) is dissolved among the DMF (50mL), 0 ℃ adds sodiumazide (4.52mmol), stirring at room 20～60 hours down.Thin up, separatory, ethyl acetate extraction, organic phase is with saturated sodium carbonate washing three times, through Na
2SO
4After the drying, concentrate, thick product purification by silica gel column chromatography obtains compound 9 (yield 95.0%).
9, compound 10---(S)-and 3-tertiary butyl dimethyl Si base-2-piperidone must synthesize
Compound 9 (3.13mmol) is dissolved among the MeOH (50mL), adds 100mg 10%Pd/C, feed the hydrogen continuously stirring under the room temperature until reacting completely.Filter, filtrate concentrates, and thick product promptly gets colourless liquid 10 (yield 75.0%) without being further purified.
10, compound 11---(S)-and 3-tertiary butyl dimethyl Si base-1-benzyloxycarbonyl-2-piperidone synthetic
Compound 10 (2.27mmol) is dissolved among the THF (35mL), and-78 ℃ add Cbz (3.75mmol) and n-Butyl Lithium (4.54mmol), successive reaction 10～60 minutes down.Add saturated NaHCO
3The cancellation reaction, separatory, water dichloromethane extraction three times, organic phase is with saturated sodium-chloride washing three times, through Na
2SO
4After the drying, concentrate, thick product purification by silica gel column chromatography obtains compound 11 (yield 87.2%).
11, compound 12---synthesizing of 2-hydroxyl-3-tertiary butyl dimethyl Si base-1-benzyloxycarbonyl-piperidines
Compound 11 (2.59mmol) is dissolved among the THF (30mL), adds diisobutyl aluminium hydride (DIBAL-H) (2.59mmol) down at-78 ℃, continuously stirring 2～10 hours.Add ice-shrend and go out, thin up is with ethyl acetate extraction three times.Organic phase is washed three times with saturated sodium-chloride.Na
2SO
4Drying concentrates, and thick product gets colourless liquid 12 (yield 96.0%) with the silicagel column column purification.
12, compound 13---synthesizing of 2-acetoxy-3-tertiary butyl dimethyl Si base-1-benzyloxycarbonyl-piperidines
Compound 12 (1.86mmol) is dissolved in CH
2Cl
2(30mL), 0 ℃ adds diacetyl oxide (2.05mmol), Et down
3The DMAP of N (3.72mmol) and catalytic amount slowly rises to room temperature, and continuously stirring 2～8 hours is used saturated NaHCO
3The cancellation reaction, separatory, water CH
2Cl
2Extract three times, organic phase is with saturated sodium chloride washing three times, through Na
2SO
4After the drying, concentrate, thick product purification by silica gel column chromatography obtains compound 13 (yield 97.1%).
13, compound 14---(2R, 3S)-3-tertiary butyl dimethyl Si base-2-allyl group-1-benzyloxycarbonyl-piperidines synthetic
Under the nitrogen protection, compound 13 (1.19mmol) is dissolved among the THF (50mL), and-78 ℃ add trimethylammonium allyl silicane (1.19mmol) and boron trifluoride diethyl etherate (1.19mmol) down.Successive reaction 2～10 hours, the reaction system thin up, with dichloromethane extraction three times, organic layer is given a baby a bath on the third day after its birth time with saturated aqueous common salt, anhydrous Na
2SO
4Drying concentrates.Thick product gets compound 14 (yield 93.8%) with the silicagel column column purification
Embodiment 2
Compound 2～4 is synthetic identical with embodiment 1 in step 1～3.
Step 4, compound 5---(S)-2-tert-butyl diphenyl siloxy-5-(benzyloxy) carboxyl-methyl valerate synthetic
Compound 4 (3.76mmol) is dissolved among the DMF (50mL), and rt. adds tert-butyl diphenyl chlorosilane (5.64mmol), continuously stirring 5～20 hours down.Thin up, separatory, ethyl acetate extraction, organic phase is with saturated sodium carbonate washing three times, through Na
2SO
4After the drying, concentrate, thick product purification by silica gel column chromatography obtains compound 5 (yield 88.3%).
Compound 6～7 is synthetic identical with embodiment 1 in step 5～6.
Step 7, compound 8---(S)-2-tert-butyl diphenyl siloxy-5-(methane sulfonyl) oxygen base-methyl valerate synthetic
Compound 7 (1.86mmol) is dissolved in CH
2Cl
2(30mL), 0 ℃ adds to methyl SULPHURYL CHLORIDE (2.05mmol) Et down
3N (3.72mmol) and DMAP (0.19mmol) slowly rise to room temperature, and continuously stirring 20～60 hours is with frozen water cancellation reaction, separatory, water CH
2Cl
2Extract three times, organic phase is with saturated sodium chloride washing three times, through Na
2SO
4After the drying, concentrate, thick product purification by silica gel column chromatography obtains compound 8 (yield 66.8%).
Compound 9～12 is synthetic identical with embodiment 1 described step in step 8～11.
Synthesizing of step 12, compound 13---2-acetoxy-3-tert-butyl diphenyl siloxy-1-benzyloxycarbonyl-piperidines
Compound 12 (1.86mmol) is dissolved in CH
2Cl
2(30mL), 0 ℃ adds Acetyl Chloride 98Min. (2.05mmol), Et down
3The DMAP of N (3.72mmol) and catalytic amount slowly rises to room temperature, and continuously stirring 2～8 hours is used saturated NaHCO
3The cancellation reaction, separatory, water CH
2Cl
2Extract three times, organic phase is with saturated sodium chloride washing three times, through Na
2SO
4After the drying, concentrate, thick product purification by silica gel column chromatography obtains compound 13 (yield 98.2%).
Step 13, compound 14---(2R, 3S)-3-tert-butyl diphenyl siloxy-2-allyl group-1-benzyloxycarbonyl-piperidines synthetic
Under the nitrogen protection, compound 13 (1.19mmol) is dissolved among the THF (50mL), and-78 ℃ add trimethylammonium allyl silicane (1.19mmol) and tin tetrachloride (1.19mmol) down.Successive reaction 2～10 hours, the reaction system thin up, with dichloromethane extraction three times, organic layer is given a baby a bath on the third day after its birth time with saturated aqueous common salt, anhydrous Na
2SO
4Drying concentrates.Thick product gets compound 14 (yield 73.3%) with the silicagel column column purification.
Embodiment 3
Compound 2～10 is synthetic identical with step described in the embodiment 1 in step 1～9.
Step 10, compound 11---(S)-3-tertiary butyl dimethyl Si base-1-tert-butoxycarbonyl-2-piperidone synthetic
Compound 10 (2.27mmol) is dissolved in CH
2Cl
2(50mL), 0 ℃ adds (Boc) down
2O (3.75mmol) and Et
3N (4.54mmol), successive reaction 2～10 hours.Add saturated NaHCO
3The cancellation reaction, separatory, water dichloromethane extraction three times, organic phase is with saturated sodium-chloride washing three times, through Na
2SO
4After the drying, concentrate, thick product purification by silica gel column chromatography obtains compound 11 (yield 80.4%).
Compound 12～14 is synthetic identical with step described in the embodiment 1 in step 11～13.
Claims (13)
1, a kind of synthetic (2R, 3S)-method of 3-alkyl siloxy-2-allyl group-1-alkoxy carbonyl-piperidines, it is characterized in that: its synthesis step comprises:
(1): synthetic compound 2---(S)-2-amino-5-(benzyloxy) carboxyl-valeric acid
With the concentrated acid is solvent, makes compound 1---(L)-L-glutamic acid and alcohols with 1: 1～1: 3 mol ratio 0～100 ℃ of following successive reaction 2～10 hours, through extraction, concentrate, dry compound 2;
(2): synthetic compound 3---(S)-2-hydroxyl-5-(benzyloxy) carboxyl-valeric acid
With the organic acid is solvent, with compound 2 and inorganic salt with 1: 1～1: 3 mol ratio successive reaction 2～10 hours under 0 ℃～rt., filter, concentrate compound 3;
(3): synthetic compound 4---(S)-2-hydroxyl-5-(benzyloxy) carboxyl-methyl valerate
In organic solvent, under the alkaline condition, compound 3 and halohydrocarbon were reacted 20～60 hours under continuously stirring with 1: 1～1: 3 mol ratio, through extraction, dry, concentrate, behind the silica gel column chromatography compound 4;
(4): synthetic compound 5---(S)-2-tertiary butyl dimethyl Si base-5-(benzyloxy) carboxyl-methyl valerate
In organic solvent, under the alkaline condition, compound 4 and organic silica-based halides were reacted under continuously stirring 5～20 hours with 1: 1～1: 2 mol ratio, through extraction, dry, concentrate, purification by silica gel column chromatography gets compound 5;
(5): synthetic compound 6---(S)-4-tertiary butyl dimethyl Si base-5-(methoxyl group) carboxyl-valeric acid
In organic solvent, under the effect of palladium carbon, make compound 5 and hydrogen complete reaction at room temperature, filter, concentrate compound 6; Wherein the amount of palladium carbon is 5%～10% of compound 5 molar weights.
(6): synthetic compound 7---(S)-4-tertiary butyl dimethyl Si base-5-(methoxyl group) carboxyl-amylalcohol
In ether solvent, make compound 6 and reductive agent with 1: 0.5～1: 2 mol ratio successive reaction 5～20 hours under 0 ℃～rt., through filtration, concentrate compound 7;
(7): synthetic compound 8---synthetic (S)-2-tertiary butyl dimethyl Si base-5-(p-toluenesulfonyl) oxygen base-methyl valerate
In halogenated hydrocarbon solvent, under the katalysis of pyridine base, make compound 7 and acyl chlorides and tertiary amine with 1: 1: 1～1: 2: 2 mol ratio successive reaction 20～60 hours under 0 ℃～rt., through extraction, dry, concentrate, silica gel column chromatography gets compound 8; Wherein the amount of pyridine base is 5%～10% of compound 7 molar weights.
(8): synthetic compound 9---(S)-2-tertiary butyl dimethyl Si base-5-azido--methyl valerate
In basic solvent, make compound 8 and sodiumazide with 1: 0.1～1: 2 mol ratio successive reaction 20～60 hours under 0 ℃～rt., through extraction, dry, concentrate compound 9;
(9): synthetic compound 10---synthetic (S)-3-tertiary butyl dimethyl Si base-2-piperidone
In alcoholic solvent or ether solvent, under the effect of palladium carbon, make compound 8 and hydrogen complete reaction at room temperature, filter, concentrate compound 10; Wherein the amount of palladium carbon is 5%～10% of compound 8 molar weights.
(10): synthetic compound 11---(S)-3-tertiary butyl dimethyl Si base-1-benzyloxycarbonyl-2-piperidone
In ether solvent or halogenated hydrocarbon solvent, under alkaline condition, make compound 10 and alkoxy compound with 1: 1～1: 5 mol ratio in-78～0 ℃ of reaction 10～60 minutes, through extraction, concentrate, the silicagel column purifying gets compound 11;
(11): synthetic compound 12---Synthetic 2-hydroxyl-3-tertiary butyl dimethyl Si base-1-benzyloxycarbonyl-piperidines
In alcoholic solvent or halohydrocarbon, make compound 11 and reductive agent with 1: 1～1: 5 mol ratio-78～0 ℃ of reaction 2～10 hours down, through extraction, concentrate, the silicagel column purifying gets compound 12;
(12): synthetic compound 13---Synthetic 2-acetoxy-3-tertiary butyl dimethyl Si base-1-benzyloxycarbonyl-piperidines
In halogenated hydrocarbon solvent, under alkaline condition, with compound 12 and acyl chlorides or acid anhydrides with 1: 1～1: 5 mol ratio successive reaction 2～8 hours under 0 ℃～rt., through extraction, concentrate, the silicagel column purifying gets compound 13;
(13): synthesising target compound 14---(2R, 3S)-3-tertiary butyl dimethyl Si base-2-allyl group-1-benzyloxycarbonyl-piperidines
In halogenated hydrocarbon solvent, under the Lewis acid effect, make compound 13 and organosilicon reagent with 1: 1～1: 3 mol ratio in-78～0 ℃ of following successive reaction 2～10 hours, through extraction, dry, concentrate, silica gel column chromatography gets compound 14; Wherein lewis acidic amount is 5%～10% of compound 13 molar weights.
2, synthetic according to claim 1 (2R, 3S)-method of 3-alkyl siloxy-2-allyl group-1-alkoxy carbonyl-piperidines, it is characterized in that: the 1. described concentrated acid of step is the vitriol oil; Described alcohols is C
1～C
7Alcohol.
3, synthetic according to claim 1 (2R, 3S)-method of 3-alkyl siloxy-2-allyl group-1-alkoxy carbonyl-piperidines, it is characterized in that: the 2. described organic acid of step is formic acid, acetate or propyl alcohol; Described inorganic salt are Sodium Nitrite.
4, synthetic according to claim 1 (2R, 3S)-method of 3-alkyl siloxy-2-allyl group-1-alkoxy carbonyl-piperidines, it is characterized in that: the 3. described organic solvent of step is N, dinethylformamide or dimethyl sulfoxide (DMSO); Described alkaline condition is the condition that yellow soda ash, sodium bicarbonate, salt of wormwood or saleratus exist; Described halohydrocarbon is a methyl iodide.
5, synthetic according to claim 1 (2R, 3S)-and the method for 3-alkyl siloxy-2-allyl group-1-alkoxy carbonyl-piperidines, it is characterized in that: the 4. described organic silica-based halides of step is TERT-BUTYL DIMETHYL CHLORO SILANE, tert-butyl diphenyl chlorosilane, tert-butyl diphenyl chlorosilane or methyl SULPHURYL CHLORIDE; Described organic solvent is N, dinethylformamide or dimethyl sulfoxide (DMSO); Described alkaline condition is the condition that imidazoles, pyridine or triethylamine exist.
6, synthetic according to claim 1 (2R, 3S)-method of 3-alkyl siloxy-2-allyl group-1-alkoxy carbonyl-piperidines, it is characterized in that: 5. step is alcoholic solvent or ether solvent with the 9. described organic solvent of step; Wherein alcoholic solvent is methyl alcohol, ethanol and the trimethyl carbinol, and ether solvent is alicyclic ether or tetrahydrofuran (THF).
It is 7, synthetic according to claim 1 that (2R, 3S)-method of 3-alkyl siloxy-2-allyl group-1-alkoxy carbonyl-piperidines, it is characterized in that: the 6. described ether solvent of step is C
2～C
4Aliphatic ether, alicyclic ether; Described reductive agent is borine tetrahydrofuran (THF) and borine dimethyl sulphide.
It is 8, synthetic according to claim 1 that (2R, 3S)-method of 3-alkyl siloxy-2-allyl group-1-alkoxy carbonyl-piperidines, it is characterized in that: the 7. described halohydrocarbon of step is for referring to C
1～C
4Halohydrocarbon; Described acyl chlorides is a SULPHURYL CHLORIDE; Described tertiary amine is imidazoles and triethylamine; Described pyridine base is the 4-methylamino pyridine.
It is 9, synthetic according to claim 1 that (2R, 3S)-method of 3-alkyl siloxy-2-allyl group-1-alkoxy carbonyl-piperidines, it is characterized in that: the 8. described basic solvent of step is N, dinethylformamide or N, N-diethylformamide.
10, synthetic according to claim 1 (2R, 3S)-method of 3-alkyl siloxy-2-allyl group-1-alkoxy carbonyl-piperidines, it is characterized in that: the 10. described ether solvent of step is the alicyclic ether tetrahydrofuran (THF); Described halohydrocarbon is C
1～C
4Halohydrocarbon; Described alkaline condition is the condition that pyridine, N-picoline, triethylamine or n-Butyl Lithium exist; Described alkoxy compound is the carbonyl oxycompound: Carbobenzoxy Chloride or tertbutyloxycarbonyl acid anhydrides.
It is 11, synthetic according to claim 1 that (2R, 3S)-method of 3-alkyl siloxy-2-allyl group-1-alkoxy carbonyl-piperidines, it is characterized in that: the described alcoholic solvent of step 11 is C
1～C
3Fatty Alcohol(C12-C14 and C12-C18); Described halohydrocarbon is C
1～C
4Halohydrocarbon; Described reductive agent is sodium borohydride or diisobutyl aluminium hydride.
It is 12, synthetic according to claim 1 that (2R, 3S)-method of 3-alkyl siloxy-2-allyl group-1-alkoxy carbonyl-piperidines, it is characterized in that: the described halohydrocarbon of step 12 is for referring to C
1～C
4Halohydrocarbon; Described acyl chlorides is phenylsulfinyl chlorine or Acetyl Chloride 98Min.; Described acid anhydrides is a diacetyl oxide; Described alkaline condition is the condition that tertiary amine exists.
It is 13, synthetic according to claim 1 that (2R, 3S)-method of 3-alkyl siloxy-2-allyl group-1-alkoxy carbonyl-piperidines, it is characterized in that: said halohydrocarbon is for referring to C
1～C
4Hydrochloric ether; Described organosilicon reagent is trimethylammonium allyl silicane or dimethyl tertiary butyl allyl silicane; Described Lewis acid is tin tetrachloride or boron trifluoride diethyl etherate.
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| CN103204799A (en) * | 2013-05-06 | 2013-07-17 | 青岛农业大学 | (2S,3R)-1-substituted benzyl-2-allyl-3-hydroxypiperidine and preparation method thereof |
| CN109836451A (en) * | 2017-11-28 | 2019-06-04 | 复旦大学 | 3- hydroxyl 2- piperidine amides skeleton orixine (ketone) and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103204799A (en) * | 2013-05-06 | 2013-07-17 | 青岛农业大学 | (2S,3R)-1-substituted benzyl-2-allyl-3-hydroxypiperidine and preparation method thereof |
| CN109836451A (en) * | 2017-11-28 | 2019-06-04 | 复旦大学 | 3- hydroxyl 2- piperidine amides skeleton orixine (ketone) and preparation method thereof |
| CN109836451B (en) * | 2017-11-28 | 2021-09-07 | 复旦大学 | Preparation method of 3-hydroxy 2-piperidineamide skeleton dichroine or dichroone intermediate |
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