CN102167700A - 3-trifluoromethyl-5-tert-butoxycarbonyl-2,5-diheterobicyclo[2.2.1]heptane and preparation method thereof - Google Patents

3-trifluoromethyl-5-tert-butoxycarbonyl-2,5-diheterobicyclo[2.2.1]heptane and preparation method thereof Download PDF

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CN102167700A
CN102167700A CN2010101138805A CN201010113880A CN102167700A CN 102167700 A CN102167700 A CN 102167700A CN 2010101138805 A CN2010101138805 A CN 2010101138805A CN 201010113880 A CN201010113880 A CN 201010113880A CN 102167700 A CN102167700 A CN 102167700A
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tertbutyloxycarbonyl
trifluoromethyl
heptane
diazabicyclo
preparation
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张永明
彭宣嘉
胡利红
汪秀
董径超
吴颢
马汝建
陈曙辉
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Yaomingkangde New Medicine Development Co Ltd Wuxi
Wuxi Apptec Co Ltd
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Yaomingkangde New Medicine Development Co Ltd Wuxi
Wuxi Apptec Co Ltd
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Abstract

The invention discloses 3-trifluoromethyl-5-tert-butoxycarbonyl-2,5-diheterobicyclo[2.2.1]heptane and a preparation method thereof. The invention mainly solves the technical problems that when a methyl derivative is introduced to the 3-site of the 2,5-diheterobicyclo[2.2.1]heptane compound, the synthesis steps are complicated, the water solubility is poor and the total yield is low. The structural formula of the compounds is shown as below, wherein R is NH or O; when R is NH, the compound is 3-trifluoromethyl-5-tert-butoxycarbonyl-2,5-diazabicyclo[2.2.1]heptane; and when R is O, the compound is 3-trifluoromethyl-5-tert-butoxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptane. The obtained compounds are mainly used to effectively connect the pharmacophore unit.

Description

3-trifluoromethyl-5-tertbutyloxycarbonyl-2,5-two assorted dicyclo [2.2.1] heptane and preparation methods
Technical field
The present invention relates to a kind of 3-trifluoromethyl-5-tertbutyloxycarbonyl-2,5-two assorted dicyclo [2.2.1] heptane and preparation methods, 3-trifluoromethyl-5-tertbutyloxycarbonyl-2 particularly, 5-diazabicyclo [2.2.1] heptane and 3-trifluoromethyl-5-tertbutyloxycarbonyl-2-oxa--5-azabicyclo [2.2.1] heptane and preparation method.
Background technology:
2,5-two assorted dicyclo [2.2.1] iieptanes compounds are that a class formation is than specific molecule, the pharmacophore unit of key effectively can be connected and be incorporated in its rigid structure, formation has the molecule of special space configuration/conformation, thereby can mate the space structure of different biomacromolecules in the organism, produce different biological activity or effectiveness, as with 2,5-two assorted dicyclo [2.2.1] heptane are connected in the anodyne carbostyril compound, have good analgesic activities (J.Med.Chem.; 31; 1988; 1598-1611).At present, 2 of bibliographical information, the synthetic of 5-two assorted dicyclo [2.2.1] heptane substantially all is the preparation that centers on substitution compound on endocyclic relative configuration and the nitrogen.For the synthetic report that the substituting group compound is arranged on the bridged ring then seldom, has only document (J.Med.Chem.; 35; 1992; 2898-2909) reported the preparation and the document (Eur.J.Org.Chem. of 3 methyl substituted derivatives; 18; 2005; 3987-3993) introduced the preparation of 3 n-propyl substitutive derivatives.The introducing of 3 bit substituents can increase by 2, and the flexibility of assorted dicyclo [2.2.1] the heptane structures of 5-two and compound fat-soluble increases the diversity of molecule simultaneously.The present invention introduces trifluoromethyl, reaches the purpose of improving its quasi-medicated property matter in the hope of electronic effect and the steric effect that changes molecular structure, and the synthetic method of this class novel cpd is provided for 3 of 5-two assorted dicyclo [2.2.1] heptane 2.Efficiently solve the unicity of the bridged ring compounds synthetic method of present two assorted dicyclo [2.2.1] heptane structures simultaneously, with the lower section be in the document disclosed and with the more closely-related synthetic methods of the technology of the present invention.
Document J.Org.Chem.; 55; 1990; 1684-1687; reported (1R; 4R)-2-methyl-2; the preparation of 5-diazabicyclo [2.2.1] heptane hydrobromate; see formula 1; this route is by (2R; 4R)-2-formic acid-4-hydroxyl pyrrolidine 1.1 is a starting raw material; through acidic alcohol esterification salify; Tosyl chloride becomes ester to get 1.3; 4 α hydroxyls get compound 1.4 through tetra-n-butyl amine acetate configuration inversion; through the potassium hydroxide hydrolysis; sodium borohydride, the boron trifluoride diethyl etherate reduction; the esterification of biconjugate tolylsulfonyl gets compound 1.7, through methylamine alcohol solution close encircle compound 1.8; again Hydrogen bromide take off p-toluenesulfonyl totally 8 go on foot target compound (1R; 4R)-and 2-methyl-2,5-diazabicyclo [2.2.1] heptane hydrobromate 1.9, total recovery is 21%.
Formula 1
The document is also mentioned (1S; 4S)-2-methyl-2; the preparation of 5-diazabicyclo [2.2.1] heptane hydrobromate; see formula 2; this route is by (2S; 4R)-2-formic acid-4-hydroxyl pyrrolidine is that starting raw material becomes ester to get 2.2 through Tosyl chloride; sodium borohydride, boron trifluoride diethyl etherate reduce 2.3; the esterification of biconjugate tolylsulfonyl gets compound 2.4; through methylamine alcohol solution close encircle compound 2.5, again Hydrogen bromide take off p-toluenesulfonyl totally 5 go on foot target compound (1S, 4S)-2-methyl-2; 5-diazabicyclo [2.2.1] heptane hydrobromate 2.6, total recovery is 40%.
Formula 2
Figure GSA00000037749600022
Document J.Med.Chem.; 33; 1990; 1344-1352; reported (1R; 4R)-2; the preparation of 5-diazabicyclo [2.2.1] heptane hydrobromate; see formula 3; this route is by (2R; 4R)-2-formic acid-4-hydroxyl pyrrolidine is that starting raw material is through acidic alcohol esterification salify; Tosyl chloride becomes ester to get 3.3; 4 α hydroxyls get compound 3.4 through tetra-n-butyl amine acetate configuration inversion, reduce through lithium borohydride; the esterification of biconjugate tolylsulfonyl gets compound 3.6, through benzylamine toluene close encircle compound 3.7; Hydrogen bromide takes off p-toluenesulfonyl again; the palladium hydrocarbonize take off benzyl totally 8 go on foot target compound (1R; 4R)-2,5-diazabicyclo [2.2.1] heptane hydrobromate 3.9, total recovery is 18%.
Formula 3
Figure GSA00000037749600031
Document J.Med.Chem.; 35; 1992; 2898-2909 has reported (1R; 4R)-3-methyl-2; the preparation of 5-diazabicyclo [2.2.1] heptane hydrobromate; see formula 4; this route is by (2S; 4R)-2-formic acid-4-hydroxyl pyrrolidine is a starting raw material; through acetylize; salify gets compound 4.2; tosylation gets compound 4.3 again; the yellow soda ash methanol-water solves compound 4.4; with TERT-BUTYL DIMETHYL CHLORO SILANE to 4 hydroxyls protect compound 4.5, become acid with the potassium hydroxide ethanol hydrolysis again; get compound 4.6 through the Weinreb amidation, with Lithium Aluminium Hydride reduce aldehyde compound 4.7; through the methyl grignard reagent react compound 4.8; hydrochloric acid takes off tertiary butyl dimethyl-silicon and gets compound 4.9, tosylation again, and benzyl ammonia closes ring; take off p-toluenesulfonyl; benzyl totally 15 step synthetic compound (1R are taken off in hydrogenation; 4R)-and 3-methyl-2,5-diazabicyclo [2.2.1] heptane hydrobromate 4.13, total recovery is 7.6%.
Formula 4
Figure GSA00000037749600032
Document J.Med.Chem.; 31; 1988; 1598-1611 has reported (1S; 4S)-2; the preparation of 5-diazabicyclo [2.2.1] heptane hydrobromate; see formula 5; with (2S; 4R)-N-tertbutyloxycarbonyl-2-(methylol)-4-((tertiary butyl dimethyl is silica-based) oxygen) tetramethyleneimine be starting raw material through last methyl sulphonyl, azide, take off tertiary butyl methyl silica-based, go up methyl sulphonyl, hydrogenation close 5 steps of ring synthetic (1S, 4S)-2,5-diazabicyclo [2.2.1] heptane hydrobromate 5.6.
The document is also mentioned (1R; 4R)-preparation of N-tertbutyloxycarbonyl-2-oxygen-5-azabicyclo [2.2.1] heptane; see formula 6; with (2R; 4R)-N-tertbutyloxycarbonyl-2-(methylol)-4-((tertiary butyl dimethyl is silica-based) oxygen) tetramethyleneimine is starting raw material through last methyl sulphonyl, take off that tertiary butyl methyl is silica-based, intramolecular cyclization gained under the catalysis at fluorine atom (1R, 4R)-N-tertbutyloxycarbonyl-2-oxygen-5-azabicyclo [2.2.1] heptane 6.3.
Formula 5
Figure GSA00000037749600041
Formula 6
Figure GSA00000037749600042
Though we can see much 2 from top example, 5-two assorted twin nucleis synthetic mainly is to center on the configuration difference of bridged ring carbon atom and unfolded, wherein document (J.Med.Chem.; 35; 1992; 2898-2909) reported at 3 and introduced the synthetic of methyl-derivatives, but step various (15 step), and total recovery is lower than 8%.Present twin nuclei depends on 2 nitrogen and 5 nitrogen mostly and removes to modify or be connected other group, thereby the space extends and be restricted, and can't satisfy the various enzymes of organism, acceptor diversity structurally.And present a lot of azabicyclos are not owing to there is hydrophilic radical, and the certain structure rigidity is arranged, thereby cause the poorly water-soluble of most compounds, and bioavailability is not high.
Summary of the invention:
The objective of the invention is to be to provide a kind of 3-trifluoromethyl-5-tertbutyloxycarbonyl-2,5-two assorted dicyclo [2.2.1] heptane and preparation methods, 3-trifluoromethyl-5-tertbutyloxycarbonyl-2 particularly, 5-diazabicyclo [2.2.1] heptane and 3-trifluoromethyl-5-tertbutyloxycarbonyl-2-oxa--5-azabicyclo [2.2.1] heptane and preparation method.Mainly solve 2,5-two assorted dicyclo [2.2.1] iieptanes compounds are various at 3 synthesis steps of having introduced methyl-derivatives, poorly water-soluble, the technical problem that total recovery is low.
Technical scheme is: a kind of 3-trifluoromethyl-5-tertbutyloxycarbonyl-2, and 5-two assorted dicyclo [2.2.1] heptane, its structural formula is as follows:
Figure GSA00000037749600051
Described R is NH or O, is the trifluoromethyl of 3-shown in the formula I-5-tertbutyloxycarbonyl-2,3-trifluoromethyl shown in 5-diazabicyclo [2.2.1] heptane or the formula II-5-tertbutyloxycarbonyl-2-oxa--5-azabicyclo [2.2.1] heptane:
Figure GSA00000037749600052
Above-claimed cpd is the endocyclic compound of a class formation novelty, does not have its structure of any bibliographical information and synthetic method at present.
The present invention also provides 3-trifluoromethyl-5-tertbutyloxycarbonyl-2, the preparation method of 5-diazabicyclo [2.2.1] heptane I, and the principal reaction formula is as follows:
Figure GSA00000037749600053
3-trifluoromethyl-5-tertbutyloxycarbonyl-2; the preparation method of 5-diazabicyclo [2.2.1] heptane I; may further comprise the steps: with compound (2S; 4S)-N-tertbutyloxycarbonyl-4-is amino, and tetrahydro pyrrolidine-2-methyl-formiate 1 is a starting raw material; through benzylamine protect (2S; 4S)-the amino tetrahydro pyrrolidine 2 of N-tertbutyloxycarbonyl-2-methoxycarbonyl-4-dibenzyl; compound 2 hydrolysis under alkaline condition gets (2S; 4S)-the amino tetrahydro pyrrolidine 3 of N-tertbutyloxycarbonyl-2-carboxyl-4-dibenzyl; gained compound 3 gets (2S through Wen Lebai (Weinreb) amidation; 4S)-the amino tetrahydro pyrrolidine 4 of N-tertbutyloxycarbonyl-2-(N-methyl-N-methoxyl group amine formyl)-4-dibenzyl; compound 4 usefulness Lithium Aluminium Hydrides or diisobutyl aluminium hydride reduce aldehyde compound (2S; 4S)-the amino tetrahydro pyrrolidine 5 of N-tertbutyloxycarbonyl-2-formaldehyde-4-dibenzyl; compound 5 reacts under alkaline catalysts catalysis with trifluoromethyl reagent and generates (2S; 4S)-N-tertbutyloxycarbonyl-2-(2; 2; 2-three fluoro-1-hydroxyethyls)-the amino tetrahydro pyrrolidine 6 of 4-dibenzyl; compound 6 and sulfonylation agent react (2S; 4S)-N-tertbutyloxycarbonyl-2-(2; 2; 2-three fluoro-1-((first sulfo group) oxygen) ethyl)-the amino tetrahydro pyrrolidine 7 of 4-dibenzyl; compound 7 selective hydration debenzylations get (2S; 4S)-N-tertbutyloxycarbonyl-2-(2; 2; 2-three fluoro-1-((first sulfo group) oxygen) ethyl)-the amino tetrahydro pyrrolidine 8 of 4-benzyl; compound 8 encircle in alkaline condition ShiShimonoseki compound 2-benzyl-3-trifluoromethyl-5-tertbutyloxycarbonyl-2; 5-diazabicyclo [2.2.1] heptane 9; compound 9 can obtain 3-trifluoromethyl-5-tertbutyloxycarbonyl-2 through the over hydrogenation debenzylation, 5-diazabicyclo [2.2.1] heptane I.Total recovery is 17.2%.
Wherein, compound 1 and aromatics amido protecting agent in the presence of alkali, react in the organic solvent, used aromatics amido protecting agent is benzyl bromine, benzyl chlorine, replaces the benzyl bromine, replaces benzyl chlorine, Tosyl chloride, chloroformic acid benzyl ester etc., is optimum condition with the benzyl bromine; Used alkali is a kind of in triethylamine, pyridine, sodium hydride, potassium hydroxide, sodium hydroxide, salt of wormwood, the yellow soda ash, is optimum condition with the triethylamine; Used solvent is acetonitrile, tetrahydrofuran (THF), methylene dichloride, trichloromethane, 1,2-ethylene dichloride, dioxane, ethyl acetate, toluene, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, N, in N-diethylformamide, dimethyl sulfoxide (DMSO), the N-Methyl pyrrolidone one or more are optimum condition with the acetonitrile; The temperature of reaction of described N alkylation or acylations is 20～45 ℃, and the reaction times is 4～24 hours.
Compound 2 and alkali, with reacting in the presence of the organic solvent, used alkali is a kind of in potassium hydroxide, sodium hydroxide, salt of wormwood, yellow soda ash, the lithium hydroxide, is optimum condition with the lithium hydroxide at water; Used solvent is water, methyl alcohol, ethanol, tetrahydrofuran (THF), acetonitrile, dioxane, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, N, one or more mixed solvents in N-diethylformamide, dimethyl sulfoxide (DMSO), the N-Methyl pyrrolidone are optimum condition with methyl alcohol and water mixed solvent; Described esterolytic temperature of reaction is 20～45 ℃, and the reaction times is 1～12 hour.
Compound 3 and N, the O-dimethyl hydroxylamine hydrochloride, in the presence of condensing agent and alkali and additive, in organic solvent, react, used additive is I-hydroxybenzotriazole (HOBT), 1-hydroxyl-7-azepine benzotriazole (HOAT), phosphofluoric acid O-(7-azepine benzo triazol-1-yl)-N, N, N ', a kind of in N '-tetramethyl-urea (HATU), hydroxy thiosuccinimide (NHS), the N-hydroxy-succinamide (HOSu); Used condensing agent is a kind of in carbonyl dimidazoles (CDI), DIC (DIC), dicyclohexylcarbodiimide (DCC), 1-(3-the dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI), additive is optimum condition with HOBT, and condensing agent is optimum condition with EDCI; Used alkali is a kind of in triethylamine, pyridine, salt of wormwood, yellow soda ash, the sodium bicarbonate, is optimum condition with the triethylamine; Used organic solvent is methylene dichloride, trichloromethane, 1,2-ethylene dichloride, dioxane, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, N, in N-diethylformamide, dimethyl sulfoxide (DMSO), the N-Methyl pyrrolidone one or more, with N, dinethylformamide is an optimum condition; The amidated temperature of reaction of described Weinreb is 20～45 ℃, and the reaction times is 8～24 hours.
Compound 4 with go back original reagent, in organic solvent, react, the used original reagent of going back is Lithium Aluminium Hydride, diisobutyl aluminium hydride or other reductive agents, is optimum condition with the diisobutyl aluminium hydride; Used organic solvent is one or more in acetonitrile, methyl alcohol, ethanol, water, tetrahydrofuran (THF), dioxane, ether, benzene, toluene, trifluoroacetic acid, the acetate, is optimum condition with the tetrahydrofuran (THF); The temperature of reaction of described reduction reaction is-15～25 ℃, and the reaction times is 2～4 hours.
Compound 5 and trifluoromethyl reagent under the alkaline catalysts effect, react in organic solvent, and used trifluoromethyl reagent is trifluoromethyl trimethyl silane, trifluoromethyl methyl iodide etc., is optimum condition with the trifluoromethyl trimethyl silane; Used alkaline catalysts is three hydration tetra-n-butyl Neutral ammonium fluorides, cesium fluoride etc., is optimum condition with three hydration tetra-n-butyl Neutral ammonium fluorides; Used organic solvent is methylene dichloride, trichloromethane, 1, and one or more in 2-ethylene dichloride, dioxane, tetrahydrofuran (THF), acetonitrile, toluene, the ether are optimum condition with the tetrahydrofuran (THF); The temperature of reaction of described trifluoromethylation reaction is-15～25 ℃, and the reaction times is 2～12 hours.
Compound 6 and sulfonylation agent, under base catalysis, react in organic solvent, used sulfonylation agent is one or more of trifluoromethyl SULPHURYL CHLORIDE, Methanesulfonyl chloride, ethyl chloride, phenyl SULPHURYL CHLORIDE or other replacement SULPHURYL CHLORIDE, is optimum condition with the Methanesulfonyl chloride; Used alkali is a kind of in triethylamine, pyridine, salt of wormwood, the yellow soda ash, is optimum condition with salt of wormwood; Solvent for use is methylene dichloride, trichloromethane, 1, and one or more in 2-ethylene dichloride, dioxane, tetrahydrofuran (THF), acetonitrile, toluene, the ether are optimum condition with the acetonitrile; The temperature of reaction of described sulfonylation is 0～25 ℃, and the reaction times is 2～12 hours.
Compound 7 reduces by hydrogen hydrogenation and takes off benzyl, and the hydrogenation catalyst system therefor comprises that weight percent is 10% palladium carbon, palladium hydroxide etc., is optimum condition with 10% palladium carbon; Solvent is methyl alcohol, ethanol, water, tetrahydrofuran (THF), dioxane, ethyl acetate, methylene dichloride, trichloromethane, N, dinethylformamide, N, N-diethylformamide, N, one or more mixed solvents in N-diethylformamide, dimethyl sulfoxide (DMSO), the ether are optimum condition with methyl alcohol; Perhaps compound 7 reacts gained with chloroformic acid α chloro-ethyl ester, chloroformic acid α vinylchlorid ester, Vinyl chloroformate etc. in acetonitrile, methyl alcohol, ethanol, water, tetrahydrofuran (THF), dioxane, ether, benzene, toluene, trifluoroacetic acid, acetate or other solvents; The temperature of reaction of described hydrogenation is 20～45 ℃, and the reaction times is 6～24 hours.
Compound 8 reacts in organic solvent in the presence of alkali, and used alkali is a kind of in potassium tert.-butoxide, sodium tert-butoxide, pyridine, sodium hydride, salt of wormwood, the yellow soda ash, is optimum condition with salt of wormwood; Used organic solvent is acetonitrile, toluene, tetrahydrofuran (THF), dioxane, ethyl acetate, toluene, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, N, one or more in N-diethylformamide, dimethyl sulfoxide (DMSO), the N-Methyl pyrrolidone are optimum condition with the acetonitrile; The temperature of reaction of described ring closure reaction is 80～120 ℃, and the reaction times is 6～24 hours.
Compound 9 its process debenzylations obtain 2, and 5-diazabicyclo [2.2.1] heptane-3-trifluoromethyl-5-tertbutyloxycarbonyl I, hydrogenation catalyst system therefor comprise that weight percent is 10% palladium carbon, palladium hydroxide etc., are optimum condition with 10% palladium carbon; Solvent is methyl alcohol, ethanol, water, tetrahydrofuran (THF), dioxane, ethyl acetate, methylene dichloride, trichloromethane, N, dinethylformamide, N, N-diethylformamide, N, one or more mixed solvents in N-diethylformamide, dimethyl sulfoxide (DMSO), the ether are optimum condition with methyl alcohol; Perhaps compound 9 reacts gained with chloroformic acid α chloro-ethyl ester, chloroformic acid α vinylchlorid ester, Vinyl chloroformate etc. in acetonitrile, methyl alcohol, ethanol, water, tetrahydrofuran (THF), dioxane, ether, benzene, toluene, trifluoroacetic acid, acetate or other solvents; The temperature of reaction of described catalytic hydrogenation debenzylation reaction is 20～45 ℃, and the reaction times is 6～24 hours.
Simultaneously, the present invention also provides the preparation method of 3-trifluoromethyl-5-tertbutyloxycarbonyl-2-oxa--5-azabicyclo [2.2.1] heptane II, and the principal reaction formula is as follows:
Figure GSA00000037749600081
It is characterized in that, compound (2S, 4R)-N-tertbutyloxycarbonyl-4-((methylsulfonyl) oxygen) tetrahydro pyrrolidine-2-formaldehyde 10 (referenced patent US5317016 is synthetic) and trifluoromethyl reagent, under the alkaline catalysts effect, assorted dicyclo [2.2.1] the heptane II of ring closure reaction gained compound 3-trifluoromethyl-5-tertbutyloxycarbonyl-2-oxygen-5-nitrogen-two in organic solvent, used trifluoromethyl reagent is trifluoromethyl trimethyl silane, trifluoromethyl methyl iodide etc., is optimum condition with the trifluoromethyl trimethyl silane; Used alkaline catalysts is three hydration tetra-n-butyl Neutral ammonium fluorides, cesium fluoride etc., is optimum condition with three hydration tetra-n-butyl Neutral ammonium fluorides; Solvent for use is methylene dichloride, trichloromethane, 1, and one or more in 2-ethylene dichloride, dioxane, tetrahydrofuran (THF), acetonitrile, toluene, the ether are optimum condition with the tetrahydrofuran (THF); The temperature of reaction of described trifluoromethylation ring closure reaction is 0～45 ℃, and the reaction times is 6～24 hours.
Beneficial effect of the present invention: we introduce trifluoromethyl, further improve its quasi-medicated property matter with the electronic effect and the steric effect that change molecular structure for 3 of 5-two assorted dicyclo [2.2.1] heptane 2.We provide the method for preparing such novel cpd, for 3-trifluoromethyl-5-tertbutyloxycarbonyl-2, and the preparation of 5-diazabicyclo [2.2.1] heptane, our synthetic method had only for 9 steps, and total recovery brings up to 18%.And the preparation of 3-trifluoromethyl-5-tertbutyloxycarbonyl-2-oxa--5-azabicyclo [2.2.1] heptane, we are only with can preparing from known raw material once going on foot, and yield reaches 77%.
Embodiment: enumerate embodiment so that the present invention is done detailed description, but the present invention is not limited to these embodiment.Embodiment 1:(2S, 4S)-N-tertbutyloxycarbonyl-2-methoxycarbonyl-preparation of the amino tetrahydro pyrrolidine 2 of 4-dibenzyl
Figure GSA00000037749600082
Operation steps:
Under the nitrogen protection; in an exsiccant three-necked bottle, add compound (2S; 4S)-the amino tetrahydro pyrrolidine of N-tertbutyloxycarbonyl-4--2-methyl-formiate 1 (20 grams; 81.96 mmole) and acetonitrile (100 milliliters); triethylamine (33.1 grams; 327.84 mmole), under ice bath, slowly add cylite (41.80 grams, 246 moles).Reaction solution stirred 1 hour at 0 ℃, slowly rise to room temperature (20～30 ℃) and stir spend the night (12～16 hours), use the saturated aqueous ammonium chloride cancellation, transferring pH with the 1N aqueous sodium hydroxide solution is 7, filters, concentrated filtrate, add entry, use ethyl acetate extraction, dry the concentrating through column chromatography of organic phase gets 30.5 gram product (2S, 4S)-and the amino tetrahydro pyrrolidine 2 of N-tertbutyloxycarbonyl-2-methoxycarbonyl-4-dibenzyl, yield 87.7%.
HNMR(CDCl 3)δ：7.30-7.21(m，10H)，4.19-4.08(m，1H)，3.78-3.54(m，8H)，3.43-3.29(m，2H)，2.40-2.23(m，1H)，1.98-1.85(m，1H)，1.36(s，9H)。
Embodiment 2:(S2,4S)-N-tertbutyloxycarbonyl-2-methoxycarbonyl-preparation of the amino tetrahydro pyrrolidine 2 of 4-dibenzyl
Figure GSA00000037749600091
Operation steps:
Under the nitrogen protection; in an exsiccant three-necked bottle, add compound (2S; 4S)-the amino tetrahydro pyrrolidine of N-tertbutyloxycarbonyl-4--2-methyl-formiate 1 (10 grams; 40.98 mmole) and methylene dichloride (100 milliliters); Anhydrous potassium carbonate (16.6 grams; 122.94 mmole), under ice bath, slowly add Benzyl Chloride (15.5 grams, 122.94 moles).Reaction solution stirred 1 hour at 0 ℃, slowly rise to stirred overnight at room temperature, use the saturated aqueous ammonium chloride cancellation, transferring pH with the 1N aqueous sodium hydroxide solution is 7, filters, concentrated filtrate, add entry, use ethyl acetate extraction, dry the concentrating through column chromatography of organic phase gets 14.2 gram product (2S, 4S)-and the amino tetrahydro pyrrolidine 2 of N-tertbutyloxycarbonyl-2-methoxycarbonyl-4-dibenzyl, yield 82%.
The compound nuclear-magnetism is with embodiment 1.
Embodiment 3:(2S, 4S)-N-tertbutyloxycarbonyl-2-carboxyl-preparation of the amino tetrahydro pyrrolidine 3 of 4-dibenzyl
Figure GSA00000037749600092
Operation steps:
(2S, 4S)-the amino tetrahydro pyrrolidine 2 of N-tertbutyloxycarbonyl-2-methoxycarbonyl-4-dibenzyl (20 grams, 47.16 mmole), lithium hydroxide (2 grams, 72 mmoles) be dissolved in the mixed solvent of forming by 100 ml methanol and 50 ml waters, this reaction solution was at stirring at room 2-3 hour, TLC follows the tracks of reaction, after the reaction end, be acid with the 1N hydrochloric acid conditioning solution, methyl alcohol is removed in decompression then, water ethyl acetate extraction 3 times, merge organic phase with using 10% sodium bicarbonate successively, water washing is to neutral, and organic phase is behind anhydrous sodium sulfate drying, filter, under reduced pressure concentrate 18 digest compound (2R, 4R)-the amino tetrahydro pyrrolidine 3 of N-tertbutyloxycarbonyl-2-carboxyl-4-dibenzyl, yield 95%.
HNMR(CDCl 3)δ：7.25-7.19(m，10H)，4.19-4.11(m，2H)，3.71-3.61(m，3H)，3.53-3.33(m，2H)，3.26-3.23(m，1H)，2.44-2.20(m，2H)，1.36(s，9H)。
Embodiment 4:(2S, 4S)-N-tertbutyloxycarbonyl-2-carboxyl-preparation of the amino tetrahydro pyrrolidine 3 of 4-dibenzyl
Operation steps:
(2S, 4S)-the amino tetrahydro pyrrolidine 2 of N-tertbutyloxycarbonyl-2-methoxycarbonyl-4-dibenzyl (10 grams, 23.58 mmole), salt of wormwood (16.6 grams, 122.94 mmole) be dissolved in the mixed solvent of forming by 100 milliliters of ethanol and 50 ml waters, this reaction solution was stirring at room 2～3 hours, TLC follows the tracks of reaction, after the reaction end, be acid with the 1N hydrochloric acid conditioning solution, ethanol is removed in decompression then, water ethyl acetate extraction 3 times, merge organic phase with using 10% sodium bicarbonate successively, water washing is to neutral, and organic phase is behind anhydrous sodium sulfate drying, filter, under reduced pressure concentrate 9 digest compound (2R, 4R)-the amino tetrahydro pyrrolidine 3 of N-tertbutyloxycarbonyl-2-carboxyl-4-dibenzyl, yield 95%.
The compound nuclear-magnetism is with embodiment 3.
Embodiment 5:(2S, 4S)-N-tertbutyloxycarbonyl-2-(N-methyl-N-methoxyl group amine formyl)-preparation of the amino tetrahydro pyrrolidine 4 of 4-dibenzyl
Figure GSA00000037749600102
Operation steps:
Under the nitrogen protection; in an exsiccant three-necked bottle, add (2S; 4S)-the amino tetrahydro pyrrolidine 3 of N-tertbutyloxycarbonyl-2-carboxyl-4-benzyl (15 grams; 36.6 mmole); I-hydroxybenzotriazole (HOBT) (7.4 grams; 54.9 mmole); 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI) (10.5 grams; 54.9 mmole) and 50 milliliters of anhydrous N, dinethylformamide, this reaction solution stirring reaction 5～6 hours at room temperature then; add triethylamine (18.5 grams; 183 mmoles) and N, O-dimethyl hydroxylamine hydrochloride (7.1 grams, 73.2 mmoles).Reaction solution continue to stir in room temperature and spends the night, wait reaction to finish after, concentration of reaction solution gets resistates, use acetic acid ethyl dissolution, washes with water two to three times, merge organic phase with anhydrous sodium sulfate drying after, filter, concentrated the thick product of yellow oily.Thick product column chromatography obtain the faint yellow oily product of 12 grams (2S, 4S)-the amino tetrahydro pyrrolidine 4 of N-tertbutyloxycarbonyl-2-(N-methyl-N-methoxyl group amine formyl)-4-dibenzyl, yield 75%.
HNMR(CDCl 3)δ：7.35-7.24(m，10H)，4.64-4.51(m，1H)，3.83-3.75(m，2H)，3.72-3.60(m，6H)，?3.46-3.40(m，2H)，3.22(s，3H)，2.47-2.33(m，1H)，1.90-1.86(m，1H)，1.45(s，9H)。
Embodiment 6:(2S, 4S)-N-tertbutyloxycarbonyl-2-(N-methyl-N-methoxyl group amine formyl)-preparation of the amino tetrahydro pyrrolidine 4 of 4-dibenzyl
Operation steps:
Under the nitrogen protection; in an exsiccant three-necked bottle, add (2S; 4S)-the amino tetrahydro pyrrolidine 3 of N-tertbutyloxycarbonyl-2-carboxyl-4-benzyl (10 grams; 24.4 mmole); 1-hydroxyl-7-azepine benzotriazole (HOAT) (5.0 grams; 36.6 mmole); carbonyl dimidazoles (CDI) (5.93 grams; 36.6 mmole) and 50 milliliters of anhydrous N, dinethylformamide, this reaction solution stirring reaction 5～6 hours at room temperature then; add triethylamine (9.3 grams; 92 mmoles) and N, O-dimethyl hydroxylamine hydrochloride (4.19 grams, 43.2 mmoles).Reaction solution continue to stir in room temperature and spends the night, wait reaction to finish after, concentration of reaction solution gets resistates, use acetic acid ethyl dissolution, washes with water two to three times, merge organic phase with anhydrous sodium sulfate drying after, filter, concentrated the thick product of yellow oily.Thick product column chromatography obtain the faint yellow oily product of 8 grams (2S, 4S)-the amino tetrahydro pyrrolidine 4 of N-tertbutyloxycarbonyl-2-(N-methyl-N-methoxyl group amine formyl)-4-dibenzyl, yield 75%.
The compound nuclear-magnetism is with embodiment 6.
Embodiment 7:(2S, 4S)-N-tertbutyloxycarbonyl-2-formyl radical-preparation of the amino tetrahydro pyrrolidine 5 of 4-dibenzyl
Figure GSA00000037749600112
Operation steps:
Under the nitrogen protection; in 100 milliliters of round-bottomed flasks of an exsiccant, add anhydrous tetrahydro furan (40 milliliters); (2S; 4S)-the amino tetrahydro pyrrolidine 4 of N-tertbutyloxycarbonyl-2-(N, N-methyl methoxy base methane amide)-4-dibenzyl (8 grams, 17.7 mmoles); this reaction solution is cooled to-78 ℃ with dry ice acetone bath; slowly be added dropwise to diisobutyl aluminium hydride (35 milliliters, 35 mmoles), rise to room temperature then naturally and continue reaction 2～3 hours.After reaction solution is used the saturated aqueous ammonium chloride cancellation, under reduced pressure remove and desolvate, the resistates acetic acid ethyl dissolution washes with water.Organic phase is dry concentrate obtain 6.5 gram oily products (2S, 4S)-the amino tetrahydro pyrrolidine 5 of N-tertbutyloxycarbonyl-2-formyl radical-4-dibenzyl, yield 93%.
HNMR(CDCl 3)δ：9.49(s，0.4H)，9.38(s，0.6H)，7.32-7.24(m，10H)，3.75-3.54(m，6H)，3.42-3.33(m，2H)，2.19-2.12(m，1H)，1.95-1.86(m，1H)，1.43(s，9H)。
Embodiment 8:(2S, 4S)-N-tertbutyloxycarbonyl-2-formyl radical-preparation of the amino tetrahydro pyrrolidine 5 of 4-dibenzyl
Figure GSA00000037749600121
Operation steps:
Under the nitrogen protection; in 100 milliliters of round-bottomed flasks of an exsiccant, add anhydrous methylene chloride (40 milliliters); (740 milligrams of Lithium Aluminium Hydrides; 19.47 mmole); contain 0 ℃ of slow down dropping (2S, 4S)-the amino tetrahydro pyrrolidine 4 of N-tertbutyloxycarbonyl-2-(N, N-methyl methoxy base methane amide)-4-dibenzyl (8 grams; 17.7 anhydrous methylene chloride solution mmole) (20 milliliters) rises to room temperature then naturally and continues reaction 1～2 hour.After reaction solution is used the saturated aqueous ammonium chloride cancellation, under reduced pressure remove and desolvate, the resistates acetic acid ethyl dissolution washes with water.Organic phase is dry concentrate obtain 6.5 gram oily products (2S, 4S)-the amino tetrahydro pyrrolidine 5 of N-tertbutyloxycarbonyl-2-formyl radical-4-dibenzyl, yield 93%.
The compound nuclear-magnetism is with embodiment 7.
Embodiment 9:(2S, 4S)-N-tertbutyloxycarbonyl-2-(2,2,2-three fluoro-1-hydroxyethyls)-preparation of the amino tetrahydro pyrrolidine 6 of 4-dibenzyl
Figure GSA00000037749600122
Operation steps:
Under the nitrogen protection; (2S; 4S)-the amino tetrahydro pyrrolidine 5 of N-tertbutyloxycarbonyl-2-formyl radical-4-dibenzyl (5 grams; 12.6 mmole) be dissolved in 30 milliliters of anhydrous tetrahydro furans, this reaction solution is cooled to 0 ℃ with ice bath, adds three hydration tetra-n-butyl Neutral ammonium fluorides (0.33 gram then; 1.26 mmole) and the trifluoromethyl trimethyl silane (2.68 the gram; 18.9 mmole), continued stirring reaction 1-2 hour, be raised to room temperature naturally and stirring reaction spends the night at 0 ℃.Reaction solution concentrates, and behind the acetic acid ethyl dissolution, washes with water 2-3 time, organic phase drying, filtration, concentrate crude product, through column chromatography get compound (2S, 4S)-N-tertbutyloxycarbonyl-2-(2,2,2-three fluoro-1-hydroxyethyls)-amino tetrahydro pyrrolidine 64.5 grams of 4-dibenzyl.Yield 77%.
HNMR(CDCl 3)δ：7.25-7.15(m，10H)，4.14-4.02(m，1H)，3.84-3.77(m，1H)，3.72-3.62(m，3H)，3.53-3.49(m，2H)，3.15-3.07(m，1H)，3.04-2.98(m，1H)，2.28-2.22(m，1H)，1.82-1.76(m，1H)，1.36(s，9H)。
Embodiment 10:(2S, 4S)-N-tertbutyloxycarbonyl-2-(2,2,2-three fluoro-1-hydroxyethyls)-preparation of the amino tetrahydro pyrrolidine 6 of 4-dibenzyl
Figure GSA00000037749600131
Operation steps:
Under the nitrogen protection; (2S; 4S)-the amino tetrahydro pyrrolidine 5 of N-tertbutyloxycarbonyl-2-formyl radical-4-dibenzyl (5 grams; 12.6 mmole) be dissolved in 30 milliliters of anhydrous tetrahydro furans, this reaction solution is cooled to-78 ℃ with acetone the dry ice bath, adds cesium fluoride (0.19 gram then; 1.26 mmole) and CF3I (3.69 the gram; 18.9 mmole), continued stirring reactions 1～2 hour, be raised to room temperature naturally and stirring reaction spends the night at-78 ℃.Reaction solution concentrates, behind the acetic acid ethyl dissolution, with 10% salt acid elution 1～2 time, wash with water 2～3 times, organic phase drying, filtration, concentrate crude product, get 4.5 through column chromatography and digest compound (2S, 4S)-N-tertbutyloxycarbonyl-2-(2,2,2-three fluoro-1-hydroxyethyls)-the amino tetrahydro pyrrolidine 6 of 4-dibenzyl, yield 77%.
The compound nuclear-magnetism is with embodiment 9.
Embodiment 11:(2S, 4S)-N-tertbutyloxycarbonyl-2-(2,2,2-three fluoro-1-((first sulfo group) oxygen) ethyl)-preparation of the amino tetrahydro pyrrolidine 7 of 4-dibenzyl
Figure GSA00000037749600132
Operation steps:
Under the nitrogen protection; in 100 milliliters of round-bottomed flasks of an exsiccant, add anhydrous tetrahydro furan (30 milliliters); (2S, 4S)-N-tertbutyloxycarbonyl-2-(2,2; 2-three fluoro-1-hydroxyethyls)-the amino tetrahydro pyrrolidine 6 of 4-dibenzyl (3 grams; 6.45 mmole) and triethylamine (1.95 gram, 19.4 mmoles), 0 ℃ adds Methanesulfonyl chloride (1.10 grams down; 9.68 mmole), rose room temperature reaction naturally 2～3 hours.Reaction solution pours in the saturated aqueous common salt, ethyl acetate extraction.Organic phase is dry concentrate thick product.Thick product column chromatography obtain 2.9 gram oily products (2S, 4S)-the amino tetrahydro pyrrolidine 7 of N-tertbutyloxycarbonyl-2-(2,2,2-three fluoro-1-((first sulfo group) oxygen) ethyl)-4-dibenzyl, yield 85%.
HNMR(CDCl 3)δ：7.35-7.08(m，10H)，5.37(s，0.4H)，5.23(s，0.6H)，4.39-4.26(m，1H)，3.86-3.56(m，5H)，3.24-3.18(m，1H)，3.04(s，3H)，3.03-2.98(m，1H)，2.38-2.25(m，1H)，2.18-2.06(m，1H)，1.37(s，9H)。
Embodiment 12:(2S, 4S)-N-tertbutyloxycarbonyl-2-(2,2,2-three fluoro-1-((first sulfo group) oxygen) ethyl)-preparation of the amino tetrahydro pyrrolidine 7 of 4-dibenzyl
Figure GSA00000037749600141
Operation steps:
Under the nitrogen protection; in 100 milliliters of round-bottomed flasks of an exsiccant, add anhydrous methylene chloride (30 milliliters); (2S, 4S)-N-tertbutyloxycarbonyl-2-(2,2; 2-three fluoro-1-hydroxyethyls)-the amino tetrahydro pyrrolidine 6 of 4-dibenzyl (3 grams; 6.45 mmole) and Anhydrous potassium carbonate (2.62 gram, 19.4 mmoles), 0 ℃ adds Methanesulfonyl chloride (1.10 grams down; 9.68 mmole), rose room temperature reaction naturally 2～3 hours.Reaction solution pours in the saturated aqueous common salt, ethyl acetate extraction.Organic phase is dry concentrate thick product.Thick product column chromatography obtain 2.5 gram oily products (2S, 4S)-the amino tetrahydro pyrrolidine 7 of N-tertbutyloxycarbonyl-2-(2,2,2-three fluoro-1-((first sulfo group) oxygen) ethyl)-4-dibenzyl, yield 72%.
The compound nuclear-magnetism is with embodiment 11.
Embodiment 13:(2S, 4S)-N-tertbutyloxycarbonyl-2-(2,2,2-three fluoro-1-((first sulfo group) oxygen) ethyl)-preparation of the amino tetrahydro pyrrolidine 8 of 4-benzyl
Figure GSA00000037749600142
Operation steps:
(2S, 4S)-N-tertbutyloxycarbonyl-2-(2,2,2-three fluoro-1 ((first sulfo group) oxygen) ethyl)-the amino tetrahydro pyrrolidine 7 of 4-dibenzyl (2.5 grams, 4.6 mmole) be dissolved in the methyl alcohol (20 milliliters), add 10% palladium carbon, 0.25 gram, hydrogen catalyzed stirring under normal pressure, TLC follows the tracks of reaction, when raw material disappears, stopped reaction removes by filter palladium carbon, and concentration of reaction solution gets 1.2 through column chromatography and digests compound (2S, 4S)-N-tertbutyloxycarbonyl-2-(2,2,2-three fluoro-1-((first sulfo group) oxygen) ethyl)-the amino tetrahydro pyrrolidine 8 of 4-benzyl, yield 60%.
HNMR(CDCl 3)δ：7.31-7.18(m，5H)，5.75(s，0.4H)，5.52(s，0.6H)，4.12-3.97(m，1H)，3.74-3.70(m，2H)，3.44-3.38(m，1H)，3.24-3.03(m，1H)，3.00(s，3H)，2.98-2.82(m，1H)，2.29-2.17(m，1H)，1.91-1.85(m，1H)，1.40(s，9H)。
Embodiment 14:(2S, 4S)-N-tertbutyloxycarbonyl-2-(2,2,2-three fluoro-1-((first sulfo group) oxygen) ethyl)-preparation of the amino tetrahydro pyrrolidine 8 of 4-benzyl
Figure GSA00000037749600151
Operation steps:
(2S, 4S)-N-tertbutyloxycarbonyl-2-(2,2,2-three fluoro-1 ((first sulfo group) oxygen) ethyl)-the amino tetrahydro pyrrolidine 7 of 4-dibenzyl (2.5 grams, 4.6 mmole) be dissolved in the ethanol (20 milliliters), add 10% palladium hydroxide, 0.25 gram, hydrogen catalyzed stirring under normal pressure, TLC follows the tracks of reaction, when raw material disappears, stopped reaction removes by filter palladium hydroxide, and concentration of reaction solution gets 1.2 through column chromatography and digests compound (2S, 4S)-N-tertbutyloxycarbonyl-2-(2,2,2-three fluoro-1-((first sulfo group) oxygen) ethyl)-the amino tetrahydro pyrrolidine 8 of 4-benzyl, yield 60%.
The compound nuclear-magnetism is with embodiment 13.
Embodiment 15:2-benzyl-3-trifluoromethyl-5-tertbutyloxycarbonyl-2, the preparation of 5-diazabicyclo [2.2.1] heptane 9
Figure GSA00000037749600152
Operation steps:
Under the nitrogen protection, (2S, 4S)-N-tertbutyloxycarbonyl-2-(2; 2,2-three fluoro-1 ((first sulfo group) oxygen) ethyl)-acetonitrile solution of the amino tetrahydro pyrrolidine 8 of 4-benzyl (0.50 gram, 1.10 mmoles) in; add Anhydrous potassium carbonate (0.455 gram, 3.3 mmoles), reflux to stir and spend the night.Concentration of reaction solution, be dissolved in the ethyl acetate (30 milliliters), use the washing of 10% hydrochloric acid soln (5 milliliters) and water (10 milliliters) successively, organic phase is dry to be concentrated to such an extent that get 0.30 through column chromatography and digest compound 2-benzyl-3-trifluoromethyl-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2.2.1] heptane 9, yield 76%.
HNMR(CDCl 3)δ：7.31-7.26(m，4H)，7.18-7.16(m，1H)，4.65(s，0.4H)，4.52(s，0.6H)，3.84(d，J＝14Hz，1H)，3.54(d，J＝14Hz，1H)，3.27(s，1H)，3.20-3.14(m，3H)，1.78(d，J＝10Hz，1H)，1.66(d，J＝10Hz，1H)，1.37(s，9H)。
Embodiment 16:2-benzyl-3-trifluoromethyl-5-tertbutyloxycarbonyl-2, the preparation of 5-diazabicyclo [2.2.1] heptane 9
Figure GSA00000037749600153
Operation steps:
Under the nitrogen protection, (2S, 4S)-N-tertbutyloxycarbonyl-2-(2; 2,2-three fluoro-1 ((first sulfo group) oxygen) ethyl)-the DMF solution of the amino tetrahydro pyrrolidine 8 of 4-benzyl (1.50 grams, 3.3 mmoles) in; add anhydrous tertiary butanol potassium (1.11 grams, 9.9 mmoles), be heated to 110 ℃ of stirrings and spend the night.Concentration of reaction solution, be dissolved in the ethyl acetate (30 milliliters), use the washing of 10% hydrochloric acid soln (5 milliliters) and water (10 milliliters) successively, organic phase is dry to be concentrated to such an extent that get 0.90 through column chromatography and digest compound 2-benzyl-3-trifluoromethyl-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2.2.1] heptane 9, yield 76%.
The compound nuclear-magnetism is with embodiment 15.
Embodiment 17:3-trifluoromethyl-5-tertbutyloxycarbonyl-2, the preparation of 5-diazabicyclo [2.2.1] heptane I
Figure GSA00000037749600161
Operation steps:
2-benzyl-3-trifluoromethyl-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2.2.1] heptane 9 (0.2 gram, 0.561 mmole) be dissolved in the methyl alcohol (20 milliliters), add 10% palladium carbon, 0.05 gram, hydrogen catalyzed stirring is spent the night under normal pressure, removes by filter palladium carbon, and concentration of reaction solution gets 0.14 and digests compound 3-trifluoromethyl-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2.2.1] heptane I, yield 94%.
HNMR(CDCl 3)δ：4.68(s，0.4H)，4.55(s，0.6H)，3.79-3.71(m，1H)，3.70-3.61(m，1H)，3.36-3.28(m，1H)，3.24-3.18(m，1H)，1.92-1.86(m，1H)，1.74-1.71(m，1H)，1.40(s，9H)。
Embodiment 18:3-trifluoromethyl-5-tertbutyloxycarbonyl-2, the preparation of 5-diazabicyclo [2.2.1] heptane I
Figure GSA00000037749600162
Operation steps:
2-benzyl-3-trifluoromethyl-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2.2.1] heptane 9 (0.20 gram, 0.561 mmole) be dissolved in the methylene dichloride (20 milliliters), under ice-water bath, add α ethyl chloroformate (0.162 gram, 1.13 mmole), continued stirring reaction 1 hour down at 0 ℃, remove methylene dichloride under the decompression, resistates dissolves with methyl alcohol (10 milliliters), back flow reaction 2～3 hours, concentration of reaction solution, be dissolved in the ethyl acetate (30 milliliters), water (10 milliliters) washing, organic phase is dry to be concentrated to such an extent that 0.12 digest compound 3-trifluoromethyl-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2.2.1] heptane I, yield 80%.The compound nuclear-magnetism is with embodiment 17.
The preparation of embodiment 19:3-trifluoromethyl-5-tertbutyloxycarbonyl-2-oxa--5-azabicyclo [2.2.1] heptane II
Figure GSA00000037749600171
Operation steps:
Under the nitrogen protection; (2S; 4R)-N-tertbutyloxycarbonyl-4-((methylsulfonyl) oxygen) tetrahydro pyrrolidine-2-formaldehyde 10 (0.5 gram; 1.71 mmole) be dissolved in 10 milliliters of anhydrous tetrahydro furans, this reaction solution is cooled to 0 ℃ with ice bath, adds three hydration tetra-n-butyl Neutral ammonium fluorides (0.11 gram then; 0.42 mmole) and the trifluoromethyl trimethyl silane (0.485 the gram; 3.42 mmole), continued stirring reaction 1-2 hour, be raised to room temperature naturally and stirring reaction spends the night at 0 ℃.Reaction solution concentrates, behind the acetic acid ethyl dissolution, wash with water 2-3 time, organic phase drying, filtration, concentrate crude product, get 350 milligrams of compound 3-trifluoromethyl-5-tertbutyloxycarbonyl-2-oxa-s-5-azabicyclo [2.2.1] heptane II, yield 77% through column chromatography.
HNMR(CDCl 3)δ：4.65(s，1H)，4.61-4.47(m，1H)，4.11-4.00(m，1H)，3.36-3.26(m，2H)，2.00-1.98(m，1H)，1.76-1.71(m，1H)，1.41(s，9H)。
The preparation of embodiment 20:3-trifluoromethyl-5-tertbutyloxycarbonyl-2-oxa--5-azabicyclo [2.2.1] heptane II
Figure GSA00000037749600172
Operation steps:
Under the nitrogen protection; (2S; 4R)-N-tertbutyloxycarbonyl-4-((methylsulfonyl) oxygen) tetrahydro pyrrolidine-2-formaldehyde 10 (1 gram; 3.42 mmole) be dissolved in 10 milliliters of anhydrous methylene chlorides, this reaction solution is cooled to 0 ℃ with ice bath, adds cesium fluoride (0.19 gram then; 1.26 mmole) and the trifluoromethyl trimethyl silane (0.97 the gram; 6.84 mmole), continued stirring reaction 1～2 hour, be raised to room temperature naturally and stirring reaction spends the night at 0 ℃.Reaction solution concentrates, behind the acetic acid ethyl dissolution, wash with water 2～3 times, organic phase drying, filtration, concentrate crude product, get 350 milligrams of compound 3-trifluoromethyl-5-tertbutyloxycarbonyl-2-oxa-s-5-azabicyclo [2.2.1] heptane II, yield 77% through column chromatography.
The compound nuclear-magnetism is with embodiment 19.

Claims (23)

1. 3-trifluoromethyl-5-tertbutyloxycarbonyl-2,5-two assorted dicyclo [2.2.1] heptane, its structural formula is as follows:
Figure FSA00000037749500011
Described R is NH or O, when R is NH, is the trifluoromethyl of 3-shown in the formula I-5-tertbutyloxycarbonyl-2, and 5-diazabicyclo [2.2.1] heptane when R is O, is the trifluoromethyl of 3-shown in the formula II-5-tertbutyloxycarbonyl-2-oxa--5-azabicyclo [2.2.1] heptane:
Figure FSA00000037749500012
2. the described 3-trifluoromethyl of claim 1-5-tertbutyloxycarbonyl-2, the preparation method of 5-diazabicyclo [2.2.1] heptane is characterized in that, may further comprise the steps:
The first step: with compound (2S; 4S)-N-tertbutyloxycarbonyl-4-is amino, and tetrahydro pyrrolidine-the 2-methyl-formiate is a starting raw material; through aromatics amido protecting agent benzylamine protect (2S, 4S)-N-tertbutyloxycarbonyl-2-methoxycarbonyl-the amino tetrahydro pyrrolidine of 4-dibenzyl
Second step: (2S, 4S)-N-tertbutyloxycarbonyl-2-methoxycarbonyl-hydrolysis under alkaline condition of the amino tetrahydro pyrrolidine of 4-dibenzyl get (2S, 4S)-the amino tetrahydro pyrrolidine of N-tertbutyloxycarbonyl-2-carboxyl-4-dibenzyl,
The 3rd step: (2S, 4S)-N-tertbutyloxycarbonyl-2-carboxyl-the amino tetrahydro pyrrolidine of 4-dibenzyl through temperature rein in primary amideization get (2S, 4S)-the amino tetrahydro pyrrolidine of N-tertbutyloxycarbonyl-2-(N-methyl-N-methoxyl group amine formyl)-4-dibenzyl,
The 4th step: (2S; 4S)-the amino tetrahydro pyrrolidine of N-tertbutyloxycarbonyl-2-(N-methyl-N-methoxyl group amine formyl)-4-dibenzyl with reductive agent Lithium Aluminium Hydride or diisobutyl aluminium hydride reduce aldehyde compound (2S; 4S)-the amino tetrahydro pyrrolidine of N-tertbutyloxycarbonyl-2-formaldehyde-4-dibenzyl
The 5th step: (2S, 4S)-the amino tetrahydro pyrrolidine of N-tertbutyloxycarbonyl-2-formaldehyde-4-dibenzyl and trifluoromethyl reagent under alkaline catalysts catalysis, react generation (2S, 4S)-N-tertbutyloxycarbonyl-2-(2,2,2-three fluoro-1-hydroxyethyls)-the amino tetrahydro pyrrolidine of 4-dibenzyl
The 6th step: (2S, 4S)-N-tertbutyloxycarbonyl-2-(2,2; 2-three fluoro-1-hydroxyethyls)-the amino tetrahydro pyrrolidine of 4-dibenzyl and sulfonylation agent react (2S, 4S)-N-tertbutyloxycarbonyl-2-(2,2; 2-three fluoro-1-((first sulfo group) oxygen) ethyl)-the amino tetrahydro pyrrolidine of 4-dibenzyl
The 7th step: (2S, 4S)-N-tertbutyloxycarbonyl-2-(2,2,2-three fluoro-1-((first sulfo group) oxygen) ethyl)-the amino tetrahydro pyrrolidine selective hydration of 4-dibenzyl debenzylation gets (2S, 4S)-N-tertbutyloxycarbonyl-2-(2,2,2-three fluoro-1-((first sulfo group) oxygen) ethyl)-the amino tetrahydro pyrrolidine of 4-benzyl, or (2S, 4S)-N-tertbutyloxycarbonyl-2-(2,2,2-three fluoro-1-((first sulfo group) oxygen) ethyl)-the amino tetrahydro pyrrolidine of 4-dibenzyl and chloromethane acids ester get at solvent reaction (2S, 4S)-N-tertbutyloxycarbonyl-2-(2,2,2-three fluoro-1-((first sulfo group) oxygen) ethyl)-the amino tetrahydro pyrrolidine of 4-benzyl
The 8th step: (2S, 4S)-the amino tetrahydro pyrrolidine of N-tertbutyloxycarbonyl-2-(2,2,2-three fluoro-1-((first sulfo group) oxygen) ethyl)-4-benzyl encircle in alkaline condition ShiShimonoseki compound 2-benzyl-3-trifluoromethyl-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2.2.1] heptane
The 9th step: 2-benzyl-3-trifluoromethyl-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2.2.1] heptane obtains 3-trifluoromethyl-5-tertbutyloxycarbonyl-2 through the over hydrogenation debenzylation, 5-diazabicyclo [2.2.1] heptane, or 2-benzyl-3-trifluoromethyl-5-tertbutyloxycarbonyl-2,5-diazabicyclo [2.2.1] heptane and chloromethane acids ester get 3-trifluoromethyl-5-tertbutyloxycarbonyl-2 at solvent reaction, 5-diazabicyclo [2.2.1] heptane.
3. 3-trifluoromethyl according to claim 2-5-tertbutyloxycarbonyl-2; the preparation method of 5-diazabicyclo [2.2.1] heptane; it is characterized in that; the described the first step is reflected under the existence of alkali; react in the organic solvent; used aromatics amido protecting agent is the benzyl bromine; benzyl chlorine; replace the benzyl bromine; replace benzyl chlorine; a kind of in Tosyl chloride or the chloroformic acid benzyl ester; used alkali is triethylamine; pyridine; sodium hydride; potassium hydroxide; sodium hydroxide; salt of wormwood; a kind of in the yellow soda ash; used solvent is an acetonitrile; tetrahydrofuran (THF); methylene dichloride; trichloromethane; 1; the 2-ethylene dichloride; dioxane; ethyl acetate; toluene; N; dinethylformamide; N; the N-N,N-DIMETHYLACETAMIDE; N, the N-diethylformamide; in dimethyl sulfoxide (DMSO) or the N-Methyl pyrrolidone one or more.
4. 3-trifluoromethyl according to claim 3-5-tertbutyloxycarbonyl-2, the preparation method of 5-diazabicyclo [2.2.1] heptane is characterized in that used aromatics amido protecting agent is the benzyl bromine, and used alkali is triethylamine, and used solvent is an acetonitrile.
5. 3-trifluoromethyl according to claim 2-5-tertbutyloxycarbonyl-2, the preparation method of 5-diazabicyclo [2.2.1] heptane, it is characterized in that, described second step is reflected at organic solvent carries out under existing, and used alkali is a kind of in potassium hydroxide, sodium hydroxide, salt of wormwood, yellow soda ash, the lithium hydroxide; Used organic solvent is water, methyl alcohol, ethanol, tetrahydrofuran (THF), acetonitrile, dioxane, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, N, one or more mixed solvents in N-diethylformamide, dimethyl sulfoxide (DMSO) or the N-Methyl pyrrolidone.
6. 3-trifluoromethyl according to claim 5-5-tertbutyloxycarbonyl-2, the preparation method of 5-diazabicyclo [2.2.1] heptane is characterized in that used alkali is lithium hydroxide, used organic solvent is methyl alcohol and water mixed solvent.
7. 3-trifluoromethyl according to claim 2-5-tertbutyloxycarbonyl-2, the preparation method of 5-diazabicyclo [2.2.1] heptane, it is characterized in that, described three-step reaction carries out in organic solvent, used additive is I-hydroxybenzotriazole, 1-hydroxyl-7-azepine benzotriazole, phosphofluoric acid O-(7-azepine benzo triazol-1-yl)-N, N, N ', a kind of in N '-tetramethyl-urea, hydroxy thiosuccinimide or the N-hydroxy-succinamide; Used condensing agent is a kind of in carbonyl dimidazoles, DIC, dicyclohexylcarbodiimide or 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride; Used alkali is a kind of in triethylamine, pyridine, salt of wormwood, yellow soda ash, the sodium bicarbonate; Used organic solvent is methylene dichloride, trichloromethane, 1,2-ethylene dichloride, dioxane, N, dinethylformamide, N,N-dimethylacetamide, N, one or more in N-diethylformamide, dimethyl sulfoxide (DMSO) or the N-Methyl pyrrolidone.
8. 3-trifluoromethyl according to claim 7-5-tertbutyloxycarbonyl-2, the preparation method of 5-diazabicyclo [2.2.1] heptane, it is characterized in that, used additive is an I-hydroxybenzotriazole, used condensing agent is 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, used alkali is triethylamine, and used organic solvent is N, dinethylformamide.
9. 3-trifluoromethyl according to claim 2-5-tertbutyloxycarbonyl-2, the preparation method of 5-diazabicyclo [2.2.1] heptane, it is characterized in that, described four-step reaction carries out in organic solvent, and used organic solvent is one or more in acetonitrile, methyl alcohol, ethanol, water, tetrahydrofuran (THF), dioxane, ether, benzene, toluene, trifluoroacetic acid or the acetate.
10. 3-trifluoromethyl according to claim 9-5-tertbutyloxycarbonyl-2, the preparation method of 5-diazabicyclo [2.2.1] heptane is characterized in that used reductive agent is a diisobutyl aluminium hydride, used organic solvent is a tetrahydrofuran (THF).
11. 3-trifluoromethyl according to claim 2-5-tertbutyloxycarbonyl-2, the preparation method of 5-diazabicyclo [2.2.1] heptane, it is characterized in that, described the 5th step is reflected in the organic solvent carries out, and used trifluoromethyl reagent is trifluoromethyl trimethyl silane or trifluoromethyl methyl iodide; Used alkaline catalysts is three hydration tetra-n-butyl Neutral ammonium fluoride or cesium fluorides; Used organic solvent is methylene dichloride, trichloromethane, 1, and one or more in 2-ethylene dichloride, dioxane, tetrahydrofuran (THF), acetonitrile, toluene or the ether.
12. 3-trifluoromethyl according to claim 11-5-tertbutyloxycarbonyl-2, the preparation method of 5-diazabicyclo [2.2.1] heptane, it is characterized in that, used trifluoromethyl reagent is the trifluoromethyl trimethyl silane, used alkaline catalysts is three hydration tetra-n-butyl Neutral ammonium fluorides, and used organic solvent is a tetrahydrofuran (THF).
13. 3-trifluoromethyl according to claim 2-5-tertbutyloxycarbonyl-2, the preparation method of 5-diazabicyclo [2.2.1] heptane, it is characterized in that, described six-step process is under base catalysis, carry out in organic solvent, used sulfonylation agent is one or more of trifluoromethyl SULPHURYL CHLORIDE, Methanesulfonyl chloride, ethyl chloride or phenyl SULPHURYL CHLORIDE; Used alkali is a kind of in triethylamine, pyridine, salt of wormwood or the yellow soda ash; Used organic solvent is methylene dichloride, trichloromethane, 1, one or more in 2-ethylene dichloride, dioxane, tetrahydrofuran (THF), acetonitrile, toluene or the ether.
14. 3-trifluoromethyl according to claim 13-5-tertbutyloxycarbonyl-2, the preparation method of 5-diazabicyclo [2.2.1] heptane is characterized in that used sulfonylation agent is a Methanesulfonyl chloride, and used alkali is salt of wormwood, and used organic solvent is an acetonitrile.
15. 3-trifluoromethyl according to claim 2-5-tertbutyloxycarbonyl-2, the preparation method of 5-diazabicyclo [2.2.1] heptane, it is characterized in that described the 7th step is reflected at carries out in the organic solvent and add catalyzer, catalyst system therefor 10% palladium carbon or the palladium hydroxide that be weight percentage; Organic solvent is methyl alcohol, ethanol, water, tetrahydrofuran (THF), dioxane, ethyl acetate, methylene dichloride, trichloromethane, N, dinethylformamide, N, N-diethylformamide, N, one or more in N-diethylformamide, dimethyl sulfoxide (DMSO) or the ether; Used chloromethane acids ester is a kind of in chloroformic acid α chloro-ethyl ester, chloroformic acid α vinylchlorid ester or the Vinyl chloroformate, and used solvent is a kind of in acetonitrile, methyl alcohol, ethanol, water, tetrahydrofuran (THF), dioxane, ether, benzene, toluene, trifluoroacetic acid or the acetate.
16. 3-trifluoromethyl according to claim 15-5-tertbutyloxycarbonyl-2, the preparation method of 5-diazabicyclo [2.2.1] heptane is characterized in that, the used catalyzer 10% palladium carbon that is weight percentage, and organic solvent is a methyl alcohol.
17. 3-trifluoromethyl according to claim 2-5-tertbutyloxycarbonyl-2, the preparation method of 5-diazabicyclo [2.2.1] heptane, it is characterized in that, described the 8th step is reflected in the organic solvent and carries out, and used alkali is a kind of in potassium tert.-butoxide, sodium tert-butoxide, pyridine, sodium hydride, salt of wormwood or the yellow soda ash; Used organic solvent is acetonitrile, toluene, tetrahydrofuran (THF), dioxane, ethyl acetate, toluene, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, N, one or more in N-diethylformamide, dimethyl sulfoxide (DMSO) or the N-Methyl pyrrolidone.
18. 3-trifluoromethyl according to claim 17-5-tertbutyloxycarbonyl-2, the preparation method of 5-diazabicyclo [2.2.1] heptane is characterized in that used alkali is salt of wormwood, and used organic solvent is an acetonitrile.
19. 3-trifluoromethyl according to claim 2-5-tertbutyloxycarbonyl-2, the preparation method of 5-diazabicyclo [2.2.1] heptane, it is characterized in that described the 9th step is reflected at carries out in the organic solvent and add catalyzer, catalyst system therefor 10% palladium carbon or the palladium hydroxide that be weight percentage; Organic solvent is methyl alcohol, ethanol, water, tetrahydrofuran (THF), dioxane, ethyl acetate, methylene dichloride, trichloromethane, N, dinethylformamide, N, N-diethylformamide, N, one or more in N-diethylformamide, dimethyl sulfoxide (DMSO) or the ether; Used chloromethane acids ester is a kind of in chloroformic acid α chloro-ethyl ester, chloroformic acid α vinylchlorid ester or the Vinyl chloroformate, and used solvent is a kind of in acetonitrile, methyl alcohol, ethanol, water, tetrahydrofuran (THF), dioxane, ether, benzene, toluene, trifluoroacetic acid or the acetate.
20. 3-trifluoromethyl according to claim 19-5-tertbutyloxycarbonyl-2, the preparation method of 5-diazabicyclo [2.2.1] heptane is characterized in that, the used catalyzer 10% palladium carbon that is weight percentage, and organic solvent is a methyl alcohol.
21. the preparation method of the described 3-trifluoromethyl of claim 1-5-tertbutyloxycarbonyl-2-oxa--5-azabicyclo [2.2.1] heptane; it is characterized in that; with (2S; 4R)-tetrahydro pyrrolidine-2-formaldehyde 10 is starting raw material to N-tertbutyloxycarbonyl-4-((methylsulfonyl) oxygen); with trifluoromethyl reagent; get compound 3-trifluoromethyl-5-tertbutyloxycarbonyl-2-oxa--5-azabicyclo [2.2.1] heptane II at next step ring closure reaction of base catalysis, reaction formula is as follows:
Figure FSA00000037749500041
22. the preparation method of 3-trifluoromethyl according to claim 21-5-tertbutyloxycarbonyl-2-oxa--5-azabicyclo [2.2.1] heptane is characterized in that used trifluoromethyl reagent is trifluoromethyl trimethyl silane or trifluoromethyl methyl iodide; Used alkaline catalysts is three hydration tetra-n-butyl Neutral ammonium fluoride or cesium fluorides; Solvent for use is methylene dichloride, trichloromethane, 1, and one or more in 2-ethylene dichloride, dioxane, tetrahydrofuran (THF), acetonitrile, toluene or the ether.
23. the preparation method of 3-trifluoromethyl according to claim 21-5-tertbutyloxycarbonyl-2-oxa--5-azabicyclo [2.2.1] heptane, it is characterized in that, used trifluoromethyl reagent is the trifluoromethyl trimethyl silane, used alkaline catalysts is three hydration tetra-n-butyl Neutral ammonium fluorides, and solvent for use is a tetrahydrofuran (THF).
CN2010101138805A 2010-02-25 2010-02-25 3-trifluoromethyl-5-tert-butoxycarbonyl-2,5-diheterobicyclo[2.2.1]heptane and preparation method thereof Pending CN102167700A (en)

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CN102633804A (en) * 2012-04-19 2012-08-15 中南大学 Method for preparing 7-Azabicyclo[2.2.1]heptane
CN103755710A (en) * 2014-01-14 2014-04-30 昆明理工大学 2,5-diazabicyclo heptane compound and application thereof
CN109970648A (en) * 2019-03-25 2019-07-05 西华大学 Amidine and the like is catalyzed the list guard method of diaza cycloaliphatic ring tertbutyloxycarbonyl
CN110028510A (en) * 2019-05-22 2019-07-19 南京合巨药业有限公司 A kind of preparation method of 3- methyl -3,6- diaza-bicyclic [3,1,1] heptane dihydrochloride
CN110343134A (en) * 2019-08-04 2019-10-18 张震 A kind of preparation method of bis- (2,4,6- trimethylbenzoyl) phenyl phosphine oxides of photoinitiator
CN113698409A (en) * 2021-08-10 2021-11-26 上海凌凯医药科技有限公司 Multipurpose diazabicyclo compound, preparation method and application in synthetic drugs
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CN102633804A (en) * 2012-04-19 2012-08-15 中南大学 Method for preparing 7-Azabicyclo[2.2.1]heptane
CN102633804B (en) * 2012-04-19 2014-09-24 中南大学 Method for preparing 7-Azabicyclo[2.2.1]heptane
CN103755710A (en) * 2014-01-14 2014-04-30 昆明理工大学 2,5-diazabicyclo heptane compound and application thereof
CN103755710B (en) * 2014-01-14 2015-08-12 昆明理工大学 One class 2,5-diazabicyclo iieptanes compound and application thereof
CN109970648A (en) * 2019-03-25 2019-07-05 西华大学 Amidine and the like is catalyzed the list guard method of diaza cycloaliphatic ring tertbutyloxycarbonyl
CN109970648B (en) * 2019-03-25 2022-05-20 西华大学 Method for catalyzing single protection of diaza aliphatic ring tert-butyloxycarbonyl by amidine and analogue thereof
CN110028510A (en) * 2019-05-22 2019-07-19 南京合巨药业有限公司 A kind of preparation method of 3- methyl -3,6- diaza-bicyclic [3,1,1] heptane dihydrochloride
CN110343134A (en) * 2019-08-04 2019-10-18 张震 A kind of preparation method of bis- (2,4,6- trimethylbenzoyl) phenyl phosphine oxides of photoinitiator
CN110343134B (en) * 2019-08-04 2022-03-15 张震 Preparation method of photoinitiator bis (2,4, 6-trimethylbenzoyl) phenylphosphine oxide
CN113999239A (en) * 2021-07-14 2022-02-01 上海凌富药物研究有限公司 Method for synthesizing diaza-bridge compound
CN113999239B (en) * 2021-07-14 2022-11-11 上海凌富药物研究有限公司 Method for synthesizing diaza-bridge compound
CN113698409A (en) * 2021-08-10 2021-11-26 上海凌凯医药科技有限公司 Multipurpose diazabicyclo compound, preparation method and application in synthetic drugs

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