CN114853768A - Method for synthesizing chiral 3-fluoro-1-azabicyclo [2,2,1] heptane - Google Patents
Method for synthesizing chiral 3-fluoro-1-azabicyclo [2,2,1] heptane Download PDFInfo
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Abstract
The invention relates to a method for synthesizing chiral 3-fluoro-1-azabicyclo [2,2,1] heptane. Firstly, N-tert-butyloxycarbonyl-3-fluoro-4-piperidone is used as a raw material to perform a Wittig reaction with a ylide reagent and alkali, a carbon-oxygen double bond of a 4-carbonyl group of the N-tert-butyloxycarbonyl-3-fluoro-4-piperidone is converted into olefin, then the olefin, a borane complex, the alkali and hydrogen peroxide are subjected to a hydroboration oxidation reaction, an obtained product is added with p-toluenesulfonyl chloride and pyridine, and the obtained mixture is respectively subjected to resolution by utilizing high performance liquid chromatography and a chiral supercritical fluid chromatography technology to obtain 4 chiral 3-fluoro-1-azabicyclo [2,2,1] heptanes. The invention utilizes common reagents to synthesize 4 novel chiral 3-fluoro-1-azabicyclo [2,2,1] heptane isomers, the reaction process has easily obtained raw materials, simple and convenient synthesis steps, feasible chemical technology and high yield, and is a feasible method for synthesizing a large amount of the compound.
Description
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and relates to synthesis of hectogram chiral 3-fluoro-1-azabicyclo [2,2,1] heptane.
Background
Heterocyclic compounds have been widely used in various fields such as pesticides, medicines, dyes and the like due to their unique properties, particularly in the development of the pesticide ranks (Zhang-Shi-nationality, research on nitrogen-containing heterocyclic compounds [ J]Petrochemical, 2011, 40, 579.). Fluorine has the characteristics of small atomic volume and large electronegativity, fluorine atoms or fluorine-containing groups are introduced in the design of medicines, the physicochemical characteristics of substances can be adjusted, the bioavailability of the medicines is improved, the mutual binding capacity of ligands and target proteins and the selectivity of other target proteins can be enhanced by influencing the conformation of compounds, and the metabolic stability of the medicines is improved by blocking easily-metabolized sites, so that the fluorine atoms play an important role in the aspects of medicines and pesticides (Zhao Fano, the main application of the fluorine atoms in the design of medicines and the introduction method [ J]Culture and art, 2019, 247.). Nowadays, fluorine-containing heterocyclic compounds are important to the development of novel pesticides and pharmaceutical intermediates, and azabicyclo [2,2,1]Heptane is the molecular framework in part of the drug intermediate (Johnson, c. r., Kangas, b. d., Jutkiewicz, e. m., Winger, g., Bergman, j., Coop, a., Woods, j. H).J Pharmacol Exp Ther.,2021, 377, 336.) to 3-fluoro-1-azabicyclo [2,2,1] s]Heptane has potential for pharmaceutical applications. Fluorine atoms also play a good role in the design of ferroelectric materials, and the Curie temperature of the ferroelectric materials is usually improved by using a single fluorine atom substitution design strategy, researches show that the introduction of F atoms generally enhances the biocompatibility of the F atoms and does not influence the change of polar point groups, and the introduction of the F atoms can induce symmetry defects to enhance the Curie temperature, spontaneous polarization and other physical properties, such as 1-azabicyclo [2,2,1]]Heptane, quinuclidine, which, when substituted by fluorine atoms, raises the curie temperature of the original ferroelectric, has been reported in the literature (Liu, h.y., Zhang, h.y., Chen, x.g., Xiong, r.g.). J. Am. Chem. Soc.,2020, 142, 15205.). E.g. fluoro-substituted 4-fluoro-1-azabicyclo [2,2,1]]Heptane (Tang, y., Xie, y., Zeng, y. l., Liu, j. c., He, w. h., Huang, x. q., Xiong, r. G).Adv. Mater.,2020, 32, 2003530.) and 4-fluoroquinuclidine (Tang, y., Xie, y., Ai, y., Liao, w. q., Li, p. f., Nakamura, t., Xion, kg, R. G. J. Am. Chem. Soc.,2020, 142, 21932.) compounds belonging to the class of fluorine substituted amines can be used for the design of molecular ferroelectric materials.
In the search of the literature, it was found that although researchers had already conducted on 3-fluoro-1-azabicyclo [2,2,1]]Heptane was synthesized but using the starting material 3-hydroxy-1-azabicyclo [2,2,1] bicyclo]Heptane is required to be synthesized in multiple steps by known compounds. 3-fluoro-1-azabicyclo [2,2,1] synthesized by the method]Heptane, gives no clear yield of the product, nor data on the product, and is not involved in the synthesis of its chiral product molecule (MacLeod, a. m., Herbert, r., Hoogsteen, K).J. Chem. Soc. Chem. Comm.,1990, 100.). And chiral 3-fluoro-substituted-1-azabicyclo [2,2,1]Heptane is not directly commercially available and has not heretofore been suitable for the large scale synthesis of chiral 3-fluoro-1-azabicyclo [2,2,1]]A heptane process.
Disclosure of Invention
The invention aims to provide a method for synthesizing chiral 3-fluoro-1-azabicyclo [2,2,1] heptane by using cheap raw materials. The reaction process has the advantages of easily available raw materials, simple and convenient synthesis steps, feasible chemical technology and high yield, and is a feasible experimental method for synthesizing the compound in large quantity.
A method for synthesizing chiral 3-fluoro-1-azabicyclo [2,2,1] heptane takes N-tert-butyloxycarbonyl-3-fluoro-4-piperidone as a raw material, and realizes the synthesis of 4 novel chiral 3-fluoro-1-azabicyclo [2,2,1] heptane isomers through five-step reaction and chiral supercritical fluid chromatographic separation. The method specifically comprises the following steps that in the first step, N-tert-butyloxycarbonyl-3-fluoro-4-piperidone, a ylide reagent and alkali are subjected to a Wittig reaction, and carbon-oxygen double bonds of carbonyl groups are converted into carbon-carbon double bonds; secondly, adding borane complex, hydrogen peroxide and alkali into the compound II generated in the first step to perform hydroboration oxidation reaction with carbon-carbon double bonds, so as to change the double bonds of the compound II into hydroxymethyl; the third step is to use a reagent M to convert hydroxyl into an isomer mixture obtained by easily-leaving-OTs group under the condition of alkali action, two racemic mixtures IVa and IVb can be obtained by High Performance Liquid Chromatography (HPLC) separation, and two pairs of enantiomers Va and Vb, Vc and Vd can be obtained by chiral supercritical fluid chromatographic resolution;
the fourth step of reaction is that after a t-butyloxycarbonyl protecting group (Boc) on an N atom is removed from Va, Vb, Vc or Vd under an acidic condition, a compound VIa, VIb, VIc or VId is obtained; the fifth step is that nucleophilic substitution ring closing reaction is carried out under the alkaline condition, and 4 new chiral 3-fluoro-1-azabicyclo [2,2,1] heptane isomers VIIa and VIIb, VIIc and VIId are obtained after extraction, solvent removal and concentration.
The ylide reagent from N-tert-butyloxycarbonyl-3-fluoro-4-piperidone to the compound II in the first step is methyl triphenyl phosphonium chloride, methyl triphenyl phosphonium bromide or methyl triphenyl phosphonium iodide, and the alkali is methyl triphenyl phosphonium chloride, methyl triphenyl phosphonium bromide or methyl triphenyl phosphonium iodidet-BuONa、t-BuOK, pyridine, KOH, NaOH or K 2 CO 3 。
The borane complex of the second reaction from compound II to compound III comprises borane dimethylsulfide complex, borane tetrahydrofuran complex, borane ammonia complex or borane trimethylamine complex, and the base ist-BuONa、t-BuOK, pyridine, KOH, NaOH or K 2 CO 3 。
The reagent M for converting the hydroxyl group into a readily leaving group in the third reaction step may be p-toluenesulfonyl chloride (TosCl), methanesulfonyl chloride (MsCl) or trifluoromethanesulfonic anhydride (OTf) 2 ) (ii) a The base ist-BuONa、t-BuOK, pyridine, KOH, NaOH or K 2 CO 3 . The fourth step of reaction is carried out by reacting compound Va, Vb, Vc or Vd with acid of compound VIa, VIb, VIc or VId, wherein the acid is formic acid, acetic acid, hydrochloric acid, trifluoroacetic acid, p-tert-butyl acetateToluene sulfonic acid, oxalic acid, sulfuric acid, trifluoromethanesulfonic acid, nitric acid, or phosphoric acid.
Reacting the compound VIa, VIb, VIc or VId to the target product VIIa, VIIb in the fifth step; VIIc, VIId baset-BuONa、t-BuOK, pyridine, KOH, NaOH or K 2 CO 3 。
The solvent used in the reactions from the first step to the fifth step is N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, 1, 4-dioxane, acetonitrile, diethyl ether, ethylene glycol dimethyl ether or tetrahydrofuran.
The reaction temperature in the five-step reaction is 0-100 DEG o And C, the reaction time is 1-48 h.
Compared with the prior art, the invention has the following advantages:
1. the N-tert-butyloxycarbonyl-3-fluoro-4-piperidone used as the raw material for synthesizing the target heterocyclic compound is a cheap and easily available commodity;
2. the conditions of the five-step reaction in the route are all under mild conditions (not more than 80 percent) o C) The reaction can be carried out, and the total yield is higher;
3. the reaction can realize the synthesis of target products of hectogram level with high yield.
Detailed Description
The invention is further described in the following by the detailed description
Example 1: synthesis of chiral 3-fluoro-1-azabicyclo [2,2,1] heptane
Synthesis procedure of Compound II:
dissolving methyl triphenyl phosphonium bromide (822 g, 2.30 mol, 2 eq) in THF (1.5L), adding potassium tert-butoxide (258 g, 2.30 mol, 2 eq) in the solution, and reacting at 15-25% o C and nitrogen atmosphere, stirring for 30min, adding THF (1.0L) solution containing compound I (250 g, 1.15 mol, 1 eq) into the mixed solution,holding 15 to 25 o And C, reacting for 16h under a nitrogen atmosphere. After completion of the TLC detection of the reaction of Compound I, the reaction mixture was taken up at 20 o Add water (5L) and stir under C, extract inorganic layer with ethyl acetate (EtOAc) (3.00L × 2), wash organic layer with brine (3.00L × 1), anhydrous Na 2 SO 4 Dried and filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO) 2 Petroleum ether/ethyl acetate = 10/1). Compound II was a pale yellow oily liquid (200 g, 0.93 mol, yield 80.7%).
Compound II: 1 H NMR (400 MHz, DMSO) δ 1.40 (s, 9H), 2.14 ~ 2.20 (m, 1H), 2.29 ~ 2.37 (m, 1H), 2.98 (s, 1H), 3.23 ~ 3.34 (m, 1H), 3.87(s, 2H), 4.90 ~ 5.03 (m, 2H), 5.11 (s, 1H);
19 F NMR (400MHz, DMSO ) δ -181.05 ~ 180.37 (m, 1F).
synthesis procedure for Compound III:
compound II (400 g, 1.86 mol, 1.00 eq) was dissolved in a solution of tetrahydrofuran (4.00L) at 0 o Borane dimethyl sulfide (10.0M, 278 mL, 1.50 eq) was added dropwise at C. Mixing the mixture in N 2 Environment and 0 o Stirring for 1h under C, and finishing at 15 o Stirring for 15h under C. The progress of the reaction was monitored by TLC (petroleum ether: ethyl acetate = 5: 1), and after completion of the reaction, 0 o NaOH (3.00M, 1052 mL, 1.70 eq) was added dropwise at C. Reaction mixture in N 2 And 0 o And stirring and reacting for 15min under the environment of C. Then at 0 o C under dropwise addition of H 2 O 2 (632 g, 5.58 mol, 534 mL, 30.0% purity, 3.00 eq) for 15 min. Will react at 15 o Stirred for 15h at C and checked by TLC (petroleum ether: ethyl acetate = 5: 1, Rf = 0.07) until compound II was completely consumed. The reaction mixture is left at rest at 0 o Adding Na under C 2 S 2 O 3 The saturated solution (1.00L) was stirred and extracted by addition of DCM (500 mL × 3). Will be organicThe layers were combined, washed with brine (500 mL x 1), and then washed with Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. Compound III (400 g, crude) was obtained as a yellow oil.
Synthesis of Compounds Va, Vb, Vc, Vd:
in a solution of compound III (800 g, 3.43 mol, 1.00 eq) and TosCl (982 g, 5.15 mol, 1.50 eq) in DCM (8.00L) at 0 ℃ and N 2 Pyridine (1027 g, 13.0 mol, 1050 mL, 3.80 eq) was added dropwise to the atmosphere. Then heated to 25 ℃ and stirred for 12 h. By TLC (Petroleum ether: ethyl acetate =1:1, Rf) 1 = 0.64，Rf 2 = 0.56) check reaction progress, when the reactant has been completely consumed, pour reaction mixture into 1200mL ice water and stir for 20 min. The aqueous phase was extracted with DCM (40.0 mL × 3). The combined organic phases were washed with brine (4.00L) and then with anhydrous Na 2 SO 4 Dried and then concentrated by vacuum filtration. Purification by silica gel column chromatography (petroleum ether/ethyl acetate = 10: 1) and High Performance Liquid Chromatography (HPLC) gave a yellow oily racemate mixture IVa and another white solid racemate mixture IVb. The two mixtures were further separated by chiral Supercritical Fluid Chromatography (SFC) to give compound Va (220 g, 563 mmol, 16.4% yield, 99.2% purity) as a white solid, compound Vb (215 g, 552 mmol, 16.1% yield, 99.6% purity) as a white solid, compound Vc (215 g, 545 mmol, 15.9% yield, 98.3% purity) as a white solid, 15.9% yield, 98.3% purity, and compound Vd (205 g, 525 mmol, 15.3% yield, 99.3% purity) as a white solid.
Racemic mixture IVa: 1 H NMR (400 MHz, DMSO)δ 1.15 ~ 1.25 (m, 1H), 1.38 (s, 9H), 1.66 ~ 1.71 (m, 1H), 1.96 ~ 2.07 (m, 1H), 2.42(s, 3H), 2.76 (s, 2H), 3.72 ~ 3.76 (d, 1H, J = 13.00 Hz ), 4.05 ~ 4.12 (m, 3H), 4.19 ~ 4.37 (m, 1H), 7.47 ~ 7.50 (d, 2H, J = 8.12 Hz), 7.79 ~ 7.81 (d, 2H, J = 8.28 Hz);
19 F NMR (400MHz, DMSO ) δ -186.16.
racemic mixture IVb: 1 H NMR (400 MHz, DMSO) δ1.17 ~ 1.27 (m, 1H), 1.36 (s, 9H), 1.42 ~ 1.46 (dd, 1H, J = 13.20 , 2.88 Hz), 2.03 ~ 2.13 (m, 1H), 2.42 (s, 3H), 2.58 ~ 3.01 (m, 2H), 3.87 ~ 4.00 (m, 3H ), 4.17 (s, 1H), 4.65 ~ 4.77 (d, 1H, J = 48.16 Hz), 7.47 ~ 7.49 (d, 2H, J = 8.08 Hz), 7.79 ~ 7.81 (d, 2H, J = 8.24 Hz);
19 F NMR (400MHz, DMSO ) δ -203.27.
compound Va: 1 H NMR (400MHz, DMSO) δ1.16~1.26 (m, 1H), 1.36 (s, 9H), 1.42~1.46 (dd, 1H, J = 13.16 , 3.00 Hz), 2.00~2.16 (m, 1H), 2.43 (s, 3H), 2.66~3.01 (m, 2H), 3.86~4.00 (m, 3H), 4.16 (s, 1H), 4.64~4.76 (d, 1H, J = 48.12 Hz), 7.48~4.50 (d, 2H, J = 8.04 Hz), 7.79~7.81(d, 2H, J = 8.32 Hz);
19 F NMR (400MHz, DMSO ) δ -203.04;
13 C NMR (100MHz, DMSO ) δ21.62 (s, 1C), 25.71 (s, 1C), 28.46 (s, 1C), 40.90 (s, 1C), 70.32 ~70.35 (d, 1C), 79.83 (s, 1C), 86.31~88.06 (d, 1C), 128.17 (s, 2C), 130.76 (s, 2C), 132.55 (s, 1C), 145.61 (s, 1C), 154.18 (s,1C).
compound Vb: 1 H NMR (400 MHz, DMSO) δ 1.16~1.26 (m, 1H), 1.36 (s, 9H), 1.42~1.46 (dd, 1H, J = 13.24 , 3.16 Hz), 2.00~2.16 (m, 1H), 2.42 (s, 3H), 2.66~3.01 (m, 2H), 3.86~4.00 (m, 3H), 4.16 (s, 1H), 4.64~4.76 (d, 1H, J = 48.08 Hz), 7.48~4.50 (d, 2H, J = 8.00 Hz), 7.79~7.81(d, 2H, J = 8.32 Hz);
19 F NMR (400MHz, DMSO ) δ -203.04;
13 C NMR (100MHz, DMSO ) δ 21.62 (s, 1C), 25.74 (s, 1C), 28.46 (s, 1C), 40.91 (s, 1C),70.31~70.34 (d, 1C) , 79.83 (s, 1C), 86.31~88.06 (d, 1C), 128.16 (s, 2C), 130.75 (s, 2C), 132.56 (s, 1C), 145.61 (s, 1C), 154.17 (s, 1C).
compound Vc: 1 H NMR (400MHz, DMSO) δ 1.14~1.25 (m, 1H), 1.38 (s, 9H), 1.66~1.71 (dt, 1H, J = 13.68 , 3.52 Hz), 1.97~2.06 (m, 1H), 2.43 (s, 3H), 2.76~2.95 (m, 2H), 3.72~3.75 (d, 1H, J = 13.2 Hz), 4.05~4.12 (m, 3H), 4.19~4.37 (m, 1H), 7.48~4.50 (d, 2H, J = 8.04 Hz), 7.79~7.81(d, 2H, J = 8.32Hz);
19 F NMR (400MHz, DMSO ) δ-186.11 (s, 1F);
13 C NMR (100MHz, DMSO )δ21.63 (s, 1C), 22.08 (s, 1C), 22.19 (s, 1C), 28.51 (s, 1C), 38.25 (s, 1C), 38.44 (s, 1C), 70.65 ~70.69 (d, 1C), 79.36 (s, 1C), 84.85 (s, 1C), 86.60 (s, 1C), 128.17 (s, 2C), 130.75 (s, 2C), 132.56 (s, 1C), 145.59 (s, 1C), 154.73 (s, 1C).
compound Vd: 1 H NMR (400MHz, DMSO) δ 1.15~1.25 (m, 1H), 1.38 (s, 9H), 1.66~1.72 (dt, 1H, J = 17.44 , 3.76 Hz), 1.96~2.07 (m, 1H), 2.42 (s, 3H), 2.76~2.84 (m, 2H), 3.72~3.75 (d, 1H, J = 13.16 Hz), 4.05~4.12 (m, 3H), 4.19~4.37 (m, 1H), 7.48~4.50 (d, 2H, J = 8.04 Hz), 7.79~7.81(d, 2H, J = 8.32Hz);
19 F NMR (400MHz, DMSO ) δ -186.12 (s, 1F);
13 C NMR (100MHz, DMSO ) δ 21.62 (s, 1C), 22.13 (s, 1C), 22.28 (s, 1C), 28.51 (s, 1C), 38.25 (s, 1C), 38.45 (s, 1C), 70.65~70.69 (d, 1C), 79.36 (s, 1C), 84.86 (s, 1C), 86.60 (s, 1C), 84.86~86.60 (d, 1C), 128.17 (s, 2C), 130.74 (s, 2C), 132.57 (s, 1C), 145.59 (s, 1C), 154.72 (s, 1C).
the synthesis steps of the compounds VIa, VIb, VIc and VId are as follows:
compound Va (220 g, 567 mmol, 1.00 eq) was dissolved in ethyl acetate (EtOAc) (1.10L) at 25 o HCl/EtOAc (1.10L) was added under C. The mixture is at 25 o Stirring for 3 h under C. By TLC (petroleum ether: ethyl acetate = 3:1, Rf = 0.0)3) Detection indicated that the reactants had been completely consumed. The mixture was concentrated in vacuo to give the hydrochloride salt of compound VIa (180 g, crude) as a white solid.
The synthesis procedures for compounds VIb, VIc, and VId were similar to those for compound VIa, and the results are shown in the following tables.
The synthesis steps from the compounds VIa, VIb, VIc, VId to the target products VIIa, VIIb, VIIc, VIId are as follows:
compound VIa (180 g, 627 mmol, 1.00 eq) was dissolved in MeCN (3.60L) and K was added 2 CO 3 (260 g, 1881 mmol, 3.00 eq.) and NaI (9.41 g, 62.7 mmol, 0.10 eq.) the mixture was stirred at 80 deg.C o Stirring for 16h under C. After LC-MS monitoring indicated that the reactants had been completely consumed, the reaction mixture was filtered and the filtrate was at 80 deg.C o C. Most of the solvent was distilled off at 15 psi to give a residue containing product, MeCN (3.6L), at 0 o Add HCl/EtOAc (4M) to pH = 4-5 under C, then concentrate in vacuo. The crude product was taken up in 1200mL of ethyl acetate (EtOAc) at 25 o C is precipitated for 1h, then filtered and the filter cake is collected and concentrated in vacuo to give the hydrochloride salt of the target product vila (45.8 g, 302 mmol, 48.2% yield, 100% purity, HCl) as a white solid.
Target products VIIb, VIIc, VIId are synthesized in a similar manner to target product VIIa, and the results are shown in the following table.
Compound VIIa: 1 H NMR (400 MHz, DMSO)δ1.43 ~ 1.49 (m, 1H), 1.94 ~ 2.04 (m, 1H), 3.00 ~ 3.06 (m, 2H), 3.18 ~ 3.38 (m, 4H), 3.59 ~ 3.69 (m, 1H), 4.97 ~ 5.12 (dd, 1H, J = 56.04, 5.24 Hz), 11.47 (s, 1H);
19 F NMR (400MHz, DMSO ) δ -168.19 (s, 1F);
13 C NMR (75MHz, DMSO ) δ20.31~20.43 (d, 1C), 51.10 (s, 1C), 56.28, (s, 1C), 59.80 (s,1C) , 60.15 (s, 1C) , 90.03 ~ 92.49 (d, 1C).
compound VIIb: 1 H NMR (400 MHz, DMSO) δ1.44 ~ 1.51 (m, 1H), 1.95 ~ 2.05 (m, 1H), 3.02 ~ 3.08 (m, 2H), 3.21 ~ 3.34 (m, 4H), 3.62 ~ 3.71 (m, 1H), 4.98 ~ 5.14 (dd, 1H, J = 56.04, 5.44 Hz), 11.75 (s,1H);
19 F NMR (400MHz, DMSO )δ -168.19 (s, 1F);
13 C NMR (75MHz, DMSO ) δ 20.31~20.43 (d, 1C), 51.02 (s, 1C), 56.25, (s, 1C), 59.73 (s,1C) , 60.09 (s, 1C) , 90.06 ~ 92.51 (d, 1C).
compound VIIc: 1 H NMR (400 MHz, DMSO) δ1.95 ~ 2.00 (m, 2H), 3.09 ~ 3.24 (m, 3H), 3.24 ~ 3.42 (m, 3H), 3. 59 ~ 3.69 (m, 1H), 5.33 ~ 5.51 (m, 1H), 11.79 (s,1H);
19 F NMR (400MHz, DMSO )δ -193.99 (s, 1F);
13 C NMR (75MHz, DMSO ) δ18.88~19.03 (d, 1C), 51.42 (s, 1C), 56.75, (s, 1C), 57.12 (s,1C) , 57.39~57.46 (d, 1C) , 87.90 ~ 90.38 (d, 1C).
compound VIId: 1 H NMR (300 MHz, DMSO) δ1.90~2.06(m, 2H), 3.08 ~ 3.23 (m, 3H), 3.23 ~ 3.44 (m, 3H), 3.56 ~ 3.70 (m, 1H), 5.29 ~ 5.53 (m, 1H), 11.56 (s,1H)；
19 F NMR (400MHz, DMSO )δ -193.99 (s, 1F);
13 C NMR (75 MHz, DMSO ) δ 18.90~19.04 (d, 1C), 51.40 (s, 1C), 56.75, (s, 1C), 57.13 (s,1C) , 57.37~57.44 (d, 1C) , 87.91 ~ 90.39 (d, 1C).
although the invention has been described and illustrated in some detail, it should be understood that various modifications may be made to the described embodiments or equivalents may be substituted, as will be apparent to those skilled in the art, without departing from the spirit of the invention.
Claims (8)
1. A method for synthesizing chiral 3-fluoro-1-azabicyclo [2,2,1] heptane is characterized in that N-tert-butyloxycarbonyl-3-fluoro-4-piperidone is used as a raw material, and the synthesis of 4 novel chiral 3-fluoro-1-azabicyclo [2,2,1] heptane isomers is realized through five-step reaction and chiral supercritical fluid chromatographic separation; the method specifically comprises the following steps: the first step is that N-tert-butyloxycarbonyl-3-fluoro-4-piperidone, ylide reagent and alkali are subjected to Wittig reaction to convert the carbon-oxygen double bond of carbonyl into carbon-carbon double bond; secondly, adding borane complex, hydrogen peroxide and alkali into the compound II generated in the first step to perform hydroboration oxidation reaction with carbon-carbon double bonds, so as to change the double bonds of the compound II into hydroxymethyl; the third step is to use a reagent M to convert hydroxyl into an isomer mixture obtained by easily-leaving-OTs group under the condition of alkali action, separate the isomer mixture by high performance liquid chromatography to obtain two racemic mixtures IVa and IVb, and then use chiral supercritical fluid chromatography to split the racemic mixtures to obtain two pairs of enantiomers Va, Vb, Vc and Vd;
the fourth step of reaction is that after a t-butyloxycarbonyl protecting group Boc on an N atom is removed from Va, Vb, Vc or Vd under an acidic condition, a compound VIa, VIb, VIc or VId is obtained; the fifth step is that nucleophilic substitution ring closing reaction is carried out under the alkaline condition, and 4 new chiral 3-fluoro-1-azabicyclo [2,2,1] heptane isomers VIIa and VIIb, VIIc and VIId are obtained after extraction, solvent removal and concentration.
2. A method of synthesizing chiral 3-fluoro-1-azabicyclo [2,2,1] as defined in claim 1]A process for producing heptane, characterized in that the ylide reagent for the first reaction from N-t-butoxycarbonyl-3-fluoro-4-piperidone to the compound 2 is methyl triphenyl phosphonium chloride, methyl triphenyl phosphonium bromide or methyl triphenyl phosphonium iodide, and the base is methyl triphenyl phosphonium chloride, methyl triphenyl phosphonium bromide or methyl triphenyl phosphonium iodidet-BuONa、t-BuOK, pyridine, KOH, NaOH or K 2 CO 3 。
3. A method of synthesizing chiral 3-fluoro-1-azabicyclo [2,2,1] as defined in claim 1]A process for preparing heptane, characterized in that the borane complex from compound II to compound III of the second reaction stage comprises borane dimethyl sulfide complex, borane tetrahydrofuran complex, borane ammonia complex or borane trimethylamine complex, and the base ist-BuONa、t-BuOK, pyridine, KOH, NaOH or K 2 CO 3 。
4. A method of synthesizing chiral 3-fluoro-1-azabicyclo [2,2,1] as defined in claim 1]A heptane process, characterized in that, in the third step, the reagent M for converting the hydroxyl group into a readily leaving group is p-toluenesulfonyl chloride, methanesulfonyl chloride or trifluoromethanesulfonic anhydride; the base ist-BuONa、t-BuOK, pyridine, KOH, NaOH or K 2 CO 3 。
5. The method for synthesizing chiral 3-fluoro-1-azabicyclo [2,2,1] heptane as claimed in claim 1 wherein the acid from compound Va, Vb, Vc or Vd to compound VIa, VIb, VIc or VId in the fourth reaction step is formic acid, acetic acid, hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, oxalic acid, sulfuric acid, trifluoromethanesulfonic acid, nitric acid or phosphoric acid.
6. A method of synthesizing chiral 3-fluoro-1-azabicyclo [2,2,1] as defined in claim 1]A process for producing heptane, characterized in that in the fifth step, the base reacting the compound VIa, VIb, VIc or VId to the target product VIIa, VIIb, VIIc or VIId ist-BuONa、t-BuOK, pyridine, KOH, NaOH or K 2 CO 3 。
7. The method for synthesizing chiral 3-fluoro-1-azabicyclo [2,2,1] heptane as claimed in claim 1, wherein the solvent used in the first to fifth reaction steps is selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, azomethylpyrrolidone, dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, 1, 4-dioxane, acetonitrile, diethyl ether, ethylene glycol dimethyl ether and tetrahydrofuran.
8. A method of synthesizing chiral 3-fluoro-1-azabicyclo [2,2,1] as defined in claim 1]The heptane method is characterized in that the reaction temperature in the five-step reaction is 0-100 o And C, the reaction time is 1-48 h.
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