CN114105860A - Catalytic asymmetric synthesis method and application of chiral oxindole spiro-analogue - Google Patents
Catalytic asymmetric synthesis method and application of chiral oxindole spiro-analogue Download PDFInfo
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Abstract
Five-membered and six-membered carbocyclic chiral oxindole spiro frameworks are widely present in active natural products and drug molecules, and development of efficient synthetic methods for such chiral spiro compounds and analogues thereof will promote development of new drugs. The invention adopts cheap and easily obtained indolone and an amphiphilic alkylation reagent as raw materials, develops novel and efficient [4+1] and [5+1] cyclization reactions under the condition of asymmetric phase transfer catalysis, thereby realizing the universal synthesis for rapidly constructing the chiral oxindole spiro containing five-membered carbocycle and six-membered carbocycle in one step and realizing the one-step synthesis of the key chiral spiro intermediate of the drug ubrogetant. The method has the advantages of mild reaction conditions, simple process, no need of anhydrous and anaerobic operation to obtain the target compound, low requirement on production equipment, wide application range of the substrate and extremely high industrial application value.
Description
Technical Field
The invention belongs to the field of organic synthesis methodology, and particularly relates to a method for preparing chiral five-membered and six-membered carbocyclic oxoindole spiro compounds and analogues thereof, and a novel method is applied to synthesis of key intermediates of a medicament ubrogetant.
Background
Five-membered and six-membered carbocyclic chiral oxindole spiro frameworks are widely existed in active natural products and drug molecules, and have important drug development value. For example, paraherquamide a, a metabolite isolated from penicillium sp, which contains a five-membered carbocyclic oxoindole spiro core backbone, exhibits good antiparasitic activity (nat. caltal. 2020,3, 497-506.); clinical medicine Satavaptan for improving ascites due to cirrhosis of patient comprises six-membered carbocyclic ring of oxoindole spiro core skeleton (Nature Clinical Practice Gastroenterology)&Hepatology 2008,5,534.). In particular, the drug ubrogetant (ubralvety) approved by the U.S. Food and Drug Administration (FDA) for the treatment of migraine in adults was marketed in 2019TM) Also comprising a spiro core structure of 7-aza-indol-2-one (Drugs 2020,80, 323-328). In view of this, the development of the efficient synthesis method of the chiral oxindole spiro compound and the analogues thereof not only has important scientific research value, but also has potential industrial application value.
Structurally, chiral oxindole spiro compounds are a class of compounds with high tensile properties. In particular, the molecule contains a quaternary carbon center with larger steric hindrance (namely, four different substituents are connected to the carbon atom of the quaternary carbon center), so how to construct the quaternary carbon chiral center with high stereoselectivity is a very challenging task in the field of catalytic asymmetry at present. In the literature, a few catalytic asymmetric methods for constructing chiral oxoindole spiro-skeleton have been reported.
In 2010, Gong topic group (org. Lett.2010,12,1008-1011.) utilizes a bifunctional catalyst of chiral tertiary amine urea to realize the [4+2] cyclization reaction of 3-methylene oxoindole, and a series of chiral indole spiro compounds with six-membered rings are prepared, wherein the yield is up to 97%, and the ee value is up to 98%.
In 2011, a Barbas subject group (J.Am.chem.Soc.2011,133,4672-4675.) takes (R, R) -Ph-BPE as a catalyst, so that the catalytic asymmetric [3+2] cycloaddition reaction between 3-methylene indolone and Morita-Baylis-Hillman reagent is realized, a series of five-membered carbocyclic chiral indole spiro products are prepared, the yield is up to 91%, and the ee value is up to 99%.
In 2014, the moraxedo company (Angew. chem., int. Ed.2014,53, 8375-8378) developed a bis-quaternary ammonium salt phase transfer catalyst derived from cinchona alkaloid, which can effectively catalyze the intramolecular asymmetric alkylation reaction of 3-benzyl oxindole oxide to obtain the chiral oxindole spiro analog, wherein the yield is up to 99%, and the ee value is up to 96%.
In 2018, the You topic group (Angew. chem., int. Ed.2018,57,2653-2656.) utilizes chiral phosphoric acid as a catalyst to realize the catalytic asymmetric dearomatization reaction of the indolinone compound, so that a plurality of high enantioselectivity indoline spiro compounds are obtained, the yield is 98% at most, and the ee value is 97% at most.
In addition, there is little report in the literature on the synthesis of the drug molecule ubrogenatant. In 2012, the mshonto company filed a patent WO2012064910, disclosing a synthetic route to ubrogenant chiral oxindole spiro key intermediates. The method takes pyridine-2, 3-dicarboxylic acid as a raw material, and obtains the bis-OMs substituted pyridinium bromide after esterification, bromination, reduction and methylsulfonyl protection. And then, carrying out double alkylation, coupling, deprotection and ester hydrolysis reaction on the bromide and a pyridine amide raw material protected by 2- (trimethylsilyl) ethoxymethyl SEM) in sequence to finally obtain a key chiral spiro intermediate of the ubrogenatant medicament. It is worth pointing out that the preparation of the chiral intermediate is achieved by a method of chiral resolution.
In 2017, another synthetic route for ubrogenant drugs was developed by msandong (org. process res.dev.2017,21, 1851-. The new route takes 2, 3-dibromo-5 chloropyridine as an initial raw material, and obtains a key chiral spiro intermediate of the ubrogenant drug through eleven steps of two-step formalization reduction, hydroxyl protection and 7-aza-indole-2-ketone condensation, sodium borohydride reduction, hydroxyl deprotection and chlorination, and finally intramolecular cyclization reaction and carbonylation reaction through a phase transfer catalyst.
In conclusion, although the methods can realize the synthesis of five-membered and six-membered carbocyclic chiral oxindole spiro rings, the methods still have some defects:
(1) the raw materials involved in the above reactions have complex structures, long synthesis routes and high preparation cost;
(2) the chiral ligand involved in the above reaction is difficult to prepare, which is not beneficial to large-scale production;
(3) the method is suitable for synthesizing single five-membered or six-membered chiral spiro compounds, and unified and universal synthesis of two important spiro structural compounds cannot be realized.
(4) The synthesis route of the drug ubrogetant key chiral spiro intermediate is long, and the chiral intermediate is prepared by adopting a chiral resolution method, so that the raw material utilization rate is extremely low, and the cost is high.
Disclosure of Invention
Aiming at the limitation of the synthesis method, the invention adopts cheap and easily-obtained indolone and an amphiphilic alkylation reagent as raw materials, develops novel and efficient [4+1] and [5+1] cyclization reaction under the condition of asymmetric phase transfer catalysis, thereby realizing the universal synthesis for rapidly constructing the chiral oxindole spiro containing five-membered and six-membered carbocycle in one step and realizing the one-step synthesis of the key chiral spiro intermediate of the drug ubrogenatant.
The method has mild conditions and simple operation, does not need strict anhydrous and oxygen-free operation, and does not need noble metal or expensive ligand to participate, and the five-membered and six-membered carbocyclic chiral indole spiro compound and the drug ubrogetant key intermediate can be obtained with high yield and high enantioselectivity. In addition, the method has wide substrate application range and high product application value.
The invention provides a novel general synthetic method for preparing five-membered and six-membered chiral spiro compounds by catalyzing asymmetric [4+1] and [5+1] cyclization reactions, which has the following reaction formula:
wherein a may be a phenyl ring, furan, thiophene, pyrazole, imidazole, pyridine, pyrazine, pyridazine, pyrimidine, naphthalene ring, and a may be unsubstituted or optionally substituted with one or more substituents independently selected from: alkyl (which includes but is not limited to methyl, ethyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, benzyl, cyclohexyl, etc.), alkoxy (which includes but is not limited to methoxy, ethoxy, etc.), aryl (which includes but is not limited to phenyl, alkoxyphenyl, 3, 5-dialkoxyphenyl, 2, 6-dialkoxyphenyl, alkylphenyl 3, 5-dialkylphenyl, 2, 6-dialkylphenyl, halophenyl, 3, 5-dihalophenyl, 2, 6-dihalophenyl, etc.), halogen (fluorine, chlorine, bromine, iodine, etc.), alkoxycarbonyl (which includes but is not limited to methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl, etc.), cyano, trifluoromethyl, nitro, etc.
Wherein B may be a phenyl ring, furan, thiophene, pyrazole, imidazole, pyridine, pyrazine, pyridazine, pyrimidine, naphthalene ring, and B may be unsubstituted or optionally substituted with one or more substituents independently selected from: alkyl (which includes but is not limited to methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, benzyl, cyclohexyl, etc.), alkoxy (which includes but is not limited to methoxy, ethoxy, etc.), aryl (which includes but is not limited to phenyl, alkoxyphenyl, 3, 5-dialkoxyphenyl, 2, 6-dialkoxyphenyl, alkylphenyl, 3, 5-dialkylphenyl, 2, 6-dialkylphenyl, halophenyl, 3, 5-dihalophenyl, 2, 6-dihalophenyl, etc.), halogen (fluorine, chlorine, bromine, iodine, etc.), alkoxycarbonyl (which includes but is not limited to methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, etc.), cyano, trifluoromethyl, nitro, etc.
Wherein R is1As the protecting group, there may be mentioned an alkoxycarbonyl group (which includes, but is not limited to, a protecting group such as a t-butyloxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), a methoxycarbonyl group, an ethoxycarbonyl group, an adamantyloxycarbonyl group, a 2,2, 2-trichloroethoxycarbonyl group Troc); alkyl (such groups include, but are not limited to, methyl, ethyl, isopropyl, tert-butyl, benzyl (Bn), p-methoxybenzyl (PMB), p-methylbenzyl, p-bromobenzyl, 2, 4-dimethoxybenzyl, and the like); acyl (which includes but is not limited to acetyl (Ac), trifluoroacetyl, pivaloyl chloride, benzoyl (Bz), p-methylbenzoyl, p-bromobenzoyl, and the like); sulfonyl (such groups include, but are not limited to, methanesulfonyl (Ms), trifluoromethanesulfonyl (Tf), benzenesulfonyl, p-methylbenzenesulfonyl (Ts), p-nitrobenzenesulfonyl (Ns), o-nitrobenzenesulfonyl, p-trifluoromethylbenzenesulfonyl, and the like). For general description and instructions for use of protecting groups, see references: greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1991.
Wherein R is2And R3There may be alkyl groups (such groups include, but are not limited to, methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, benzyl, cyclohexyl, etc.), aryl groups (such groups include, but are not limited to, phenyl, alkoxyphenyl, 3, 5-dialkoxyphenyl, 2, 6-dialkoxyphenyl, alkylphenyl, 3, 5-dialkylphenyl, 2, 6-dialkylphenyl, halophenyl, 3, 5-dihalophenyl, 2, 6-dihalophenyl, etc.), halogens (fluorine, chlorine, bromine, iodine, etc.).
Wherein X1And X2For a leaving group, "leaving group" refers to a group well known in the art, see for example Advanced Organic Chemistry, jeri macch, 5 th edition, 351-357, John willi father publishing company (John Wiley and Sons), new york (n.y). The leaving group includes, but is not limited to, halogen, sulfonyl, optionallySubstituted alkylsulfonyl, optionally substituted arylsulfonyl, acyl, and the like. Examples of suitable leaving groups include chloro, bromo, iodo, acetyl, methanesulfonyl, isopropylsulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, toluenesulfonyl, p-nitrophenylsulfonyl, o-nitrobenzenesulfonyl and like substituents.
The technical scheme comprises the following operations in real time:
placing the reaction substrate and the phase transfer catalyst in a reaction tube, adding a certain amount of proper solvent, placing the reaction tube at a certain temperature, adding alkali at the temperature for reaction, and tracking and monitoring by Thin Layer Chromatography (TLC). After the reaction is completed, adding saturated ammonium chloride solution, and extracting the aqueous solution with ethyl acetate. Combining the extracts, removing the ethyl acetate solvent, separating and purifying the residue by silica gel column chromatography or recrystallization to obtain the product.
In this reaction case, the compound (2 or 3): nucleophilic substrate (1): the molar ratio of the base may be (1-2) to (1-10), and the optimum molar ratio is 1.0:1.2:5 or 1.0:1.2: 3.
In this reaction case, the reaction catalyst is a phase transfer catalyst, and the catalyst structure is as follows:
wherein R is4Hydrogen, alkoxy (which includes but is not limited to methoxy, ethoxy, isopropoxybenzene, tert-butoxy, benzyloxy, and the like), aryl (which includes but is not limited to phenyl, alkoxyphenyl, 3, 5-dialkoxyphenyl, 2, 6-dialkoxyphenyl, alkylphenyl, 3, 5-dialkylphenyl, 2, 6-dialkylphenyl, halophenyl, 3, 5-dihalophenyl, 2, 6-dihalophenyl, 3,4, 5-trihalophenyl, and the like).
Wherein R is5Hydrogen, alkyl (which includes but is not limited to methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, benzyl, cyclohexyl, etc.), allyl (which may optionally be substituted with one or more substituents)Substituted with one substituent independently selected from: hydrogen, halogen, alkyl, alkoxy, etc.), acyl (which includes, but is not limited to, benzoyl, alkylbenzoyl, 3, 5-dialkylbenzoyl, 2,4, 6-trialkylbenzoyl, halobenzoyl, 1-naphthoyl, 2-naphthoyl, pivaloyl, adamantanoyl, etc.), silyl (which includes, but is not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, etc.).
Wherein R is6And are substituents such as hydrogen, alkyl (which includes but is not limited to methyl, ethyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, benzyl, cyclohexyl, and the like), alkenyl (which may be optionally substituted with one or more substituents independently selected from hydrogen, halogen, alkyl, alkoxy, phenyl, and the like), and the like.
Wherein R is7Hydrogen, alkyl (which includes but is not limited to methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, benzyl, cyclohexyl, etc.), aryl (which includes but is not limited to phenyl, alkoxyphenyl, 3, 5-dialkoxyphenyl, 2, 6-dialkoxyphenyl, alkylphenyl, 3, 5-dialkylphenyl, 2, 6-dialkylphenyl, halophenyl, 3, 5-dihalophenyl, 2, 6-dihalophenyl, 3,4, 5-trihalophenyl, etc.).
Wherein R is8，R9May be hydrogen, alkyl (which includes but is not limited to methyl, ethyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, benzyl, cyclohexyl, etc.), alkoxy (which includes but is not limited to methoxy, ethoxy, isopropoxybenzene, t-butoxy, benzyloxy, etc.), alkoxycarbonyl (which includes but is not limited to t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methoxycarbonyl, ethoxycarbonyl, 9-fluorenylmethyl chloroformate (Fmoc), 2,2, 2-trichloroethoxycarbonyl Troc, etc.); alkyl (such groups include, but are not limited to, methyl, ethyl, isopropyl, tert-butyl, benzyl (Bn), p-methoxybenzyl (PMB), p-methylbenzyl, and the like); acyl radical(such groups include, but are not limited to, acetyl (Ac), trifluoroacetyl, pivaloyl, benzoyl (Bz), p-methylbenzoyl, and the like); sulfonyl (such groups include, but are not limited to, methanesulfonyl (Ms), trifluoromethanesulfonyl (Tf), benzenesulfonyl, p-methylbenzenesulfonyl (Ts), p-nitrobenzenesulfonyl (Ns), o-nitrobenzenesulfonyl, p-trifluoromethylbenzenesulfonyl, and the like), phosphonoxy (including, but not limited to, dimethoxyphosphono, diethoxyphosphonyl, diisopropyloxyphosphonyl, di-tert-butoxyphosphonyl, dibenzyloxyphosphonyl, and the like).
Wherein R is10，R11Hydrogen, alkyl (which includes but is not limited to methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, benzyl, cyclohexyl, etc.), aryl (which includes but is not limited to phenyl, alkoxyphenyl, 3, 5-dialkoxyphenyl, 2, 6-dialkoxyphenyl, alkylphenyl, 3, 5-dialkylphenyl, 2, 6-dialkylphenyl, halophenyl, 3, 5-dihalophenyl, 2, 6-dihalophenyl, 3,4, 5-trihalophenyl, etc.).
Wherein Ar is an aryl group (such groups include, but are not limited to, phenyl, p-alkoxyphenyl, o-alkoxyphenyl, m-alkoxyphenyl, 3, 5-dialkoxyphenyl, 2, 6-dialkoxyphenyl, p-alkylphenyl, o-alkylphenyl, m-alkylphenyl, 3, 5-dialkylphenyl, 2, 6-dialkylphenyl, p-halophenyl, o-halophenyl, m-halophenyl, 3, 5-dihalophenyl, 2, 6-dihalophenyl, 3,4, 5-trihalophenyl, 3, 5-diphenyl-4-dimethyl-t-butylsiloxyphenyl, 1-naphthyl, 2-phenyl-1-naphthyl, 3-phenyl-1-naphthyl, 7-phenyl-1-naphthyl, 2-naphthyl, 9-anthryl, etc.), 9-phenanthryl, pyrenyl, and the like).
Wherein X3The anion is halogen anion (including anion such as fluorine, chlorine, bromine, iodine, etc.), inorganic acid anion (the group includes but is not limited to sulfate anion, bisulfate anion, phosphate anion, nitrate anion, etc.), organic acid anion (the group includes but is not limited to tetrafluoroborate anion, benzenesulfonic acid anion, benzoic acid anion, tartaric acid anion, etc.).
Among them, the most preferable catalystIs R4、R7、R8And R10Is hydrogen, R9Is tert-butyloxycarbonyl (Boc), R11Is isopropyl, X3Is a bromine anion, Ar is 9-anthracenyl and R4Is methoxy, R7、R8And R10Is hydrogen, R9Is tert-butyloxycarbonyl (Boc), R11Is isopropyl, X3Is a bromine anion, Ar is 9-phenanthryl, and the structure of the compound is shown as follows:
in this reaction case, the molar percentage of the catalyst is 1 mol% to 50 mol%, with the optimum molar percentage being 10 mol%.
In the case of this reaction, the base used is an alkaline aqueous solution or a solid base, and may be sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium hydrogen carbonate, potassium phosphate, dipotassium hydrogen phosphate, or the like, with cesium hydroxide aqueous solution being the most preferable base.
In this reaction, when the alkali used is an aqueous alkali, the aqueous alkali has a mass concentration of 5% to 95%, and the most preferable mass concentration is 80%.
In this reaction case, the organic solvent used may be 1, 2-dichloroethane, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1, 4-dioxane, diethyl ether, t-butyl methyl ether, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, acetone, acetonitrile, toluene, m-xylene, o-xylene, mesitylene, fluorobenzene, chlorobenzene, bromobenzene, ethyl acetate, or the like, and may be any two mixed solvents thereof, with the most preferable solvent being a mixed solvent of toluene and dichloromethane, and toluene: dichloromethane ═ 5: 1.
In the case of this reaction, the substrate concentrations were: 0.01-2.0 mol/L, and the optimal concentration is 0.05 mol/L.
Under the reaction condition, the reaction temperature is-78-45 ℃, and the optimal temperature is-60 ℃.
In the case of this reaction, the eluents used for the separation and purification by silica gel column chromatography are a mixture of ethyl acetate and petroleum ether, petroleum ether: the ethyl acetate ratio is between 100:1 and 120: 1.
In summary, the invention has the following advantages:
1. the method has the advantages of mild reaction conditions, simple process, no need of strict control of anhydrous, oxygen-free and the like, low requirement on production equipment, wide range of applicable substrates of a reaction route, high yield, suitability for large-scale preparation of target products and higher industrial application value.
2. The method can be used for synthesizing a key chiral spiro intermediate of the drug ubrogetant, and has the advantages of cheap and easily-obtained substrate raw materials, short synthesis steps and preparation cost saving; the phase transfer catalyst has simple synthesis method, can be used for large-scale synthesis, and has higher application value.
Detailed Description
The monitoring method in any embodiment of the invention is: thin Layer Chromatography (TLC). The structural confirmation technical means are all common technical means known to those skilled in the art, such as nuclear magnetic resonance technology, high resolution mass spectrometry and the like.
Example 1:
preparation of Compound 5a
In a 10mL reaction tube, indolone substrate 1a (56mg,0.24mmol,1.2equiv), diiodo compound 3a (64mg,0.2mmol,1.0equiv), phase transfer catalyst 8a (15mg,0.02mmol, 0.1equiv) were added in this order, followed by dissolution in toluene/dichloromethane (4mL/0.8 mL). An 80% CsOH aqueous solution (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 34 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to give chiral compound 5a (40mg) in 67% yield.
A pale yellow oil.1H NMR(400MHz,CDCl3)δ7.84(d,J＝8.2Hz,1H),7.29(d,J＝ 8.0Hz,1H),7.22(d,J＝7.4Hz,1H),7.13(t,J＝7.5Hz,1H),5.05(s,1H),5.02(s, 1H),2.96(d,J＝16.1Hz,1H),2.90–2.78(m,1H),2.75–2.61(m,1H),2.51(d,J＝ 16.1Hz,1H),2.39–2.27(m,1H),2.05–1.88(m,1H),1.65(s,9H).13C NMR(100 MHz,CDCl3)δ178.91,149.61,149.35,138.40,133.89,127.86,124.55,122.31, 114.80,107.50,84.26,53.78,44.84,38.55,31.43,28.10.HRMS(ESI)m/z Calcd for [C18H21NNaO3,M+Na]+:322.14136,Found:322.14060.
Optical rotation value [ alpha ]]D 25＝-35.0(c＝0.25,CHCl3) (ii) a ee value: 90% (HPLC conditions: xylonite IC column, n-hexane/isopropanol 90:10, flow rate 1mL/min, detection wavelength 220 nm).
Example 2:
preparation of Compound 5b
In a 10mL reaction tube, indolone substrate 1b (59mg,0.24mmol,1.2equiv), diiodo compound 3a (64mg,0.2mmol,1.0equiv), phase transfer catalyst 8a (15mg,0.02mmol, 0.1equiv) were added in this order, followed by dissolution in toluene/dichloromethane (4mL/0.8 mL). An 80% CsOH aqueous solution (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 39 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to give chiral compound 5b (44mg) in 70% yield.
A pale yellow oil.1H NMR(400MHz,CDCl3)δ7.72(s,1H),7.09(d,J＝7.6Hz,1H), 6.95(d,J＝7.6Hz,1H),5.04(s,1H),5.01(s,1H),2.93(d,J＝16.0Hz,1H),2.89– 2.76(m,1H),2.73–2.60(m,1H),2.48(d,J＝15.9Hz,1H),2.38(s,3H),2.35–2.26 (m,1H),2.00–1.88(m,1H),1.65(s,9H).13C NMR(100MHz,CDCl3)δ179.19, 149.68,149.51,138.40,137.89,130.89,125.08,121.98,115.54,107.41,84.17,53.59, 44.88,38.57,31.39,28.07,27.38,21.87.HRMS(ESI)m/z Calcd for[C19H23NNaO3, M+Na]+:336.15701,Found:336.15561.
Optical rotation value [ alpha ]]D 25＝-30(c＝0.27,CHCl3) (ii) a ee value: 88% (HPLC conditions: xylonite IC-H column, n-hexane/isopropanol 90:10, flow rate 1mL/min, detection wavelength 220 nm).
Example 3:
preparation of Compound 5c
In a 10mL reaction tube, indolone substrate 1c (63mg,0.24mmol,1.2equiv), diiodo compound 3a (64mg,0.2mmol,1.0equiv), phase transfer catalyst 8a (15mg,0.02mmol, 0.1equiv) were added in this order, followed by dissolution in toluene/dichloromethane (4mL/0.8 mL). An 80% CsOH aqueous solution (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 36 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to give chiral compound 5c (43mg) in 65% yield.
A white solid.1H NMR(400MHz,CDCl3)δ7.76(d,J＝9.7Hz,1H),6.84–6.72 (m,2H),5.05(s,1H),5.02(s,1H),3.79(s,3H),2.95(d,J＝16.0Hz,1H),2.90–2.77 (m,1H),2.73–2.51(m,1H),2.49(d,J＝16.0Hz,1H),2.39–2.26(m,1H),2.02– 1.89(m,1H),1.64(s,9H).13C NMR(100MHz,CDCl3)δ178.93,156.89,149.49, 135.25,131.72,115.61,111.91,109.08,107.64,84.07,55.57,54.02,44.81,38.48, 31.30,28.08.HRMS(ESI)m/z Calcd for[C19H23NNaO4,M+Na]+:352.15193, Found:352.15065.
Optical rotation value [ alpha ]]D 25＝-51.6(c＝0.24,CHCl3) (ii) a ee value: 92% (HPLC conditions: xylonite IC-H column, n-hexane/isopropanol 90:10, flow rate 1mL/min, detection wavelength 220 nm).
Example 4:
preparation of Compound 5d
In a 10mL reaction tube, indolone substrate 1d (69mg,0.24mmol,1.2equiv), diiodo compound 3a (64mg,0.2mmol,1.0equiv), phase transfer catalyst 8a (15mg,0.02mmol, 0.1equiv) were added in this order, followed by dissolution in toluene/dichloromethane (4mL/0.8 mL). An 80% CsOH aqueous solution (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 8 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to give chiral compound 5d (46mg) in 65% yield.
A white solid.1H NMR(400MHz,CDCl3)δ7.73(d,J＝8.5Hz,1H),7.30(d,J＝ 8.5Hz,1H),7.22(s,1H),5.06(s,1H),5.02(s,1H),2.94(d,J＝16.1Hz,1H),2.89– 2.80(m,1H),2.74–2.61(m,1H),2.52(d,J＝16.1Hz,1H),2.40–2.24(m,1H), 2.04–1.92(m,1H),1.64(s,9H),1.30(s,9H).13C NMR(100MHz,CDCl3)δ179.37, 149.82,149.29,147.78,135.94,133.35,124.68,119.10,114.28,107.31,84.07,53.92, 44.79,38.56,34.51,31.49,31.41,28.07.HRMS(ESI)m/z Calcd for[C22H29NNaO3, M+Na]+:378.20396,Found:378.20256.
Optical rotation value [ alpha ]]D 25＝-40.5(c＝0.24,CHCl3) (ii) a ee value: 94% (HPLC conditions: xylonite IC-H column, n-hexane/isopropanol 90:10, flow rate 1mL/min, detection wavelength 220 nm).
Example 5:
preparation of Compound 5e
In a 10mL reaction tube, indolone substrate 1e (64mg,0.24mmol,1.2equiv), diiodo compound 3a (64mg,0.2mmol,1.0equiv), phase transfer catalyst 8a (15mg,0.02mmol, 0.1equiv) were added in this order, followed by dissolution in toluene/dichloromethane (4mL/0.8 mL). An 80% CsOH aqueous solution (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 18 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to give chiral compound 5e (50mg) in 75% yield.
A white solid.1H NMR(400MHz,CDCl3)δ7.80(d,J＝8.7Hz,1H),7.29–7.22 (m,1H),7.17(d,J＝2.3Hz,1H),5.07(s,1H),5.04(s,1H),2.95(d,J＝16.0Hz,1H), 2.89–2.78(m,1H),2.73–2.60(m,1H),2.49(d,J＝16.0Hz,1H),2.39–2.27(m, 1H),2.01–1.89(m,1H),1.63(s,9H).13C NMR(100MHz,CDCl3)δ178.08, 149.12,148.86,136.89,135.57,129.92,127.83,122.57,116.05,108.07,84.59,53.78, 44.71,38.41,31.20,28.02.HRMS(ESI)m/z Calcd for[C18H20ClNNaO3,M+Na]+: 356.10239,Found:356.10098.
Optical rotation value [ alpha ]]D 25＝-62.4(c＝0.16,CHCl3) (ii) a ee value: 93% (HPLC conditions: xylonite OD-H column, n-hexane/isopropanol 98:2, flow rate 1mL/min, detection wavelength 220 nm).
Example 6:
preparation of Compound 5f
In a 10mL reaction tube, indolone substrate 1f (59mg,0.24mmol,1.2equiv), diiodo compound 3a (64mg,0.2mmol,1.0equiv), phase transfer catalyst 8a (15mg,0.02mmol, 0.1equiv) were added in this order, followed by dissolution in toluene/dichloromethane (4mL/0.8 mL). An 80% CsOH aqueous solution (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 25 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to give chiral compound 5f (41mg) in 65% yield.
A colorless oil.1H NMR(400MHz,CDCl3)δ7.72(s,1H),7.09(d,J＝7.6Hz,1H), 6.94(d,J＝7.6Hz,1H),5.04(s,1H),5.01(s,1H),2.93(d,J＝16.0Hz,1H),2.89– 2.78(m,1H),2.73–2.59(m,1H),2.48(d,J＝16.0Hz,1H),2.38(s,3H),2.35–2.25 (m,1H),2.00–1.87(m,1H),1.65(s,9H).13C NMR(100MHz,CDCl3)δ179.17, 149.65,149.49,138.37,137.86,130.86,125.06,121.96,115.52,107.40,84.15,53.57, 44.86,38.55,31.36,28.05,21.85.HRMS(ESI)m/z Calcd for[C19H23NNaO3,M+ Na]+:336.15701,Found:336.15627.
Optical rotation value [ alpha ]]D 25＝-28.4(c＝0.25,CHCl3) (ii) a ee value: 87% (HPLC conditions: xylonite IC-H column, n-hexane/isopropanol 90:10, flow rate 1mL/min, detection wavelength 220 nm).
Example 7:
preparation of Compound 5g
In a 10mL reaction tube, 1g (63mg,0.24mmol,1.2equiv) of indolone substrate, diiodo compound 3a (64mg,0.2mmol,1.0equiv), phase transfer catalyst 8a (15mg,0.02mmol, 0.1equiv) were added in this order, followed by dissolution in toluene/dichloromethane (4mL/0.8 mL). 80% CsOH in water (6) at-60 deg.C5 μ L,1.0mmol,5.0equiv) was added to the reaction tube, and then reacted at that temperature for about 45 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to obtain 5g (40mg) of the chiral compound in 61% yield.
A pale yellow solid.1H NMR(400MHz,CDCl3)δ7.50(s,1H),7.10(d,J＝8.3Hz, 1H),6.67(d,J＝8.2Hz,1H),5.03(s,1H),5.00(s,1H),3.82(s,3H),2.93(d,J＝16.1 Hz,1H),2.88–2.77(m,1H),2.75–2.59(m,1H),2.46(d,J＝16.1Hz,1H),2.37– 2.22(m,1H),1.99–1.86(m,1H),1.65(s,9H).13C NMR(100MHz,CDCl3)δ 179.37,159.55,149.69,149.30,139.38,125.79,122.81,110.06,107.38,101.65, 84.24,55.53,53.38,44.96,38.63,31.37,28.09.HRMS(ESI)m/z Calcd for [C19H23NNaO4,M+Na]+:352.15193,Found:352.15085.
Optical rotation value [ alpha ]]D 25＝-35.2(c＝0.25,CHCl3) (ii) a ee value: 90% (HPLC conditions: xylonite IC-H column, n-hexane/isopropanol 90:10, flow rate 1mL/min, detection wavelength 220 nm).
Example 8:
preparation of Compound 5h
In a 10mL reaction tube, indolone substrate 1h (60mg,0.24mmol,1.2equiv), diiodo compound 3a (64mg,0.2mmol,1.0equiv), phase transfer catalyst 8a (15mg,0.02mmol, 0.1equiv) and then toluene/dichloromethane (4mL/0.8mL) were added in order to dissolve. An 80% CsOH aqueous solution (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 17 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4Drying, filtering, concentrating to obtain residueThe product was separated and purified by silica gel column chromatography to give chiral compound 5h (45mg) with 71% yield.
A white solid.1H NMR(400MHz,CDCl3)δ7.63(d,J＝10.3Hz,1H),7.20–7.07 (m,1H),6.88–6.77(m,1H),5.05(s,1H),5.02(s,1H),2.94(d,J＝16.0Hz,1H), 2.89–2.75(m,1H),2.72–2.58(m,1H),2.47(d,J＝16.0Hz,1H),2.39–2.22(m, 1H),2.03–1.83(m,1H),1.64(s,9H).13C NMR(100MHz,CDCl3)δ178.69, 162.27(d,J＝243.6Hz),149.21,139.39(d,J＝12.2Hz),129.23,123.14(d,J＝9.5 Hz),111.01(d,J＝22.3Hz),107.76,103.60(d,J＝29.6Hz),84.71,53.43,44.87, 38.51,31.21,28.02.HRMS(ESI)m/z Calcd for[C18H20FNNaO3,M+Na]+: 340.13194,Found:340.13074.
Optical rotation value [ alpha ]]D 25＝-38.3(c＝0.24,CHCl3) (ii) a ee value: 93% (HPLC conditions: xylonite IC-H column, n-hexane/isopropanol 90:10, flow rate 1mL/min, detection wavelength 220 nm).
Example 9:
preparation of Compound 5i
In a 10mL reaction tube, indolone substrate 1a (56mg,0.24mmol,1.2equiv), diiodo compound 3b (70mg,0.2mmol,1.0equiv), phase transfer catalyst 8a (15mg,0.02mmol, 0.1equiv) were added in sequence, followed by dissolution in toluene/dichloromethane (4mL/0.8 mL). An 80% CsOH aqueous solution (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 34 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to give chiral compound 5i (43mg) in 66% yield.
A colorless oil.1H NMR(400MHz,CDCl3)δ7.84(d,J＝8.2Hz,1H),7.33–7.23 (m,1H),7.20–7.07(m,2H),2.83(d,J＝16.0Hz,1H),2.78–2.68(m,1H),2.68– 2.57(m,1H),2.52(d,J＝16.0Hz,1H),2.36–2.20(m,1H),2.01–1.88(m,1H), 1.73(s,3H),1.65(s,9H),1.63(s,3H).13C NMR(100MHz,CDCl3)δ179.13, 149.42,138.37,134.14,132.30,127.69,124.49,124.02,122.26,114.74,84.15,54.17, 42.14,38.50,29.46,28.10,21.33,21.21.HRMS(ESI)m/z Calcd for[C20H25NNaO3, M+Na]+:350.17266,Found:350.17176.
Optical rotation value [ alpha ]]D 25＝-19.6(c＝0.25,CHCl3) (ii) a ee value: 90% (HPLC conditions: xylonite AS column, n-hexane/isopropanol 95:5, flow rate 1mL/min, detection wavelength 220 nm).
Example 10:
preparation of Compound 5j
In a 10mL reaction tube, indolone substrate 1a (56mg,0.24mmol,1.2equiv), diiodo compound 3c (76mg,0.2mmol,1.0equiv), phase transfer catalyst 8a (15mg,0.02mmol, 0.1equiv) were added in this order, followed by dissolution in toluene/dichloromethane (4mL/0.8 mL). An 80% CsOH aqueous solution (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 24 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to give chiral compound 5j (55mg) in 77% yield.
Yellow oil.1H NMR(400MHz,CDCl3)δ7.84(d,J＝8.2Hz,1H),7.35–7.21 (m,2H),7.16–7.01(m,2H),2.85(d,J＝15.9Hz,1H),2.79–2.57(m,2H),2.52(d, J＝15.9Hz,1H),2.36–2.20(m,1H),2.10(q,J＝7.6Hz,2H),2.04–1.87(m,3H), 1.65(s,9H),1.03(t,J＝7.5Hz,3H),0.92(t,J＝7.6Hz,3H).13C NMR(100MHz, CDCl3)δ179.12,149.38,138.26,136.22,134.32,131.74,127.65,124.49,122.30, 114.73,84.19,54.01,41.64,38.24,28.62,28.10,25.76,25.56,12.68,12.48.HRMS (ESI)m/z Calcd for[C22H29NNaO3,M+Na]+:374.1363,Found:374.1351.
Optical rotation value [ alpha ]]D 25＝-17.3(c＝0.25,CHCl3) (ii) a ee value: 94% (HPLC conditions: xylonite IC-H column, n-hexane/isopropanol 95:5, flow rate 1mL/min, detection wavelength 220 nm).
Example 11:
preparation of Compound 5k
In a 10mL reaction tube, indolone substrate 1a (56mg,0.24mmol,1.2equiv), diiodo compound 3d (95mg,0.2mmol,1.0equiv), phase transfer catalyst 8a (15mg,0.02mmol, 0.1equiv) were added in this order, followed by dissolution in toluene/dichloromethane (4mL/0.8 mL). An 80% CsOH aqueous solution (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 34 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to give chiral compound 5k (74mg) in 82% yield.
A pale yellow solid.1H NMR(400MHz,CDCl3)δ7.84(d,J＝7.9Hz,1H),7.40–7.21(m,7H),7.22–7.06(m,3H),3.12(d,J＝16.7Hz,1H),3.06–2.81(m,2H), 2.71(d,J＝16.7Hz,1H),2.44–2.29(m,1H),2.07–1.92(m,1H),1.65(s,9H).13C NMR(100MHz,CDCl3)δ178.68,149.22,142.60,142.36,139.47,138.42,135.57, 133.43,128.97,128.17,128.00,127.89,126.50,126.41,124.55,122.18,114.84, 84.25,53.97,44.38,38.06,31.42,28.05.HRMS(ESI)m/z Calcd for[C30H29NNaO3, M+Na]+:474.20396,Found:474.20187.
Optical rotation value [ alpha ]]D 25＝30.4(c＝0.26,CHCl3) (ii) a ee value: 89% (HPLC conditions: xylonite AD-H column, n-hexane/isopropanol 98:2, flow rate 1mL/min, detection wavelength 220 nm).
Example 12:
preparation of Compound 5l
In a 10mL reaction tube, indolone substrate 1a (56mg,0.24mmol,1.2equiv), diiodo compound 3e (78mg,0.2mmol,1.0equiv), phase transfer catalyst 8a (15mg,0.02mmol, 0.1equiv) were added in sequence, followed by dissolution in toluene/dichloromethane (4mL/0.8 mL). An 80% CsOH aqueous solution (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 34 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to give 5l (46mg) of the chiral compound in 63% yield.
A colorless oil.1H NMR(400MHz,CDCl3)δ7.83(d,J＝8.1Hz,1H),7.30–7.21 (m,1H),7.20–7.06(m,2H),2.82(d,J＝15.9Hz,1H),2.71–2.68(m,1H),2.57– 2.48(m,1H),2.53(d,J＝15.9Hz,1H),2.31–2.20(m,1H),2.20–2.12(m,2H), 2.09–1.98(m,2H),1.97–1.84(m,1H),1.64(s,9H),1.59–1.41(m,6H).13C NMR (100MHz,CDCl3)δ179.11,149.41,138.35,134.33,132.42,128.89,127.65,124.47, 122.32,114.72,84.14,53.93,41.51,38.27,31.86,31.82,28.64,28.11,27.70,27.64, 26.63.HRMS(ESI)m/z Calcd for[C23H29NNaO3,M+Na]+:390.20396,Found: 390.20235.
Optical rotation value [ alpha ]]D 25＝-20.5(c＝0.24,CHCl3) (ii) a ee value: 95% (HPLC conditions: xylonite IC-H column, n-hexane/isopropanol 90:10, flow rate 1mL/min, detection wavelength 220 nm).
Example 13:
preparation of Compound 4a
The indolone substrate 1a (56mg,0.24mmol,1.2equiv), the phase transfer catalyst 8b (16mg,0.02mmol,0.1equiv) and then toluene/dichloromethane (3 mL/0.6 mL) were added in this order to a 10mL reaction tube to dissolve, the diiodo compound 2a (74mg,0.2mmol,1.0equiv) was dissolved in toluene/dichloromethane (1mL/0.2mL) to divide into three portions, and added to the reaction every 5 to 6 hours, and an 80% CsOH aqueous solution (36. mu.L, 1.0mmol,3.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 36 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to give chiral compound 4a (46mg) in 66% yield.
Yellow solid.1H NMR(400MHz,CDCl3)δ7.90(d,J＝7.1Hz,1H),7.32–7.12 (m,4H),7.07(d,J＝7.3Hz,1H),6.98(t,J＝7.5Hz,1H),6.77(d,J＝7.4Hz,1H), 3.40(d,J＝16.3Hz,1H),3.13–2.97(m,2H),2.78(d,J＝16.3Hz,1H),2.37–2.19 (m,1H),1.93–1.84(m,1H),1.67(s,9H).13C NMR(100MHz,CDCl3)δ178.70, 149.44,138.56,135.23,133.59,132.63,129.43,128.65,128.03,126.37,126.28, 124.29,123.59,114.89,84.34,46.99,36.70,31.24,28.13,25.34.HRMS(ESI)m/z Calcd for[C22H23NNaO3,M+Na]+:372.15701,Found:372.15569.
Optical rotation value [ alpha ]]D 25＝33.3(c＝0.25,CHCl3) (ii) a ee value: 89% (HPLC conditions: xylonite IC-H column, n-hexane/isopropanol 90:10, flow rate 1mL/min, detection wavelength 220 nm).
Example 14:
preparation of Compound 4b
The indolone substrate 1i (60mg,0.24mmol,1.2equiv), the phase transfer catalyst 8b (16mg,0.02mmol,0.1equiv) and then toluene/dichloromethane (3 mL/0.6 mL) were added in this order to a 10mL reaction tube to dissolve, the diiodo compound 2a (74mg,0.2mmol,1.0equiv) was dissolved in toluene/dichloromethane (1mL/0.2mL) to divide into three portions, and added to the reaction every 5 to 6 hours, and an 80% CsOH aqueous solution (36. mu.L, 1.0mmol,3.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 36 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to give chiral compound 4b (48mg) in 65% yield.
A colorless oil.1H NMR(400MHz,CDCl3)δ7.89(dd,J＝8.9,4.7Hz,1H),7.25– 7.15(m,3H),7.08(d,J＝7.3Hz,1H),6.97(td,J＝9.0,2.4Hz,1H),6.47(dd,J＝8.1, 2.2Hz,1H),3.40(d,J＝16.3Hz,1H),3.19–2.93(m,1H),2.76(d,J＝16.3Hz,1H), 2.38–2.22(m,1H),1.95–1.80(m,1H),1.66(s,9H).13C NMR(100MHz,CDCl3) δ178.23,159.74(d,J＝243.3Hz),149.37,134.87,134.50(d,J＝2.1Hz),134.32(d, J＝8.2Hz),133.02,129.43,128.72,126.61,126.44,116.09(d,J＝7.8Hz),114.39(d, J＝22.9Hz),111.21(d,J＝24.8Hz),84.53,47.25,36.56,31.11,28.08,25.14. HRMS(ESI)m/z Calcd for[C22H22FNNaO3,M+Na]+:390.14759,Found: 390.14624.
Optical rotation value [ alpha ]]D 25＝54.3(c＝0.27,CHCl3) (ii) a ee value: 91% (HPLC conditions: xylonite OJ-H column, n-hexane/isopropanol 95:5, flow rate 1mL/min, detection wavelength 220 nm).
Example 15:
preparation of Compound 4c
In a 10mL reaction tube, indolone substrate 1f (59mg,0.24mmol,1.2equiv), phase transfer catalyst 8b (16mg,0.02mmol,0.1equiv) and then toluene/dichloromethane (3 mL/0.6 mL) were added in sequence to dissolve, diiodo compound 2a (74mg,0.2mmol,1.0equiv) was dissolved in toluene/dichloromethane (1mL/0.2mL) and divided into three portions, and added to the reaction every 5-6 hours, and 80% CsOH aqueous solution (36. mu.L, 1.0mmol,3.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 36 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to give chiral compound 4c (53mg) in 73% yield.
A colorless oil.1H NMR(400MHz,CDCl3)δ7.78(s,1H),7.24–7.13(m,3H),7.07 (d,J＝7.5Hz,1H),6.80(d,J＝7.7Hz,1H),6.65(d,J＝7.7Hz,1H),3.39(d,J＝ 16.3Hz,1H),3.15–2.97(m,2H),2.76(d,J＝16.3Hz,1H),2.36(s,3H),2.33–2.21 (m,1H),1.91–1.79(m,1H),1.67(s,9H).13C NMR(100MHz,CDCl3)δ178.95, 149.59,138.57,138.05,135.24,133.66,129.65,129.41,128.62,126.29,126.20, 124.80,123.28,115.62,84.23,46.80,36.84,31.27,28.09,25.34,21.81.HRMS(ESI) m/z Calcd for[C23H25NNaO3,M+Na]+:386.17266,Found:386.17163.
Optical rotation value [ alpha ]]D 25＝53.6(c＝0.28,CHCl3) (ii) a ee value: 97% (HPLC conditions: xylonite OD-H column, n-hexane/isopropanol 98:2, flow rate 1mL/min, detection wavelength 220 nm).
Example 16:
preparation of Compound 4d
A10 mL reaction tube was charged with indolone substrate 1a (56mg,0.24mmol,1.2equiv), phase transfer catalyst 8b (16mg,0.02mmol,0.1equiv) in that order, followed by toluene/diMethyl chloride (3 mL/0.6 mL) was dissolved, diiodo compound 2b (86mg,0.2mmol,1.0equiv) was dissolved in toluene/dichloromethane (1mL/0.2mL), divided into three batches, added to the reaction every 5-6 hours, and 80% CsOH aqueous solution (36. mu.L, 1.0mmol,3.0equiv) was added to the reaction tube at-60 ℃ and then reacted at that temperature for about 23 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to give chiral compound 4d (50mg) in 61% yield.
A white solid.1H NMR(400MHz,CDCl3)δ7.89(d,J＝8.2Hz,1H),7.29(d,J＝ 7.7Hz,1H),6.99(t,J＝7.4Hz,1H),6.81(d,J＝7.4Hz,1H),6.70(s,1H),6.54(s, 1H),3.90(s,3H),3.83(s,3H),3.34(d,J＝16.1Hz,1H),3.05–2.88(m,2H),2.68(d, J＝16.1Hz,1H),2.33–2.17(m,1H),1.84(d,J＝13.7Hz,1H),1.66(s,9H).13C NMR(100MHz,CDCl3)δ178.66,149.37,147.57,147.48,138.48,132.42,127.95, 126.79,125.19,124.22,123.62,114.79,111.93,111.26,84.27,55.83,55.79,46.96, 36.20,31.10,28.05,24.91.HRMS(ESI)m/z Calcd for[C24H27NNaO5,M+Na]+: 432.17814,Found:432.17635.
Optical rotation value [ alpha ]]D 25＝41.3(c＝0.24,CHCl3) (ii) a ee value: 93% (HPLC conditions: xylonite IC-H column, n-hexane/isopropanol 70:30, flow rate 1mL/min, detection wavelength 220 nm).
Example 17:
preparation of key chiral spiro intermediate 10 of drug ubrogetant
A10 mL reaction tube was charged with the dibromo compound 2c (58mg,0.2mmol,1.0equiv), the pyridoindolone substrate 1g (56mg,0.24mmol,1.2equiv), the phase transfer catalyst 8a (15mg,0.02mmol, 0.1equiv), toluene/dichloromethane (4mL/0.8mL) in that order, dissolved at-60 deg.CAn 80% CsOH aqueous solution (65. mu.L, 1.0mmol,5.0equiv) was added to the reaction tube at temperature, and then reacted at that temperature for about 27 hours. After completion of the reaction, 2mL of saturated ammonium chloride solution was added, and the aqueous solution was extracted 3 times with 10mL of ethyl acetate. Mixing the extractive solutions, anhydrous Na2SO4After drying, filtration and concentration, the residue was separated and purified by silica gel column chromatography to give chiral compound 4e (36mg) in 50% yield.
The resulting chiral spiro product 4e (36mg,0.1mmol,1.0equiv) was dissolved in DCM (0.2mL), trifluoroacetic acid (54 μ L,0.4mmol,4equiv) was added and the reaction was carried out at room temperature for about 1 hour, TLC monitoring, starting material disappeared, solvent was directly dried and the crude product obtained was directly subjected to the next step, which was dissolved in 0.2mL tetrahydrofuran, 3M hydrochloric acid (1.5mL) was added and the reaction was refluxed overnight, TLC monitoring, after completion of the reaction, solvent was dried by spinning to give the key intermediate product 10(25mg) in 89% yield.
A yellow solid 4e which is a solid,1H NMR(400MHz,CDCl3)δ8.76(s,1H),8.40(dd,J＝5.2,1.7 Hz,1H),7.83(s,1H),7.25–7.18(m,1H),7.03(dd,J＝7.3,5.2Hz,1H),3.80(d,J＝ 17.8Hz,1H),3.69(d,J＝16.8Hz,1H),3.34(d,J＝17.8Hz,1H),3.23(d,J＝16.8 Hz,1H),1.65(s,9H).13C NMR(100MHz,CDCl3)δ176.03,166.25,153.04,152.08, 148.61,147.36,134.92,134.26,129.82,127.03,120.38,116.68,108.51,85.52,51.32, 45.71,41.98,27.97.HRMS(ESI)m/z Calcd for[C20H18N4NaO3,M+Na]+: 385.12711,Found:385.12589.
optical rotation value [ alpha ]]D 25＝3.6(c＝0.2,CHCl3) (ii) a ee value: 89% (HPLC conditions: xylonite AD-H column, n-hexane/isopropanol 80:20, flow rate 1mL/min, detection wavelength 220 nm).
A white solid 10 is present, which is,1H NMR(600MHz,DMSO-d6) δ 11.49(s,1H),8.82(s,1H),8.17 (s,1H),8.09(d, J ═ 5.0Hz,1H),7.65(d, J ═ 7.0Hz,1H), 7.07-6.95 (m,1H), 3.45-3.38 (m,4H). nuclear magnetic data consistent with literature reports (org. process res.dev.2017,21,1851-
It is noted herein that the above-mentioned embodiments illustrate rather than limit the technical solution of the present invention, and although the present invention has been described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the present invention.
Claims (8)
1. A catalytic asymmetric synthesis method and application of chiral oxindole spiro-analogue are disclosed, wherein the reaction formula is as follows:
wherein:
a may be a phenyl ring, furan, thiophene, pyrazole, imidazole, pyridine, pyrazine, pyridazine, pyrimidine, naphthalene ring, and a may be unsubstituted or optionally substituted with one or more substituents independently selected from: alkyl (which includes but is not limited to methyl, ethyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, benzyl, cyclohexyl, etc.), alkoxy (which includes but is not limited to methoxy, ethoxy, etc.), aryl (which includes but is not limited to phenyl, alkoxyphenyl, 3, 5-dialkoxyphenyl, 2, 6-dialkoxyphenyl, alkylphenyl 3, 5-dialkylphenyl, 2, 6-dialkylphenyl, halophenyl, 3, 5-dihalophenyl, 2, 6-dihalophenyl, etc.), halogen (fluorine, chlorine, bromine, iodine, etc.), alkoxycarbonyl (which includes but is not limited to methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl, etc.), cyano, trifluoromethyl, nitro, etc.
B may be a phenyl ring, furan, thiophene, pyrazole, imidazole, pyridine, pyrazine, pyridazine, pyrimidine, naphthalene ring, and B may be unsubstituted or optionally substituted with one or more substituents independently selected from: alkyl (which includes but is not limited to methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, benzyl, cyclohexyl, etc.), alkoxy (which includes but is not limited to methoxy, ethoxy, etc.), aryl (which includes but is not limited to phenyl, alkoxyphenyl, 3, 5-dialkoxyphenyl, 2, 6-dialkoxyphenyl, alkylphenyl, 3, 5-dialkylphenyl, 2, 6-dialkylphenyl, halophenyl, 3, 5-dihalophenyl, 2, 6-dihalophenyl, etc.), halogen (fluorine, chlorine, bromine, iodine, etc.), alkoxycarbonyl (which includes but is not limited to methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, etc.), cyano, trifluoromethyl, nitro, etc.
R1As the protecting group, there may be mentioned an alkoxycarbonyl group (which includes, but is not limited to, a protecting group such as a t-butyloxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), a methoxycarbonyl group, an ethoxycarbonyl group, an adamantyloxycarbonyl group, a 2,2, 2-trichloroethoxycarbonyl group Troc); alkyl (such groups include, but are not limited to, methyl, ethyl, isopropyl, tert-butyl, benzyl (Bn), p-methoxybenzyl (PMB), p-methylbenzyl, p-bromobenzyl, 2, 4-dimethoxybenzyl, and the like); acyl (which includes but is not limited to acetyl (Ac), trifluoroacetyl, pivaloyl chloride, benzoyl (Bz), p-methylbenzoyl, p-bromobenzoyl, and the like); sulfonyl (such groups include, but are not limited to, methanesulfonyl (Ms), trifluoromethanesulfonyl (Tf), benzenesulfonyl, p-methylbenzenesulfonyl (Ts), p-nitrobenzenesulfonyl (Ns), o-nitrobenzenesulfonyl, p-trifluoromethylbenzenesulfonyl, and the like). For general description and instructions for use of protecting groups, see references: greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1991.
R2And R3There may be alkyl groups (such groups include, but are not limited to, methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, benzyl, cyclohexyl, etc.), aryl groups (such groups include, but are not limited to, phenyl, alkoxyphenyl, 3, 5-dialkoxyphenyl, 2, 6-dialkoxyphenyl, alkylphenyl, 3, 5-dialkylphenyl, 2, 6-dialkylphenyl, halophenyl, 3, 5-dihalophenyl, 2, 6-dihalophenyl, etc.), halogens (fluorine, chlorine, bromine, iodine, etc.).
X1And X2For a leaving group, "leaving group" means a group well known in the art, e.g.See Advanced Organic Chemistry, jeri macch, 5 th edition, pages 351-357, John Wiley and Sons, new york (n.y). Such leaving groups include, but are not limited to, halogen, sulfonyl, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, acyl, and the like. Examples of suitable leaving groups include chloro, bromo, iodo, acetyl, methanesulfonyl, isopropylsulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, toluenesulfonyl, p-nitrophenylsulfonyl, o-nitrobenzenesulfonyl and like substituents.
2. The method of claim 1, wherein the chiral spiro compound is synthesized by a reaction catalyst comprising a phase transfer catalyst having the following structure:
wherein:
R4hydrogen, alkoxy (which includes but is not limited to methoxy, ethoxy, isopropoxybenzene, tert-butoxy, benzyloxy, and the like), aryl (which includes but is not limited to phenyl, alkoxyphenyl, 3, 5-dialkoxyphenyl, 2, 6-dialkoxyphenyl, alkylphenyl, 3, 5-dialkylphenyl, 2, 6-dialkylphenyl, halophenyl, 3, 5-dihalophenyl, 2, 6-dihalophenyl, 3,4, 5-trihalophenyl, and the like).
R5Hydrogen, alkyl (which includes but is not limited to methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, benzyl, cyclohexyl, etc.), allyl (which may be optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, etc.), acyl (which includes but is not limited to benzoyl, alkylbenzoyl, 3, 5-dialkylbenzoyl, 2,4, 6-trialkylbenzoyl, halobenzoyl, 1-naphthoyl, 2-naphthoyl, pivaloyl, adamantyl, etc.), and the likeAlkanoyl, etc.), silyl (which includes, but is not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, etc.).
R6And are substituents such as hydrogen, alkyl (which includes but is not limited to methyl, ethyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, benzyl, cyclohexyl, and the like), alkenyl (which may be optionally substituted with one or more substituents independently selected from hydrogen, halogen, alkyl, alkoxy, phenyl, and the like), and the like.
R7Hydrogen, alkyl (which includes but is not limited to methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, benzyl, cyclohexyl, etc.), aryl (which includes but is not limited to phenyl, alkoxyphenyl, 3, 5-dialkoxyphenyl, 2, 6-dialkoxyphenyl, alkylphenyl, 3, 5-dialkylphenyl, 2, 6-dialkylphenyl, halophenyl, 3, 5-dihalophenyl, 2, 6-dihalophenyl, 3,4, 5-trihalophenyl, etc.).
R8，R9May be hydrogen, alkyl (which includes but is not limited to methyl, ethyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, benzyl, cyclohexyl, etc.), alkoxy (which includes but is not limited to methoxy, ethoxy, isopropoxybenzene, t-butoxy, benzyloxy, etc.), alkoxycarbonyl (which includes but is not limited to t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methoxycarbonyl, ethoxycarbonyl, 9-fluorenylmethyl chloroformate (Fmoc), 2,2, 2-trichloroethoxycarbonyl Troc, etc.); alkyl (such groups include, but are not limited to, methyl, ethyl, isopropyl, tert-butyl, benzyl (Bn), p-methoxybenzyl (PMB), p-methylbenzyl, and the like); acyl (which includes but is not limited to acetyl (Ac), trifluoroacetyl, pivaloyl, benzoyl (Bz), p-methylbenzoyl, and the like); sulfonyl (which includes but is not limited to methylsulfonyl (Ms), trifluoromethylsulfonyl (Tf), phenylsulfonyl, p-methylphenylsulfonyl (Ts), p-nitrophenylsulfonyl (Ns), o-nitrophenylsulfonyl, p-trifluoromethylphenylsulfonyl, etc.),phosphonoxy groups (including but not limited to dimethoxyphosphono, diethoxyphosphono, diisopropylphosphono, di-tert-butoxyphosphono, dibenzyloxyphosphono, and the like).
R10，R11Hydrogen, alkyl (which includes but is not limited to methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, benzyl, cyclohexyl, etc.), aryl (which includes but is not limited to phenyl, alkoxyphenyl, 3, 5-dialkoxyphenyl, 2, 6-dialkoxyphenyl, alkylphenyl, 3, 5-dialkylphenyl, 2, 6-dialkylphenyl, halophenyl, 3, 5-dihalophenyl, 2, 6-dihalophenyl, 3,4, 5-trihalophenyl, etc.).
Ar is an aryl group (which includes, but is not limited to, phenyl, p-alkoxyphenyl, o-alkoxyphenyl, m-alkoxyphenyl, 3, 5-dialkoxyphenyl, 2, 6-dialkoxyphenyl, p-alkylphenyl, o-alkylphenyl, m-alkylphenyl, 3, 5-dialkylphenyl, 2, 6-dialkylphenyl, p-halophenyl, o-halophenyl, m-halophenyl, 3, 5-dihalophenyl, 2, 6-dihalophenyl, 3,4, 5-trihalophenyl, 3, 5-diphenyl-4-dimethyl-t-butylsiloxyphenyl, 1-naphthyl, 2-phenyl-1-naphthyl, 3-phenyl-1-naphthyl, 7-phenyl-1-naphthyl, 2-naphthyl, 9-anthryl, m-alkoxyphenyl, p-alkylphenyl, p-halophenyl, m-alkylphenyl, m-halophenyl, m-4-di-tert-butylsiloxyphenyl, 1-naphthyl, 2-phenyl-1-naphthyl, 3-phenyl-1-naphthyl, 7-naphthyl, 2-anthryl, 9-anthryl, a-aryl, a-or a, 9-phenanthryl, pyrenyl, and the like).
X3The anion is halogen anion (including anion such as fluorine, chlorine, bromine, iodine, etc.), inorganic acid anion (the group includes but is not limited to sulfate anion, bisulfate anion, phosphate anion, nitrate anion, etc.), organic acid anion (the group includes but is not limited to tetrafluoroborate anion, benzenesulfonic acid anion, benzoic acid anion, tartaric acid anion, etc.).
3. The method of claim 1, wherein the chiral spiro compound is synthesized with a catalyst in a molar percentage of 1 mol% to 50 mol%.
4. The method of claim 1, wherein the chiral spiro compound is synthesized by sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium hydrogen carbonate, potassium phosphate, dipotassium hydrogen phosphate, or the like.
5. The method of claim 1, wherein the chiral spiro compound is synthesized at a base concentration of 5 to 95% by mass when the base is an aqueous alkaline solution.
6. The method of claim 1, wherein the chiral spiro compound is synthesized at a reaction temperature of-78 ℃ to 45 ℃.
7. The synthesis method according to claim 1, wherein the organic solvent used is selected from the group consisting of 1, 2-dichloroethane, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1, 4-dioxane, diethyl ether, t-butyl methyl ether, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, acetone, acetonitrile, toluene, m-xylene, o-xylene, mesitylene, fluorobenzene, chlorobenzene, bromobenzene, ethyl acetate, and a mixture of any two thereof.
8. The synthetic method of claim 1 wherein the substrate concentrations are: 0.01 to 2.0 mol/L.
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