WO2022233282A1 - 一种多元磺酸类化合物及其中间体和应用 - Google Patents

一种多元磺酸类化合物及其中间体和应用 Download PDF

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WO2022233282A1
WO2022233282A1 PCT/CN2022/090675 CN2022090675W WO2022233282A1 WO 2022233282 A1 WO2022233282 A1 WO 2022233282A1 CN 2022090675 W CN2022090675 W CN 2022090675W WO 2022233282 A1 WO2022233282 A1 WO 2022233282A1
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compound
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alkyl
independently
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李智
谢文斌
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上海科技大学
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    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0215—Sulfur-containing compounds
    • B01J31/0225—Sulfur-containing compounds comprising sulfonic acid groups or the corresponding salts
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
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    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
    • C07C303/22—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof from sulfonic acids, by reactions not involving the formation of sulfo or halosulfonyl groups; from sulfonic halides by reactions not involving the formation of halosulfonyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/33—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems
    • C07C309/34—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems formed by two rings
    • C07C309/35—Naphthalene sulfonic acids
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/39—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing halogen atoms bound to the carbon skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/41—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton
    • C07C309/42—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton having the sulfo groups bound to carbon atoms of non-condensed six-membered aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C333/02—Monothiocarbamic acids; Derivatives thereof
    • C07C333/04—Monothiocarbamic acids; Derivatives thereof having nitrogen atoms of thiocarbamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
    • C—CHEMISTRY; METALLURGY
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
    • C07F1/02—Lithium compounds
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    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
    • C07F1/06—Potassium compounds
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
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    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C07F9/65744—Esters of oxyacids of phosphorus condensed with carbocyclic or heterocyclic rings or ring systems

Definitions

  • the invention belongs to the technical field of organic synthesis, in particular to a polysulfonic acid compound and an application thereof.
  • the present invention is to solve the defect of less types of binaphthalene skeleton compounds used as catalysts in the prior art, and for this purpose, a polybasic sulfonic acid compound, intermediates and applications thereof are provided.
  • the polybasic sulfonic acid compound of the present invention can realize the asymmetric hydrogenation alkoxy cyclization reaction of the unactivated olefinic substrate under mild conditions, especially when the chiral polysulfonic acid compound is used as the catalyst, it can also Such oxygen-containing ring compounds are prepared with high enantioselectivity.
  • the present invention solves the above technical problems through the following technical solutions.
  • the present invention also provides a compound represented by formula I-1 or I-2;
  • A1 is a C 6-18 aryl group or does not exist (when A1 does not exist, there is no substituent on the naphthalene ring, that is, is H);
  • A1', A2 and A2' are independently C 6-18 aryl
  • R 1 and R 7 are independently H, C 1-16 alkyl or adamantyl
  • R 2 and R 2 ' are independently hydroxyl or -NR 2a R 2b ;
  • R 2a and R 2b are independently C 1-6 alkyl
  • R 3 and R 3 ′ are independently H, C 1-6 alkyl or -S(O) 2 NR 3a R 3b ;
  • R 3a and R 3b are independently C 1-6 alkyl
  • R 4 is -S(O) 2 OH or hydroxyl, or two R 4 together form When R 4 is hydroxyl, the R 2 and R 2 ' are hydroxyl;
  • R 5 , R 5 ', R 6 and R 6 ' are independently H, C 1-6 alkyl or C 1-6 alkyl substituted by R 5-1 (the number of R 5-1 is one or more (e.g. 1, 2 or 3), and R 5 , R 5' , R 6 and R 6 ' are not H at the same time;
  • R 5-1 is halogen or C 1-6 alkyl substituted by halogen (the number of halogens is 1 or more, such as 1, 2 or 3);
  • the C 6-18 aryl groups are phenyl, naphthyl, phenanthrenyl or anthracene group, preferably phenyl or naphthyl.
  • R3 or R3 ' is preferably located at the para or meta position on the phenyl to the point of attachment of the phenyl to the naphthalene ring.
  • A1 and A1' are independently phenyl
  • the It is preferably located in the meta position to the point of attachment of the phenyl group to the naphthalene ring on the phenyl group.
  • the It is preferably located at the 8th position of the naphthyl group (that is, the connection site with A1 and A1' and the naphthalene ring is the 2nd position on A1 and A1' (that is, the naphthyl group), Substitute position 8 at positions A1 and A1', e.g. ).
  • R 5 , R 5 ', R 6 or R 6 ' is preferably located at the meta position on the phenyl to the point of attachment of the phenyl to the naphthalene ring.
  • R 1 and R 7 are independently C 1-16 alkyl groups
  • the C 1-16 alkyl groups are straight-chain C 1-16 alkyl groups or branched chain C 1 -16 alkyl, preferably linear C 1-16 alkyl.
  • the straight-chain C 1-16 alkyl groups are preferably n-hexadecyl or n-octyl.
  • said branched C 1-16 alkyl is preferably branched C 3-6 alkyl, preferably tert-butyl base.
  • R 2a and R 2b are independently C 1-6 alkyl
  • the C 1-6 alkyl is methyl, ethyl, n-propyl or isopropyl, Methyl is preferred.
  • the C 1-6 alkyl groups can be methyl, ethyl, n-propyl, isopropyl or n-pentyl, preferably methyl or n-pentyl.
  • R 3a and R 3b are independently C 1-6 alkyl
  • the C 1-6 alkyl is methyl, ethyl, n-propyl or isopropyl, Methyl is preferred.
  • R 5 , R 5 ', R 6 and R 6 ' are independently C 1-6 alkyl or C 1-6 alkyl substituted by R 5-1
  • the The C 1-6 alkyl group or the C 1-6 alkyl group in the C 1-6 alkyl group substituted by R 5-1 is methyl, ethyl, n-propyl or isopropyl, preferably methyl base.
  • the halogen in the halogen or the C 1-6 alkyl substituted by halogen is F, Cl, Br or I, preferably F.
  • R 5-1 is C 1-6 alkyl substituted by halogen
  • the C 1-6 alkyl substituted by halogen is trifluoromethyl
  • R 5 , R 5 ', R 6 and R 6 ' are independently C 1-6 alkyl substituted by R 5-1 , said substituted by R 5-1
  • the C 1-6 alkyl group is trifluoromethyl or -CF(CF 3 ) 2 .
  • the general formula of the compound represented by formula I-1 is represented by I-1a, I-1b, I-1c or I-1d:
  • A1 is a C 6-18 aryl group.
  • R 1 and R 7 are independently C 1-16 alkyl or adamantyl.
  • R 2 and R 2 ' are -NR 2a R 2b .
  • R 3 and R 3 ' are independently C 1-6 alkyl or -S(O) 2 NR 3a R 3b .
  • R 4 is -S(O) 2 OH.
  • R 5 , R 5 ′, R 6 and R 6 ′ are independently C 1-6 alkyl substituted by R 5-1 .
  • A1 is C 6-18 aryl
  • A1' is a C 6-18 aryl group and the C 6-18 aryl group is a naphthyl group
  • the R 1 is a C 1-16 alkyl group or adamantyl
  • the R 2 ' is - NR 2a R 2b ;
  • A1 is C 6-18 aryl
  • R 1 is H or C 1-16 alkyl
  • R 3 is H or C 1-6 alkyl
  • R 4 is -S(O) 2 OH or hydroxyl
  • R 1 is C 1-16 alkyl
  • R 1 is H
  • R 2 and R 2 ' are independently hydroxyl, and R 4 is -S(O) 2 OH, said A1 and A1' are independently C 6-18 aryl, and said C 6- 18 aryl is naphthyl.
  • A1 is a C 6-18 aryl group; the C 6-18 aryl group is a phenyl group;
  • R 1 is C 1-16 alkyl or adamantyl
  • R 2 and R 2 ' are -NR 2a R 2b ;
  • R 3 and R 3 ' are C 1-6 alkyl
  • R 4 is -S(O) 2 OH.
  • the compound shown in formula I-1 is any of the following compounds and/or isomers thereof:
  • the compound shown in the formula I-2 is any of the following compounds and/or isomers thereof:
  • the present invention provides a preparation method of the above-mentioned compound represented by formula I-1 or I-2, which is the following method 1, 2, 3 or 4:
  • the preparation method of the compound represented by the formula I-1 includes the following steps: under an acidic reagent, the compound II-a is acidified in a solvent according to the following formula reaction to obtain the compound of formula I-1;
  • Z and Z' are independently hydroxyl or -SO 3 M 1a ;
  • M 1a is independently Na or K;
  • R 13 and R 13' are independently -ONa, -OK or -NR 2a R 2b ;
  • R 2a and R 2b are as defined above;
  • the preparation method of the compound represented by the formula I-1 includes the following steps: in the presence of an acidic reagent or BBr 3 , the compound II-b is subjected to a deprotection reaction of the following formula in a solvent , to obtain the compound of formula I-1;
  • R 15 and R 15' are independently hydroxyl protecting groups or C 1-3 alkyl groups;
  • M 2a and M 2b are independently Na or K;
  • the preparation method of the compound shown in the formula I-1 comprises the following steps:
  • Step (1) carry out esterification with compound I-1 and phosphorus oxychloride obtained in method 2 in a solvent to obtain a mixed solution;
  • Step (2) the mixed solution obtained in step (1) is subjected to hydrolysis reaction in water to obtain the compound of formula I-1;
  • the preparation method of the compound represented by formula I-1 or I-2 includes the following steps: in the presence of an oxidizing agent and formic acid, compound II-d is dissolved in a solvent In the oxidation reaction of the following formula is carried out to obtain the compound shown in the formula I-1 or I-2;
  • R 16a and R 16b are independently C 1-3 alkyl
  • R 18 is R 3 and R 18a is -S(O 2 )R 2 ; alternatively, R 18 is R 5 and R 18a is R 6 ;
  • R 19 is -S(O 2 )R 2' , and R 19a is R 3' ; or, R 19 is R 6' , and R 19a is R 5' ;
  • R 2 , R 2' , R 3 , R 3' , R 5 , R 5' , R 6 and R 6' are as defined above.
  • the conditions and operations of the acidification reaction can be the conventional conditions and operations of this type of acidification reaction in the art, and the present invention particularly preferably the following conditions and operations:
  • the acidification reaction is carried out on a cation exchange resin (eg, Amberlyst 15) (eg, using an alcoholic solvent (eg, methanol) as the eluent).
  • a cation exchange resin eg, Amberlyst 15
  • an alcoholic solvent eg, methanol
  • the conditions and operations of the deprotection reaction can be conventional conditions and operations of this type of reaction in the art.
  • the present invention particularly prefers the following conditions and operations:
  • the acidic reagent can be hydrochloric acid (for example, 12 mol/L hydrochloric acid).
  • the molar ratio of the acidic reagent to the compound II-b may be 5:1-25:1 (eg 10:1).
  • the solvent can be an ether solvent (eg dioxane).
  • the temperature of the deprotection reaction may be 30-80°C (eg, 60°C).
  • the present invention particularly prefers the following conditions and operations:
  • the acidic reagent can be hydrochloric acid (for example, 12 mol/L hydrochloric acid).
  • the molar ratio of the BBr 3 to the compound II-b may be 5:1-25:1 (eg 10:1).
  • the solvent may be a halogenated hydrocarbon solvent (eg dichloromethane).
  • the temperature of the deprotection reaction can be -78--60°C (eg -78°C).
  • the progress of the deprotection reaction can be monitored by conventional methods in the art (eg, TLC, LC-MS).
  • the end point of the reaction is that the compound II-b no longer reacts or disappears.
  • the time for the deprotection reaction is 2-16 hours (eg, 5 hours).
  • the conditions and operations of the described esterification reaction can be the conventional conditions and operations of this type of reaction in the art, and the present invention is particularly preferably the following conditions and operations:
  • the solvent may be pyridine.
  • the molar ratio of the phosphorus oxychloride to the compound I-1 can be 1:1-6:1 (for example, 4:1).
  • the temperature of the esterification reaction may be 50-110°C (eg, 95°C).
  • the conditions and operations of the esterification reaction can be conventional conditions and operations of this type of reaction in the art, for example, hydrolysis at 100° C. for 4 hours.
  • the conditions and operations of the described oxidation reaction can be the conventional conditions and operations of this type of reaction in the art, and the present invention particularly preferably the following conditions and operations:
  • the oxidant may be hydrogen peroxide.
  • the molar ratio of the oxidant to the compound II-d may be 1:1-3:1 (eg 1.3:1).
  • the solvent may be a chlorinated hydrocarbon solvent (eg, dichloromethane).
  • the method for preparing the compound of formula I-1 or formula I-2 may further include the following steps: at 280-300° C., subjecting compound III-d to a rearrangement reaction to obtain the compound of formula I-1. compound II-d;
  • the conditions of the rearrangement reaction can be conventional conditions and operations for such reactions in the field, such as reaction under protective gas (eg nitrogen); reaction at 290° C. for 45 minutes.
  • protective gas eg nitrogen
  • the preparation method of the compound of formula I-1 or formula I-2 may further include the following steps: in the presence of a basic reagent, reacting compound IV-d and compound V-d in a solvent, to obtain the compound III-d;
  • the alkaline reagent can be NaH.
  • the solvent can be an amide solvent (eg N,N-dimethylformamide).
  • the temperature of the reaction may be 50-100°C (eg, 85°C).
  • the present invention provides an application of the above-mentioned compound represented by formula I-1 or I-2 as a catalyst in the preparation of compound B;
  • the preparation method of the compound B comprises the following steps: in the presence of the compound represented by the formula I-1 or I-2 and the titanium salt, the compound A is subjected to the cyclization reaction of the following formula in a solvent to obtain the compound B;
  • R 8-1 is C 1-6 alkyl
  • R 8-2 is C 2-6 alkenyl or hydroxyl
  • any two adjacent substituents of R 8 , R 9 , R 10 and R 11 together with the carbon atom to which they are attached form C 3-6 cycloalkyl, C 6-18 aryl or
  • R 12 and R 13 are independently H, C 1-6 alkyl or C 6-18 aryl, or, R 12 and R 13 together with the carbon atom to which they are attached form C 3-6 cycloalkyl;
  • n 1, 2 or 3.
  • R 8 , R 9 , R 10 and R 11 are independently C 1-6 alkyl or -OC 1-6 alkyl
  • the C 1-6 alkyl or The C 1-6 alkyl group in the -OC 1-6 alkyl group is methyl, ethyl, n-propyl or isopropyl, such as methyl.
  • R 8 , R 9 , R 10 and R 11 are independently C 3-6 cycloalkyl
  • the C 3-6 cycloalkyl is cyclopropyl, cyclobutyl cyclopentyl or cyclohexyl, for example cyclohexyl.
  • R 8 , R 9 , R 10 and R 11 are independently C 6-18 aryl or C 6-18 aryl substituted by R 8-1
  • the C The 6-18 aryl group or the C 6-18 aryl group in the C 6-18 aryl group substituted by R 8-1 is phenyl, naphthyl, phenanthryl or anthracenyl, preferably phenyl.
  • R 8-1 is a C 1-6 alkyl group
  • the C 1-6 alkyl group is methyl, ethyl, n-propyl or isopropyl, such as methyl .
  • R 8-2 is C 2-6 alkenyl
  • the C 2-6 alkenyl is vinyl or propenyl
  • the C 3-6 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, eg cyclohexyl.
  • the C 6 -18 Aryl is phenyl, naphthyl, phenanthryl or anthracenyl, such as phenyl (ie, in compound A is naphthyl, e.g. ).
  • R 12 and R 13 are independently C 1-6 alkyl
  • the C 1-6 alkyl is methyl, ethyl, n-propyl or isopropyl, For example methyl.
  • R 12 and R 13 are independently C 6-18 aryl groups
  • the C 6-18 aryl groups are phenyl, naphthyl, phenanthryl or anthracenyl, such as benzene base.
  • the C 3-6 cycloalkyl group is cyclopropyl, cyclobutyl, Cyclopentyl or cyclohexyl, eg cyclohexyl.
  • the compound A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoe
  • the conditions and operations of the described cyclization reaction can be the conventional conditions and operations of this type of reaction in the field, and the present invention particularly preferably the following conditions and operations:
  • the organic solvent is preferably an alkane solvent (such as cyclohexane), an aromatic hydrocarbon solvent (such as toluene) and a halogenated hydrocarbon solvent (such as 1,2-dichloroethane). one or more of.
  • alkane solvent such as cyclohexane
  • aromatic hydrocarbon solvent such as toluene
  • halogenated hydrocarbon solvent such as 1,2-dichloroethane
  • the molar concentration of the compound of formula A in the organic solvent may be 0.005-1 mol/L.
  • the titanium salt is preferably titanium tetramethanol, titanium tetraisopropoxide, titanium tetra-tert-butoxide, titanium tetraisobutoxide, titanium tetrachloride, titanium triisopropoxide chloride, isopropoxide
  • titanium octoxide such as titanium isooctoxide.
  • the molar ratio of the titanium salt to the compound of formula A may be 0.02:1-0.2:1 (for example, 0.1:1).
  • the molar ratio of the compound represented by formula I-1 or I-2 to the compound of formula A is preferably 0.02:1-0.2:1 (for example, 0.05:1).
  • the reaction temperature of the cyclization reaction is preferably 40-200°C, for example, 70-90°C.
  • the progress of the cyclization reaction can be monitored using conventional monitoring methods in the art, such as TLC, HPLC or NMR.
  • the reaction end point is taken when the compound of formula A no longer reacts.
  • the time of the cyclization reaction is preferably 20-26 hours, such as 24 hours.
  • the present invention also provides a catalyst composition comprising the above-mentioned compound represented by formula I-1 or I-2 and a titanium salt.
  • the titanium salt is preferably titanium tetramethoxide, titanium tetraisopropoxide, titanium tetra-tert-butoxide, titanium tetraisobutoxide, titanium tetrachloride, titanium triisopropoxide chloride, isopropoxide
  • titanium octoxide such as titanium isooctoxide.
  • the present invention also provides the application of the above-mentioned catalyst composition as a catalyst in the preparation of the above-mentioned compound B;
  • the preparation method of the compound B comprises the following steps: in the presence of the compound represented by the formula I-1 and/or I-2 and the titanium salt, the compound A is subjected to a cyclization reaction of the following formula in a solvent , to obtain the compound B;
  • the present invention also provides the above-mentioned compound II-a, the above-mentioned compound II-b, the above-mentioned compound II-d, the above-mentioned compound III-d or the above-mentioned compound IV-d:
  • the compound II-a, the compound II-b, the compound II-d, the compound III-d or the compound IV-d are as follows general formula:
  • the compound II-a, the compound II-b, the compound II-d, the compound III-d or the compound IV-d are as follows Any compound and/or its isomers:
  • the compound "compound” represented by formula I-1 or I-2 may have one or more chiral carbon atoms, so optically pure isomers, such as pure enantiomers, can be separated and obtained isomers, or racemates, or mixed isomers. Pure single isomers can be obtained by separation methods in the art, such as chiral crystallization into salts, or chiral preparative column separation.
  • stereoisomer refers to a cis-trans isomer or an optical isomer. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, spin chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.) It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or forming salts (physical bonding, etc.).
  • single stereoisomer means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.
  • alkyl refers to a straight or branched chain alkyl group having the specified number of carbon atoms (eg, C1 -C16).
  • Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl Wait.
  • cycloalkyl refers to a saturated monocyclic cyclic group consisting of only carbon atoms having the specified number of carbon atoms (eg, C3 - C6 ). Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • aryl refers to a cyclic group consisting of only carbon atoms having a specified number of carbon atoms (eg C 6 -C 10 ), which is monocyclic or polycyclic, and at least one ring is aromatic ( complies with Huckel's rule).
  • Aryl groups are attached to other segments of the molecule through rings that are aromatic or non-aromatic.
  • Aryl groups include, but are not limited to, phenyl, naphthyl, and the like.
  • alkenyl refers to a straight or branched chain hydrocarbon group ("C2 - C20 alkenyl)" having 2-10 carbon atoms, one or more carbon-carbon double bonds, and no carbon-carbon triple bonds.
  • the one or more carbon-carbon double bonds may be internal (eg, in 2-butenyl) or terminal (eg, in 1-butenyl).
  • hydroxy protecting group is well known in the art and includes those protecting groups described in detail in Organic Synthesis (Protecting Groups in Organic Synthesis), T.W. Greene and P.G.M. Wuts, Third Edition, John Wiley International Publishing Company (John Wiley & Sons), 1999, incorporated herein by reference.
  • oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), (phenyldimethylsilyl)methoxymethyl (SMOM) ), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacol methyl (GUM) ), tert-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2-(trimethylsilyl) Ethoxymethyl (SEMOR), Tetrahydropyranyl (THP), 4-Methoxytetrahydropyranyl (MTHP), 1-[(2-Chloro-4-methyl)phenyl]-4 -Methoxypiperidin-4-yl (CTMP), 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, 2-
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive improvement effect of the present invention is that the polysulfonic acid compound of the present invention can realize the asymmetric hydrogenation alkoxy cyclization reaction of unactivated olefin under mild conditions, especially when the chiral polysulfonic acid compound is used as the When used as a catalyst, such oxygen-containing ring compounds can also be prepared with high enantioselectivity.
  • the present embodiment is the preparation method of the compound of formula 15, which is divided into 2 steps, and the synthetic route is as follows:
  • the reaction conditions for the amination of route a are: adding a tetrahydrofuran solution of dimethylamine (2.0 equiv.) to a round-bottomed flask of suitable capacity (the added volume is such that the molar concentration of the compound of formula 13 is 1.0 mol/L).
  • the brominated benzenesulfonyl chloride compound formula 13 (1.0 equiv.), triethylamine (1.1 equiv.) and 4-dimethylaminopyridine (0.2 equiv.) were sequentially added thereto, and the mixture was stirred at room temperature for 12 hours.
  • the reaction was analyzed for completion by TLC spot plate analysis.
  • the reaction conditions for the esterification of route b are: add a tetrahydrofuran solution of sodium hydride (1.1 equivalents) in a round-bottomed flask with a suitable capacity (the added volume makes the molar concentration of the compound of formula 13 2.2 mol/L), cool down to After 0°C, ethanol (1.0 equiv.) was slowly added thereto, and the mixture was heated to room temperature and stirred for 1 hour. The temperature was further lowered to 0°C, brominated benzenesulfonyl chloride compound formula 13 (1.1 equiv.) was slowly added, and the mixture was stirred at 0°C for 2 hours.
  • the boronic esterification reaction conditions in routes a and b are the same, and the details are as follows: under nitrogen protection, in a round-bottomed flask with a suitable capacity, the brominated sulfonamide compound or sulfonic acid ethyl ester compound obtained in the first step is 14 (1.0 equiv) was dissolved in tetrahydrofuran (0.65 mol/L) and cooled to -78°C. n-Butyllithium (1.2 equiv.) was slowly added dropwise to the above reaction solution.
  • the present embodiment is the preparation method of the compound of formula (R)-1, which is divided into 8 steps, and the synthetic route is as follows:
  • the halogenation reaction conditions are: under nitrogen protection, the starting material formula (R)-3 (1.0 equiv.) is dissolved in tetrahydrofuran (0.1 mol/L) in a round-bottomed flask with a suitable capacity, and then the temperature is lowered to -78 °C. Slowly add n-butyllithium (3.5 equivalents) dropwise to the above reaction solution, keep stirring at -78°C for 30 minutes after the dropwise addition, then warm up to room temperature and stir for 3 hours until there is light brown turbidity thing generated. Subsequently, the temperature was lowered to -78° C., and elemental iodine (3.75 equivalents) was added.
  • the synthesis of formula (R)-4d is different. Due to the different types of starting materials, preferably, the synthesis steps of the compound of formula (R)-4d are as follows: under nitrogen protection, sodium hydride (60%, dispersed in mineral oil, 2.10 g, 52.5 mmol) was added to a 100 mL round-bottomed flask. Dissolved in 40 mL of tetrahydrofuran, then cooled to 0°C. The formula (R)-3d (8.50 g, 15.0 mmol) was slowly added to the above reaction solution, and the mixture was kept at 0° C. and stirred for 1.5 hours after the addition.
  • Bromomethyl methyl ether (5.62 g, 45.0 mmol) was then added slowly and kept stirring at 0°C for 30 minutes. Spot plate analysis by thin-layer chromatography, once the reaction is over, quench the reaction with saturated aqueous ammonium chloride solution at 0°C, extract with ethyl acetate three times, wash the extracted ethyl acetate solution with saturated brine, and dry over anhydrous sodium sulfate.
  • the coupling reaction conditions are: under nitrogen protection, in a three-necked flask equipped with a reflux condenser, the halogenated product formula (R)-4 (1.0 equivalent) obtained in the first step is successively added, and the obtained in the second step of Example 1 contains SO2NMe2 group boronate compound formula 15a-f (3.0 equiv), tetrakistriphenylphosphine palladium (0.1 equiv), potassium carbonate (3.0 equiv), 1,2-dimethoxyethane and water (The volume ratio is 6 to 1, and the halogenated compound is 0.1 mol/L). The resulting mixture was stirred at 85°C for 16 hours.
  • the deprotection reaction conditions are: in a round-bottomed flask equipped with a reflux condenser, the coupling products of formula (R)-5 (1.0 equivalents) and 1,4-dioxane obtained in the second step of formula are sequentially added (0.1 mol/L), concentrated hydrochloric acid (10.0 equivalent) was added thereto, and the resulting mixture was stirred at 60° C. for 5 hours.
  • the acylation reaction conditions are: under nitrogen protection, in a round-bottomed flask equipped with a reflux condenser, the deprotected compound formula (R)-6 (1.0 equivalent) and N, N-dimethylformamide (0.5 mol/L) was cooled to 0°C, sodium hydride (5.0 equiv.) was added in batches, the temperature was raised to room temperature and stirred for 10 minutes, and then dimethylaminothiocarbonyl chloride (5.0 equiv.) was added. , the resulting mixture was then warmed to 85°C and maintained at that temperature for 18 hours with stirring.
  • the rearrangement reaction conditions are: under nitrogen protection, the acylated product of formula (R)-7 obtained in the fourth step is placed at 290° C. and stirred for 45 minutes. After the reaction is completed, it is lowered to room temperature, and purified by silica gel column chromatography (eluents are petroleum ether and ethyl acetate) to obtain the rearranged product formula (R)-8.
  • the oxidation reaction conditions are: adding the rearranged compound formula (R)-8 (1.0 equivalent) obtained in the fifth step and a mixture of methanol and tetrahydrofuran (volume ratio of 1 to 1, 0.25 mol/L) into the round-bottomed flask ), cooled to 0°C, N-chlorosuccinimide (6.0 equiv.) was added in portions, then warmed to 15°C and stirred at that temperature for 30 minutes.
  • the hydrolysis reaction conditions are: add the oxidation product dibasic sulfonyl chloride compound formula (R)-9 (1.0 equivalent) and methanol (0.04mol/L) obtained in the sixth step into the round-bottomed flask, and then add solid sodium hydroxide (50.0 equiv), then warmed to 70°C and stirred at that temperature for 5 hours.
  • the pH of the reaction was adjusted to 8 with 1M HCl, extracted three times with ethyl acetate, and the extracted ethyl acetate solution was washed with saturated brine, dried over anhydrous sodium sulfate, and removed by rotary evaporation under reduced pressure.
  • solvent, and the residue was purified by silica gel column chromatography (eluents were ethyl acetate and methanol) to obtain the hydrolyzed product of sodium dibasic sulfonate compound formula (R)-10.
  • the acidification conditions are: dissolving the hydrolyzed product sodium sulfonate compound formula (R)-10 obtained in step 7 in methanol, and then passing the methanol solution through a cation exchange resin Amberlyst 15 (10cm 3 /200mg formula (R) )-10), eluted twice with methanol, the methanol in the solution was removed by rotary evaporation under reduced pressure, and then the obtained solid was vacuum-dried at 50 ° C for 6 hours to obtain the final product chiral binaphthalene dibasic sulfonic acid formula (R )-1.
  • the method for product (R)-1m preferably, the specific steps are as follows: add the compound of formula (R)-8m (55.0 mg, 0.04 mmol) and 1 mL of dichloromethane to a 10 mL round-bottomed flask, and then add 1.5 mL of Formic acid and hydrogen peroxide (145.6 mg, 1.3 mmol) were stirred at room temperature for 10 hours.
  • the present embodiment is the preparation method of the compound of formula (R)-2a, 2b, 2c, which is divided into 3 steps, and the synthetic route is as follows:
  • the reaction conditions for the cleavage of the nitrogen-sulfur bond are: under nitrogen protection, add the hydrolysis product formula (R)-10 (1.0 equivalent) obtained in the seventh step of Example 2 into a round-bottomed flask, cool down to 0 °C, and then add Methyl trifluoromethanesulfonate (160.0 equiv.) was slowly added thereto, and after the addition was completed, the temperature was raised to 100° C. and stirring was continued for 20 hours. Cool to room temperature, add appropriate amount of water and stir at room temperature for 1 hour. Then an appropriate amount of saturated aqueous ammonium chloride solution was added, and extracted three times with dichloromethane.
  • the hydrolysis reaction conditions are: adding the tetrabasic methyl sulfonate compound formula (R)-11 (1.0 equivalent) and methanol (0.05mol/L) obtained in the first step into the round-bottomed flask, and then adding solid sodium hydroxide (50.0 equiv), then warmed to 70°C and stirred at that temperature for 5 hours.
  • the acidification conditions are: dissolving the hydrolyzate obtained in the second step, the tetrabasic sodium sulfonate compound formula (R)-12, in water, then passing the aqueous solution through a cation exchange resin Amberlyst 15 (10cm 3 /200mg hydrolyzate), using water After washing twice, the water in the system was azeotropically removed by heating with toluene, and then the obtained solid was vacuum-dried at 50° C. for 6 hours to obtain the final product chiral binaphthyl tetrabasic sulfonic acid formula (R)-2a-c.
  • the present embodiment is the preparation method of the compound of formula (R)-2d, 2e, 2f, which is divided into 2 steps, and the synthetic route is as follows:
  • the coupling reaction conditions are: under nitrogen protection, in a three-necked flask equipped with a reflux condenser, successively add the halogenated product formula (R)-4 (1.0 equivalent) obtained in the first step in Example 2, in Example 1
  • the resulting mixture was stirred at 60°C for 12 hours.
  • the acidification conditions are: the coupling product of formula (R)-5m-o (1.0 equiv.) obtained in the first step is dissolved in methanol (0.01 mol/L), followed by the addition of concentrated hydrochloric acid (10.0 equiv.). The resulting mixture was stirred at 60°C for 5 hours. After the reaction was completed, the temperature was lowered to room temperature, and the solvent was removed by rotary evaporation under reduced pressure.
  • the present embodiment is the preparation method of the compound of formula (R)-2g, and the steps are as follows:
  • the present invention also catalyzes the cyclization reaction of other compounds similar to formula A, and obtains a series of products similar to compounds of formula B, and the results are shown in Table 3 below.
  • the test results show that the above-mentioned various compounds prepared by the method of the present invention have excellent catalytic activity.

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Abstract

公开了一种多元磺酸类化合物及其中间体和应用。多元磺酸类化合物如式I-1或I-2所示。在化合物催化下，可以实现未活化烯烃类底物的不对称加氢烷氧基环化反应。

Description

一种多元磺酸类化合物及其中间体和应用
本申请要求申请日为2021年5月6日的中国专利申请202110491437X的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于有机合成技术领域，具体涉及一种多元磺酸化合物及其应用。
背景技术
在现代有机不对称合成中，设计实用且对环境无害的手性催化剂是实现高度对映体选择性控制以获得光学纯对映体化合物的重要手段。在这方面，衍生自手性(R)或(S)-1,1’-联-2-萘酚的手性布朗斯特酸已被广泛用作手性有机催化剂或用作金属催化的手性配体。相对于常见的手性联萘二元羧酸、联萘磷酸、联萘磷酰胺，手性(R)或(S)-1,1’-联萘二元磺酸是一种更强的布朗斯特酸，这使得联萘二元或多元磺酸在不对称催化上具有巨大的发展潜力。早在2008年Ishihara课题组报道了首例简单的(R)-1,1’-联萘-2,2’-二元磺酸的合成，该合成方法总共需要5步，并成功将合成二元磺酸应用在不对称曼尼希型反应中。 [1]随后List及Ishihara课题组分别对该简单手性二元磺酸的3位或6位通过连接一些不同的取代基来调节其催化不同反应时候的化学选择性和对映选择性。 [2]另外，这类手性二元磺酸还被证明是金属介导下对映选择性催化的有效手性配体。 [3]虽然这类手性二元磺酸在不对称催化中体现出了与众不同的优越性，尤其是在某些不对称催化反应中体现出了独一无二的催化特性，但是由于合成原料种类受限、合成方法欠缺，合成效率低等困难，十几年来关于(R)或(S)-1,1’-联萘二元磺酸的报道仍然屈指可数，仅局限于上述文献中提到的几篇案例，而关于手性的联萘多元磺酸则是至今没有被报道过。
[1].Hatano,M.；Maki,T.；Moriyama,K.；Arinobe,M.；Ishihara,K.,J.Am.Chem.Soc.2008,130,16858.
[2].(a)Garcia-Garcia,P.；Lay,F.；Garcia-Garcia,P.；Rabalakos,C.；List,B.,Angew.Chem.Int.Ed.Engl.2009,48,4363.(b)Hatano,M.；Ozaki,T.；Nishikawa,K.；Ishihara,K.,J.Org.Chem.2013,78,10405.(c)Satake,S.；Kurihara,T.；Nishikawa,K.；Mochizuki,T.；Hatano,M.；Ishihara,K.；Yoshino,T.；Matsunaga,S.,Nat.Catal.2018,1,585.
[3].(a)Hatano,M.；Hattori,Y.；Furuya,Y.；Ishihara,K.,Org.Lett.2009,11,2321.(b)Lalonde,R.L.；Wang,Z.J.；Mba,M.；Lackner,A.D.；Toste,F.D.,Angew.Chem.Int.Ed.Engl.2010,49,598.(c)Hatano,M.；Nishikawa,K.；Ishihara,K.,J.Am.Chem.Soc.2017,139,8424。
发明内容
本发明是为了解决现有技术中作为催化剂的联萘骨架类化合物种类较少的缺陷，为此，提供一种多元磺酸类化合物及其中间体和应用。本发明的多元磺酸类化合物，可以在温和条件下，实现未活化烯烃类底物的不对称加氢烷氧基环化反应，尤其当以手性多元磺酸类化合物作为催化剂时，还可以高 对映选择性制备此类含氧环类化合物。
本发明通过以下技术方案解决上述技术问题的。
本发明还提供了一种如式I-1或I-2所示的化合物；
Figure PCTCN2022090675-appb-000001
其中，A1为C 6-18芳基或不存在(当A1不存在的情况，此处在萘环上没有取代基，即
Figure PCTCN2022090675-appb-000002
为H)；
A1’、A2和A2’独立地为C 6-18芳基；
R 1和R 7独立地为H、C 1-16烷基或金刚烷基；
R 2和R 2’独立地为羟基或-NR 2aR 2b；
R 2a和R 2b独立地为C 1-6烷基；
R 3和R 3’独立地为H、C 1-6烷基或-S(O) 2NR 3aR 3b；
R 3a和R 3b独立地为C 1-6烷基；
R 4为-S(O) 2OH或羟基，或者两个R 4一起形成
Figure PCTCN2022090675-appb-000003
当R 4为羟基时，所述的R 2和R 2’为羟基；
R 5、R 5’、R 6和R 6’独立地为H、C 1-6烷基或被R 5-1取代的C 1-6烷基(R 5-1个数为1个或多个，例如1、2或3个)，且R 5、R 5’、R 6和R 6’不同时为H；
R 5-1为卤素或被卤素取代的C 1-6烷基(卤素个数为1个或多个，例如1、2或3个)；
且所述的如式I-2所示的化合物不为
Figure PCTCN2022090675-appb-000004
在本发明一优选技术方案中，当A1、A1’、A2和A2’独立地为C 6-18芳基时，所述的C 6-18芳基为苯基、萘基、菲基或蒽基，优选为苯基或萘基。
当A1和A1’独立地为苯基时，所述的R 3或R 3’优选位于苯基上所述的苯基与萘环连接位点的对位或间位。
当A1和A1’独立地为苯基时，所述的
Figure PCTCN2022090675-appb-000005
优选位于苯基上所述的苯基与萘环连接位点的间位。
当A1和A1’独立地为萘基时，所述的
Figure PCTCN2022090675-appb-000006
优选位于所述的萘基的8号位(即以A1和A1’与萘环连接位点为A1和A1’(即萘基)上的2号位，
Figure PCTCN2022090675-appb-000007
取代位置为A1和A1’的8号位，例如
Figure PCTCN2022090675-appb-000008
)。
当A2和A2’独立地为苯基时，所述的R 5、R 5’、R 6或R 6’优选位于苯基上所述的苯基与萘环连接位点的间位。
在本发明一优选技术方案中，当R 1和R 7独立地为C 1-16烷基时，所述的C 1-16烷基为直链C 1-16烷基或支链的C 1-16烷基，优选为直链的C 1-16烷基。
当所述的R 1和R 7独立地为直链的C 1-16烷基时，所述的直链的C 1-16烷基优选为正十六烷基或正辛基。
当所述的R 1和R 7独立地为支链C 1-16烷基时，所述的支链的C 1-16烷基优选为支链的C 3-6烷基，优选为叔丁基。
在本发明一优选技术方案中，当R 2a和R 2b独立地为C 1-6烷基时，所述的C 1-6烷基为甲基、乙基、正丙基或异丙基，优选为甲基。
在本发明一优选技术方案中，当R 3和R 3’独立地为C 1-6烷基时，所述的C 1-6烷基可以为甲基、乙基、正丙基、异丙基或正戊基，优选为甲基或正戊基。
在本发明一优选技术方案中，当R 3a和R 3b独立地为C 1-6烷基时，所述的C 1-6烷基为甲基、乙基、正丙基或异丙基，优选为甲基。
在本发明一优选技术方案中，当R 5、R 5’、R 6和R 6’独立地为C 1-6烷基或被R 5-1取代的C 1-6烷基时，所述的C 1-6烷基或所述的被R 5-1取代的C 1-6烷基中的C 1-6烷基为甲基、乙基、正丙基或异丙基， 优选为甲基。
在本发明一优选技术方案中，当R 5-1为卤素或被卤素取代的C 1-6烷基时，所述的卤素或所述的被卤素取代的C 1-6烷基中的卤素为F、Cl、Br或I，优选为F。
在本发明一优选技术方案中，当R 5-1为被卤素取代的C 1-6烷基时，所述的被卤素取代的C 1-6烷基为三氟甲基。
在本发明一优选技术方案中，当R 5、R 5’、R 6和R 6’独立地为被R 5-1取代的C 1-6烷基时，所述的被R 5-1取代的C 1-6烷基为三氟甲基或-CF(CF 3) 2。
在本发明一优选技术方案中，所述的如式I-1所示的化合物的通式为
Figure PCTCN2022090675-appb-000009
在本发明一优选技术方案中，所述的如式I-2所示的化合物的通式为
Figure PCTCN2022090675-appb-000010
在本发明一优选技术方案中，所述的如式I-1所示的化合物的通式为I-1a、I-1b、I-1c或I-1d所示：
Figure PCTCN2022090675-appb-000011
在本发明一优选技术方案中，A1为C 6-18芳基。
在本发明一优选技术方案中，R 1和R 7独立地为C 1-16烷基或金刚烷基。
在本发明一优选技术方案中，R 2和R 2’为-NR 2aR 2b。
在本发明一优选技术方案中，R 3和R 3’独立地为C 1-6烷基或-S(O) 2NR 3aR 3b。
在本发明一优选技术方案中，R 4为-S(O) 2OH。
在本发明一优选技术方案中，R 5、R 5’、R 6和R 6’独立地为被R 5-1取代的C 1-6烷基。
在本发明一优选技术方案中，
Figure PCTCN2022090675-appb-000012
独立地为
Figure PCTCN2022090675-appb-000013
Figure PCTCN2022090675-appb-000014
在本发明一优选技术方案中，
Figure PCTCN2022090675-appb-000015
独立地为
Figure PCTCN2022090675-appb-000016
在本发明一优选技术方案中，
Figure PCTCN2022090675-appb-000017
为
Figure PCTCN2022090675-appb-000018
(例如
Figure PCTCN2022090675-appb-000019
)、
Figure PCTCN2022090675-appb-000020
(例如
Figure PCTCN2022090675-appb-000021
)、
Figure PCTCN2022090675-appb-000022
(例如
Figure PCTCN2022090675-appb-000023
)、
Figure PCTCN2022090675-appb-000024
(例如
Figure PCTCN2022090675-appb-000025
)、
Figure PCTCN2022090675-appb-000026
(例如
Figure PCTCN2022090675-appb-000027
)、
Figure PCTCN2022090675-appb-000028
(例如
Figure PCTCN2022090675-appb-000029
)、
Figure PCTCN2022090675-appb-000030
(例如
Figure PCTCN2022090675-appb-000031
(例如
Figure PCTCN2022090675-appb-000032
)。
在本发明一优选技术方案中，所述的如式I-1所示的化合物中：
A1为C 6-18芳基；
当A1’为C 6-18芳基，所述的C 6-18芳基为萘基时，所述的R 1为C 1-16烷基或金刚烷基；所述的R 2’为-NR 2aR 2b；
当R 4为羟基时，所述的R 3和R 3’为H。
在本发明一优选技术方案中，所述的如式I-1所示的化合物中：
A1为C 6-18芳基；
R 1为H或C 1-16烷基；
R 3为H或C 1-6烷基；
R 4为-S(O) 2OH或羟基；
当R 2和R 2’独立地为-NR 2aR 2b时，所述的R 1为C 1-16烷基；
当R 2和R 2’独立地为羟基时，所述的R 1为H；
当R 2和R 2’独立地为羟基，R 4为-S(O) 2OH时，所述的A1和A1’独立地为C 6-18芳基，所述的C 6- 18芳基为萘基。
在本发明一优选技术方案中，所述的如式I-1所示的化合物中：
A1为C 6-18芳基；所述的C 6-18芳基为苯基；
R 1为C 1-16烷基或金刚烷基；
R 2和R 2’为-NR 2aR 2b；
R 3和R 3’为C 1-6烷基；
R 4为-S(O) 2OH。
在本发明一优选技术方案中，所述的如式I-1所示的化合物为如下任一化合物和/或其异构体：
Figure PCTCN2022090675-appb-000033
所述的如式I-2所示的化合物为如下任一化合物和/或其异构体：
Figure PCTCN2022090675-appb-000034
本发明提供了一种上述的如式I-1或I-2所示的化合物的制备方法，其为如下方法1、2、3或4：
方法1：
当R 4为-S(O) 2OH时，所述的如式I-1所示的化合物的制备方法包括如下步骤：在酸性试剂下，将化合物II-a在溶剂中进行如下式的酸化反应，得到所述的如式I-1化合物；
Figure PCTCN2022090675-appb-000035
其中，Z和Z’独立地为羟基或-SO 3M 1a；M 1a独立地为Na或K；R 13和R 13‘独立地为-ONa、-OK或-NR 2aR 2b；R 2a和R 2b定义均如前所述；
方法2：
当R 4为OH时，所述的如式I-1所示的化合物的制备方法包括如下步骤：在酸性试剂或BBr 3存在下，将化合物II-b在溶剂中进行如下式的脱保护反应，得到所述的如式I-1化合物；
Figure PCTCN2022090675-appb-000036
其中，R 15和R 15’独立地为羟基保护基或C 1-3烷基；M 2a和M 2b独立地为Na或K；
方法3：
当两个R 4一起形成
Figure PCTCN2022090675-appb-000037
时，所述的如式I-1所示的化合物的制备方法包括如下步骤：
步骤(1)：将方法2中得到化合物I-1和三氯氧磷在溶剂中进行酯化反应，得到混合溶液；
步骤(2)：将步骤(1)得到混合溶液在水中进行水解反应，得到所述的如式I-1化合物；
Figure PCTCN2022090675-appb-000038
方法4：
当R 4为-S(O) 2OH时，所述的如式I-1或I-2所示的化合物的制备方法包括如下步骤：在氧化剂和甲酸存在下，将化合物II-d在溶剂中进行如下式的氧化反应，得到所述的如式I-1或I-2所示的化合物；
Figure PCTCN2022090675-appb-000039
其中，R 16a和R 16b独立地为C 1-3烷基；
R 18为R 3，R 18a为-S(O 2)R 2；或者，R 18为R 5，R 18a为R 6；
R 19为-S(O 2)R 2’，R 19a为R 3’；或者，R 19为R 6’，R 19a为R 5’；
R 2、R 2’、R 3、R 3’、R 5、R 5’、R 6和R 6’的定义均同前所述。
方法1中，所述的酸化反应的条件和操作可以为本领域中该类酸化反应的常规的条件和操作，本发明特别优选如下条件和操作：
方法1中，所述的酸化反应在阳离子交换树脂(例如Amberlyst 15)上进行(例如采用醇类溶剂(例如甲醇)作为洗脱剂)。
方法2中，所述的脱保护反应的条件和操作可以为本领域中该类反应的常规的条件和操作。
当所述的脱保护反应在酸性试剂存在下进行时，本发明特别优选如下条件和操作：
所述的酸性试剂可以为盐酸(例如12mol/L盐酸)。
所述的酸性试剂与所述的化合物II-b的摩尔比可以为5:1-25:1(例如10:1)。
所述的溶剂可以为醚类溶剂(例如二氧六环)。
所述的脱保护反应的温度可以为30-80℃(例如60℃)。
当所述的脱保护反应在BBr 3存在下进行时，本发明特别优选如下条件和操作：
所述的酸性试剂可以为盐酸(例如12mol/L盐酸)。
所述的BBr 3与所述的化合物II-b的摩尔比可以为5:1-25:1(例如10:1)。
所述的溶剂可以为卤代烃类溶剂(例如二氯甲烷)。
所述的脱保护反应的温度可以为-78--60℃(例如-78℃)。
方法2中，所述的脱保护反应的进程可以采用本领域常规的方法进行监测(例如TLC、LC-MS)。本发明中，以所述的化合物II-b不再反应或者消失作为反应的终点。所述的脱保护反应的时间为2-16小时(例如5小时)。
方法3中，所述的酯化反应的条件和操作可以为本领域中该类反应的常规的条件和操作，本发明特别优选如下条件和操作：
方法3中，所述的溶剂可以为吡啶。
方法3中，所述的三氯氧磷与所述的化合物I-1的摩尔比可以为1:1-6:1(例如4:1)。
方法3中，所述的酯化反应的温度可以为50-110℃(例如95℃)。
方法3中，所述的酯化反应的条件和操作可以为本领域中该类反应的常规的条件和操作，例如在100℃水解4小时。
方法4中，所述的氧化反应的条件和操作可以为本领域中该类反应的常规的条件和操作，本发明特别优选如下条件和操作：
方法4中，所述的氧化剂可以为双氧水。
方法4中，所述的氧化剂与所述的化合物II-d的摩尔比可以为1:1-3:1(例如1.3:1)。
方法4中，所述的溶剂可以为氯代烃类溶剂(例如二氯甲烷)。
方法4中，所述的如式I-1或如式I-2化合物的制备方法还可进一步包括如下步骤：在280-300℃下，将化合物III-d进行重排反应，得到所述的化合物II-d；
Figure PCTCN2022090675-appb-000040
所述的重排反应的条件可以为本领域此类反应常规的条件和操作，例如在保护气体(例如氮气)下反应；在290℃反应45分钟。
方法4中，所述的如式I-1或如式I-2化合物的制备方法还可进一步包括如下步骤：在碱性试剂存在下，将化合物IV-d和化合物V-d在溶剂中进行反应，得到所述的化合物III-d；
Figure PCTCN2022090675-appb-000041
其中，所述的碱性试剂可以为NaH。所述的溶剂可以为酰胺类溶剂(例如N,N-二甲基甲酰胺)。所述的反应的温度可以为50-100℃(例如85℃)。
本发明提供了一种上述的如式I-1或I-2所示的化合物作为催化剂在制备化合物B中的应用；
所述的化合物B的制备方法包括以下步骤：在所述的如式I-1或I-2所示的化合物和钛盐存在下，将化合物A在溶剂中进行如下式的环合反应，得到所述的化合物B；
Figure PCTCN2022090675-appb-000042
其中，R 8、R 9、R 10和R 11独立地为H、卤素、C 1-6烷基、-O-C 1-6烷基、氰基、-C(＝O)OR 8-1、C 3- 6环烷基、C 6-18芳基或被R 8-2取代的C 6-18芳基(R 8-1个数为1个或多个，例如1、2或3个)；
R 8-1为C 1-6烷基；
R 8-2为C 2-6烯基或羟基；
或者，R 8、R 9、R 10和R 11中任意相邻的两个取代基与其相连的碳原子一起形成C 3-6环烷基、C 6-18芳基或
Figure PCTCN2022090675-appb-000043
R 12和R 13独立地为H、C 1-6烷基或C 6-18芳基，或者，R 12和R 13与其相连的碳原子一起形成C 3-6环烷基；
n为1、2或3。
在本发明一优选技术方案中，当R 8、R 9、R 10和R 11独立地为C 1-6烷基或-O-C 1-6烷基时，所述的C 1-6烷基或所述的-O-C 1-6烷基中的C 1-6烷基为甲基、乙基、正丙基或异丙基，例如甲基。
在本发明一优选技术方案中，当R 8、R 9、R 10和R 11独立地为C 3-6环烷基时，所述的C 3-6环烷基为环丙基、环丁基、环戊基或环己基，例如环己基。
在本发明一优选技术方案中，当R 8、R 9、R 10和R 11独立地为C 6-18芳基或被R 8-1取代的C 6-18芳基时，所述的C 6-18芳基或所述的被R 8-1取代的C 6-18芳基中的C 6-18芳基为苯基、萘基、菲基或蒽基，优选为苯基。
在本发明一优选技术方案中，当R 8-1为C 1-6烷基时，所述的C 1-6烷基为甲基、乙基、正丙基或异丙基，例如甲基。
在本发明一优选技术方案中，当R 8-2为C 2-6烯基时，所述的C 2-6烯基为乙烯基或丙烯基，进一步为
Figure PCTCN2022090675-appb-000044
在本发明一优选技术方案中，当R 8、R 9、R 10和R 11中任意相邻的两个取代基与其相连的碳原子一起形成C 3-6环烷基时，所述的C 3-6环烷基为环丙基、环丁基、环戊基或环己基，例如环己基。
在本发明一优选技术方案中，当R 8、R 9、R 10和R 11中任意相邻的两个取代基与其相连的碳原子一起形成C 6-18芳基时，所述的C 6-18芳基为苯基、萘基、菲基或蒽基，例如苯基(即即化合物A中
Figure PCTCN2022090675-appb-000045
为萘基，例如
Figure PCTCN2022090675-appb-000046
)。
在本发明一优选技术方案中，当R 12和R 13独立地为C 1-6烷基时，所述的C 1-6烷基为甲基、乙基、正丙基或异丙基，例如甲基。
在本发明一优选技术方案中，当R 12和R 13独立地为C 6-18芳基时，所述的C 6-18芳基为苯基、萘基、菲基或蒽基，例如苯基。
在本发明一优选技术方案中，当R 12和R 13与其相连的碳原子一起形成C 3-6环烷基时，所述的C 3- 6环烷基为环丙基、环丁基、环戊基或环己基，例如环己基。
在本发明一优选技术方案中，所述的化合物A为
Figure PCTCN2022090675-appb-000047
Figure PCTCN2022090675-appb-000048
Figure PCTCN2022090675-appb-000049
在本发明一优选技术方案中，当所述的如式I-1或I-2所示的化合物为
Figure PCTCN2022090675-appb-000050
Figure PCTCN2022090675-appb-000051
时；所述的化合物B为
Figure PCTCN2022090675-appb-000052
在本发明一优选技术方案中，当所述的如式I-1或I-2所示的化合物为
Figure PCTCN2022090675-appb-000053
Figure PCTCN2022090675-appb-000054
时；所述的化合物B为
Figure PCTCN2022090675-appb-000055
所述的环合反应的条件和操作可以为本领域此类反应常规的条件和操作，本发明特别优选以下条件和操作：
所述的环化反应中，所述的有机溶剂优选为烷烃类溶剂(例如环己烷)、芳烃类溶剂(例如甲苯)和卤代烃类溶剂(例如1,2-二氯乙烷)中的一种或多种。
所述的环化反应中，所述的式A化合物在所述的有机溶剂中的摩尔浓度可以为0.005-1mol/L。
所述的环化反应中，所述的钛盐优选四甲醇钛、四异丙醇钛、四叔丁醇钛、四异丁醇钛、四氯化 钛、氯化三异丙醇钛、异辛醇钛中的一种或多种，例如异辛醇钛。
所述的环化反应中，所述的钛盐与所述的式A化合物的摩尔比可以为0.02:1-0.2:1(例如0.1:1)。
所述的环化反应中，所述的如式I-1或I-2所示的化合物与所述的式A化合物的摩尔比优选为0.02:1-0.2:1(例如0.05:1)。
所述的环化反应的反应温度优选为40-200℃，例如70-90℃。
所述的环化反应的进程可采用本领域中的常规监测方法(如TLC、HPLC或NMR)进行监控。本发明以所述的式A化合物不再反应时作为反应终点。所述的环化反应的时间优选为20-26小时，例如24小时。
所述的环化反应的后处理可以为本领域此类反应常规的后处理，例如采用柱层析(洗脱剂为石油醚：乙酸乙酯＝50:1)进行后处理。
本发明还提供了一种催化剂组合物，其包括上述的如式I-1或I-2所示的化合物和钛盐。
所述的催化剂组合物中，所述的钛盐优选四甲醇钛、四异丙醇钛、四叔丁醇钛、四异丁醇钛、四氯化钛、氯化三异丙醇钛、异辛醇钛中的一种或多种，例如异辛醇钛。
本发明还提供了一种上述的催化剂组合物作为催化剂在制备上述的化合物B中的应用；
所述的化合物B的制备方法包括以下步骤：在所述的如式I-1和/或I-2所示的化合物和钛盐存在下，将化合物A在溶剂中进行如下式的环合反应，得到所述的化合物B；
Figure PCTCN2022090675-appb-000056
所述的化合物B的制备方法的条件和操作均同前所述。
本发明还提供了上述的化合物II-a、上述的化合物II-b、上述的化合物II-d、上述的化合物III-d或上述的化合物IV-d：
Figure PCTCN2022090675-appb-000057
Figure PCTCN2022090675-appb-000058
其中，所述的化合物IV-d不为
Figure PCTCN2022090675-appb-000059
在本发明一优选技术方案中，所述的化合物II-a、所述的化合物II-b、所述的化合物II-d、所述的化合物III-d或所述的化合物IV-d为如下通式：
Figure PCTCN2022090675-appb-000060
在本发明一优选技术方案中，所述的化合物II-a、所述的化合物II-b、所述的化合物II-d、所述的化合物III-d或所述的化合物IV-d为如下任一化合物和/或其异构体：
Figure PCTCN2022090675-appb-000061
Figure PCTCN2022090675-appb-000062
Figure PCTCN2022090675-appb-000063
Figure PCTCN2022090675-appb-000064
Figure PCTCN2022090675-appb-000065
本发明中，所述的如式I-1或I-2所示的化合物“化合物”可具有一个或多个手性碳原子，因此可以分离得到光学纯度异构体，例如纯的对映异构体，或者外消旋体，或者混合异构体。可以通过本领域的分离方法来获得纯的单一异构体，如手性结晶成盐，或者手性制备柱分离得到。
本发明中，所述的如式I-1或I-2所示的化合物如存在立体异构体，则可以以单一的立体异构体或它们的混合物(例如外消旋体)的形式存在。术语“立体异构体”是指顺反异构体或旋光异构体。这些立体异构体可以通过不对称合成方法或手性分离法(包括但不限于薄层色谱、旋转色谱、柱色谱、气相色谱、高压液相色谱等)分离、纯化及富集，还可以通过与其它手性化合物成键(化学结合等)或成盐(物理结合等)等方式进行手性拆分获得。术语“单一的立体异构体”是指本发明化合物的一种立体异构体相对于该化合物的所有立体异构体的质量含量不低于95％。
术语“烷基”是指具有指定的碳原子数(例如C 1-C 16)的直链或支链烷基。烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基、正庚基、正辛基 等。
术语“环烷基”是指具有指定的碳原子数(例如C 3～C 6)的、仅由碳原子组成的、饱和的单环环状基团。环烷基包括但不限于环丙基、环丁基、环戊基、环己基等。
术语“芳基”是指具有指定的碳原子数(例如C 6～C 10)的、仅由碳原子组成的环状基团，其为单环或多环，且至少一个环具有芳香性(符合休克尔规则)。芳基通过具有芳香性的环或不具有芳香性的环与分子中的其他片段连接。芳基包括但不限于苯基、萘基等。
结构片段中的
Figure PCTCN2022090675-appb-000066
是指该结构片段通过该位点与分子中的其他片段连接。例如，
Figure PCTCN2022090675-appb-000067
是指环己基。
术语“多个”是指2个、3个、4个或5个。
术语“烯基”是指具有2-10个碳原子、一个或多个碳碳双键并且没有碳碳三键的直链或支链的烃基团(“C 2-C 20烯基)”。该一个或多个碳碳双键可以是内部的(例如在2-丁烯基中)或末端的(例如在1-丁烯基中)。
术语“羟基保护基”在本领域是熟知的并且包括那些详细描述于在有机合成中的保护基团(Protecting Groups in Organic Synthesis)，T.W.Greene以及P.G.M.Wuts，第三版，约翰威利国际出版公司(John Wiley&Sons)，1999，通过引用结合在此。示例性氧保护基团包括但不限于，甲基、甲氧基甲基(MOM)、甲基硫代甲基(MTM)、(苯基二甲基甲硅烷基)甲氧基甲基(SMOM)、苄基氧甲基(BOM)、对甲氧基苄基氧甲基(PMBM)、(4-甲氧基苯氧基)甲基(p-AOM)、愈创木酚甲基(GUM)、叔丁氧基甲基、4-戊烯基氧甲基(POM)、硅氧基甲基、2-甲氧基乙氧基甲基(MEM)、2-(三甲基硅烷基)乙氧基甲基(SEMOR)、四氢吡喃基(THP)、4-甲氧基四氢吡喃基(MTHP)、1-[(2-氯-4-甲基)苯基]-4-甲氧基哌啶-4-基(CTMP)、1-乙氧基乙基、1-(2-氯乙氧基)乙基、2-三甲基硅烷基乙基、2-(苯基氢硒基)乙基、叔丁基、烯丙基、对氯苯基、对甲氧基苯基、2,4-二硝基苯基、苄基(Bn)、对甲氧基苄基、3,4-二甲氧基苄基、邻硝基苄基、对硝基苄基、对卤代苄基、三甲基硅烷基(TMS)、三乙基甲硅烷基(TES)、三异丙基甲硅烷基(TIPS)、二甲基异丙基甲硅烷基(IPDMS)、二乙基异丙基甲硅烷基(DEIPS)、二甲基己基甲硅烷基、叔丁基二甲基甲硅烷基(TBDMS)、叔丁基二苯基甲硅烷基(TBDPS)、三苄基甲硅烷基、三-对二甲苯基甲硅烷基、三苯基甲硅烷基、二苯基甲基甲硅烷基(DPMS)、叔丁基甲氧基苯基甲硅烷基(TBMPS)、甲酸酯、9-芴基甲基碳酸酯(Fmoc)、2-(三甲基硅烷基)乙基碳酸酯(TMSEC)、2-(苯磺酰基)乙基碳酸酯(Psec)、2-(三苯基磷基)乙基碳酸酯(Peoc)、硫酸酯、甲磺酸酯(mesylate)、苄基磺酸酯以及甲苯磺酸酯(Ts)。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的多元磺酸类化合物，可以在温和条件下，实现未活化烯烃的不对称加氢烷氧基环化反应，尤其当以手性多元磺酸类化合物作为催化剂时，还可以高对映选择性 制备此类含氧环类化合物。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1
本实施例为式15化合物的制备方法，共分2步，合成路线如下:
Figure PCTCN2022090675-appb-000068
包括以下步骤：
(1.1)第1步：
优选地，对于路线a胺化的反应条件是：在容量合适的圆底烧瓶中加入二甲胺(2.0当量)的四氢呋喃溶液(所加体积使式13化合物摩尔浓度为1.0mol/L)，向其中依次加入溴化苯磺酰氯化合物式13(1.0当量)，三乙胺(1.1当量)和4-二甲氨基吡啶(0.2当量)，室温下搅拌12小时。通过薄层色谱点板分析该反应是否进行完全。随后该反应用1M的盐酸溶液淬灭，乙酸乙酯萃取三次后所得的有机相用饱和食盐水洗涤一次，无水硫酸钠干燥后减压下旋转蒸发除去溶剂，剩余物通过硅胶柱色谱纯化(洗脱剂为石油醚和乙酸乙酯)，得到对应溴化苯磺酰胺产物式14a-f。
优选地，对于路线b酯化的反应条件是：在容量合适的圆底烧瓶中加入氢化钠(1.1当量)的四氢呋喃溶液(所加体积使式13化合物摩尔浓度为2.2mol/L)，降温至0℃后向其中缓慢加入乙醇(1.0当量)，升温至室温下搅拌1小时。再降温至0℃，缓慢加入溴化苯磺酰氯化合物式13(1.1当量)，并于0℃下搅拌2小时。反应完毕后用水淬灭，乙酸乙酯萃取三次后所得的有机相用饱和食盐水洗涤一次，无水硫酸钠干燥后减压下旋转蒸发除去溶剂，剩余物通过硅胶柱色谱纯化(洗脱剂为石油醚和乙酸乙酯)，得到对应溴化磺酸乙酯产物式14g-i。
式14a化合物的合成
Figure PCTCN2022090675-appb-000069
通过使用优选的路线a胺化反应条件，从溴化苯磺酰氯化合物式13a得到白色固体化合物14a(大于99％收率)。R f＝0.32(PE/EA＝30/1). 1H NMR(400MHz,CDCl 3)δ7.98(d,J＝2.2Hz,1H),7.54(dd,J＝8.2,2.2Hz,1H),7.17(d,J＝8.2Hz,1H),2.79(s,6H),2.53(s,3H). 13C NMR(101MHz,CDCl 3)δ137.8, 136.9,135.6,134.4,132.5,119.5,37.1,20.2.IR(neat)3084,2933,1463,1318,1136,1059,960,821,739,582,489cm -1.HRMS(ESI+)m/z:[M+H] +计算值C 9H 13BrNO 2S +277.9845,测量值277.9837.
式14b化合物的合成
Figure PCTCN2022090675-appb-000070
通过使用优选的路线a胺化反应条件，从溴化苯磺酰氯化合物式13b得到白色固体化合物14b(大于99％收率)。R f＝0.36(PE/EA＝10/1). 1H NMR(500MHz,CDCl 3)δ7.91(s,1H),7.77–7.70(dd,J＝7.7Hz,2H),7.47(t,J＝7.5Hz,1H),2.74(s,6H). 13C NMR(126MHz,CDCl 3)δ137.1,135.4,130.4,130.0,125.9,122.7,37.5.IR(neat)2970,1570,1461,1339,1167,953,777,679,584,475cm -1.HRMS(ESI+)m/z:[M+H] +计算值C 8H 11BrNO 2S +263.9689,测量值263.9675.
式14c化合物的合成
Figure PCTCN2022090675-appb-000071
通过使用优选的路线a胺化反应条件，从溴化苯磺酰氯化合物式13c得到无色液体化合物14c(大于99％收率)。R f＝0.48(PE/EA＝30/1). 1H NMR(400MHz,CDCl 3)δ7.99(d,J＝2.1Hz,1H),7.59(dd,J＝8.3,2.2Hz,1H),7.24(d,J＝8.3Hz,1H),2.95–2.86(m,2H),2.81(s,6H),1.67–1.55(m,2H),1.40–1.23(m,4H),0.87(t,J＝12.6,8.9,7.9Hz,3H). 13C NMR(101MHz,CDCl 3)δ142.2,137.6,135.7,133.5,132.6,119.4,37.2,32.9,32.1,31.4,27.0,22.6,14.1.HRMS(APCI+)m/z:[M+H] +计算值C 13H 21BrNO 2S +334.0471,测量值334.0454.
式14d化合物的合成
Figure PCTCN2022090675-appb-000072
通过使用优选的路线a胺化反应条件，从溴化苯磺酰氯化合物式13d得到白色固体化合物14d(92％收率)。R f＝0.25(PE/EA＝10/1). 1H NMR(500MHz,CDCl 3)δ8.93(s,1H),8.21(d,J＝7.3Hz,1H),8.03(d,J＝8.2Hz,1H),7.79(d,J＝8.7Hz,1H),7.67(d,J＝8.8,1.9Hz,1H),7.57(t,J＝7.8Hz,1H),2.82(s,6H). 13C NMR(126MHz,CDCl 3)δ134.0,132.6,132.0,131.0,130.3,130.1,129.9,127.6,124.5,122.7,37.2.HRMS(ESI+)m/z:[M+H] +计算值C 12H 13BrNO 2S +313.9845,测量值313.9845.
式14e化合物的合成
Figure PCTCN2022090675-appb-000073
与所述的路线a胺化反应条件比较，式14e化合物的合成方法有所不同。本步反应中用二乙胺(2.0当量)代替所述合成路线中的二甲胺(2.0当量)，其余操作或当量使用不作改变。从溴化苯磺 酰氯化合物式13a得到白色固体化合物14e(93％收率)。R f＝0.33(PE/EA＝30/1). 1H NMR(400MHz,CDCl 3)δ8.01(d,J＝2.2Hz,1H),7.51(dd,J＝8.1,2.2Hz,1H),7.15(d,J＝8.1Hz,1H),3.30(q,J＝7.2Hz,4H),2.51(s,3H),1.12(t,J＝7.2Hz,6H). 13C NMR(101MHz,CDCl 3)δ140.4,136.5,135.3,134.3,132.1,119.4,41.0,19.9,13.8.HRMS(ESI+)m/z:[M+H] +计算值C 11H 17BrNO 2S +306.0158,测量值306.0156.
式14f化合物的合成
Figure PCTCN2022090675-appb-000074
与所述的路线a胺化反应条件比较，式14f化合物的合成方法有所不同。本步反应中二甲胺的使用量为4.0当量来代替所述路线中的2.0当量，其余操作或当量使用不作改变。从溴化苯磺酰氯化合物式13f得到白色固体化合物14f(70％收率)。R f＝0.54(DCM). 1H NMR(500MHz,CDCl 3)δ8.08(s,2H),8.02(s,1H),2.76(s,12H). 13C NMR(126MHz,CDCl 3)δ139.3,134.0,125.0,124.2,37.9.HRMS(ESI+)m/z:[M+H] +计算值C 10H 16BrN 2O 4S 2 +370.9730,测量值370.9720.
式14g化合物的合成
Figure PCTCN2022090675-appb-000075
通过使用优选的路线b酯化反应条件，从溴化苯磺酰氯化合物式13a得到白色固体化合物14g(84％收率)。R f＝0.20(PE/EA＝30/1). 1H NMR(400MHz,CDCl 3)δ8.07(d,J＝2.2Hz,1H),7.60(dd,J＝8.2,2.2Hz,1H),7.22(d,J＝8.2Hz,1H),4.10(q,J＝7.1Hz,2H),2.56(s,3H),1.30(t,J＝7.1Hz,3H). 13C NMR(101MHz,CDCl 3)δ137.2,136.5,136.4,134.2,132.4,119.5,67.4,19.7,14.8.HRMS(ESI+)m/z:[M+H] +计算值C 9H 12BrO 3S +278.9686,测量值278.9686.
式14h化合物的合成
Figure PCTCN2022090675-appb-000076
通过使用优选的路线b酯化反应条件，从溴化苯磺酰氯化合物式13b得到无色液体化合物14h(87％收率)。R f＝0.48(PE/EA＝10/1). 1H NMR(500MHz,CDCl 3)δ8.05(s,1H),7.85(d,J＝7.9Hz,1H),7.79(d,J＝7.3Hz,1H),7.46(t,J＝8.0Hz,1H),4.17(q,J＝7.1Hz,2H),1.34(t,J＝7.2Hz,3H). 13C NMR(126MHz,CDCl 3)δ137.9,136.6,130.6,130.5,126.2,123.0,67.4,14.6.HRMS(ESI+)m/z:[M+H] +计算值C 8H 10BrO 3S +264.9529,测量值264.9524.
式14i化合物的合成
Figure PCTCN2022090675-appb-000077
通过使用优选的路线b酯化反应条件，从溴化苯磺酰氯化合物式13d得到白色固体化合物14i(82％ 收率)。R f＝0.20(PE/EA＝10/1). 1H NMR(500MHz,CDCl 3)δ8.79(s,1H),8.29(d,J＝7.4Hz,1H),8.09(d,J＝8.3Hz,1H),7.81(d,J＝8.7Hz,1H),7.70(dd,J＝8.8,1.9Hz,1H),7.58(t,J＝7.8Hz,1H),4.11(q,J＝7.1Hz,2H),1.28(t,J＝7.1Hz,3H).HRMS(ESI+)m/z:[M+H] +计算值C 12H 12BrO 3S +314.9686,测量值314.9677.
(1.2)第2步：
优选地，路线a和b中的硼酸酯化反应条件相同，具体如下：氮气保护下，在容量合适的圆底烧瓶里将第1步得到的溴化磺酰胺化合物或磺酸乙酯化合物式14(1.0当量)溶解在四氢呋喃(0.65mol/L)中，然后降温至-78℃。向上述的反应溶液中慢慢地滴加正丁基锂(1.2当量)，滴加完后保持在-78℃下搅拌1.5小时，然后慢慢加入异丙醇频哪硼酸酯(3.0当量)，加完后缓慢升温至室温，并在室温下搅拌12小时。反应结束后，用饱和氯化铵水溶液淬灭反应，用乙醚萃取三次，萃取出的乙醚溶液用水、饱和食盐水依次各洗涤一次，无水硫酸镁干燥后减压下旋转蒸发除去溶剂，剩余物通过硅胶柱色谱纯化(洗脱剂为石油醚和乙酸乙酯)得到各自的硼酸酯产物式15。
式15a化合物的合成
Figure PCTCN2022090675-appb-000078
通过使用优选的硼酸酯化反应条件，从磺酰胺化合物式14a得到白色固体化合物15a(99％收率)。R f＝0.32(PE/EA＝30/1). 1H NMR(400MHz,CDCl 3)δ8.28(d,J＝1.3Hz,1H),7.84(dd,J＝7.5,1.3Hz,1H),7.30(d,J＝7.5Hz,1H),2.79(s,6H),2.62(s,3H),1.32(s,12H). 13C NMR(101MHz,CDCl 3)δ141.2,139.0,136.3,135.6,133.6,132.3,84.3,37.2,25.0,21.0.IR(neat)2978,1316,1275,1138,965,851,719,668,555cm -1.HRMS(ESI+)m/z:[M+H] +计算值C 15H 25BNO 4S +326.1592,测量值326.1590.
式15b化合物的合成
Figure PCTCN2022090675-appb-000079
通过使用优选的硼酸酯化反应条件，从磺酰胺化合物式14b得到白色固体化合物15b(99％收率)。R f＝0.36(PE/EA＝10/1). 1H NMR(400MHz,CDCl 3)δ8.20(s,1H),8.03(d,J＝7.4,1.3Hz,1H),7.86(d,J＝8.0,1.6Hz,1H),7.55(t,J＝2.7Hz,1H),2.72(s,6H),1.35(s,12H). 13C NMR(101MHz,CDCl 3)δ138.9,135.0,133.7,131.6,130.2,128.3,84.4,38.0,24.9.IR(neat)2977,1335,1142,956,749,584cm -1.HRMS(ESI+)m/z:[M+H] +计算值C 14H 23BNO 4S +312.1436,测量值312.1433.
式15c化合物的合成
Figure PCTCN2022090675-appb-000080
通过使用优选的硼酸酯化反应条件，从磺酰胺化合物式14c得到无色液体化合物15c(99％收率)。R f＝0.48(PE/EA＝30/1). 1H NMR(500MHz,CDCl 3)δ8.27(d,J＝1.4Hz,1H),7.87(dd,J＝7.6,1.3Hz,1H),7.35(d,J＝7.6Hz,1H),3.00–2.93(m,2H),2.78(s,6H),1.67–1.57(m,2H),1.42–1.33(m,3H),1.32(s,12H),0.87(t,3H). 13C NMR(126MHz,CDCl 3)δ146.3,138.9,136.4,135.2,131.3,84.2,37.1,33.5,32.1,31.4,27.0,24.9,22.6,14.1.HRMS(ESI+)m/z:[M+H] +计算值C 19H 33BNO 4S +382.2218,测量值382.2214.
式15d化合物的合成
Figure PCTCN2022090675-appb-000081
通过使用优选的硼酸酯化反应条件，从磺酰胺化合物式14d得到白色固体化合物15d(99％收率)。R f＝0.25(PE/EA＝10/1). 1H NMR(500MHz,CDCl 3)δ9.19(s,1H),8.20(d,J＝7.3,1.2Hz,1H),8.03(d,J＝8.3Hz,1H),7.93(d,J＝8.2Hz,1H),7.88(d,J＝8.2Hz,1H),7.55(t,J＝7.8Hz,1H),2.84(s,6H),1.36(s,12H). 13C NMR(126MHz,CDCl 3)δ139.9,134.1,133.8,133.0,130.9,129.7,129.5,126.6,124.5,124.1,75.1,37.5,24.9.HRMS(ESI+)m/z:[M+H] +计算值C 18H 25BNO 4S +362.1592,测量值362.1589.
式15e化合物的合成
Figure PCTCN2022090675-appb-000082
通过使用优选的硼酸酯化反应条件，从磺酰胺化合物式14e得到淡黄色固体化合物15e(99％收率)。R f＝0.33(PE/EA＝30/1). 1H NMR(500MHz,CDCl 3)δ8.32(s,1H),7.83(d,J＝7.5Hz,1H),7.28(d,J＝7.4Hz,1H),3.32(q,J＝7.4Hz,4H),2.61(s,3H),1.34(s,12H),1.13(t,J＝8.2,5.8Hz,6H). 13C NMR(126MHz,CDCl 3)δ140.9,138.8,138.2,135.8,132.2,131.7,84.3,40.8,25.0,20.7,13.8. 11B NMR(160MHz,CDCl 3)δ30.8.HRMS(ESI+)m/z:[M+H] +计算值C 17H 29BNO 4S +354.1905,测量值354.1903.
式15f化合物的合成
Figure PCTCN2022090675-appb-000083
通过使用优选的硼酸酯化反应条件，从磺酰胺化合物式14f得到固体化合物15f(99％收率)。 1H NMR(400MHz,CDCl 3)δ8.37(d,J＝1.9Hz,2H),8.22(t,J＝1.9Hz,1H),2.76(s,12H),1.36(s,12H). 13C NMR(126MHz,CDCl 3)δ137.3,134.0,129.0,126.3,85.1,38.1,25.0.HRMS(ESI+)m/z:[M+H] +计算值C 16H 28BN 2O 6S 2 +419.1477,测量值419.1476.
式15g化合物的合成
Figure PCTCN2022090675-appb-000084
通过使用优选的硼酸酯化反应条件，从磺酸乙酯化合物式14g得到白色固体化合物15g(63％收率)。R f＝0.20(PE/EA＝30/1). 1H NMR(400MHz,CDCl 3)δ8.40(d,J＝1.3Hz,1H),7.92(dd,J＝7.5,1.3Hz,1H),7.36(d,J＝7.6Hz,1H),4.09(q,J＝7.1Hz,2H),2.67(s,3H),1.35(s,12H),1.33–1.24(m,3H). 13C NMR(101MHz,CDCl 3)δ141.2,139.8,136.0,134.2,132.0,126.1,84.3,66.7,24.8,20.5,14.7.HRMS(ESI+)m/z:[M+H] +计算值C 15H 24BO 5S +327.1433,测量值327.1430.
式15h化合物的合成
Figure PCTCN2022090675-appb-000085
通过使用优选的硼酸酯化反应条件，从磺酸乙酯化合物式14h得到白色固体化合物15h(75％收率)。R f＝0.50(PE/EA＝10/1). 1H NMR(400MHz,CDCl 3)δ8.35(s,1H),8.06(d,J＝7.4Hz,1H),7.98(d,J＝8.0Hz,1H),7.56(t,J＝7.6Hz,1H),4.13(q,J＝7.1Hz,2H),1.36(s,12H),1.30(d,J＝7.1Hz,3H). 13C NMR(101MHz,CDCl 3)δ139.8,135.8,133.8,130.2,128.6,84.5,67.0,24.9,24.8,14.7.HRMS(ESI+)m/z:[M+H] +计算值C 14H 22BO 5S +313.1276,测量值313.1268.
式15i化合物的合成
Figure PCTCN2022090675-appb-000086
通过使用优选的硼酸酯化反应条件，从磺酸乙酯化合物式14i得到白色固体化合物15i(90％收率)。R f＝0.20(PE/EA＝10/1). 1H NMR(500MHz,CDCl 3)δ9.08(s,1H),8.28(dd,J＝7.4,1.2Hz,1H),8.10(d,J＝8.2Hz,1H),7.98(d,J＝8.1Hz,1H),7.92(d,J＝8.2Hz,1H),7.57(t,J＝7.8Hz,1H),4.14(q,J＝7.1Hz,2H),1.38(s,12H),1.28(t,J＝7.1Hz,3H). 13C NMR(126MHz,CDCl 3)δ135.6,135.0,132.4,132.2,131.9,130.2,127.8,127.8,124.9,84.2,67.1,25.0,24.9,14.7.HRMS(ESI+)m/z:[M+H] +计算值C 18H 24BO 5S +363.1433,测量值363.1430.
实施例2
本实施例为式(R)-1化合物的制备方法，共分8步，合成路线如下：
Figure PCTCN2022090675-appb-000087
包括以下步骤：
(2.1)第1步：
优选地，卤化反应条件是：氮气保护下，在容量合适的圆底烧瓶里将起始原料式(R)-3(1.0当量)溶解在四氢呋喃(0.1mol/L)中，然后降温至-78℃。向上述的反应溶液中慢慢地滴加正丁基锂(3.5当量),滴加完后保持在-78℃下搅拌30分钟，随后升温至室温下再搅拌3小时，直到有浅棕色的浑浊物生成。随后再降温至-78℃，加入碘单质(3.75当量)，加完后缓慢升温至室温，并在室温下搅拌12小时。反应结束后，用饱和亚硫酸钠水溶液淬灭反应，用乙醚进行萃取，萃取出的乙醚溶液依次用水、饱和食盐水洗涤，无水硫酸钠干燥后减压下旋转蒸发除去溶剂，剩余物通过硅胶柱色谱纯化(洗脱剂为石油醚和乙酸乙酯)得到卤化产物式(R)-4。
式(R)-4b化合物的合成
Figure PCTCN2022090675-appb-000088
通过使用优选的卤化反应条件，从起始原料式(R)-3b化合物得到黄褐色油状化合物(R)-4b(27％收率)。R f＝0.62(PE/EA＝30/1). 1H NMR(500MHz,CDCl 3)δ8.47(s,2H),7.54(s,2H),7.16(d,J＝8.7,1.6Hz,2H),7.12(d,J＝8.7,2.0Hz,2H),4.81(d,J＝5.7Hz,2H),4.70(d,J＝5.7Hz,2H),2.73(t,J＝7.7Hz,4H),2.62(s,6H),1.68(m,J＝7.3Hz,4H),1.28(m,52H),0.90(t,J＝6.7Hz,6H). 13C NMR(126MHz,CDCl 3)δ151.5,151.5,140.6,139.5,132.6,132.4,128.8,126.5,126.3,125.1,99.5,92.4,56.6,35.9,32.1,31.2,29.8,29.8,29.8,29.7,29.6,29.5,29.5,22.8,14.3.HRMS(APCI+)m/z:[M+H] +计算值C 56H 85I 2O 4 +1075.4537,测量值1075.4547.
式(R)-4c化合物的合成
Figure PCTCN2022090675-appb-000089
通过使用优选的卤化反应条件，从起始原料式(R)-3c化合物得到白色固体物化合物式(R)-4c(70％收率)。R f＝0.55(PE/EA＝30/1). 1H NMR(400MHz,CDCl 3)δ8.49(s,2H),7.62(d,J＝2.0Hz,2H),7.37(dd,J＝9.0,2.0Hz,2H),7.12(d,J＝8.9Hz,2H),4.77(d,J＝5.5Hz,2H),4.67(d,J＝5.5Hz,2H),2.63(s,6H),2.15–2.09(m,6H),1.95(d,J＝2.9Hz,12H),1.78(m,12H). 13C NMR(101MHz,CDCl 3)δ151.5,149.0,140.1,132.6,132.2,126.3,126.1,125.6,121.8,99.4,92.1,56.8,43.1,36.9,36.4,29.0.HRMS(APCI+)m/z:[M+H] +计算值C 44H 49I 2O 4 +895.1715,测量值895.1719.
式(R)-4d化合物的合成
Figure PCTCN2022090675-appb-000090
与所述的卤化条件比较，式(R)-4d的合成有所不同。由于起始原料类型不同，优选地，式(R)-4d化合物合成步骤如下：氮气保护下，在100mL圆底烧瓶里将氢化钠(60％，分散于矿物油中，2.10g,52.5mmol)溶解在40mL的四氢呋喃中，然后降温至0℃。向上述的反应溶液中慢慢加入式(R)-3d(8.50g,15.0mmol),加完后保持在0℃下搅拌1.5小时。随后缓慢加入溴甲基甲基醚(5.62g,45.0mmol)，并保持在0℃下搅拌30分钟。通过薄层色谱点板分析，一旦反应结束，0℃下用饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取三次，萃取出的乙酸乙酯溶液用饱和食盐水洗涤，无水硫酸钠干燥后减压下旋转蒸发除去溶剂，剩余物通过硅胶柱色谱纯化(洗脱剂为石油醚：乙酸乙酯＝20:1)，得到淡黄色固体化合物(R)-4d(8.40g,87％收率)。[α] D 19.2＝+10.8(c＝0.26,CHCl 3,(R)). 1H NMR(400MHz,CDCl 3)δ8.22(s,2H),7.70(s,2H),7.39(d,J＝8.9Hz,2H),7.13(d,J＝8.8Hz,2H),4.80(s,4H),2.61(s,6H),1.37(s,18H). 13C NMR(101MHz,CDCl 3)δ149.6,149.0,133.0,131.7,131.4,127.2,126.4,126.0,122.0,117.2,99.2,56.5,34.9,31.3.IR(neat)2956,1468,1352,1156,963,826,633cm -1.HRMS(APCI+)m/z:[M+H] +计算值C 32H 37Br 2O 4 +645.1033,测量值645.1043.
式(R)-4a’化合物的合成
Figure PCTCN2022090675-appb-000091
通过使用优选的卤化反应条件，从起始原料式(R)-3a’化合物得到式(R)-4a’化合物(25％收率)。 1H NMR(400MHz,CDCl 3)δ8.44(s,1H),7.88(d,J＝9.1Hz,1H),7.62(s,1H),7.57–7.50(m,2H),7.17–7.05(m,4H),5.11(d,J＝6.9Hz,1H),5.03(d,J＝6.9Hz,1H),4.73(d,J＝5.2Hz,1H),4.68(d,J＝5.3Hz, 1H),3.19(s,3H),2.74–7.68(m,7H),1.73–1.59(m,4H),1.37–1.25(m,20H),0.88(t,J＝6.5Hz,6H). 13C NMR(101MHz,CDCl 3)δ152.42,150.95,140.42,138.89,138.83,132.80,132.42,132.38,129.90,129.57,128.58,128.49,126.53,126.26,126.18,125.52,125.23,120.43,116.48,99.26,95.12,92.87,56.93,56.08,35.98,35.94,32.02,32.01,31.36,31.30,29.62,29.60,29.55,29.45,29.40,29.39,22.85,22.80,14.25,14.24.HRMS(APCI+)m/z:[M+H] +计算值C 40H 54IO 4 +725.3062,测量值725.3069.
(2.2)第2步：
优选地，偶联反应条件是：氮气保护下，在装有回流冷凝管的三口烧瓶中依次加入第1步所得卤化产物式(R)-4(1.0当量)，实施例1第2步所得含有SO 2NMe 2基团的硼酸酯化合物式15a-f(3.0当量)，四三苯基膦钯(0.1当量)，碳酸钾(3.0当量)，1,2-二甲氧基乙烷和水(体积比6比1，使卤化化合物0.1mol/L)。所得的混合液在85℃下搅拌16小时。反应完毕后降至室温，用饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取三次，萃取出的乙酸乙酯溶液用饱和食盐水洗涤一次，无水硫酸钠干燥后减压下旋转蒸发除去溶剂，剩余物通过硅胶柱色谱纯化(洗脱剂为石油醚和乙酸乙酯)得到偶联产物式(R)-5。
式(R)-5a化合物的合成
Figure PCTCN2022090675-appb-000092
通过使用优选的偶联反应条件，从卤化产物式(R)-4a和芳基硼酸酯化合物式15a得到黄褐色固体化合物式(R)-5a(86％收率)。R f＝0.15(PE/EA＝5/1).[α] D 18.8＝-36.0(c＝0.25,CHCl 3,(R)). 1H NMR(500MHz,CDCl 3)δ8.23(s,2H),7.89(d,J＝8.6Hz,4H),7.67(s,2H),7.42(d,J＝7.9Hz,2H),7.21(d,J＝8.7Hz,2H),7.16(dd,J＝8.7,1.7Hz,2H),4.38(d,J＝5.6Hz,2H),4.30(d,J＝5.6Hz,2H),2.88(s,12H),2.73(t,J＝7.7Hz,4H),2.69(s,6H),2.39(s,6H),1.69(m,J＝7.4Hz,4H),1.35–1.24(m,20H),0.87(t,J＝6.6Hz,6H). 13C NMR(126MHz,CDCl 3)δ150.3,140.3,137.4,137.0,136.4,133.9,133.6,132.9,132.3,131.2,130.7,130.2,128.6,126.6,126.5,126.4,98.7,56.2,37.3,36.0,32.0,31.3,29.6,29.5,29.4,25.0,22.8,20.6,14.2.IR(neat)2922,1459,1325,1156,969,733,588,508cm -1.HRMS(APCI+)m/z:[M+H] +计算值C 58H 77N 2O 8S 2 +993.5116,测量值993.5114.
式(R)-5b化合物的合成
Figure PCTCN2022090675-appb-000093
通过使用优选的偶联反应条件，从卤化产物式(R)-4b和芳基硼酸酯化合物式15a得到黄色油状化 合物式(R)-5b(48％收率)。R f＝0.52(PE/EA＝3/1). 1H NMR(400MHz,CDCl 3)δ8.23(d,J＝1.9Hz,2H),7.92–7.86(m,4H),7.66(s,2H),7.42(d,J＝8.0Hz,2H),7.21(d,J＝8.7Hz,2H),7.16(dd,J＝8.7,1.7Hz,2H),4.38(d,J＝5.6Hz,2H),4.30(d,J＝5.5Hz,2H),2.88(s,12H),2.72(t,J＝7.8Hz,4H),2.69(s,6H),2.39(s,6H),1.72–1.63(m,4H),1.32–1.21(m,52H),0.87(t,J＝6.6Hz,6H). 13C NMR(101MHz,CDCl 3)δ150.3,140.3,137.4,137.0,136.4,133.9,133.6,132.9,132.3,131.2,130.7,130.2,128.6,126.6,126.5,126.4,98.7,56.2,37.3,36.0,32.1,31.3,29.8,29.8,29.8,29.7,29.6,29.5,25.0,22.8,20.6,14.3.HRMS(APCI+)m/z:[M+H] +计算值C 74H 109N 2O 8S 2 +1217.7625,测量值1217.7614.
式(R)-5c化合物的合成
Figure PCTCN2022090675-appb-000094
通过使用优选的偶联反应条件，从卤化产物式(R)-4c和芳基硼酸酯化合物式15a得到黄色固体化合物式(R)-5c(85％收率)。R f＝0.22(PE/EA＝5/1). 1H NMR(400MHz,CDCl 3)δ8.22(d,J＝1.9Hz,2H),7.92(s,2H),7.88(dd,J＝7.9,2.0Hz,2H),7.77(d,J＝2.0Hz,2H),7.43–7.15(m,4H),7.25–7.21(d,J＝8.9Hz,2H),4.38(d,J＝5.5Hz,2H),4.31(d,J＝5.6Hz,2H),2.88(s,12H),2.69(s,6H),2.39(s,6H),2.12(s,6H),1.99(d,J＝2.9Hz,12H),1.85–1.73(m,12H). 13C NMR(101MHz,CDCl 3)δ150.4,148.6,137.5,136.9,136.3,136.0,133.9,133.4,132.9,132.2,131.0,130.7,126.4,125.2,123.1,98.7,83.6,56.2,43.2,37.3,37.0,36.5,29.1,20.6.HRMS(ESI+)m/z:[M+H] +计算值C 62H 73N 2O 8S 2 +1037.4803,测量值1037.4813.
式(R)-5d化合物的合成
Figure PCTCN2022090675-appb-000095
由于使用优选的偶联反应条件不能成功地合成化合物式(R)-5d，所以在此提供对于化合物式(R)-5d来说更为优选的反应条件，具体步骤如下：氮气保护下，在装有回流冷凝管的三口烧瓶中依次加入式(R)-4d化合物(5.00g,8.0mmol)，式15b化合物(7.70g,24.0mmol)，四三苯基膦钯(0.92g,0.8mmol)，八水合氢氧化钡(7.57g,24.0mmol)，60mL的1,4-二氧六环和20mL的水。所得的混合液在85℃下搅拌16小时。反应完毕后降至室温，用饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取三次，萃取出的乙酸乙酯溶液用饱和食盐水洗涤，无水硫酸钠干燥后减压下旋转蒸发除去溶剂，剩余物通过硅胶柱色谱纯化(洗脱剂为石油醚：乙酸乙酯＝3:1)，得到淡黄色固体化合物(R)-5d(3.35g,74％收率)。R f＝0.16(PE/EA＝3/1).[α] D 19.3＝-30.6(c＝0.26,CHCl 3,(R)). 1H NMR(400MHz,CDCl 3)δ8.15(s,2H),8.03(d,J＝7.8Hz,2H),7.95(s,2H),7.86–7.73(m,4H),7.65(t,J＝7.8Hz,2H),7.42(d,J＝9.2Hz,2H),7.23(d,J＝9.2Hz,2H),4.38(d,J＝5.6Hz,2H),4.32(d,J＝5.8Hz,2H),2.78(s,12H),2.41(s,6H),1.40(s, 18H). 13C NMR(101MHz,CDCl 3)δ150.5,148.5,140.5,135.9,134.3,133.7,132.2,131.0,130.9,129.0,128.7,126.5,126.3,126.2,123.2,98.8,56.2,38.2,34.9,31.3,25.0.IR(neat)2956,1461,1345,1163,970,710,584cm -1.HRMS(APCI+)m/z:[M+H] +计算值C 48H 57N 2O 8S 2 +853.3551,测量值853.3553.
式(R)-5e化合物的合成
Figure PCTCN2022090675-appb-000096
由于使用优选的偶联反应条件不能成功地合成化合物式(R)-5e，所以在此提供对于化合物式(R)-5e来说更为优选的反应条件，具体步骤如下：氮气保护下，在装有回流冷凝管的三口烧瓶中依次加入式(R)-4e化合物(508.0mg,0.9mmol)，式14c化合物(749.7mg,2.2mmol)，四三苯基膦钯(104.0mg,0.09mmol)，碳酸钾(309.6mg,2.2mmol)，6mL的1,2-二甲氧基乙烷和1mL的水。所得的混合液在85℃下搅拌16小时。反应完毕后降至室温，用饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取三次，萃取出的乙酸乙酯溶液用饱和食盐水洗涤，无水硫酸钠干燥后减压下旋转蒸发除去溶剂，剩余物通过硅胶柱色谱纯化(洗脱剂为石油醚：乙酸乙酯＝5:1)，得到白色固体化合物(R)-5e(757.6mg,99％收率)。R f＝0.48(PE/EA＝5/1). 1H NMR(500MHz,CDCl 3)δ8.25(d,J＝1.9Hz,2H),7.99(s,2H),7.97–7.87(m,4H),7.49–7.40(m,4H),7.30(ddd,J＝8.1,6.7,1.3Hz,2H),7.22(dd,J＝8.5,1.1Hz,2H),3.17(s,6H),3.07–3.01(m,4H),2.85(s,12H),1.75–1.68(m,4H),1.47–1.35(m,8H),0.93(t,J＝6.9Hz,6H). 13C NMR(126MHz,CDCl 3)δ153.9,142.3,136.7,135.9,134.0,133.6,133.3,131.9,130.9,130.8,130.5,128.3,126.9,126.0,125.9,125.5,60.8,37.3,33.1,32.2,31.5,27.1,22.7,14.2.HRMS(ESI+)m/z:[M+H] +计算值C 48H 57N 2O 6S 2 +821.3653,测量值821.3641.
式(R)-5f化合物的合成
Figure PCTCN2022090675-appb-000097
通过使用优选的偶联反应条件，从卤化产物式(R)-4a和芳基硼酸酯化合物式15d得到淡黄色固体化合物式(R)-5f(73％收率)。R f＝0.14(PE/EA＝5/1). 1H NMR(500MHz,CDCl 3)δ9.09(s,2H),8.27(d,J＝7.5Hz,2H),8.12(d,J＝8.2Hz,2H),8.03(d,J＝2.4Hz,4H),8.00(s,2H),7.70(d,J＝1.7Hz,2H),7.58(t,J＝7.8Hz,2H),7.33(d,J＝8.6Hz,2H),7.21(d,J＝8.7Hz,2H),4.39(d,J＝5.6Hz,2H),4.35(d,J＝5.6Hz,2H),2.89(s,12H),2.76(t,J＝7.8Hz,4H),2.31(s,6H),1.74–1.66(m,4H),1.36–1.25(m,20H),0.87(t,J＝6.6Hz,6H). 13C NMR(126MHz,CDCl 3)δ150.5,140.2,139.2,135.0,134.2,133.6,133.1,132.4,131.3,130.9,130.7,129.3,129.1,128.7,128.5,126.8,126.6,126.5,125.8,124.3,98.8,56.0,37.5,36.1,32.0,31.4,29.6,29.5,29.4,22.8,14.2.HRMS(ESI+)m/z:[M+H] +计算值C 64H 77N 2O 8S 2 +1065.5116,测量值 1065.5109.
式(R)-5g化合物的合成
Figure PCTCN2022090675-appb-000098
通过使用优选的偶联反应条件，从卤化产物式(R)-4a和芳基硼酸酯化合物式15e得到黄色油状化合物式(R)-5g(91％收率)。R f＝0.14(PE/EA＝5/1). 1H NMR(400MHz,CDCl 3)δ8.26(d,J＝1.9Hz,2H),7.90–7.80(m,4H),7.66(d,J＝1.6Hz,2H),7.39(d,J＝7.9Hz,2H),7.21(d,J＝8.7Hz,2H),7.15(dd,J＝8.7,1.7Hz,2H),4.36(d,J＝5.6Hz,2H),4.30(d,J＝5.6Hz,2H),3.39(q,J＝7.1Hz,8H),2.73(t,J＝7.7Hz,4H),2.67(s,6H),2.36(s,6H),1.68(p,J＝7.2Hz,4H),1.39–1.24(m,20H),1.18(t,J＝7.1Hz,12H),0.86(t,J＝6.9Hz,6H). 13C NMR(101MHz,CDCl 3)δ150.4,140.2,138.9,137.2,136.6,133.7,133.5,132.8,132.3,131.2,130.2,130.1,128.5,126.7,126.5,126.4,98.6,56.1,41.2,36.0,32.0,31.3,29.6,29.5,29.4,22.8,20.2,14.2,14.0.HRMS(ESI+)m/z:[M+H] +计算值C 62H 85N 2O 8S 2 +1049.5747,测量值1049.5727.
式(R)-5h化合物的合成
Figure PCTCN2022090675-appb-000099
由于使用优选的偶联反应条件不能成功地合成化合物式(R)-5h，所以在此提供对于化合物式(R)-5h来说更为优选的反应条件，具体步骤如下：使用合成式(R)-5d化合物相同的反应条件，通过式(R)-4a化合物和式15f化合物反应，得到黄色固体化合物式(R)-5h(66％收率)。R f＝0.31(PE/EA＝2/1). 1H NMR(500MHz,CDCl 3)δ8.35(s,4H),8.17(s,2H),7.93(s,2H),7.72(s,2H),7.22(q,J＝8.7Hz,4H),4.38(d,J＝5.5Hz,2H),4.29(d,J＝5.5Hz,2H),2.83(s,24H),2.78–2.74(m,4H),2.50(s,6H),1.70(t,J＝7.2Hz,4H),1.31(d,J＝43.3Hz,20H),0.87(t,J＝6.6Hz,6H). 13C NMR(126MHz,CDCl 3)δ149.8,141.7,140.9,137.7,132.6,132.2,132.1,130.9,130.5,129.4,126.7,126.4,126.1,125.1,98.9,56.3,38.0,35.9,31.9,31.1,29.5,29.4,29.3,24.9,22.7,14.1.HRMS(ESI+)m/z:[M+H] +计算值C 60H 83N 4O 12S 4 +1179.4885,测量值1179.4869.
式(R)-5i化合物的合成
Figure PCTCN2022090675-appb-000100
通过使用优选的偶联反应条件，从卤化产物式(R)-4a’和芳基硼酸酯化合物式15a得到淡黄色油状化合物式(R)-5i(85％收率)。HRMS(ESI+)m/z:[M+H] +计算值C 49H 66NO 6S +708.4082,测量值796.4600.
式(R)-5j化合物的合成
Figure PCTCN2022090675-appb-000101
通过使用优选的偶联反应条件，从卤化产物式(R)-4f和芳基硼酸酯化合物式15b得到白色固体化合物式(R)-5j(97％收率)。R f＝0.17(PE/EA＝4/1). 1H NMR(500MHz,CDCl 3)δ8.17(s,2H),8.05(d,J＝7.8Hz,2H),8.00(s,2H),7.94(d,J＝8.0Hz,2H),7.82(d,J＝7.6Hz,2H),7.67(t,J＝7.8Hz,2H),7.47(t,J＝7.4Hz,2H),7.36–7.28(m,4H),4.39(d,J＝5.6Hz,2H),4.32(d,J＝5.7Hz,2H),2.79(s,12H),2.40(s,6H). 13C NMR(126MHz,CDCl 3)δ151.0,140.2,136.0,134.2,134.0,133.8,131.0,130.9,129.1,128.6,128.2,127.1,126.6,126.6,126.4,125.8,98.8,56.1,38.1.HRMS(ESI+)m/z:[M+H] +计算值C 40H 41N 2O 8S 2 +741.2299,测量值741.2290.
式(R)-5k化合物的合成
Figure PCTCN2022090675-appb-000102
通过使用优选的偶联反应条件，从卤化产物式(R)-4f和芳基硼酸酯化合物式15d得到黄色固体化合物式(R)-5k(99％收率)。R f＝0.28(PE/EA＝3/1). 1H NMR(500MHz,CDCl 3)δ9.10(s,2H),8.27(d,J＝7.3Hz,2H),8.13(d,J＝8.1Hz,2H),8.06(d,J＝20.4Hz,6H),7.95(d,J＝8.2Hz,2H),7.59(t,J＝7.8Hz,2H),7.47(t,J＝7.1Hz,3H),7.41(d,J＝8.3Hz,2H),7.37(d,J＝6.5Hz,2H),4.40(d,J＝5.6Hz,2H),4.36(d,J＝5.7Hz,2H),2.89(s,12H),2.31(s,6H). 13C NMR(126MHz,CDCl 3)δ151.2,138.8,135.0,134.1,133.8,133.5,133.0,131.2,130.9,130.8,129.2,128.8,128.6,128.1,126.8,126.7,126.5,125.7,125.5,124.3,98.7,55.9,37.3,24.9.HRMS(ESI+)m/z:[M+H] +计算值C 48H 45N 2O 8S 2 +841.2612,测量值841.2607.
式(R)-5l化合物的合成
Figure PCTCN2022090675-appb-000103
由于使用优选的偶联反应条件不能成功地合成化合物式(R)-5l，所以在此提供对于化合物式(R)-5l来说更为优选的反应条件，具体步骤如下：使用合成式(R)-5d化合物相同的反应条件，通过将式(R)- 4f化合物和式15j化合物反应，得到黄色固体化合物式(R)-5l(78％收率)。R f＝0.30(PE/EA＝30/1). 1H NMR(400MHz,CDCl 3)δ8.02(s,1H),7.97(d,J＝6.7Hz,2H),7.92(d,J＝8.2Hz,1H),7.65(d,J＝7.8Hz,1H),7.60(t,J＝7.7Hz,1H),7.50–7.41(m,1H),7.36–7.25(m,2H),4.40(d,J＝5.9Hz,1H),4.35(d,J＝5.9Hz,1H),2.40(s,3H). 13C NMR(101MHz,CDCl 3)δ151.4,140.0,134.3,134.0,133.4,131.0,130.9,128.9,128.2,127.0,126.6,126.5,126.4,125.7,124.2,124.2,98.9,56.1. 19F NMR(376MHz,CDCl 3)δ-62.4.IR(neat)2970,1339,1128,970,805,704cm -1.HRMS(ESI+)m/z:[M+H] +计算值C 38H 29F 6O 4 +663.1965,测量值663.1969.
(2.3)第3步：
优选地，去保护反应条件是：在装有回流冷凝管的圆底烧瓶中依次加入式第2步所得的偶联产物式(R)-5(1.0当量)和1,4-二氧六环(0.1mol/L)，向其中加入浓盐酸(10.0当量)，所得的混合液在60℃下搅拌5个小时。反应完毕后降至室温，用饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取三次，萃取出的乙酸乙酯溶液用饱和食盐水洗涤，无水硫酸钠干燥后减压下旋转蒸发除去溶剂，剩余物通过硅胶柱色谱纯化(洗脱剂为石油醚和乙酸乙酯)得到所需的去保护产物式(R)-6。
式(R)-6a化合物的合成
Figure PCTCN2022090675-appb-000104
通过使用优选的去保护反应条件，从偶联产物式(R)-5a得到淡黄色固体化合物(R)-6a(98％收率)。R f＝0.15(PE/EA＝5/1).[α] D 18.9＝+55.2(c＝0.26,CHCl 3,(R)). 1H NMR(400MHz,CDCl 3)δ8.29(d,J＝1.9Hz,2H),7.99(s,2H),7.85(dd,J＝7.9,2.0Hz,2H),7.71(s,2H),7.42(d,J＝7.9Hz,2H),7.20(dd,J＝8.6,1.7Hz,2H),7.13(d,J＝8.6Hz,2H),5.25(s,2H),2.83(s,12H),2.74(t,J＝7.7Hz,4H),2.69(s,6H),1.67(t,J＝6.9Hz,4H),1.30–1.23(m,20H),0.87(t,J＝6.0Hz,6H). 13C NMR(101MHz,CDCl3)δ149.5,139.4,137.1,135.8,135.7,133.7,132.8,131.3,131.2,131.2,129.6,129.6,128.6,127.0,124.0,111.8,37.2,35.8,31.9,31.4,29.5,29.3,29.3,22.7,20.6,14.1.IR(neat)3430,2930,1452,1322,1132,952,726,585,497cm -1.HRMS(APCI+)m/z:[M+H] +计算值C 58H 77N 2O 8S 2 +905.4592,测量值905.4571.
式(R)-6b化合物的合成
Figure PCTCN2022090675-appb-000105
通过使用优选的去保护反应条件，从偶联产物式(R)-5b得到黄色液体化合物式(R)-6b(92％收率)。R f＝0.52(PE/EA＝3/1). 1H NMR(500MHz,CDCl 3)δ8.31(d,J＝1.9Hz,2H),8.00(s,2H),7.86(dd,J＝ 7.9,2.0Hz,2H),7.72(d,J＝1.7Hz,2H),7.42(d,J＝8.0Hz,2H),7.21(dd,J＝8.7,1.8Hz,2H),7.15(d,J＝8.6Hz,2H),5.32(s,2H),2.83(s,12H),2.75(t,J＝8.9,6.5Hz,4H),2.69(s,6H),1.69(m,J＝7.6Hz,4H),1.46–1.19(m,52H),0.89(t,J＝6.8Hz,6H). 13C NMR(126MHz,CDCl 3)δ149.6,139.4,137.1,135.9,135.7,133.7,132.8,131.4,131.3,131.2,129.7,129.6,128.7,127.1,124.1,112.0,37.3,35.9,32.0,31.5,29.8,29.8,29.7,29.7,29.6,29.4,22.8,20.6,14.2.HRMS(APCI+)m/z:[M+H] +计算值C 70H 101N 2O 8S 2 +1129.7096,测量值1129.7083.
式(R)-6c化合物的合成
Figure PCTCN2022090675-appb-000106
通过使用优选的去保护反应条件，从偶联产物式(R)-5c得到淡黄色固体化合物式(R)-6c(88％收率)。R f＝0.22(PE/EA＝5/1). 1H NMR(400MHz,CDCl 3)δ8.30(d,J＝1.9Hz,2H),8.04(s,2H),7.88–7.82(m,4H),7.47–7.38(m,4H),7.18(d,J＝8.8Hz,2H),5.30(s,2H),2.83(s,12H),2.69(s,6H),2.13(s,6H),1.98(d,J＝2.9Hz,12H),1.79(m,12H). 13C NMR(101MHz,CDCl 3)δ149.8,147.8,137.2,136.0,133.8,132.9,131.9,131.3,129.6,128.6,126.4,124.0,120.0,116.9,111.8,83.6,72.9,43.2,37.4,36.9,29.0,20.7.HRMS(ESI+)m/z:[M+H] +计算值C 58H 65N 2O 8S 2 +949.4279,测量值949.4269.
式(R)-6d化合物的合成
Figure PCTCN2022090675-appb-000107
通过使用优选的去保护反应条件，从偶联产物式(R)-5d得到黄色固体化合物式(R)-6d(88％收率)。R f＝0.16(PE/EA＝3/1). 1H NMR(500MHz,CDCl 3)δ8.21(d,J＝1.9Hz,2H),8.09(s,2H),8.03–7.98(m,2H),7.91(s,2H),7.79(d,J＝7.7Hz,2H),7.65(t,J＝7.8Hz,2H),7.48(dt,J＝8.8,1.5Hz,2H),7.20(d,J＝8.9Hz,2H),5.32(s,2H),2.74(s,12H),1.41(s,18H). 13C NMR(101MHz,CDCl 3)δ149.7,147.8,138.9,135.4,133.9,132.2,131.3,129.5,129.1,129.0,128.7,127.3,126.7,124.0,123.9,111.8,38.2,34.8,31.3.IR(neat)3511,2960,1447,1339,1163,956,710,584,497cm -1.HRMS(APCI+)m/z:[M+H] +计算值C 44H 49N 2O 6S 2 +765.3027,测量值765.3022.
式(R)-6e化合物的合成
Figure PCTCN2022090675-appb-000108
由于使用优选的去保护反应条件不能成功地合成化合物式(R)-6e，所以在此提供对于化合物式(R)-6e来说更为优选的反应条件，具体步骤如下：在100mL的圆底烧瓶中依次加入式(R)-5e化合物(821.1mg,1.0mmol)和20mL的二氯甲烷，随后降温至-78℃，缓慢向其中滴加三溴化硼(2.50g,10.0mmol)。将所得的混合液缓慢升至室温后搅拌30分钟。反应完毕后用冰水淬灭，二氯甲烷萃取三次，萃取出的二氯甲烷溶液用饱和食盐水洗涤，无水硫酸钠干燥后减压下旋转蒸发除去溶剂，剩余物通过硅胶柱色谱纯化(洗脱剂为石油醚：乙酸乙酯＝5:1)，得到淡黄色固体化合物(R)-6e(814.3mg,99％收率)。R f＝0.48(PE/EA＝5/1). 1H NMR(500MHz,CDCl 3)δ8.29(d,J＝2.0Hz,2H),8.06(s,2H),7.97–7.91(m,2H),7.88(dd,J＝8.0,1.9Hz,2H),7.47(d,J＝8.0Hz,2H),7.41(ddd,J＝8.1,6.9,1.2Hz,2H),7.34(ddd,J＝8.4,6.0,4.6Hz,2H),7.22–7.18(m,2H),5.45(s,2H),3.06–2.99(m,4H),2.81(s,12H),1.70(ddd,J＝15.5,9.4,6.2Hz,4H),1.48–1.31(m,8H),0.92(t,J＝7.0Hz,6H).HRMS(ESI+)m/z:[M+H] +计算值C 46H 53N 2O 6S 2 +793.3340,测量值793.3251.
式(R)-6f化合物的合成
Figure PCTCN2022090675-appb-000109
通过使用优选的去保护反应条件，从偶联产物式(R)-5f得到黄色固体化合物式(R)-6f(57％收率)。R f＝0.48(PE/EA＝5/1). 1H NMR(400MHz,CDCl 3)δ9.13(s,2H),8.23(dd,J＝7.4,1.3Hz,2H),8.11(d,J＝8.4Hz,4H),8.01(s,4H),7.75(s,2H),7.57(t,J＝7.8Hz,2H),7.24(s,4H),5.41(s,2H),2.84(s,12H),2.75(t,J＝7.7Hz,4H),1.75–1.65(m,4H),1.39–1.25(m,21H),0.87(d,J＝7.4Hz,6H). 13C NMR(126MHz,CDCl 3)δ149.9,139.4,137.8,134.1,133.7,133.1,131.9,131.5,130.8,130.3,129.9,129.6,129.3,129.0,128.6,127.3,126.0,124.4,124.3,112.3,37.6,36.0,32.0,31.5,29.6,29.6,29.5,29.4,22.8,14.2.HRMS(ESI+)m/z:[M+H] +计算值C 60H 69N 2O 6S 2 +977.4592,测量值977.4592.
式(R)-6g化合物的合成
Figure PCTCN2022090675-appb-000110
通过使用优选的去保护反应条件，从偶联产物式(R)-5g得到黄色液体化合物式(R)-6g(96％收率)。R f＝0.14(PE/EA＝5/1). 1H NMR(500MHz,CDCl 3)δ8.31(s,2H),7.98(s,2H),7.83(d,J＝7.9Hz,2H),7.71(s,2H),7.39(d,J＝7.9Hz,2H),7.21(s,2H),7.14(d,J＝8.6Hz,2H),5.25(s,2H),3.35(q,J＝7.2Hz,8H),2.74(t,J＝7.7Hz,4H),2.66(s,6H),1.68(p,J＝7.7,7.2Hz,4H),1.39–1.23(m,20H),1.15(t,J＝7.2Hz,12H),0.87(t,J＝6.6Hz,6H). 13C NMR(126MHz,CDCl 3)δ149.6,139.5,138.5,136.8,135.8,133.5,132.7,131.4,131.3,130.7,129.8,129.6,128.9,127.2,124.2,112.0,41.0,36.0,32.0,31.5,29.6,29.5,29.4,22.8,20.2,14.2,13.9.HRMS(ESI+)m/z:[M+H] +计算值C 58H 77N 2O 6S 2 +961.5206,测量值961.5223.
式(R)-6h化合物的合成
Figure PCTCN2022090675-appb-000111
通过使用优选的去保护反应条件，从偶联产物式(R)-5h得到黄色固体化合物式(R)-6h(89％收率)。R f＝0.31(PE/EA＝2/1). 1H NMR(400MHz,CDCl 3)δ8.43–8.38(m,4H),8.11(d,J＝34.0Hz,4H),7.77(s,2H),7.31–7.26(m,2H),7.13(d,J＝8.6Hz,2H),5.47(s,2H),2.81(s,24H),2.76(t,J＝7.9Hz,4H),1.69(p,J＝7.3Hz,4H),1.39–1.19(m,20H),0.87(t,J＝6.5Hz,6H). 13C NMR(101MHz,CDCl 3)δ149.2,140.4,140.3,137.4,136.6,132.5,131.9,130.6,129.7,127.4,127.0,125.3,124.1,112.1,43.0,38.1,32.0,31.4,29.6,29.4,29.4,22.8,14.2.HRMS(ESI+)m/z:[M+H] +计算值C 56H 75N 4O 10S 4 +1091.4361,测量值1091.4335.
式(R)-6i化合物的合成
Figure PCTCN2022090675-appb-000112
通过使用优选的去保护反应条件，从偶联产物式(R)-5i得到黄色液体化合物式(R)-6i(95％收率)。 1H NMR(400MHz,CDCl 3)δ8.28(d,J＝2.0Hz,1H),7.97(s,1H),7.91(d,J＝8.9Hz,1H),7.84(dd,J＝7.8,2.0Hz,1H),7.68(dd,J＝14.1,1.7Hz,2H),7.38(dd,J＝21.1,8.4Hz,2H),7.23–7.10(m,3H),7.07(d,J＝8.6Hz,1H),5.22(s,1H),5.08(s,1H),2.82(s,6H),2.77–2.66(m,7H),1.66(m,4H),1.39–1.20(m,20H),0.91–0.83(m,6H). 13C NMR(101MHz,CDCl 3)δ152.3,149.5,139.4,138.9,137.1,136.1,135.8,133.8,132.8,131.8,131.5,131.2,131.2,131.1,129.8,129.7,129.5,129.3,128.6,128.2,127.1,127.0,125.0,124.2,117.8,112.3,110.8,38.1,37.4,35.9,35.9,32.0,31.5,31.5,29.6,29.5,29.5,29.4,22.8,20.7,14.2.HRMS(ESI+)m/z:[M+H] +计算值C 45H 58NO 4S +708.4082,测量值708.4085.
式(R)-6j化合物的合成
Figure PCTCN2022090675-appb-000113
通过使用优选的去保护反应条件，从偶联产物式(R)-5j得到白色固体化合物式(R)-6j(97％收率)。R f＝0.25(PE/EA＝3/1). 1H NMR(500MHz,CDCl 3)δ8.23(s,2H),8.12(s,2H),8.05–7.96(m,4H),7.81(d,J＝7.7Hz,2H),7.68(t,J＝7.8Hz,2H),7.47(t,J＝7.5Hz,2H),7.40(t,J＝7.5Hz,2H),7.24(d,J＝8.3Hz,2H),5.45(s,2H),2.76(s,12H). 13C NMR(126MHz,CDCl 3)δ150.1,138.6,135.4,133.8,133.2,132.1,129.5,129.0,128.8,128.7,128.2,126.7,124.9,124.1,111.9,38.1.HRMS(ESI+)m/z:[M+H] +计算值C 36H 33N 2O 6S 2 +653.1775,测量值653.1759.
式(R)-6k化合物的合成
Figure PCTCN2022090675-appb-000114
通过使用优选的去保护反应条件，从偶联产物式(R)-5k得到白色固体化合物式(R)-6k(99％收率)。R f＝0.48(PE/EA＝1/1). 1H NMR(500MHz,CDCl 3)δ9.14(s,2H),8.21(d,J＝7.3Hz,2H),8.16(s,2H),8.09(d,J＝8.2Hz,2H),8.00(s,4H),7.96(d,J＝8.1Hz,2H),7.55(t,J＝7.8Hz,2H),7.42(t,J＝7.4Hz,2H),7.36(t,J＝7.6Hz,2H),7.30(d,J＝8.4Hz,2H),5.52(s,2H),2.83(s,12H). 13C NMR(126MHz,CDCl 3)δ150.5,137.5,134.1,133.7,133.1,132.9,132.4,130.7,130.4,129.6,129.2,128.9,128.8,128.7,127.9,125.9,124.7,124.4,124.2,112.2,37.5.HRMS(ESI+)m/z:[M+H] +计算值C 44H 37N 2O 6S 2 +753.2088,测量值753.2081.
式(R)-6l化合物的合成
Figure PCTCN2022090675-appb-000115
通过使用优选的去保护反应条件，从偶联产物式(R)-5l得到淡黄色固体化合物式(R)-6l(95％收率)。R f＝0.30(PE/EA＝30/1). 1H NMR(400MHz,CDCl 3)δ8.06(d,J＝15.3Hz,4H),8.00–7.93(m,4H),7.67(d,J＝7.9Hz,2H),7.60(d,J＝7.8Hz,2H),7.47–7.34(m,4H),7.23(d,J＝8.3Hz,2H),5.36(s,2H). 13C NMR(101MHz,CDCl 3)δ150.2,138.4,133.2,133.1,132.1,129.6,129.4,128.9,128.8,128.2,126.7,124.9,124.5,124.2,121.4,112.1. 19F NMR(376MHz,CDCl 3)δ-62.5.IR(neat)3524,2963,1622,1331,1237,1117,868,753,700cm -1.HRMS(ESI+)m/z:[M+H] +计算值C 34H 21F 6O 2 +575.1440,测量值575.1440.
(2.4)第4步：
优选地，酰化反应条件是：在氮气保护下，在装有回流冷凝管的圆底烧瓶中依次加入式第3步所得去保护后的化合物式(R)-6(1.0当量)和N,N-二甲基甲酰胺(0.5mol/L)，降温至0℃后向其中分批加入氢化钠(5.0当量)，升至室温搅拌10分钟后加入二甲氨基硫代甲酰氯(5.0当量)，随后将所得的混合液升温至85℃并维持在该温度下搅拌18小时。反应完毕后降至室温，用2％氢氧化钾水溶液淬灭反应，大量不溶物析出，用砂芯漏斗过滤并用2％氢氧化钾水溶液洗涤，将过滤后的不溶物溶解于二氯甲烷，所得溶液依次用水、饱和食盐水洗涤，无水硫酸钠干燥后减压下旋转蒸发除去溶剂，剩余物通过硅胶柱色谱纯化(洗脱剂为石油醚和乙酸乙酯)得到酰化产物式(R)-7。
式(R)-7a化合物的合成
Figure PCTCN2022090675-appb-000116
通过使用优选的酰化反应条件，从去保护产物式(R)-6a得到黄色固体化合物(R)-7a(86％收率)。R f＝0.30(PE/EA＝2/1).[α] D 18.9＝-53.7(c＝0.26,CHCl 3,(R)). 1H NMR(500MHz,CDCl 3)δ8.22–7.02(m,14H),3.20–0.82(m,64H). 13C NMR(126MHz,CDCl 3,only major of three rotational isomers for each signal reported)δ185.5,162.6,146.5,141.0,136.9,136.8,135.4,133.7,133.1,133.0,132.0,131.5,131.2,129.9,128.2,126.1,126.0,60.5,42.8,37.5,37.0,36.0,32.0,31.4,31.1,29.6,29.3,22.8,20.5,14.2.IR(neat)2922,1660,1526,1375,1316,1142,955,728,588 494cm -1.HRMS(APCI+)m/z:[M+H] +计算值C 60H 79N 4O 6S 4 +1079.4877,测量值1079.4868.
式(R)-7b化合物的合成
Figure PCTCN2022090675-appb-000117
通过使用优选的酰化反应条件，从去保护产物式(R)-6b得到淡黄色固体化合物式(R)-7b(73％收率)。R f＝0.31(PE/EA＝3/1). 1H NMR(400MHz,CDCl 3)δ8.23–7.01(m,14H),3.65–0.81(m,96H). 13C NMR(101MHz,CDCl 3,only major of three rotational isomers for each signal reported)δ194.9,185.5,163.1,146.5,141.0,136.9,136.9,135.4,133.8,133.1,132.0,131.5,131.2,129.9,128.2,126.1,126.0,42.8,38.4,37.5,37.0,36.1,32.0,31.2,29.8,29.7,29.5,22.8,20.5,14.2.HRMS(APCI+)m/z:[M+H] +计算值 C 76H 111N 4O 6S 4 +1303.7381,测量值1303.7391.
式(R)-7c化合物的合成
Figure PCTCN2022090675-appb-000118
通过使用优选的酰化反应条件，从去保护产物式(R)-6c得到淡黄色固体化合物式(R)-7c(49％收率)。R f＝0.45(PE/EA＝2/1). 1H NMR(400MHz,CDCl 3)δ8.23–7.27(m,14H),3.23–1.72(m,60H). 13C NMR(101MHz,CDCl 3,only major of three rotational isomers for each signal reported)δ185.6,149.1,146.6,137.0,136.8,135.3,133.8,133.0,133.0,131.9,131.2,130.5,130.0,128.1,125.7,124.8,122.9,43.2,42.8,37.5,37.1,36.9,29.0,20.5.HRMS(APCI+)m/z:[M+H] +计算值C 64H 75N 4O 6S 4 +1123.4564,测量值1123.4559.
式(R)-7d化合物的合成
Figure PCTCN2022090675-appb-000119
通过使用优选的酰化反应条件，从去保护产物式(R)-6d得到淡黄色固体化合物式(R)-7d(45％收率)。R f＝0.40(PE/EA＝2/1).[α] D 19.3＝+7.8(c＝0.26,CHCl 3,(R)). 1H NMR(400MHz,CDCl 3)δ8.16–7.30(m,16H),3.19–1.34(m,42H). 13C NMR(101MHz,CDCl 3,only major of three rotational isomers for each signal reported)δ185.5,162.6,149.1,146.6,139.9,135.5,133.8,133.2,131.7,130.6,129.8,129.1,128.5,128.1,126.3,125.6,123.0,42.2,38.1,34.9,31.3.IR(neat)2967,1675,1528,1345,1160,956,714,584,489cm -1.HRMS(APCI+)m/z:[M+H] +计算值C 50H 59N 4O 6S 4 +939.3312,测量值939.3310.
式(R)-7e化合物的合成
Figure PCTCN2022090675-appb-000120
通过使用优选的酰化反应条件，从去保护产物式(R)-6e得到黄色固体化合物式(R)-7e(83％收率)。R f＝0.52(PE/EA＝5/1). 1H NMR(400MHz,CDCl 3)δ8.23–7.20(m,16H),3.33–0.71(m,46H).HRMS (ESI+)m/z:[M+H] +计算值C 52H 62N 4O 6S 4 +967.3625,测量值967.3602.
式(R)-7f化合物的合成
Figure PCTCN2022090675-appb-000121
通过使用优选的酰化反应条件，从去保护产物式(R)-6f得到黄色固体化合物式(R)-7f(64％收率)。R f＝0.60(PE/EA＝1/1). 1H NMR(500MHz,CDCl 3)δ9.12–7.04(m,20H),3.18–0.80(m,58H). 13C NMR(126MHz,CDCl 3,only major of three rotational isomers for each signal reported)δ185.5,146.9,140.8,138.7,134.9,134.0,133.4,133.0,131.9,131.5,130.4,129.4,129.3,129.0,128.4,127.9,126.0,125.9,125.9,124.1,42.6,38.6,37.9,37.7,37.3,36.0,31.9,31.1,29.5,29.5,29.3,29.3,22.7,14.1.HRMS(ESI+)m/z:[M+H] +计算值C 66H 79N 4O 6S 4 +1151.4877,测量值1151.4852.
式(R)-7g化合物的合成
Figure PCTCN2022090675-appb-000122
通过使用优选的酰化反应条件，从去保护产物式(R)-6g得到白色固体化合物式(R)-7g(50％收率)。R f＝0.64(PE/EA＝2/1). 1H NMR(400MHz,CDCl 3)δ8.26–7.02(m,14H),3.52–0.71(m,72H). 13C NMR(101MHz,CDCl 3,only major of three rotational isomers for each signal reported)δ185.5,146.5,141.0,137.9,136.8,136.5,133.5,133.3,132.8,132.1,131.6,131.0,129.9,128.3,128.2,126.1,126.0,42.8,40.7,38.4,36.1,32.0,31.2,29.6,29.4,22.8,20.1,14.2,13.8.HRMS(APCI+)m/z:[M+H] +计算值C 64H 75N 4O 6S 4 +1135.5508,测量值1135.5501.
式(R)-7h化合物的合成
Figure PCTCN2022090675-appb-000123
通过使用优选的酰化反应条件，从去保护产物式(R)-6h得到黄色固体化合物式(R)-7h(76％收率)。 R f＝0.48(PE/EA＝1/1). 1H NMR(500MHz,CDCl 3)δ8.28–7.09(m,14H),3.68–0.69(m,70H). 13C NMR(126MHz,CDCl 3,only major of three rotational isomers for each signal reported)δ184.7,154.5,141.8,137.5,137.2,137.0,132.7,132.5,132.2,131.9,131.5,130.2,126.7,126.6,38.1,38.1,37.9,31.9,31.4,29.5,29.3,22.7,14.2.HRMS(ESI+)m/z:[M+H] +计算值C 62H 85N 6O 10S 6 +1265.4646,测量值1265.4637.
式(R)-7i化合物的合成
Figure PCTCN2022090675-appb-000124
通过使用优选的酰化反应条件，从去保护产物式(R)-6i得到黄色固体化合物式(R)-7i(78％收率)。R f＝0.40(PE/EA＝2/1). 1H NMR(400MHz,CDCl 3)δ8.21–7.01(m,12H),3.58–0.79(m,55H).HRMS(ESI+)m/z:[M+H] +计算值C 51H 68N 3O 4S 3 +882.4367,测量值882.4361.
式(R)-7j化合物的合成
Figure PCTCN2022090675-appb-000125
通过使用优选的酰化反应条件，从去保护产物式(R)-6j得到淡黄色固体化合物式(R)-7j(83％收率)。R f＝0.25(PE/EA＝2/1). 1H NMR(500MHz,CDCl 3)δ8.09(m,18H),3.19–2.53(m,24H). 13C NMR(126MHz,CDCl 3,仅报道三种旋转异构体中的主要异构体信号)δ185.2,147.6,146.9,139.5,135.5,133.7,133.2,131.7,130.6,129.8,128.9,128.3,127.8,127.3,126.0,125.8,125.1,42.7,42.3,38.1,38.0.HRMS(ESI+)m/z:[M+H] +计算值C 42H 43N 4O 6S 4 +827.2060,测量值827.2066.
式(R)-7k化合物的合成
Figure PCTCN2022090675-appb-000126
通过使用优选的酰化反应条件，从去保护产物式(R)-6k得到白色固体化合物式(R)-7k(76％收率)。R f＝0.30(PE/EA＝1/1). 1H NMR(500MHz,CDCl 3)δ9.17–7.34(m,22H),3.21–1.53(m,24H). 13C NMR(126MHz,CDCl 3,仅报道三种旋转异构体中的主要异构体信号)δ162.7,138.6,135.2,134.1,133.6,133.3,131.9,131.1,129.5,129.4,129.1,128.7,128.6,127.8,126.4,126.3,126.1,124.3,42.8,38.8,38.0,37.5,36.6,31.6.HRMS(ESI+)m/z:[M+H] +计算值C 50H 47N 4O 6S 4 +927.2373,测量值927.2373.
式(R)-7l化合物的合成
Figure PCTCN2022090675-appb-000127
通过使用优选的酰化反应条件，从去保护产物式(R)-6l得到白色固体化合物式(R)-7l(51％收率)。R f＝0.50(PE/EA＝10/1). 1H NMR(400MHz,CDCl 3)δ8.18–7.16(m,18H),3.24–1.96(m,12H). 13C NMR(101MHz,CDCl 3,only major of three rotational isomers for each signal reported)δ185.4,147.1,139.2,133.6,133.1,131.8,130.7,130.2,129.8,129.2,128.5,127.9,126.6,126.1,125.8,124.1,123.0,42.7,37.7. 19F NMR(376MHz,CDCl 3)δ-62.5.IR(neat)2950,1539,1324,1121,805,749,704cm -1.HRMS(ESI+)m/z:[M+H] +计算值C 40H 31F 6N 2O 2S 2 +749.1726,测量值749.1733.
式(R)-7m化合物的合成
Figure PCTCN2022090675-appb-000128
通过使用优选的酰化反应条件，从去保护产物式(R)-6m得到黄色固体化合物式(R)-7m(61％收率)。R f＝0.50(PE/EA＝30/1). 1H NMR(500MHz,CDCl 3)δ8.28–7.28(m,16H),3.23–1.41(m,12H). 13C NMR(126MHz,CDCl 3,only major of three rotational isomers for each signal reported)δ185.0,146.7,140.8,133.4,131.8,131.0,130.4,129.9,128.8,128.3,128.1,127.3,127.0,126.7,126.2,121.5,119.5,42.6,37.3. 19F NMR(471MHz,CDCl 3)δ-75.42,-75.45,-75.49,-75.52,-75.54.HRMS(ESI+)m/z:[M+H] +计算值C 50H 29F 28N 2O 2S 2 +1285.1218,测量值1285.1209.
(2.5)第5步：
优选地，重排反应条件是：在氮气保护下，将第4步所得酰化后产物式(R)-7置于290℃下搅拌45分钟。反应完毕后降至室温，通过硅胶柱色谱纯化(洗脱剂为石油醚和乙酸乙酯)得到重排产物式(R)-8。
式(R)-8a化合物的合成
Figure PCTCN2022090675-appb-000129
通过使用优选的重排反应条件，从酰化产物式(R)-7a得到淡黄色固体化合物(R)-8a(79％收率)。R f＝0.48(PE/EA＝3/2).[α] D 19.0＝-10.8(c＝0.25,CHCl 3,(R)). 1H NMR(500MHz,CDCl 3)δ8.08(d,J＝2.0Hz,2H),7.87(s,2H),7.71(dd,J＝7.8,1.9Hz,2H),7.65(s,2H),7.34(d,J＝7.9Hz,2H),7.17–7.09(m,4H),2.84(s,12H),2.72(t,J＝7.7Hz,4H),2.68(s,6H),2.45(s,12H),1.65(t,J＝7.2Hz,4H),1.35–1.25(m,20H),0.87(t,J＝6.8Hz,6H). 13C NMR(126MHz,CDCl 3)δ165.4,144.5,142.5,142.2,140.2,136.3,134.9,134.5,133.7,131.8,131.3,131.2,129.1,128.1,127.7,126.1,126.0,37.2,36.0,31.9,31.1,29.5,29.3,29.3,22.7,20.5,14.1.IR(neat)2930,1666,1455,1322,1160,1090,953,733,589,507cm -1.HRMS(APCI+)m/z:[M+H] +计算值C 60H 79N 4O 6S 4 +1079.4877,测量值1079.4872.
式(R)-8b化合物的合成
Figure PCTCN2022090675-appb-000130
通过使用优选的重排反应条件，从酰化产物式(R)-7b得到黄色固体化合物式(R)-8b(51％收率)。R f＝0.30(PE/EA＝2/1). 1H NMR(400MHz,CDCl 3)δ8.08(s,2H),7.88(s,2H),7.72(d,J＝9.7Hz,2H),7.65(s,2H),7.34(d,J＝7.9Hz,2H),7.16–7.08(m,4H),2.84(s,12H),2.73(t,J＝7.5Hz,4H),2.68(s,6H),2.45(s,12H),1.68–1.60(m,4H),1.35–1.20(m,52H),0.87(t,J＝6.7Hz,6H). 13C NMR(101MHz,CDCl 3)δ165.4,144.5,142.5,142.2,140.2,136.3,134.9,134.5,133.7,131.8,131.3,131.2,129.1,128.1,127.7,126.1,126.0,37.2,36.0,31.9,31.2,29.7,29.7,29.6,29.5,29.4,29.4,22.7,20.5,14.1.HRMS(APCI+)m/z:[M+H] +计算值C 76H 111N 4O 6S 4 +1303.7381,测量值1303.7385.
式(R)-8c化合物的合成
Figure PCTCN2022090675-appb-000131
通过使用优选的重排反应条件，从酰化产物式(R)-7c得到白色固体化合物式(R)-8c(30％收率)。R f＝0.40(PE/EA＝3/2). 1H NMR(400MHz,CDCl 3)δ8.07(d,J＝1.9Hz,2H),7.92(s,2H),7.77(d,J＝1.9Hz,2H),7.72(dd,J＝7.8,1.9Hz,2H),7.34(td,J＝6.6,6.2,3.0Hz,4H),7.17(d,J＝9.0Hz,2H),2.84(s,12H),2.68(s,6H),2.42(s,12H),2.11(s,6H),1.96(d,J＝2.9Hz,12H),1.82–1.73(m,12H). 13C NMR(101MHz,CDCl 3)δ165.6,150.5,144.5,142.6,140.4,136.4,135.1,134.7,133.7,131.9,131.4,131.2,129.8,127.6,126.3,124.9,122.8,68.1,43.1,37.4,36.9,36.6,29.0,20.7.HRMS(ESI+)m/z:[M+H] +计算值C 64H 75N 4O 6S 4 +1123.4564,测量值1123.4562.
式(R)-8d化合物的合成
Figure PCTCN2022090675-appb-000132
通过使用优选的重排反应条件，从酰化产物式(R)-7d得白色固体化合物式(R)-8d(64％收率)。R f＝0.27(PE/EA＝2/1). 1H NMR(400MHz,CDCl 3)δ8.03(d,J＝1.8Hz,2H),7.96(s,2H),7.91–7.81(m,4H),7.76(dt,J＝7.9,1.5Hz,2H),7.56(t,J＝7.8Hz,2H),7.38(dd,J＝8.9,2.0Hz,2H),7.18(d,J＝9.0Hz,2H),2.74(s,12H),2.45(s,12H),1.37(s,18H). 13C NMR(101MHz,CDCl 3)δ165.5,150.5,144.4,143.3,142.6,134.9,134.6,133.6,131.2,129.9,129.6,128.0,127.6,126.2,126.2,125.8,122.9,38.2,35.1,31.3.IR(neat)2963,1665,1345,1159,1089,707,584cm -1.HRMS(APCI+)m/z:[M+H] +计算值C 50H 59N 4O 6S 4 +939.3312,测量值939.3311.
式(R)-8e化合物的合成
Figure PCTCN2022090675-appb-000133
通过使用优选的重排反应条件，从酰化产物式(R)-7e得到淡黄色固体化合物式(R)-8e(24％收率)。R f＝0.48(PE/EA＝1/1). 1H NMR(500MHz,CDCl 3)δ8.07(d,J＝1.9Hz,2H),7.97(s,2H),7.90(d,J＝8.3Hz,2H),7.75(dd,J＝7.8,2.0Hz,2H),7.48(ddd,J＝8.1,6.5,1.5Hz,2H),7.39(d,J＝7.9Hz,2H),7.30–7.21(m,4H),3.10–2.98(m,4H),2.83(s,12H),2.47(s,12H),1.75–1.64(m,4H),1.48–1.33(m,8H),0.92(t,J＝6.9Hz,6H).HRMS(ESI+)m/z:[M+H] +计算值C 52H 62N 4O 6S 4 +967.3625,测量值967.3601.
式(R)-8f化合物的合成
Figure PCTCN2022090675-appb-000134
通过使用优选的重排反应条件，从酰化产物式(R)-7f得到固体化合物式(R)-8f(64％收率)。R f＝0.10(PE/EA＝3/1). 1H NMR(500MHz,CDCl 3)δ8.87(s,2H),8.22(d,J＝7.3Hz,2H),8.11(d,J＝8.2Hz,2H),7.95(dd,J＝16.4,6.1Hz,6H),7.68(s,2H),7.56(t,J＝7.9Hz,2H),7.23(d,J＝8.7Hz,2H),7.14(d,J＝8.8Hz,2H),2.82(s,12H),2.75(t,J＝7.9Hz,4H),2.35(s,12H),1.70–1.63(m,4H),1.40–1.23(m,20H),0.87(t,J＝6.7Hz,6H). 13C NMR(101MHz,CDCl 3)δ165.5,144.7,144.2,142.3,142.2,134.1,133.9,133.4,132.9,131.3,130.6,130.2,129.6,128.7,128.1,128.0,127.6,126.5,126.4,126.2,124.0,37.6,36.2,32.0,31.3,29.6,29.5,29.4,22.8,14.2.HRMS(ESI+)m/z:[M+H] +计算值C 66H 79N 4O 6S 4 +1151.4877,测量值1151.4867.
式(R)-8g化合物的合成
Figure PCTCN2022090675-appb-000135
通过使用优选的重排反应条件，从酰化产物式(R)-7g得到黄色固体化合物式(R)-8g(81％收率)。R f＝0.44(PE/EA＝2/1). 1H NMR(400MHz,CDCl 3)δ8.09(s,2H),7.87(s,2H),7.73–7.64(m,4H),7.32(d,J＝7.8Hz,2H),7.13(q,J＝8.7Hz,4H),3.35(q,J＝7.1Hz,8H),2.72(t,J＝7.6Hz,4H),2.66(s,6H),2.45(s,12H),1.70–1.62(m,4H),1.38–1.22(m,20H),1.14(t,J＝7.1Hz,12H),0.87(t,J＝6.5Hz,6H). 13C NMR(101MHz,CDCl 3)δ165.5,144.6,142.8,142.2,140.2,137.5,136.0,134.3,133.8,131.8,131.3,130.8,129.2,128.2,127.8,126.3,126.1,41.2,36.1,32.0,31.2,29.6,29.4,29.3,22.8,20.2,14.2,14.1.HRMS(APCI+)m/z:[M+H] +计算值C 64H 75N 4O 6S 4 +1135.5508,测量值1135.5504.
式(R)-8h化合物的合成
Figure PCTCN2022090675-appb-000136
通过使用优选的重排反应条件，从酰化产物式(R)-7h得到黄色固体化合物式(R)-8h(38％收率)。R f＝0.32(PE/EA＝1/1). 1H NMR(400MHz,CDCl 3)δ8.26(d,J＝1.7Hz,4H),8.13(s,2H),7.96(s,2H),7.71(s,2H),7.17(d,J＝8.6Hz,2H),7.11(d,J＝8.6Hz,2H),2.79(s,24H),2.74(t,J＝7.8Hz,4H),2.49(s,12H),1.67(t,J＝7.4Hz,4H),1.37–1.23(m,20H),0.86(t,J＝6.1Hz,6H). 13C NMR(126MHz,CDCl 3)δ165.0,144.6,144.5,143.0,140.9,136.4,133.8,133.3,131.7,129.7,129.1,127.5,126.5,125.3,125.0,38.2,36.1,32.0,31.3,29.6,29.4,29.4,22.8,14.2.HRMS(ESI+)m/z:[M+H] +计算值C 62H 85N 6O 10S 6 +1265.4646,测量值1265.4610.
式(R)-8i化合物的合成
Figure PCTCN2022090675-appb-000137
通过使用优选的重排反应条件，从酰化产物式(R)-7i得到白色固体化合物式(R)-8i(53％收率)。R f＝0.30(PE/EA＝2/1). 1H NMR(400MHz,CDCl 3)δ8.08(d,J＝1.9Hz,1H),7.91–7.85(m,2H),7.77–7.69(m,2H),7.69–7.62(m,2H),7.33(d,J＝7.9Hz,1H),7.16–7.07(m,3H),7.04(d,J＝8.7Hz,1H),2.86–2.77(m,12H),2.75–2.66(m,7H),2.38(s,6H),1.72–1.61(m,4H),1.38–1.23(m,20H),0.87(m,J＝6.5Hz,6H). 13C NMR(101MHz,CDCl 3)δ166.6,165.5,144.1,142.7,142.3,141.6,141.5,140.3,136.4,135.0,134.7,133.9,133.6,133.3,132.0,131.7,131.5,131.4,129.4,128.5,127.8,127.7,127.5,127.3,127.1,126.4,126.3,126.2,37.4,36.2,36.1,32.0,31.3,31.3,29.6,29.5,29.5,29.4,22.8,20.7,14.2.HRMS(ESI+)m/z:[M+H] +计算值C 51H 68N 3O 4S 3 +882.4367,测量值882.4360.
式(R)-8j化合物的合成
Figure PCTCN2022090675-appb-000138
通过使用优选的重排反应条件，从酰化产物式(R)-7j得到黄色固体化合物式(R)-8j(63％收率)。 R f＝0.20(PE/EA＝1/1). 1H NMR(500MHz,CDCl 3)δ8.05(s,2H),8.00(s,2H),7.92(d,J＝8.2Hz,2H),7.87(d,J＝7.6Hz,2H),7.77(d,J＝7.6Hz,2H),7.57(t,J＝7.8Hz,2H),7.51(t,J＝7.3Hz,2H),7.27(dt,J＝19.0,8.3Hz,4H),2.75(s,12H),2.47(s,12H). 13C NMR(126MHz,CDCl 3)δ165.1,144.5,142.9,142.5,134.8,134.5,133.5,132.7,129.8,129.4,128.0,127.8,127.6,127.2,126.8,126.2,68.0,38.1,25.6.HRMS(ESI+)m/z:[M+H] +计算值C 42H 43N 4O 6S 4 +827.2060,测量值827.2044.
式(R)-8k化合物的合成
Figure PCTCN2022090675-appb-000139
通过使用优选的重排反应条件，从酰化产物式(R)-7k得到白色固体化合物式(R)-8k(74％收率)。R f＝0.22(PE/EA＝1/1). 1H NMR(500MHz,CDCl 3)δ8.89(s,2H),8.23(d,J＝7.3Hz,2H),8.11(d,J＝8.2Hz,2H),8.05(s,2H),7.98–7.92(m,6H),7.56(t,J＝7.8Hz,2H),7.51(t,J＝2.4Hz,2H),7.34–7.28(m,4H),2.82(s,12H),2.35(s,12H). 13C NMR(126MHz,CDCl 3)δ165.1,144.6,144.1,141.8,134.0,133.6,133.3,132.8,132.6,130.5,130.0,129.9,128.5,128.0,127.7,127.6,127.6,127.4,126.4,126.3,124.0,37.5.HRMS(ESI+)m/z:[M+H] +计算值C 50H 47N 4O 6S 4 +927.2373,测量值927.2372.
式(R)-8l化合物的合成
Figure PCTCN2022090675-appb-000140
通过使用优选的重排反应条件，但此步反应中将原有的反应温度290℃改为250℃，反应时间45分钟改为80分钟，其余操作不变，最终从酰化产物式(R)-7l得到淡黄色固体化合物式(R)-8l(71％收率)。R f＝0.15(PE/EA＝10/1). 1H NMR(400MHz,CDCl 3)δ7.96(s,2H),7.92–7.77(m,8H),7.60(d,J＝7.8Hz,2H),7.55–7.45(m,4H),7.28(d,J＝2.7Hz,2H),2.46(s,12H). 13C NMR(101MHz,CDCl 3)δ165.4,144.5,142.7,142.7,133.9,133.6,132.8,129.7,129.5,127.9,127.8,127.6,127.2,126.8,125.8,123.7,123.1,36.8,34.4. 19F NMR(376MHz,CDCl 3)δ-62.3.IR(neat)2949,1665,1339,1075,896,707,458cm -1.HRMS(ESI+)m/z:[M+H] +计算值C 40H 31F 6N 2O 2S 2 +749.1726,测量值749.1730.
式(R)-8m化合物的合成
Figure PCTCN2022090675-appb-000141
通过使用优选的重排反应条件，从酰化产物式(R)-7m得到固体化合物式(R)-8m(22％收率)。R f＝0.18(PE/EA＝30/1). 1H NMR(500MHz,CDCl 3)δ8.05–8.00(m,4H),7.99(s,2H),7.95(d,J＝8.2Hz,2H),7.81(s,2H),7.56–7.51(m,2H),7.32(t,J＝7.4Hz,2H),7.22(d,J＝8.5Hz,2H),2.46(s,12H). 13C NMR(126MHz,CDCl 3)δ179.0,143.9,141.6,133.5,130.7,130.6,130.0,128.0,127.9,127.4,127.1,127.0,121.8,121.5,119.3,36.1. 19F NMR(471MHz,CDCl 3)δ-75.48,-75.50.HRMS(ESI+)m/z:[M+H] +计算值C 50H 29F 28N 2O 2S 2 +1285.1218,测量值1285.1177.
(2.6)第6步：
优选地，氧化反应条件是：在圆底烧瓶中加入第5步所得重排化合物式(R)-8(1.0当量)和甲醇与四氢呋喃的混合液(体积比为1比1，0.25mol/L)，降温至0℃，分批次加入N-氯代丁二酰亚胺(6.0当量)，随后升温至15℃并在该温度下搅拌30分钟。加水淬灭反应，减压旋转蒸发下尽可能多的除去有机溶剂，随后用二氯甲烷萃取三次，萃取出的二氯甲烷溶液用饱和食盐水洗涤，无水硫酸钠干燥后减压下旋转蒸发除去溶剂，剩余物通过硅胶柱色谱纯化(洗脱剂为石油醚和乙酸乙酯)得到氧化产物二元磺酰氯化合物式(R)-9。
式(R)-9a化合物的合成
Figure PCTCN2022090675-appb-000142
通过使用优选的氧化反应条件，从重排产物式(R)-8a得到黄色固体化合物(R)-9a(99％收率)。R f＝0.25(PE/EA＝2/1).[α] D 19.1＝+42.0(c＝0.25,CHCl 3,(R)). 1H NMR(500MHz,CDCl 3)δ8.16(d,J＝69.0Hz,2H),7.92(s,2H),7.73(s,2H),7.69(d,J＝7.8Hz,2H),7.42(d,J＝7.9Hz,2H),7.35(d,J＝10.1Hz,2H),7.09(d,J＝8.7Hz,2H),2.83(s,12H),2.79(t,J＝7.8Hz,4H),2.72(s,6H),1.69(t,J＝7.6Hz,4H),1.40–1.20(m,20H),0.86(t,J＝6.8Hz,6H). 13C NMR(126MHz,CDCl 3)δ171.2,146.7,138.9,138.0,137.4,137.3,135.6,135.1,134.9,134.1,132.3,132.2,130.9,130.2,128.1,126.7,37.2,36.2,32.0,30.9,29.5,29.5,29.3,28.0,22.8,14.2.IR(neat)2923,1382,1160,959,733,560,518cm -1.HRMS(APCI+)m/z:[M+H] +计算值C 54H 67Cl 2N 2O 8S 4 +1069.3152,测量值1069.3148.
式(R)-9b化合物的合成
Figure PCTCN2022090675-appb-000143
通过使用优选的氧化反应条件，从重排产物式(R)-8b得到黄色固体化合物式(R)-9b(67％收率)。R f＝0.70(PE/EA＝2/1). 1H NMR(400MHz,CDCl 3)δ8.17(d,J＝51.4Hz,2H),7.92(s,2H),7.73(s,2H),7.69(d,J＝7.7Hz,2H),7.42(d,J＝7.9Hz,2H),7.34(d,J＝9.0Hz,2H),7.09(d,J＝8.8Hz,2H),2.83(s,12H),2.78(t,J＝7.9Hz,4H),2.73(s,6H),1.75–1.64(m,4H),1.39–1.20(m,52H),0.87(t,J＝6.6Hz,6H). 13C NMR(101MHz,CDCl 3)δ146.7,138.9,138.0,137.4,137.3,135.6,135.2,134.9,134.1,132.3,132.1,130.9,130.7,130.2,128.1,126.7,37.2,36.2,32.1,30.9,29.8,29.8,29.7,29.6,29.5,29.5,22.8,20.7,14.3.HRMS(APCI+)m/z:[M+H] +计算值C 70H 99Cl 2N 2O 8S 4 +1293.5656,测量值1293.5659.
式(R)-9c化合物的合成
Figure PCTCN2022090675-appb-000144
通过使用优选的氧化反应条件，从重排产物式(R)-8c得到白色固体化合物式(R)-9c(99％收率)。R f＝0.70(PE/EA＝2/1). 1H NMR(400MHz,CDCl 3)δ8.16(d,J＝55.7Hz,2H),7.97(s,2H),7.84(d,J＝2.0Hz,2H),7.72–7.65(m,2H),7.57(s,2H),7.42(d,J＝7.8Hz,2H),7.12(d,J＝9.1Hz,2H),2.82(s,12H),2.72(s,6H),2.13(s,6H),1.97(d,J＝3.0Hz,12H),1.86–1.72(m,12H). 13C NMR(101MHz,CDCl 3)δ171.2,154.6,138.8,138.0,137.4,137.3,135.3,135.2,134.8,134.6,132.3,132.1,130.0,128.0,127.7,123.6,42.8,37.0,36.7,28.8,28.0,20.7.HRMS(ESI+)m/z:[M+H] +计算值C 58H 63Cl 2N 2O 8S 4 +1113.2839,测量值1113.2824.
式(R)-9d化合物的合成
Figure PCTCN2022090675-appb-000145
通过使用优选的氧化反应条件，从重排产物式(R)-8d得到淡黄色固体化合物式(R)-9d(73％收率)。 R f＝0.90(PE/EA＝2/1). 1H NMR(400MHz,CDCl 3)δ8.12–7.98(m,4H),7.94–7.80(m,6H),7.67–7.56(m,4H),7.14(d,J＝9.1Hz,2H),2.76(s,12H),1.40(s,18H). 13C NMR(101MHz,CDCl 3)δ171.2,154.7,154.7,140.5,138.8,137.2,135.4,134.9,134.7,134.6,130.0,129.7,128.4,128.0,127.4,123.7,38.2,31.0,28.0.IR(neat)1963,1735,1342,1159,956,717,559,548cm -1.HRMS(APCI+)m/z:[M+H] +计算值C 44H 47Cl 2N 2O 8S 4 +929.1587,测量值929.1584.
式(R)-9e化合物的合成
Figure PCTCN2022090675-appb-000146
通过使用优选的氧化反应条件，从重排产物式(R)-8e得到固体化合物式(R)-9e(96％收率)。R f＝0.78(PE/EA＝1/1). 1H NMR(400MHz,CDCl 3)δ8.26–8.03(m,2H),8.04(s,2H),8.00(d,J＝8.3Hz,2H),7.79–7.69(m,4H),7.49(p,J＝6.8,6.1Hz,4H),7.18(d,J＝8.6Hz,2H),2.92(s,16H),1.89–1.55(m,4H),1.52–1.37(m,8H),0.94(t,J＝6.9Hz,6H). 13C NMR(101MHz,CDCl 3)δ143.3,139.8,137.3,136.8,135.7,135.2,134.8,134.6,132.3,131.7,131.0,131.0,129.2,129.1,128.5,128.2,37.2,33.2,32.2,31.5,28.0,22.7.HRMS(ESI+)m/z:[M+H] +计算值C 46H 51Cl 2N 2O 8S 4 +957.1900,测量值957.1887.
式(R)-9f化合物的合成
Figure PCTCN2022090675-appb-000147
通过使用优选的氧化反应条件，从重排产物式(R)-8f得到固体化合物式(R)-9f(89％收率)。R f＝0.80(PE/EA＝1/1). 1H NMR(500MHz,CDCl 3)δ9.05–8.77(m,2H),8.35–8.13(m,4H),8.07–7.97(m,4H),7.91–7.72(m,4H),7.62(q,J＝7.7Hz,2H),7.36(d,J＝8.1Hz,2H),7.19(q,J＝10.2,8.7Hz,2H),2.79(s,12H),2.73(t,4H),1.69(q,J＝8.0Hz,4H),1.34–1.21(m,20H),0.86(t,J＝6.8Hz,6H). 13C NMR(126MHz,CDCl 3)δ146.6,146.5,139.4,139.0,137.3,137.0,134.9,134.5,134.3,134.2,133.9,132.8,130.7,130.3,130.2,129.0,128.3,127.6,126.9,126.3,124.7,37.6,36.3,32.0,30.9,29.6,29.5,29.3,22.8,18.6,14.2.HRMS(ESI+)m/z:[M+H] +计算值C 60H 67Cl 2N 2O 8S 4 +1141.3152,测量值1141.3136.
式(R)-9g化合物的合成
Figure PCTCN2022090675-appb-000148
通过使用优选的氧化反应条件，从重排产物式(R)-8g得到白色固体化合物式(R)-9g(75％收率)。R f＝0.80(PE/EA＝2/1). 1H NMR(400MHz,CDCl 3)δ8.21(d,J＝69.8Hz,2H),7.92(s,2H),7.74(s,2H),7.67(d,J＝7.0Hz,2H),7.40(d,J＝7.9Hz,2H),7.35(d,J＝9.1Hz,2H),7.10(d,J＝8.8Hz,2H),3.48–3.19(m,8H),2.79(t,J＝7.8Hz,4H),2.69(s,6H),1.70(s,4H),1.41–1.23(m,20H),1.11(t,J＝7.1Hz,12H),0.87(t,J＝6.5Hz,6H). 13C NMR(101MHz,CDCl 3)δ146.6,138.9,138.1,137.6,137.4,137.2,135.7,134.9,134.0,132.0,131.7,130.8,130.7,130.1,128.1,126.7,40.6,36.2,31.9,30.9,29.5,29.5,29.3,22.8,20.2,14.2,13.6.HRMS(APCI+)m/z:[M+H] +计算值C 58H 75Cl 2N 2O 8S 4 +1125.3783,测量值1125.3789.
式(R)-9h化合物的合成
Figure PCTCN2022090675-appb-000149
通过使用优选的氧化反应条件，从重排产物式(R)-8h得到淡黄色固体化合物式(R)-9h(63％收率)。R f＝0.84(PE/EA＝2/1). 1H NMR(500MHz,CDCl 3)δ8.26(d,J＝12.5Hz,4H),8.18(s,2H),7.96(s,2H),7.79(s,2H),7.41(d,J＝8.9Hz,2H),7.13(d,J＝8.8Hz,2H),2.80(m,28H),1.74–1.66(m,4H),1.40–1.21(m,20H),0.86(t,J＝6.7Hz,6H). 13C NMR(126MHz,CDCl 3)δ147.3,141.5,138.2,137.2,134.5,133.7,133.4,132.6,131.3,131.3,130.0,127.9,126.7,126.0,37.9,37.9,37.8,36.0,31.7,30.6,29.2,29.2,29.0,22.5,14.0.HRMS(ESI+)m/z:[M+H] +计算值C 56H 73Cl 2N 4O 12S 6 +1255.2921,测量值1255.2858.
式(R)-9i化合物的合成
Figure PCTCN2022090675-appb-000150
通过使用优选的氧化反应条件，从重排产物式(R)-8i得到固体化合物式(R)-9i(46％收率)。R f＝0.65(PE/EA＝5/1). 1H NMR(400MHz,CDCl 3)δ8.24(d,J＝9.0Hz,1H),8.14(d,J＝9.0Hz,1H),7.94(s,1H),7.81(s,1H),7.75–7.66(m,2H),7.42(d,J＝7.9Hz,1H),7.33(s,1H),7.29–7.23(m,1H),7.20(d,J＝8.7Hz,1H),6.95(d,J＝8.8Hz,1H),2.91–2.64(m,13H),1.69(m,4H),1.41–1.22(m,20H),0.87(m,J＝ 7.0Hz,6H). 13C NMR(101MHz,CDCl 3)δ146.6,145.9,139.4,138.0,137.2,135.8,135.8,135.5,135.3,134.9,134.4,134.0,132.2,132.1,130.6,130.6,130.5,130.2,128.2,128.0,127.0,126.7,123.5,37.2,36.2,36.2,31.9,31.9,30.9,30.8,29.5,29.5,29.4,29.4,29.3,29.3,29.3,22.8,22.7,20.7,14.2.HRMS(ESI+)m/z:[M+H] +计算值C 45H 56Cl 2NO 6S 3 +872.2642,测量值872.2635.
式(R)-9j化合物的合成
Figure PCTCN2022090675-appb-000151
通过使用优选的氧化反应条件，从重排产物式(R)-8j得到白色固体化合物式(R)-9j(99％收率)。R f＝0.65(PE/EA＝1/1). 1H NMR(500MHz,CDCl 3)δ8.13–7.99(m,6H),7.93–7.82(m,4H),7.77(t,J＝7.7Hz,2H),7.66(t,J＝7.9Hz,2H),7.58–7.49(m,2H),7.20(d,J＝8.6Hz,2H),2.76(s,12H). 1H NMR(500MHz,DMSO)δ7.98(d,J＝8.1Hz,2H),7.92(s,2H),7.82(d,J＝14.4Hz,4H),7.69(d,J＝7.7Hz,2H),7.65(d,J＝7.6Hz,2H),7.51(t,J＝7.5Hz,2H),7.28(t,J＝7.8Hz,2H),6.92(d,J＝8.8Hz,2H),2.64(s,12H). 13C NMR(126MHz,DMSO)δ144.6,138.8,137.0,134.6,133.2,133.1,132.7,131.4,130.1,129.4,128.2,128.1,128.0,127.7,127.1,125.9,38.3.HRMS(ESI+)m/z:[M+H] +计算值C 36H 31Cl 2N 2O 8S 4 +817.0335,测量值817.0330.
式(R)-9k化合物的合成
Figure PCTCN2022090675-appb-000152
通过使用优选的氧化反应条件，从重排产物式(R)-8k得到白色固体化合物式(R)-9k(99％收率)。R f＝0.51(PE/EA＝2/1). 1H NMR(500MHz,CDCl 3)δ9.07–8.82(m,2H),8.24(d,J＝7.3Hz,2H),8.19–8.08(m,4H),8.06–7.98(m,4H),7.86(dd,J＝34.9,8.7Hz,2H),7.76(s,2H),7.64(t,J＝7.7Hz,2H),7.53(d,J＝8.0Hz,2H),7.29(m,2H),2.79(s,6H),2.73(s,6H). 13C NMR(126MHz,CDCl 3)δ139.4,137.5,137.3,135.1,134.9,134.9,134.7,134.5,134.2,134.1,133.1,132.2,131.8,131.3,131.0,130.5,129.3,128.8,128.6,128.0,126.7,125.1,38.4,37.9,37.4.HRMS(ESI+)m/z:[M+H] +计算值C 44H 35Cl 2N 2O 8S 4 +917.0648,测量值917.0650.
式(R)-9l化合物的合成
Figure PCTCN2022090675-appb-000153
通过使用优选的氧化反应条件，从重排产物式(R)-8l得到白色固体化合物式(R)-9l(84％收率)。R f＝0.16(PE/EA＝10/1). 1H NMR(400MHz,CDCl 3)δ8.08–7.98(m,4H),7.90(s,2H),7.82(d,J＝7.8Hz,2H),7.75(t,J＝8.0Hz,4H),7.60(t,J＝7.8Hz,2H),7.52(t,J＝7.6Hz,2H),7.22(d,J＝8.7Hz,2H). 13C NMR(101MHz,CDCl 3)δ139.8,139.7,137.4,136.0,134.6,134.6,133.6,131.9,131.0,129.2,128.5,128.2,127.9,127.0,125.1,125.1. 19F NMR(376MHz,CDCl 3)δ-62.5.IR(neat)1387,1310,1125,805,703,528,468cm -1.HRMS(ESI+)m/z:[M+H] +计算值C 34H 19C l2F 6O 4S 2 +739.0001,测量值739.0005.
(2.7)第7步：
优选地，水解反应条件是：在圆底烧瓶中加入第6步所得氧化产物二元磺酰氯化合物式(R)-9(1.0当量)和甲醇(0.04mol/L)，然后加入氢氧化钠固体(50.0当量)，随后升温至70℃并在该温度下搅拌5小时。反应完毕后降至室温，用1M HCl调节该反应的pH至8，用乙酸乙酯萃取三次，萃取出的乙酸乙酯溶液用饱和食盐水洗涤，无水硫酸钠干燥后减压下旋转蒸发除去溶剂，剩余物通过硅胶柱色谱纯化(洗脱剂为乙酸乙酯和甲醇)得到水解产物二元磺酸钠化合物式(R)-10。
式(R)-10a化合物的合成
Figure PCTCN2022090675-appb-000154
通过使用优选的水解反应条件，从氧化产物式(R)-9a得到白色固体化合物(R)-10a(76％收率)。R f＝0.13(EA/MeOH＝10/1).[α] D 18.6＝+70.9(c＝0.25,MeOH,(R)). 1H NMR(400MHz,CD 3OD)δ8.19(s,2H),7.81(d,J＝8.2Hz,2H),7.63(s,2H),7.59(s,2H),7.36(d,J＝7.9Hz,2H),7.09(d,J＝7.1Hz,2H),7.01(d,J＝8.8Hz,2H),2.84(s,12H),2.68(m,10H),1.64(t,J＝7.4Hz,4H),1.35–1.23(m,20H),0.87(t,J＝6.5Hz,6H). 13C NMR(101MHz,CD 3OD)δ142.1,141.6,138.3,137.0,136.7,135.4,134.8,133.3,132.9,131.8,131.6,131.0,130.3,127.9,127.7,125.5,36.4,35.5,31.7,31.0,29.2,29.1,29.0,22.3,19.5,13.1.IR(neat)3445,2930,1459,1159,1036,956,737,588,507cm -1.HRMS(ESI-)m/z:[M-2Na+H] -计算值C 70H 98N 2NaO 10S 4 -1031.3684,测量值1031.3675.
式(R)-10b化合物的合成
Figure PCTCN2022090675-appb-000155
通过使用优选的水解反应条件，从氧化产物式(R)-9b得到白色固体化合物式(R)-10b(95％收率)。R f＝0.06(EA/MeOH＝10/1). 1H NMR(400MHz,CD 3OD)δ8.17(s,2H),7.80(d,J＝7.9Hz,2H),7.61(d,J＝15.4Hz,4H),7.36(d,J＝7.9Hz,2H),7.08(d,J＝8.8Hz,2H),6.98(d,J＝8.8Hz,2H),2.82(s,12H),2.72–2.64(m,10H),1.69–1.57(m,4H),1.37–1.23(m,52H),0.89(t,J＝6.6Hz,6H). 13C NMR(101MHz,CD 3OD)δ143.3,143.2,143.1,138.3,138.1,136.9,136.2,134.8,134.4,133.1,133.1,132.4,131.8,129.2,129.1,127.0,37.7,36.9,33.1,32.3,30.8,30.8,30.7,30.7,30.7,30.6,30.6,30.5,30.4,23.7,20.8,14.5.HRMS(ESI-)m/z:[M-Na] -计算值C 70H 98N 2NaO 10S 4 -1277.6007,测量值1277.6000.
式(R)-10c化合物的合成
Figure PCTCN2022090675-appb-000156
通过使用优选的水解反应条件，从氧化产物式(R)-9c得到白色固体化合物式(R)-10c(60％收率)。R f＝0.10(EA/MeOH＝10/1). 1H NMR(400MHz,CD 3OD)δ8.17(s,2H),7.82(d,J＝7.8Hz,2H),7.72(d,J＝2.0Hz,2H),7.68(s,2H),7.42–7.30(m,4H),7.02(d,J＝9.0Hz,2H),2.83(s,12H),2.68(s,6H),2.08(s,6H),1.99(d,J＝3.0Hz,12H),1.85–1.77(m,12H). 13C NMR(101MHz,CD 3OD)δ151.1,143.5,139.8,138.2,137.9,136.8,136.3,134.7,134.2,133.2,132.9,132.3,132.1,129.1,125.7,123.5,44.1,37.9,37.7,37.4,30.4,20.8.HRMS(ESI-)m/z:[M-Na] -计算值C 58H 62N 2NaO 10S 4 -1097.3190,测量值1097.3188.
式(R)-10d化合物的合成
Figure PCTCN2022090675-appb-000157
通过使用优选的水解反应条件，从氧化产物式(R)-9d得到淡黄色固体化合物式(R)-10d(76％收率)。R f＝0.20(EA/MeOH＝10/1). 1H NMR(500MHz,CD 3OD)δ8.15(s,2H),7.96(s,2H),7.80(s,2H),7.74(d,J＝7.8Hz,2H),7.70(s,2H),7.59(t,J＝7.7Hz,2H),7.38(d,J＝9.1Hz,2H),7.05(d,J＝9.1Hz,2H),2.76(s,12H),1.36(s,18H). 13C NMR(126MHz,CD 3OD)δ151.0,146.4,139.6,138.3,137.7,136.2,134.4,134.1,132.8,132.1,129.0,128.4,126.8,126.6,123.6,79.5,38.6,35.6,31.5.HRMS(ESI-)m/z:[M-Na] -计算值 C 44H 46N 2NaO 10S 4 -913.1938,测量值913.1931.
式(R)-10e化合物的合成
Figure PCTCN2022090675-appb-000158
通过使用优选的水解反应条件，从氧化产物式(R)-9e得到白色固体化合物式(R)-10e(81％收率)。R f＝0.72(EA/MeOH＝10/1). 1H NMR(500MHz,CD 3OD)δ8.17(s,2H),7.86(d,J＝8.1Hz,4H),7.74(s,2H),7.48–7.39(m,4H),7.23(ddd,J＝8.3,6.8,1.3Hz,2H),7.08(d,J＝8.7Hz,2H),3.04(s,4H),2.82(s,12H),1.79–1.69(m,4H),1.52–1.37(m,8H),0.97(t,J＝7.0Hz,6H). 13C NMR(126MHz,CD 3OD)δ143.2,142.0,140.5,138.5,138.1,136.1,134.6,134.4,134.2,133.1,132.2,131.5,129.2,128.5,128.1,127.5,37.7,34.3,33.3,32.8,23.6,14.4.HRMS(ESI-)m/z:[M-2Na+H] -计算值C 46H 51N 2O 10S 4 -919.2432,测量值919.2416.
式(R)-10f化合物的合成
Figure PCTCN2022090675-appb-000159
通过使用优选的水解反应条件，从氧化产物式(R)-9f得到白色固体化合物式(R)-10f(85％收率)。R f＝0.18(EA/MeOH＝10/1). 1H NMR(500MHz,CD 3OD)δ8.92(s,2H),8.17(t,J＝8.7Hz,4H),8.11–8.01(m,2H),7.96(s,2H),7.71(s,2H),7.63–7.53(m,4H),7.10(s,4H),2.81(s,12H),2.69(t,J＝7.7Hz,4H),1.65(t,J＝7.6Hz,4H),1.35–1.23(m,20H),0.87(t,J＝6.9Hz,6H). 13C NMR(126MHz,CD 3OD)δ144.0,141.7,138.5,136.8,133.9,133.4,133.0,132.3,131.7,130.4,129.7,128.3,128.1,127.6,126.5,125.6,123.2,36.7,35.5,31.7,31.0,29.2,29.1,29.0,22.3,13.1.HRMS(ESI-)m/z:[M-2Na+H] -计算值C 60H 67N 2O 10S 4 -1103.3684,测量值1103.3665.
式(R)-10g化合物的合成
Figure PCTCN2022090675-appb-000160
通过使用优选的水解反应条件，从氧化产物式(R)-9g得到淡黄色固体化合物式(R)-10g(94％收率)。R f＝0.10(EA/MeOH＝10/1). 1H NMR(400MHz,CD 3OD)δ8.26(d,J＝14.2Hz,2H),7.93–7.81(m,2H), 7.75–7.59(m,4H),7.38(d,J＝7.8Hz,2H),7.18–6.98(m,4H),3.44(q,J＝7.1Hz,8H),2.78–2.65(m,10H),1.67(p,J＝7.2Hz,4H),1.44–1.28(m,20H),1.20(t,J＝7.1Hz,12H),0.91(t,J＝6.6Hz,6H). 13C NMR(101MHz,CD 3OD)δ143.3,142.9,139.6,138.4,138.0,137.4,136.3,135.7,134.3,132.9,132.5,132.2,131.6,129.2,129.0,126.9,42.2,36.9,33.0,32.3,30.5,30.5,30.3,23.7,20.3,14.5,14.4.HRMS(ESI-)m/z:[M-2Na+H] -计算值C 58H 75N 2O 10S 4 -1087.4310,测量值1087.4297.
式(R)-10h化合物的合成
Figure PCTCN2022090675-appb-000161
通过使用优选的水解反应条件，从氧化产物式(R)-9h得到固体化合物式(R)-10h(92％收率)。R f＝0.20(EA/MeOH＝10/1). 1H NMR(500MHz,CD 3OD)δ8.37(d,J＝60.4Hz,4H),8.07(s,2H),7.73(s,2H),7.68(s,2H),7.17(d,J＝8.9Hz,2H),7.06(d,J＝8.8Hz,2H),2.81(s,24H),2.72(t,J＝7.7Hz,4H),1.66(dt,J＝6.4,3.4Hz,4H),1.39–1.21(m,20H),0.87(t,J＝6.9Hz,6H). 13C NMR(126MHz,CD 3OD)δ147.7,143.2,139.3,137.5,136.6,135.9,134.7,134.0,133.1,131.4,129.4,129.0,126.9,125.8,38.3,36.7,32.8,32.1,30.4,30.3,30.2,23.5.HRMS(ESI-)m/z:[M-Na] -计算值C 56H 72N 4NaO 14S 6 -1239.3272,测量值1239.3236.
式(R)-10i化合物的合成
Figure PCTCN2022090675-appb-000162
通过使用优选的水解反应条件，从氧化产物式(R)-9i得到固体化合物式(R)-10i(55％收率)。R f＝0.15(EA/MeOH＝10/1).HRMS(ESI-)m/z:[M-Na] -计算值C 45H 55NNaO 8S 3 -856.2992,测量值856.2999.
式(R)-10j化合物的合成
Figure PCTCN2022090675-appb-000163
通过使用优选的水解反应条件，从氧化产物式(R)-9j得到白色固体化合物式(R)-10j(82％收率)。R f＝0.70(EA/MeOH＝5/1). 1H NMR(500MHz,CD 3OD)δ8.17(s,2H),7.98(s,2H),7.89(d,J＝8.1Hz,2H),7.76(d,J＝6.4Hz,4H),7.61(t,J＝7.8Hz,2H),7.48(t,J＝7.5Hz,2H),7.26(t,J＝7.9Hz,2H),7.12 (d,J＝8.5Hz,2H),2.78(s,12H). 13C NMR(126MHz,CD 3OD)δ146.1,140.2,138.3,137.8,136.1,134.4,134.3,133.9,131.9,130.8,129.0,128.4,128.2,128.0,127.4,126.7,38.4.HRMS(ESI-)m/z:[M-2Na+H] -计算值C 36H 31N 2O 10S 4 -779.0867,测量值779.0870.
式(R)-10k化合物的合成
Figure PCTCN2022090675-appb-000164
通过使用优选的水解反应条件，从氧化产物式(R)-9k得到白色固体化合物式(R)-10k(80％收率)。R f＝0.70(EA/MeOH＝2/1). 1H NMR(400MHz,CD 3OD)δ8.52(d,J＝4.2Hz,2H),7.61(d,J＝7.4Hz,2H),7.54(s,2H),7.49(d,J＝8.3Hz,2H),7.40(s,4H),7.36(d,J＝8.1Hz,2H),6.95(t,J＝7.7Hz,2H),6.82(t,J＝7.1Hz,2H),6.79–6.73(m,2H),6.68(d,J＝8.8Hz,2H),2.22(s,12H).HRMS(ESI-)m/z:[M-2Na+H] -计算值C 44H 35N 2O 10S 4 -879.1180,测量值879.1155.
式(R)-10l化合物的合成
Figure PCTCN2022090675-appb-000165
通过使用优选的水解反应条件，从氧化产物式(R)-9l得到白色固体化合物式(R)-10l(99％收率)。R f＝0.20(EA/MeOH＝10/1). 1H NMR(400MHz,CD 3OD)δ7.24(s,2H),7.18(d,J＝7.8Hz,2H),7.06(d,J＝8.2Hz,2H),6.95(s,2H),6.85(d,J＝7.9Hz,2H),6.74(t,J＝7.8Hz,2H),6.66(t,J＝7.5Hz,2H),6.43(td,J＝7.1,6.7,3.4Hz,2H),6.34(d,J＝8.6Hz,2H). 13C NMR(101MHz,CD 3OD)δ145.8,140.1,138.6,137.9,135.3,134.4,134.1,132.3,130.1,129.8,129.1,128.5,128.3,128.2,127.6,124.0. 19F NMR(376MHz,CD 3OD)δ-63.2.HRMS(ESI-)m/z:[M-Na] -计算值C 34H 18F 6NaO 6S 2 -723.0352,测量值723.0353.
(2.8)第8步：
优选地，酸化条件是：将第7步所得水解产物二元磺酸钠化合物式(R)-10溶解于甲醇中，随后将该甲醇溶液通过阳离子交换树脂Amberlyst 15(10cm 3/200mg式(R)-10)，用甲醇洗脱两次，减压下旋转蒸发除去溶液中的甲醇，然后将所得固体于50℃下真空干燥6小时，得到最终产物手性联萘二元磺酸式(R)-1。
式(R)-1a化合物的合成
Figure PCTCN2022090675-appb-000166
通过使用优选的酸化条件，从水解产物式(R)-10a得到淡黄色固体化合物(R)-1a(99％收率)。[α] D 18.0＝+62.9(c＝0.11,MeOH,(R)). 1H NMR(500MHz,CD 3OD)δ8.10(s,2H),7.75–7.69(m,4H),7.67(s,2H),7.39(d,J＝7.8Hz,2H),7.15(d,J＝8.4Hz,2H),7.01(d,J＝8.4Hz,2H),2.82(s,12H),2.71(t,J＝7.8Hz,4H),2.68(s,6H),1.65(t,J＝7.5Hz,4H),1.35–1.25(m,20H),0.87(t,J＝6.7Hz,6H). 13C NMR(126MHz,CD 3OD)δ142.7,141.1,137.1,136.7,136.3,135.9,134.3,133.9,133.4,131.4,131.3,131.2,130.9,128.2,127.7,125.8,36.3,35.5,31.6,30.9,29.2,29.1,29.0,22.3,19.4,13.1. 1H NMR(400MHz,CDCl 3)δ7.94(s,2H),7.71(s,2H),7.60(s,6H),7.15(d,J＝8.9Hz,2H),6.98(d,J＝8.8Hz,2H),2.80–2.63(m,16H),2.57(s,6H),1.64(t,J＝7.6Hz,4H),1.30(m,J＝23.2,11.1,5.8Hz,20H),0.87(t,J＝6.5Hz,6H). 13C NMR(101MHz,CDCl 3)δ143.9,140.3,137.5,136.9,136.1,134.6,134.3,133.9,133.5,132.3,131.9,131.2,130.0,129.5,128.0,126.2,37.3,36.1,32.0,31.0,29.6,29.6,29.4,22.8,20.6,14.2.IR(neat)3441,2930,1315,1139,1033,952,737,589,508cm -1.HRMS(ESI-)m/z:[M-H] -计算值C 70H 99N 2O 10S 4 -1031.3684,测量值1031.3678.
式(R)-1b化合物的合成
Figure PCTCN2022090675-appb-000167
通过使用优选的酸化条件，从水解产物式(R)-10b得到褐色固体化合物式(R)-1b(94％收率)。[α] D 18.3＝+10.9(c＝1.01,MeOH,(R)). 1H NMR(400MHz,CD 3OD)δ8.11(s,2H),7.73–7.62(m,4H),7.58(s,2H),7.36(d,J＝7.8Hz,2H),7.09(d,J＝8.9Hz,2H),7.03(d,J＝8.9Hz,2H),2.81(s,12H),2.72–2.58(m,10H),1.68–1.52(m,4H),1.39–1.14(m,52H),0.87(t,J＝6.5Hz,6H). 13C NMR(101MHz,CD 3OD)δ143.9,142.4,138.5,138.1,137.7,137.2,135.6,135.3,134.7,132.7,132.6,132.3,129.6,129.1,127.2,79.5,37.7,36.9,33.1,32.3,30.9,30.8,30.8,30.8,30.7,30.6,30.5,30.5,23.8,20.8,14.6.IR(neat)3388,2922,1465,1143,738,594cm -1.HRMS(ESI-)m/z:[M-H] -计算值C 70H 99N 2O 10S 4 -1255.6188,测量值1255.6179.
式(R)-1c化合物的合成
Figure PCTCN2022090675-appb-000168
通过使用优选的酸化条件，从水解产物式(R)-10c得到灰色固体化合物式(R)-1c(99％收率)。[α] D 18.4＝+52.9(c＝0.21,MeOH,(R)). 1H NMR(500MHz,CD 3OD)δ8.11(s,2H),7.73(dd,J＝24.4,8.3Hz,6H),7.42–7.36(m,4H),7.03(d,J＝9.1Hz,2H),2.83(s,12H),2.68(s,6H),2.06(s,6H),1.97(s,12H),1.79(m,J＝9.7Hz,12H). 13C NMR(126MHz,CD 3OD)δ152.1,142.5,138.3,137.9,137.8,137.3,135.7,135.2,134.6,132.8,132.6,128.9,126.4,123.8,44.0,37.8,37.7,37.5,30.4,30.3,20.8.IR(neat)3341,2904,1318,1139,903,734,590cm -1.HRMS(ESI-)m/z:[M-H] -计算值C 58H 63N 2O 10S 4 -1075.3371,测量值1075.3372.
式(R)-1d化合物的合成
Figure PCTCN2022090675-appb-000169
通过使用优选的酸化条件，从水解产物式(R)-10d得到褐色固体化合物式(R)-1d(97％收率)。[α] D 18.7＝+72.0(c＝0.25,CHCl 3,(R)). 1H NMR(400MHz,CD 3OD)δ8.08(s,2H),7.87(d,J＝12.8Hz,4H),7.77(d,J＝14.2Hz,4H),7.61(t,J＝7.8Hz,2H),7.43(d,J＝9.2Hz,2H),7.06(d,J＝9.2Hz,2H),2.74(s,12H),1.36(s,18H). 13C NMR(101MHz,CD 3OD)δ152.0,145.5,138.2,138.0,137.9,135.9,134.9,134.5,132.7,132.6,130.8,128.9,128.7,127.1,123.9,79.5,38.6,35.7,31.5.IR(neat)3440,2967,1475,1335,1153,949,710,584,518cm -1.HRMS(ESI-)m/z:[M-H] -计算值C 44H 47N 2O 10S 4 -891.2119,测量值891.2115.
式(R)-1e化合物的合成
Figure PCTCN2022090675-appb-000170
通过使用优选的酸化条件，从水解产物式(R)-10e得到褐色固体化合物式(R)-1e(86％收率)。[α] D 22.7＝+45.5(c＝0.15,MeOH,(R)). 1H NMR(500MHz,CD 3OD)δ8.10(s,2H),7.91(d,J＝8.2Hz,2H),7.82(s,2H),7.77(d,J＝7.9Hz,2H),7.51(t,J＝7.4Hz,2H),7.45(d,J＝7.8Hz,2H),7.28(t,J＝7.8Hz,2H),7.10(d,J＝8.7Hz,2H),3.04(s,4H),2.81(s,12H),1.78–1.69(m,4H),1.47–1.39(m,8H),0.96(t,J＝6.8Hz,6H). 13C NMR(126MHz,CD 3OD)δ142.5,142.2,138.7,138.5,138.2,135.7,134.9,134.5,134.3,132.8, 132.7,131.8,129.0,128.9,128.8,128.0,37.7,34.3,33.3,32.8,23.6,14.4.IR(neat)3436,2932,1698,1310,1125,1029,752,590cm -1.HRMS(ESI-)m/z:[M-H] -计算值C 46H 51N 2O 10S 4 -919.2432,测量值919.24321.
式(R)-1f化合物的合成
Figure PCTCN2022090675-appb-000171
通过使用优选的酸化条件，从水解产物式(R)-10f得到黄褐色固体化合物式(R)-1f(89％收率)。[α] D 18.0＝+77.4(c＝0.12,MeOH,(R)). 1H NMR(500MHz,CD 3OD)δ8.90(s,2H),8.20(d,J＝7.0Hz,4H),7.96(s,4H),7.78(s,2H),7.67(s,2H),7.60(t,J＝7.8Hz,2H),7.17(d,J＝8.6Hz,2H),7.11(s,2H),2.78(s,12H),2.71(t,J＝7.8Hz,4H),1.70–1.61(m,4H),1.35–1.24(m,20H),0.86(t,J＝6.8Hz,6H). 13C NMR(126MHz,CD 3OD)δ143.1,142.8,138.2,137.3,136.3,134.0,133.5,133.4,132.3,131.4,131.2,130.1,130.0,128.4,128.2,127.8,126.6,125.8,125.2,123.5,36.5,35.5,31.6,30.9,29.2,29.1,29.0,22.3,13.1.IR(neat)3463,1324,1133,838,721,584cm -1.HRMS(ESI-)m/z:[M-H] -计算值C 60H 67N 2O 10S 4 -1103.3684,测量值1103.3661.
式(R)-1g化合物的合成
Figure PCTCN2022090675-appb-000172
通过使用优选的酸化条件，从水解产物式(R)-10g得到红褐色固体化合物式(R)-1g(99％收率)。[α] D 18.4＝+44.1(c＝0.25,MeOH,(R)). 1H NMR(400MHz,CD 3OD)δ8.10(s,2H),7.75–7.65(m,6H),7.38(d,J＝7.7Hz,2H),7.15(d,J＝8.9Hz,2H),7.00(d,J＝8.8Hz,2H),3.41–3.33(q,8H),2.72(t,J＝7.6Hz,4H),2.66–2.63(m,6H),1.70–1.62(m,4H),1.29(t,J＝9.7,0.2Hz,20H),1.18–1.09(t,12H),0.87(t,J＝8.4Hz,6H). 13C NMR(101MHz,CD 3OD)δ144.0,142.4,138.6,138.3,137.9,137.8,136.8,135.2,134.8,132.8,132.5,132.3,132.1,129.5,129.1,127.2,42.6,36.9,33.0,32.3,30.6,30.5,30.4,23.7,20.3,14.5,14.4.IR(neat)3431,2939,1297,1143,1016,919,782,591cm -1.HRMS(ESI-)m/z:[M-H] -计算值C 58H 75N 2O 10S 4 -1087.4310,测量值1087.4299.
式(R)-1h化合物的合成
Figure PCTCN2022090675-appb-000173
通过使用优选的酸化条件，从水解产物式(R)-10h得到黄褐色固体化合物式(R)-1h(86％收率)。[α] D 18.0＝+68.4(c＝0.11,MeOH,(R)). 1H NMR(500MHz,CD 3OD)δ8.27(d,J＝16.7Hz,4H),8.08(s,2H),7.81(s,2H),7.73(s,2H),7.22(d,J＝8.1Hz,2H),7.08(d,J＝8.8Hz,2H),2.78(s,24H),2.73(t,J＝7.7Hz,4H),1.71–1.63(m,4H),1.30(d,J＝26.9Hz,20H),0.87(t,J＝6.7Hz,6H). 13C NMR(126MHz,CD 3OD)δ147.0,144.3,138.1,137.8,136.5,136.5,134.6,134.5,133.0,132.1,130.1,129.0,127.4,126.2,38.5,36.9,33.0,32.3,30.5,30.5,30.3,23.7,14.4.IR(neat)3446,2929,1351,1156,954,824,707,574cm -1.HRMS(ESI-)m/z:[M-H] -计算值C 56H 73N 4O 14S 6 -1217.3453,测量值1217.3423.
式(R)-1i化合物的合成
Figure PCTCN2022090675-appb-000174
通过使用优选的酸化条件，从水解产物式(R)-10i得到褐色固体化合物式(R)-1i(99％收率)。 1H NMR(400MHz,CD 3OD)δ8.10(d,J＝8.5Hz,1H),7.95(d,J＝8.9Hz,1H),7.72(d,J＝12.8Hz,3H),7.65–7.62(m,1H),7.39(d,J＝7.8Hz,1H),7.14(d,J＝8.8Hz,1H),7.07(d,J＝8.8Hz,2H),6.84(d,J＝8.8Hz,1H),2.82(s,6H),2.76–2.64(m,7H),1.70–1.58(m,4H),1.40–1.22(m,20H),0.93–0.82(m,6H). 13C NMR(101MHz,CD 3OD)δ144.2,143.4,142.4,138.4,138.0,137.3,137.2,137.1,135.7,135.6,135.4,134.8,133.3,132.8,132.7,132.7,132.6,130.8,129.5,129.3,129.2,129.0,128.6,127.3,127.1,125.5,37.7,36.9,36.8,33.0,33.0,32.3,32.2,30.6,30.5,30.5,30.4,30.3,30.3,23.7,20.8,14.4.HRMS(ESI-)m/z:[M-H] -计算值C 45H 56NO 8S 3 -834.3173,测量值834.3184.
式(R)-1j化合物的合成
Figure PCTCN2022090675-appb-000175
通过使用优选的酸化条件，从水解产物式(R)-10j得到褐色固体化合物式(R)-1j(94％收率)。 1H NMR(500MHz,CD 3OD)δ8.06(s,2H),7.91(d,J＝8.2Hz,2H),7.87(d,J＝7.5Hz,2H),7.82(s,2H),7.74(d,J＝7.9Hz,2H),7.60(t,J＝7.7Hz,2H),7.51(t,J＝7.4Hz,2H),7.29(t,J＝7.3Hz,2H),7.10(d,J＝8.0 Hz,2H),2.72(s,12H). 13C NMR(126MHz,CD 3OD)δ144.1,137.0,136.8,134.5,133.5,133.0,133.0,131.3,129.4,127.7,127.5,127.4,127.3,126.7,125.8,37.2.HRMS(ESI-)m/z:[M-H] -计算值C 36H 31N 2O 10S 4 -779.0867,测量值779.0869.
式(R)-1k化合物的合成
Figure PCTCN2022090675-appb-000176
通过使用优选的酸化条件，从水解产物式(R)-10k得到褐色固体化合物式(R)-1k(98％收率)。 1H NMR(500MHz,CD 3OD)δ8.92(s,2H),8.23(d,J＝8.2Hz,2H),8.16(s,2H),8.01(s,4H),7.87(d,J＝8.1Hz,2H),7.81(s,2H),7.62(t,J＝7.8Hz,2H),7.47(t,J＝7.5Hz,2H),7.25(t,J＝7.8Hz,2H),7.13(d,J＝8.7Hz,2H),2.82(s,13H). 13C NMR(126MHz,CD 3OD)δ140.0,135.5,135.0,134.8,134.3,133.9,132.3,129.8,129.5,128.7,128.3,127.6,124.9,38.2.HRMS(ESI-)m/z:[M-H] -计算值C 44H 35N 2O 10S 4 -879.1180,测量值879.1175.
式(R)-1l化合物的合成
Figure PCTCN2022090675-appb-000177
通过使用优选的酸化条件，从水解产物式(R)-10l得到褐色固体化合物式(R)-1l(92％收率)。[α] D 18.5＝+77.4(c＝0.19,MeOH,(R)). 1H NMR(400MHz,CD 3OD)δ7.95–7.84(m,6H),7.82(s,2H),7.64(d,J＝7.9Hz,2H),7.54(dt,J＝14.8,7.7Hz,4H),7.29(t,J＝7.8Hz,2H),7.12(d,J＝8.7Hz,2H). 13C NMR(101MHz,CD 3OD)δ145.1,138.6,138.4,135.0,134.5,134.3,132.8,130.3,130.0,129.0,128.9,128.8,128.5,128.1,127.4,124.4. 19F NMR(376MHz,CD 3OD)δ-63.8.IR(neat)3337,1338,1122,1029,807,704,673,550cm -1.HRMS(ESI-)m/z:[M-H] -计算值C 34H 19F 6O 6S 2 -701.0532,测量值701.0536.
式(R)-1m化合物的合成
Figure PCTCN2022090675-appb-000178
由于使用优选的氧化条件不能成功地将重排产物式(R)-8m氧化成式(R)-9m，所以在此提供一种从式(R)-8m出发氧化直接得到最终二元磺酸产物(R)-1m的方法，优选地，具体步骤如下：在10mL圆 底烧瓶中加入式(R)-8m化合物(55.0mg,0.04mmol)和1mL的二氯甲烷，然后依次加入1.5mL的甲酸和双氧水(145.6mg,1.3mmol)，于室温下搅拌10小时。反应完毕后减压下旋转蒸发除去溶剂，剩余物通过硅胶柱色谱纯化(洗脱剂为二氯甲烷：甲醇＝20:1)，得到固体用浓盐酸酸化，残留的水分通过与甲苯加热共沸除去，再于50℃真空干燥后得到灰白色固体化合物(R)-1m(35.9mg,72％收率)。[α] D 22.7＝+37.6(c＝0.26,MeOH,(R)). 1H NMR(500MHz,CD 3OD)δ8.24(s,4H),7.95(d,J＝8.1Hz,2H),7.81(s,4H),7.53(t,J＝7.4Hz,2H),7.37–7.31(m,2H),7.09(d,J＝8.7Hz,2H). 13C NMR(126MHz,CD 3OD)δ147.2,137.8,136.7,134.5,134.4,134.3,132.8,131.0,129.0,128.9,128.8,128.5,126.2,121.8. 19F NMR(471MHz,CD 3OD)δ-76.70,-76.94,-76.98,-77.01,-77.06.HRMS(ESI-)m/z:[M-H] -计算值C 44H 17F 28O 6S 2 -1237.0024,测量值1237.0015.
实施例3
本实施例为式(R)-2a,2b,2c化合物的制备方法，共分3步，合成路线如下：
Figure PCTCN2022090675-appb-000179
包括以下步骤：
(3.1)第1步：
优选地，氮-硫键的断裂反应条件是：氮气保护下，在圆底烧瓶中加入实施例2第7步所得的水解产物式(R)-10(1.0当量)，降温至0℃后向其中再慢慢加入三氟甲磺酸甲酯(160.0当量)，加完后升温至100℃并继续搅拌20小时。冷却至室温，加入适量水并在室温下搅拌1小时。再加入适量饱和氯化铵水溶液，用二氯甲烷萃取三次，萃取出的二氯甲烷溶液用饱和食盐水洗涤，无水硫酸钠干燥后减压下旋转蒸发除去溶剂，剩余物通过硅胶柱色谱纯化(洗脱剂为石油醚和乙酸乙酯)，得到四元磺酸甲酯化合物式(R)-11。
式(R)-11a化合物的合成
Figure PCTCN2022090675-appb-000180
通过使用优选的氮-硫键断裂反应条件，从水解产物式(R)-10a得到黄色固体化合物(R)-11a(81％ 收率)。R f＝0.48(PE/EA＝1/1). 1H NMR(500MHz,CDCl 3)δ8.20(s,2H),7.86(s,2H),7.75(s,2H),7.70(d,J＝1.7Hz,2H),7.44(d,J＝7.9Hz,2H),7.30(d,J＝8.9Hz,2H),7.13(d,J＝8.8Hz,2H),3.78(s,6H),3.40(s,6H),2.80–2.74(m,4H),2.72(s,6H),1.73–1.65(m,4H),1.46–1.14(m,20H),0.87(t,J＝6.9Hz,6H).HRMS(ESI+)m/z:[M+H] +计算值C 54H 67O 12S 4 +1035.3510,测量值1035.3572.
式(R)-11b化合物的合成
Figure PCTCN2022090675-appb-000181
通过使用优选的氮-硫键断裂反应条件，从水解产物式(R)-10j得到淡黄色固体化合物式(R)-11b(99％收率)。R f＝0.71(PE/EA＝1/1). 1H NMR(500MHz,CDCl 3)δ8.16(s,2H),8.03–7.94(m,6H),7.89(s,2H),7.68(dt,J＝20.2,7.7Hz,4H),7.50(s,2H),7.23(d,J＝8.6Hz,2H),3.82(s,6H),3.40(s,6H). 13C NMR(126MHz,CDCl 3)δ141.6,138.9,135.3,133.9,133.0,132.4,131.9,129.9,128.6,128.2,127.4,127.3,29.3,27.2.HRMS(ESI+)m/z:[M+H] +计算值C 36H 31O 12S 4 +783.0693,测量值783.0693.
式(R)-11c化合物的合成
Figure PCTCN2022090675-appb-000182
通过使用优选的氮-硫键断裂反应条件，从水解产物式(R)-10k得到黄色固体化合物式(R)-11c(74％收率)。R f＝0.21(PE/EA＝1/1). 1H NMR(500MHz,CDCl 3)δ8.79(s,2H),8.35(d,J＝7.3Hz,2H),8.22(d,J＝8.2Hz,2H),8.11–7.86(m,8H),7.69(t,J＝7.4Hz,2H),7.63(t,J＝7.8Hz,2H),7.51(t,J＝7.8Hz,2H),7.32(d,J＝9.1Hz,2H),3.76(d,J＝10.6Hz,6H),3.65–3.32(m,6H). 13C NMR(126MHz,CDCl 3)δ141.4,141.1,137.2,135.5,133.6,133.2,132.4,131.4,131.2,130.5,129.8,128.5,128.4,127.6,125.5,124.6,124.5,56.8,56.5.HRMS(ESI+)m/z:[M+H] +计算值C 44H 35O 12S 4 +883.1006,测量值883.0999.
(3.2)第2步：
优选地，水解反应条件是：在圆底烧瓶中加入第1步所得四元磺酸甲酯化合物式(R)-11(1.0当量)和甲醇(0.05mol/L)，然后加入氢氧化钠固体(50.0当量)，随后升温至70℃并在该温度下搅拌5小时。反应完毕后降至室温，用2M HCl的甲醇溶液调节该反应的pH至8，然后减压下旋转蒸发除去溶剂，剩余物通过硅胶柱色谱纯化(洗脱剂为乙酸乙酯和甲醇)得到水解产物四元磺酸钠化合物式(R)-12。
式(R)-12a化合物的合成
Figure PCTCN2022090675-appb-000183
通过使用优选的水解反应条件，从氮-硫键断裂产物式(R)-11a得到黄褐色固体化合物(R)-12a(99％收率)。R f＝0.30(EA/MeOH＝1/1). 1H NMR(400MHz,CD 3OD)δ8.21(d,J＝2.0Hz,2H),7.70–7.61(m,4H),7.58(s,2H),7.24(d,J＝7.9Hz,2H),7.06(dd,J＝8.8,1.8Hz,2H),6.94(d,J＝8.8Hz,2H),2.75–2.65(m,10H),1.67–1.60(m,4H),1.35–1.24(m,20H),0.87(t,J＝6.6Hz,6H).HRMS(ESI-)m/z:[M-Na] -计算值C 50H 54Na 3O 12S 4 -1043.2196,测量值1043.2240.
式(R)-12b化合物的合成
Figure PCTCN2022090675-appb-000184
通过使用优选的水解反应条件，从氮-硫键断裂产物式(R)-11b得到褐色固体化合物式(R)-12b(99％收率)。R f＝0.24(EA/MeOH＝3/7). 1H NMR(500MHz,CD 3OD)δ8.16(s,2H),7.88(d,J＝8.2Hz,2H),7.82(d,J＝7.9Hz,3H),7.79(s,2H),7.74(d,J＝7.6Hz,2H),7.47(q,J＝7.1Hz,4H),7.22(t,J＝7.7Hz,2H),7.02(d,J＝8.7Hz,2H). 13C NMR(126MHz,CD 3OD)δ143.5,142.7,137.7,136.7,133.1,132.9,131.0,127.8,127.3,127.1,126.6,126.3,123.6.HRMS(ESI-)m/z:[M-2Na+H] -计算值C 32H 19Na 2O 12S 4 -768.9560,测量值768.9272.
式(R)-12c化合物的合成
Figure PCTCN2022090675-appb-000185
通过使用优选的水解反应条件，从氮-硫键断裂产物式(R)-11c得到褐色固体化合物式(R)-12c(99％收率)。R f＝0.36(EA/MeOH＝1/2). 1H NMR(500MHz,CD 3OD)δ8.97(s,2H),8.20(d,J＝7.4Hz,2H),8.07–8.00(m,2H),7.96(s,2H),7.93–7.81(m,6H),7.48(dt,J＝15.0,7.7Hz,4H),7.22(d,J＝7.9Hz,2H),7.09(d,J＝7.1Hz,2H). 13C NMR(126MHz,CD 3OD)δ143.6,141.8,140.5,140.5,138.6,135.0,134.9,134.6,132.8,131.1,131.0,129.6,129.0,128.3,128.0,127.4,127.3,125.5,80.0.HRMS(ESI-)m/z:[M-2Na+H] -计算值C 40H 23Na 2O 12S 4 -868.9873,测量值868.9876.
(3.3)第3步：
优选地，酸化条件是：将第2步所得水解产物四元磺酸钠化合物式(R)-12溶解于水中，随后将该 水溶液通过阳离子交换树脂Amberlyst 15(10cm 3/200mg水解产物)，用水洗脱两次，体系中的水通过与甲苯加热共沸除去，然后将所得固体于50℃下真空干燥6小时，得到最终产物手性联萘四元磺酸式(R)-2a-c。
式(R)-2a化合物的合成
Figure PCTCN2022090675-appb-000186
通过使用优选的酸化条件，从水解产物式(R)-12a得到褐色固体化合物(R)-2a(99％收率)。[α] D 18.0＝+53.0(c＝0.10,MeOH,(R)). 1H NMR(500MHz,CD 3OD)δ8.17(s,2H),7.72–7.59(m,6H),7.26(d,J＝7.7Hz,2H),7.11(d,J＝8.8Hz,2H),6.97(d,J＝8.9Hz,2H),2.76–2.67(m,10H),1.70–1.60(m,4H),1.35–1.26(m,20H),0.87(t,J＝6.6Hz,6H). 13C NMR(126MHz,CD 3OD)δ142.2,141.0,140.6,137.7,137.0,134.3,133.3,132.2,131.4,130.9,129.8,128.5,127.8,127.7,125.6,35.5,31.6,31.0,29.2,29.1,29.0,22.3,19.1,13.0.IR(neat)3422,2929,1468,1163,1019,608cm -1.HRMS(ESI-)m/z:[M-H] -计算值C 50H 57O 12S 4 -977.2738,测量值977.2722.
式(R)-2b化合物的合成
Figure PCTCN2022090675-appb-000187
通过使用优选的酸化条件，从水解产物式(R)-12b得到褐色固体化合物式(R)-2b(99％收率)。 1H NMR(500MHz,CD 3OD)δ8.08(s,2H),7.92(d,J＝8.2Hz,2H),7.84(d,J＝7.3Hz,4H),7.80(d,J＝7.9Hz,2H),7.52(t,J＝7.6Hz,2H),7.46(t,J＝7.7Hz,2H),7.29(t,J＝7.5Hz,2H),7.10(d,J＝8.6Hz,2H). 13C NMR(126MHz,CD 3OD)δ144.6,144.2,138.9,134.4,134.2,133.7,132.8,129.9,129.2,129.0,128.8,128.7,128.6,127.8,127.8,125.2.HRMS(ESI-)m/z:[M-H] -计算值C 32H 21O 12S 4 -724.9921,测量值724.9915.
式(R)-2c化合物的合成
Figure PCTCN2022090675-appb-000188
通过使用优选的酸化条件，从水解产物式(R)-12c得到褐色固体化合物式(R)-2c(99％收率)。 1H NMR(500MHz,CD 3OD)δ9.40–8.45(m,2H),8.20(d,J＝7.2Hz,2H),8.11–7.86(m,10H),7.51(dq,J＝ 21.2,13.1,10.3Hz,4H),7.37–6.92(m,4H). 13C NMR(126MHz,CD 3OD)δ142.2,140.0,138.5,137.5,133.4,133.3,131.1,128.6,128.5,128.0,127.8,127.5,126.4,126.1,125.9,125.6,124.9,124.0,123.6.HRMS(ESI-)m/z:[M-H] -计算值C 40H 25O 12S 4 -825.0234,测量值825.0233.
实施例4
本实施例为式(R)-2d,2e,2f化合物的制备方法,共分2步，合成路线如下：
Figure PCTCN2022090675-appb-000189
包括以下步骤：
(4.1)第1步：
优选地，偶联反应条件是：氮气保护下，在装有回流冷凝管的三口烧瓶中依次加入实施例2中第1步所得卤化产物式(R)-4(1.0当量)，实施例1中第2步所得含有SO 3Et基团的硼酸酯化合物式15g-i(3.5当量)，四三苯基膦钯(0.1当量)，碳酸钾(3.5当量)和N,N-二甲基甲酰胺(使式(R)-4浓度为0.1mol/L)。所得的混合液在60℃下搅拌12小时。反应完毕后降至室温，减压下旋转蒸发除去溶剂，剩余物通过硅胶柱色谱纯化(洗脱剂为乙酸乙酯和甲醇)，得到偶联产物二元磺酸钾化合物式(R)-5m-o。
式(R)-5m化合物的合成
Figure PCTCN2022090675-appb-000190
通过使用优选的偶联反应条件，从卤化产物式(R)-4a和芳基硼酸酯化合物式15g得到白色固体化合物(R)-5m(35％收率)。R f＝0.54(EA/MeOH＝5/1). 1H NMR(400MHz,CD 3OD)δ8.32(d,J＝2.0Hz,2H),7.94(s,2H),7.73(d,J＝5.8Hz,4H),7.39(t,J＝6.7Hz,2H),7.18–7.10(m,4H),4.38(d,J＝5.6Hz,2H),4.31(d,J＝5.6Hz,2H),2.74(d,J＝3.7Hz,10H),2.34(s,6H),1.69(p,J＝7.3Hz,4H),1.31(dt,J＝21.7,5.7Hz,20H),0.90–0.84(m,6H).HRMS(ESI-)m/z:[M-2K+H] -计算值C 54H 65O 10S 2 -937.4024,测量值937.4091.
式(R)-5n化合物的合成
Figure PCTCN2022090675-appb-000191
通过使用优选的偶联反应条件，从卤化产物式(R)-4f和芳基硼酸酯化合物式15h得到白色固体化 合物式(R)-5n(84％收率)。R f＝0.63(EA/MeOH＝4/1). 1H NMR(400MHz,CD 3OD)δ8.23(s,2H),8.07(s,2H),7.99(d,J＝8.1Hz,2H),7.90–7.84(m,4H),7.56(t,J＝7.7Hz,2H),7.45(t,J＝7.2Hz,2H),7.31(t,J＝7.5Hz,2H),7.23(d,J＝8.5Hz,2H),4.40(d,J＝5.7Hz,2H),4.35(d,J＝5.8Hz,2H),2.36(s,6H).HRMS(ESI-)m/z:[M-2K+H] -计算值C 36H 29O 10S 2 -685.1207,测量值685.1200.
式(R)-5o化合物的合成
Figure PCTCN2022090675-appb-000192
通过使用优选的偶联反应条件，从卤化产物式(R)-4f和芳基硼酸酯化合物式15i得到白色固体化合物式(R)-5o(65％收率)。R f＝0.33(EA/MeOH＝4/1). 1H NMR(500MHz,CD 3OD)δ9.23(s,2H),8.29(s,2H),8.23(d,J＝7.0Hz,2H),8.03(q,J＝10.1,7.5Hz,8H),7.54(t,J＝7.7Hz,2H),7.47(t,J＝7.3Hz,2H),7.33(t,J＝7.6Hz,2H),7.27(d,J＝8.4Hz,2H),4.46(d,J＝5.6Hz,2H),4.41(d,J＝5.6Hz,2H),2.34(s,6H). 13C NMR(126MHz,CD 3OD)δ152.5,142.2,139.2,136.8,135.2,134.8,132.6,132.5,132.2,130.7,129.5,129.3,128.9,127.9,127.9,127.5,127.5,127.1,126.4,125.6,99.6,56.4.HRMS(ESI-)m/z:[M-2K+H] -计算值C 40H 25O 8S 2 -823.1079,测量值823.1080.
(4.2)第2步：
优选地，酸化条件是：将第1步所得偶联产物式(R)-5m-o(1.0当量)溶于甲醇(0.01mol/L)中，随后加入浓盐酸(10.0当量)。所得的混合液在60℃下搅拌5小时。反应完毕后降至室温，减压下旋转蒸发除去溶剂。再将所得固体溶于甲醇中，随后将该甲醇溶液通过阳离子交换树脂Amberlyst 15，用甲醇洗脱两次，减压下旋转蒸发除去甲醇，然后将所得固体于50℃下真空干燥6小时，得到最终产物联萘手性二羟基二元磺酸式(R)-2d-f。
式(R)-2d化合物的合成
Figure PCTCN2022090675-appb-000193
通过使用优选的酸化条件，从偶联产物式(R)-5m得到棕色固体化合物(R)-2d(99％收率)。 1H NMR(400MHz,CD 3OD)δ8.34(s,2H),7.89(s,2H),7.74(dd,J＝7.8,1.7Hz,2H),7.66(d,J＝1.6Hz,2H),7.34(d,J＝7.9Hz,2H),7.09(dd,J＝8.7,1.7Hz,2H),6.99(d,J＝8.6Hz,2H),2.71(d,J＝6.6Hz,10H),1.71–1.63(m,4H),1.31(d,J＝20.2Hz,20H),0.95–0.82(m,6H). 13C NMR(101MHz,CD 3OD)δ150.0,137.8,136.3,134.9,132.2,131.3,131.0,130.8,129.5,128.1,127.6,126.3,124.2,116.6,115.1,113.9,35.4,31.6,31.2,29.2,29.0,29.0,22.3,19.0,13.0.HRMS(ESI-)m/z:[M-H] -计算值C 50H 57O 8S 2 -849.3500,测量值849.3476.
式(R)-2e化合物的合成
Figure PCTCN2022090675-appb-000194
通过使用优选的酸化条件，从偶联产物式(R)-5n得到褐色固体化合物式(R)-2e(99％收率)。 1H NMR(500MHz,CD 3OD)δ8.23(s,2H),8.00(s,2H),7.92(d,J＝8.1Hz,2H),7.88(d,J＝7.8Hz,2H),7.83(d,J＝7.8Hz,2H),7.51(t,J＝7.8Hz,2H),7.31(t,J＝7.1Hz,2H),7.24(t,J＝7.6Hz,2H),7.07(d,J＝8.4Hz,2H). 13C NMR(126MHz,CD 3OD)δ151.1,139.2,134.0,131.6,130.9,130.4,129.3,128.0,127.5,126.9,126.2,124.2,124.1,123.1,114.7.HRMS(ESI-)m/z:[M-H] -计算值C 32H 21O 8S 2 -597.0683,测量值597.0675.
式(R)-2f化合物的合成
Figure PCTCN2022090675-appb-000195
通过使用优选的酸化条件，从偶联产物式(R)-5o得到红灰色固体化合物式(R)-2f(99％收率)。 1H NMR(500MHz,CD 3OD)δ9.18(s,2H),8.21(d,J＝9.8Hz,4H),8.03(t,J＝9.8Hz,4H),7.96(d,J＝8.2Hz,4H),7.51(t,J＝7.1Hz,2H),7.33(t,J＝7.3Hz,2H),7.25(t,J＝7.4Hz,2H),7.14(d,J＝8.4Hz,2H). 13C NMR(126MHz,CD 3OD)δ152.4,139.1,135.3,134.5,133.0,132.3,132.2,132.2,130.6,130.2,129.8,129.2,128.3,127.6,127.3,126.8,125.4,125.1,124.3,116.0.HRMS(ESI-)m/z:[M-H] -计算值C 40H 25O 8S 2 -697.0996,测量值697.0997.
实施例5
本实施例为式(R)-2g化合物的制备方法，步骤如下：
Figure PCTCN2022090675-appb-000196
氮气保护下，在装有回流冷凝管的三口烧瓶中依次加入式(R)-2e化合物(300.0mg,0.5mmol)和2mL的吡啶，向其中缓慢加入三氯氧磷(307.0mg,2.0mmol)。所得的混合液升温至95℃并继续搅拌16小时。降至室温，加入2mL的水后，升温至100℃并继续搅拌4小时。再降至室温，减压下旋转蒸发尽可能多的除去吡啶，缓慢加入2mL的浓盐酸，加的过程中会有固体析出，加完继续搅拌5分钟，随后减压下旋转蒸发尽可能多的除去系统中的水，随后将残留物置于-20℃，直至有大量不溶物析出，得到棕色固体化合物(R)-2g(105.0mg,34％收率)。 1H NMR(500MHz,CD 3OD)δ8.21(s, 2H),8.16(s,2H),8.10(d,J＝8.3Hz,2H),7.93(d,J＝7.8Hz,2H),7.88(d,J＝7.8Hz,2H),7.55(t,J＝7.7Hz,4H),7.36(t,J＝7.5Hz,2H),7.30(d,J＝8.6Hz,2H). 13C NMR(126MHz,CD 3OD)δ145.0,137.4,133.1,132.0,131.7,131.6,131.3,128.5,127.9,127.3,127.0,126.7,126.3,125.9,124.9,122.6. 31P NMR(202MHz,CD 3OD)δ1.7.HRMS(ESI-)m/z:[M-H] -计算值C 32H 20O 10PS 2 -659.0240,测量值659.0236.
效果实施例1
Figure PCTCN2022090675-appb-000197
步骤如下：氮气保护下，向式(R)-1a化合物(5.1mg,0.005mmol)的环己烷溶液中添加异辛醇钛Ti(EHO) 4(5.7mg,0.01mmol)，该混合液升温至60℃并搅拌30分钟。降至室温，加入0.22μL的水，再升温至75℃并搅拌8小时。冷却至室温，加入2-烯丙基苯酚A(13.4mg,0.1mmol)，再升温至75℃搅拌24小时。反应结束后直接通过硅胶柱色谱纯化(洗脱剂为石油醚：乙酸乙酯＝50:1)得到产物式B化合物。产物的ee值由超临界流体色谱法SFC(手性柱Daciel Chiralcel,OJ-H，异丙醇：二氧化碳＝1：99，喷嘴压力＝200bar CO 2，流速＝3.0mL/min，检测波长＝230nm)测定。产物：无色液体，99％收率，97％ee。 1H NMR(500MHz,CDCl 3)δ7.15(d,J＝7.3Hz,1H),7.10(t,J＝7.7Hz,1H),6.86–6.79(m,1H),6.76(d,J＝8.0Hz,1H),4.92(ddq,J＝8.9,7.7,6.2Hz,1H),3.31(dd,J＝15.4,8.8Hz,1H),2.82(dd,J＝15.3,7.7Hz,1H),1.47(d,J＝6.2Hz,3H). 13C NMR(126MHz,CDCl 3)δ159.6,128.1,127.2,125.1,120.3,109.5,79.6,37.3,21.9.[α] D 20.2＝+16.7(c＝0.12,CHCl 3)。
按照如上述的方法，将式A化合物在使用不同手性配体制备的催化剂下进行反应，结果如下表1所示：
表1
Figure PCTCN2022090675-appb-000198
Figure PCTCN2022090675-appb-000199
Figure PCTCN2022090675-appb-000200
备注：表1中“-”表示收率在1％以下，几乎不反应。
在上述条件下，采用化合物1i、1l和1m作为催化剂时，仅几乎无法得到的化合物B。发明人提高了反应的温度和减少异辛醇钛的用量后，发现化合物1i、1l或1m作为催化剂也可催化该反应。具体反应结果见表2，实验具体步骤如下：
向式(R)-1或(R)-2化合物(0.005mmol)的甲苯溶液中添加异辛醇钛Ti(EHO) 4(2.85mg,0.005mmol)，该混合液升温至60℃并搅拌30分钟。冷却至室温，加入2-烯丙基苯酚A(13.4mg,0.1mmol)，再升温至90℃搅拌24小时。反应结束后直接通过硅胶柱色谱纯化(洗脱剂为石油醚：乙酸乙酯＝50:1)得到产物式B化合物。产物的ee值由超临界流体色谱法SFC确定。
Figure PCTCN2022090675-appb-000201
表2
Figure PCTCN2022090675-appb-000202
Figure PCTCN2022090675-appb-000203
效果实施例2
按照效果实施例1的测试方法，本发明还进行了催化其他类似式A化合物的环化反应，并得到一系列类似式B化合物的产物，结果如下表3所示。测试结果表明通过本发明所述方法制备得到的上述各类化合物具有优异的催化活性。
表3
Figure PCTCN2022090675-appb-000204
Figure PCTCN2022090675-appb-000205
备注：表1、表2和表3中，收率：>＝70％高，30％(含)～70％中，收率<30％低；ee值：>＝85％A，60％(含)～85％B，15％(含)～60％C，<15％D。
应当理解，这些实施例的用途仅用于说明本发明而非意欲限制本发明的保护范围。此外，也应理解，在阅读了本发明的技术内容后，本领域的技术人员可以对本发明作各种改动、修改和/或变型，所有的这些等价形式同样落于本申请所附权利要求书所限定的保护范围之内。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (12)

  1. 一种如式I-1或I-2所示的化合物；
    Figure PCTCN2022090675-appb-100001
    其中，A1为C 6-18芳基或不存在；
    A1’、A2和A2’独立地为C 6-18芳基；
    R 1和R 7独立地为H、C 1-16烷基或金刚烷基；
    R 2和R 2’独立地为羟基或-NR 2aR 2b；
    R 2a和R 2b独立地为C 1-6烷基；
    R 3和R 3’独立地为H、C 1-6烷基或-S(O) 2NR 3aR 3b；
    R 3a和R 3b独立地为C 1-6烷基；
    R 4为-S(O) 2OH或羟基，或者两个R 4一起形成
    Figure PCTCN2022090675-appb-100002
    当R 4为羟基时，所述的R 2和R 2’为羟基；
    R 5、R 5’、R 6和R 6’独立地为H、C 1-6烷基或被R 5-1取代的C 1-6烷基，且R 5、R 5’、R 6和R 6’不同时为H；
    R 5-1为卤素或被卤素取代的C 1-6烷基；
    且所述的如式I-2所示的化合物不为
    Figure PCTCN2022090675-appb-100003
  2. 如权利要求1所述的如式I-1或I-2所示的化合物，其特征在于，所述的如式I-1或I-2所示的化合物满足如下条件中1个或多个：
    (1)当A1、A1’、A2和A2’独立地为C 6-18芳基时，所述的C 6-18芳基为苯基、萘基、菲基或蒽 基，优选为苯基或萘基；
    (2)当R 1和R 7独立地为C 1-16烷基时，所述的C 1-16烷基为直链C 1-16烷基或支链的C 1-16烷基，优选为直链的C 1-16烷基；
    (3)当R 2a和R 2b独立地为C 1-6烷基时，所述的C 1-6烷基为甲基、乙基、正丙基或异丙基，优选为甲基；
    (4)当R 3和R 3’独立地为C 1-6烷基时，所述的C 1-6烷基为甲基、乙基、正丙基、异丙基或正戊基，优选为甲基或正戊基；
    (5)当R 3a和R 3b独立地为C 1-6烷基时，所述的C 1-6烷基为甲基、乙基、正丙基或异丙基，优选为甲基；
    (6)当R 5、R 5’、R 6和R 6’独立地为C 1-6烷基或被R 5-1取代的C 1-6烷基时，所述的C 1-6烷基或所述的被R 5-1取代的C 1-6烷基中的C 1-6烷基为甲基、乙基、正丙基或异丙基，优选为甲基；
    (7)当R 5-1为卤素或被卤素取代的C 1-6烷基时，所述的卤素或所述的被卤素取代的C 1-6烷基中的卤素为F、Cl、Br或I，优选为F；
    (8)当R 5-1为被卤素取代的C 1-6烷基时，所述的被卤素取代的C 1-6烷基为三氟甲基；
    (9)所述的如式I-1所示的化合物的通式为
    Figure PCTCN2022090675-appb-100004
    和/或
    Figure PCTCN2022090675-appb-100005
    (10)所述的如式I-2所示的化合物的通式为
    Figure PCTCN2022090675-appb-100006
    和/或
    Figure PCTCN2022090675-appb-100007
    (11)所述的如式I-1所示的化合物的通式为I-1a、I-1b、I-1c或I-1d所示：
    Figure PCTCN2022090675-appb-100008
  3. 如权利要求2所述的如式I-1或I-2所示的化合物，其特征在于，所述的如式I-1或I-2所示的化合物满足如下条件中的1个或多个：
    (1)当A1和A1’独立地为苯基时，所述的R 3或R 3’位于苯基上所述的苯基与萘环连接位点的对位或间位；
    (2)当A1和A1’独立地为苯基时，所述的
    Figure PCTCN2022090675-appb-100009
    位于苯基上所述的苯基与萘环连接位点的间位；
    (3)A1和A1’独立地为萘基时，所述的
    Figure PCTCN2022090675-appb-100010
    位于所述的萘基的8号位；
    (4)当A2和A2’独立地为苯基时，所述的R 5、R 5’、R 6或R 6’位于苯基上所述的苯基与萘环连接位点的间位；
    (5)当所述的R 1和R 7独立地为直链的C 1-16烷基时，所述的直链的C 1-16烷基正十六烷基或正辛基；
    (6)当所述的R 1和R 7独立地为支链C 1-16烷基时，所述的支链的C 1-16烷基为支链的C 3-6烷基，优选为叔丁基；
    (7)当R 5、R 5’、R 6和R 6’独立地为被R 5-1取代的C 1-6烷基时，所述的被R 5-1取代的C 1-6烷基为三氟甲基或-CF(CF 3) 2。
  4. 如权利要求1所述的如式I-1或I-2所示的化合物，其特征在于，所述的如式I-1或I-2所示的化合物满足如下条件中的1个或多个：
    (1)A1为C 6-18芳基；
    (2)R 1和R 7独立地为C 1-16烷基或金刚烷基；
    (3)R 2和R 2’为-NR 2aR 2b；
    (4)R 3和R 3’独立地为C 1-6烷基或-S(O) 2NR 3aR 3b；
    (5)R 4为-S(O) 2OH；
    (6)R 5、R 5’、R 6和R 6’独立地为被R 5-1取代的C 1-6烷基；
    (7)
    Figure PCTCN2022090675-appb-100011
    独立地为
    Figure PCTCN2022090675-appb-100012
    Figure PCTCN2022090675-appb-100013
    (8)
    Figure PCTCN2022090675-appb-100014
    独立地为
    Figure PCTCN2022090675-appb-100015
    (9)
    Figure PCTCN2022090675-appb-100016
    为
    Figure PCTCN2022090675-appb-100017
    Figure PCTCN2022090675-appb-100018
    Figure PCTCN2022090675-appb-100019
    优选
    Figure PCTCN2022090675-appb-100020
    Figure PCTCN2022090675-appb-100021
  5. 如权利要求1所述的如式I-1或I-2所示的化合物，其特征在于，其为如下任一方案：
    方案1：
    所述的如式I-1所示的化合物中：
    A1为C 6-18芳基；
    当A1’为C 6-18芳基，所述的C 6-18芳基为萘基时，所述的R 1为C 1-16烷基或金刚烷基；所述的R 2’为-NR 2aR 2b；
    当R 4为羟基时，所述的R 3和R 3’为H；
    方案2：
    所述的如式I-1所示的化合物中：
    A1为C 6-18芳基；
    R 1为H或C 1-16烷基；
    R 3为H或C 1-6烷基；
    R 4为-S(O) 2OH或羟基；
    当R 2和R 2’独立地为-NR 2aR 2b时，所述的R 1为C 1-16烷基；
    当R 2和R 2’独立地为羟基时，所述的R 1为H；
    当R 2和R 2’独立地为羟基，R 4为-S(O) 2OH时，所述的A1和A1’独立地为C 6-18芳基，所述的C 6- 18芳基为萘基；
    方案3：
    所述的如式I-1所示的化合物中：
    A1为C 6-18芳基；所述的C 6-18芳基为苯基；
    R 1为C 1-16烷基或金刚烷基；
    R 2和R 2’为-NR 2aR 2b；
    R 3和R 3’为C 1-6烷基；
    R 4为-S(O) 2OH。
  6. 如权利要求1所述的如式I-1或I-2所示的化合物，其特征在于，所述的如式I-1所示的化合物为如下任一化合物和/或其异构体：
    Figure PCTCN2022090675-appb-100022
    所述的如式I-2所示的化合物为如下任一化合物和/或其异构体：
    Figure PCTCN2022090675-appb-100023
  7. 一种如权利要求1-6中任一项所述的如式I-1或I-2所示的化合物的制备方法，其特征在于，所述的制备方法为如下方法1、2、3或4：
    方法1：
    当R 4为-S(O) 2OH时，所述的如式I-1所示的化合物的制备方法包括如下步骤：在酸性试剂下，将化合物II-a在溶剂中进行如下式的酸化反应，得到所述的如式I-1化合物；
    Figure PCTCN2022090675-appb-100024
    其中，Z和Z’独立地为羟基或-SO 3M 1a；
    M 1a独立地为Na或K；
    R 13和R 13‘独立地为-ONa、-OK或-NR 2aR 2b；R 2a和R 2b定义均如权利要求1-6中任一项所述；
    方法2：当R 4为OH时，所述的如式I-1所示的化合物的制备方法包括如下步骤：在酸性试剂或BBr 3存在下，将化合物II-b在溶剂中进行如下式的脱保护反应，得到所述的如式I-1化合物；
    Figure PCTCN2022090675-appb-100025
    其中，R 15和R 15’独立地为羟基保护基或C 1-3烷基；M 2a和M 2b独立地为Na或K；
    方法3：
    当两个R 4一起形成
    Figure PCTCN2022090675-appb-100026
    时，所述的如式I-1所示的化合物的制备方法包括如下步骤：
    步骤(1)：将方法2中得到化合物I-1和三氯氧磷在溶剂中进行酯化反应，得到混合溶液；
    步骤(2)：将步骤(1)得到混合溶液在水中进行水解反应，得到所述的如式I-1化合物；
    Figure PCTCN2022090675-appb-100027
    方法4：
    当R 4为-S(O) 2OH时，所述的如式I-1或I-2所示的化合物的制备方法包括如下步骤：在氧化剂和甲酸存在下，将化合物II-d在溶剂中进行如下式的氧化反应，得到所述的如式I-1或I-2所示的化合物；
    Figure PCTCN2022090675-appb-100028
    其中，R 16a和R 16b独立地为C 1-3烷基；
    R 18为R 3，R 18a为-S(O 2)R 2；或者，R 18为R 5，R 18a为R 6；
    R 19为-S(O 2)R 2’，R 19a为R 3’；或者，R 19为R 6’，R 19a为R 5’；
    方法1-4中，R 2、R 2’、R 3、R 3’、R 5、R 5’、R 6和R 6’的定义均如权利要求1-6中任一项所述。
  8. 一种催化剂组合物，其包括如权利要求1-6中任一项所述的如式I-1或I-2所示的化合物和钛盐；
    所述的催化剂组合物中，所述的钛盐优选四甲醇钛、四异丙醇钛、四叔丁醇钛、四异丁醇钛、四氯化钛、氯化三异丙醇钛、异辛醇钛中的一种或多种，例如异辛醇钛。
  9. 一种如权利要求1-6中任一项所述的如式I-1或I-2所示的化合物或如权利要求8中所述的催化剂组合物作为催化剂在制备化合物B中的应用；
    所述的化合物B的制备方法包括以下步骤：在所述的如式I-1或I-2所示的化合物和钛盐存在下，将化合物A在溶剂中进行如下式的环合反应，得到所述的化合物B；
    Figure PCTCN2022090675-appb-100029
    其中，R 8、R 9、R 10和R 11独立地为H、卤素、C 1-6烷基、-O-C 1-6烷基、氰基、-C(＝O)OR 8-1、C 3- 6环烷基、C 6-18芳基或被R 8-2取代的C 6-18芳基；
    R 8-1为C 1-6烷基；
    R 8-2为C 2-6烯基或羟基；
    或者，R 8、R 9、R 10和R 11中任意相邻的两个取代基与其相连的碳原子一起形成C 3-6环烷基、C 6-18芳基或
    Figure PCTCN2022090675-appb-100030
    R 12和R 13独立地为H、C 1-6烷基或C 6-18芳基，或者，R 12和R 13与其相连的碳原子一起形成C 3-6环烷基；
    n为1、2或3。
  10. 如权利要求9所述的应用，其特征在于，所述的应用满足如下条件中的1个或多个：
    (1)当R 8、R 9、R 10和R 11独立地为C 1-6烷基或-O-C 1-6烷基时，所述的C 1-6烷基或所述的-O-C 1- 6烷基中的C 1-6烷基为甲基、乙基、正丙基或异丙基；
    (2)当R 8、R 9、R 10和R 11独立地为C 3-6环烷基时，所述的C 3-6环烷基为环丙基、环丁基、环戊基或环己基，例如环己基；
    (3)当R 8、R 9、R 10和R 11独立地为C 6-18芳基或被R 8-1取代的C 6-18芳基时，所述的C 6-18芳基或所述的被R 8-1取代的C 6-18芳基中的C 6-18芳基为苯基、萘基、菲基或蒽基，例如苯基；
    (4)当R 8-1为C 1-6烷基时，所述的C 1-6烷基为甲基、乙基、正丙基或异丙基，例如甲基；
    (5)当R 8-2为C 2-6烯基时，所述的C 2-6烯基为乙烯基或丙烯基，进一步为
    Figure PCTCN2022090675-appb-100031
    (6)当R 8、R 9、R 10和R 11中任意相邻的两个取代基与其相连的碳原子一起形成C 3-6环烷基时，所述的C 3-6环烷基为环丙基、环丁基、环戊基或环己基，例如环己基；
    (7)当R 8、R 9、R 10和R 11中任意相邻的两个取代基与其相连的碳原子一起形成C 6-18芳基时，所述的C 6-18芳基为苯基、萘基、菲基或蒽基，例如苯基；
    (8)当R 12和R 13独立地为C 1-6烷基时，所述的C 1-6烷基为甲基、乙基、正丙基或异丙基，例如甲基；
    (9)当R 12和R 13独立地为C 6-18芳基时，所述的C 6-18芳基为苯基、萘基、菲基或蒽基，例如苯基；
    (10)所述的化合物A为
    Figure PCTCN2022090675-appb-100032
    Figure PCTCN2022090675-appb-100033
    (11)当所述的如式I-1或I-2所示的化合物为
    Figure PCTCN2022090675-appb-100034
    时；所述的化合物B为
    Figure PCTCN2022090675-appb-100035
    (12)当所述的如式I-1或I-2所示的化合物为
    Figure PCTCN2022090675-appb-100036
    时；所 述的化合物B为
    Figure PCTCN2022090675-appb-100037
  11. 一种化合物II-a、化合物II-b、化合物II-d、化合物III-d或化合物IV-d：
    Figure PCTCN2022090675-appb-100038
    其中，Z和Z’独立地为羟基或-SO 3M 1a；M 1a独立地为Na或K；
    R 13和R 13‘独立地为-ONa、-OK或-NR 2aR 2b；
    R 15和R 15’独立地为羟基保护基或C 1-3烷基；
    M 2a和M 2b独立地为Na或K；
    R 16a和R 16b独立地为C 1-3烷基；
    R 18为R 3或R 5；R 18a为-S(O 2)R 2或R 6；
    R 19为-S(O 2)R 2’或R 6’；R 19a为R 3’或R 5’；
    R 1、R 2、R 2’、R 3、R 3’、R 5、R 5’、R 6、R 6’、R 7、R 2a和R 2b的定义均如权利要求1-6中任一项所述；且所述的化合物IV-d不为
    Figure PCTCN2022090675-appb-100039
    优选，所述的化合物II-a、所述的化合物II-b、所述的化合物II-d、所述的化合物III-d或所述的 化合物IV-d为如下通式：
    Figure PCTCN2022090675-appb-100040
  12. 一种如权利要求11所述的化合物II-a、化合物II-b、化合物II-d、化合物III-d或化合物IV-d，其特征在于，所述的化合物II-a、所述的化合物II-b、所述的化合物II-d、所述的化合物III-d或所述的化合物IV-d为如下任一化合物和/或其异构体：
    Figure PCTCN2022090675-appb-100041
    Figure PCTCN2022090675-appb-100042
    Figure PCTCN2022090675-appb-100043
    Figure PCTCN2022090675-appb-100044
    Figure PCTCN2022090675-appb-100045
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