CN114853653A - Preparation method of three-membered ring without metal catalysis - Google Patents
Preparation method of three-membered ring without metal catalysis Download PDFInfo
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Abstract
The invention discloses a novel preparation method of a three-membered ring, which comprises the following steps: under the condition of room temperature, an amino derivative or an alkyl derivative containing an electron-withdrawing group as a substrate reacts with olefin thianthrene salt in an organic solvent in the presence of alkali to obtain a three-membered ring product. The preparation method has the characteristics of mild conditions, no transition metal, small environmental pollution and high yield.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis methods, and particularly discloses a preparation method of a three-membered ring without metal catalysis.
Background
The ternary ring structures such as cyclopropane and aziridine are widely existed in natural products and bioactive molecules, and are a very important organic synthesis intermediate. The ternary ring structure has made the synthesis of cyclopropane, aziridine, etc. highly challenging due to the presence of ring tensions. Wherein, the synthesis of aziridine, the existing main synthesis method is that the nitrene analogue or precursor is subjected to insertion reaction on olefin and contains NH 2 And (3) carrying out nucleophilic substitution reaction on the ortho position in the group molecule, and carrying out addition reaction on the imine group in the molecule by the carbene analogue. Currently using NH 2 The method for synthesizing aziridine with olefin includes two methods: one is that high valence iodide is combined with sulfamide to form nitrene analogue, and then the nitrene analogue and olefin are subjected to insertion reaction to generate aziridine; the other is the synthesis of aziridines by reacting olefins under electro-redox conditions to form sulfonium salts or alkenylcationic radicals and then with primary organic amines (Nature 2021,596, 74; Chem 2021,7,255) or by reacting olefins with ammonia gas to form unprotected aziridines (Chem 2021,7, 255). However, these methods have their own limitations and are applicable to all types of NH 2 (e.g., primary amines, primary amides, primary sulfonamides, primary carboxamides, etc.) and olefins, and processes for synthesizing the azatricyclic ring by direct reaction are still in need of development. In addition, the construction of cyclopropane structure is mainly carried out by two methods, namely metal catalysis and electrocatalysis. Wherein the metal catalysis needs to be carried out by taking diazo compound as a precursor and carrying out [2+1 ] on olefin]The disadvantages of this type of process are the limitation and the danger of diazo compounds. Electrocatalytic methods are currently limited to intramolecular cyclopropane synthesis (j.am. chem. soc.2022,144, 2343). Previously, sulfonium salts have also been used to construct cyclopropane structures (RSC adv.,2017,7, 3741; J.am)Chem. soc.2021,143,12992), but such sulfonium salts are limited to vinyl-substituted substrates only. Alkenyl thianthrene salts can be prepared in large quantities from olefins by a one-step reaction with thianthrene monooxide (Angew. chem. int. Ed.2020,59,5616).
Under the condition of room temperature, the high-efficiency preparation method of aziridine and cyclopropane compounds is developed from stable and easily obtained amino derivatives or alkyl derivatives containing electron-withdrawing groups and alkenyl thianthrene salts, and has important application prospects in the fields of fine chemical engineering, material science and pharmacy.
Disclosure of Invention
In one aspect, the invention discloses a method for preparing a three-membered ring, which is characterized by comprising the following steps: in the presence of alkali, reacting a compound shown as a formula (III) with a compound shown as a formula (II-a) or (II-b) in an organic solvent to obtain a corresponding compound shown as a formula (I-a) or (I-b);
wherein the content of the first and second substances,
x is halogen, BF 4 、PF 6 、AsF 6 、SbF 6 、ClO 4 、CF 3 COO、OTf、OTs；
L is a bond, - (CH) 2 ) q -, -C (═ O) -, or-S (═ O) 2 -；
q is 0,1, 2,3,4 or 5;
each R 1 And R 2 Independently H, C 1-12 Alkyl radical, C 3-8 Cycloalkyl radical, C 6-10 Aryl or heteroaryl of 5 to 12 atoms, wherein said C 1-12 Alkyl radical, C 3-8 Cycloalkyl radical, C 6-10 Aryl and heteroaryl of 5 to 12 atoms are independently unsubstituted OR substituted by 1,2,3,4 OR 5 substituents selected from halogen, oxo, -CN, -OR a 、-NR a R b 、-C(＝O)R a 、-C(＝O)OR a 、C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Haloalkyl and C 1-6 Substituted by a substituent of alkoxy;
or R 1 、R 2 Together with the atoms to which they are attached form C 3-8 Cycloalkyl or heterocyclyl consisting of 5 to 12 atoms, wherein said C is 3-8 Cycloalkyl and heterocyclyl consisting of 5 to 12 atoms are independently unsubstituted or substituted by 1,2,3,4 or 5 substituents selected from halogen, oxo, -CN, -OH, -NH 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-C(＝O)ONH 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl and C 1-6 Substituted by a substituent of alkoxy;
R 3 is-CN, -NH 2 、C 1-12 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, C 3-12 Cycloalkyl, heterocyclic group consisting of 5 to 20 atoms, C 6-10 Aryl or heteroaryl of 5 to 20 atoms, wherein said C 1-12 Alkyl radical, C 3-12 Cycloalkyl, heterocyclic group consisting of 5 to 20 atoms, C 6-10 Aryl and heteroaryl of 5 to 20 atoms are independently unsubstituted OR substituted by 1,2,3,4 OR 5 substituents selected from halogen, oxo, -CN, -OR c 、-NR c R d 、-C(＝O)OR c 、-C(＝O)OR c R d 、-NR c C(O)R d 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 6-10 Aryl and heteroaryl of 5 to 12 atoms;
each R 4 And R 5 Independently of one another is-CN, -OR e 、-NR e R f 、-C(＝O)R e 、-C(＝O)OR e 、-S(＝O) 2 R e 、C 1-6 Alkyl radical, C 6-10 Aryl or heteroaryl of 5 to 12 atoms, wherein said C 1-6 Alkyl radical, C 6-10 Aryl and 5-12-atom heteroaryl are independently unsubstituted or substituted by 1,2,3,4 or 5 substituents selected from halogen, oxo, -CN, -OH, -NH 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-C(＝O)ONH 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl and C 1-6 Substituted by a substituent of alkoxy;
or R 4 、R 5 And the atoms to which they are attached form a 5-12 atom heterocyclyl group, wherein said 5-12 atom heterocyclyl group is unsubstituted or substituted with 1,2,3,4 or 5 substituents selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-OC(O)CH 3 、C 1-6 Alkyl radical, C 1-6 Haloalkyl and C 1-6 Substituted by a substituent of alkoxy;
R a 、R b 、R c 、R d 、R e and R f Independently is H, -OH, -NH 2 、C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 6-10 Aryl or heteroaryl of 5 to 12 atoms, wherein said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 6-10 Aryl and 5-12-atom heteroaryl are independently unsubstituted or substituted by 1,2,3,4 or 5 substituents selected from halogen, oxo, -CN, -OH, -NH 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、C 1-6 Alkyl radical, C 1-6 Haloalkyl and C 1-6 Substituted by a substituent of alkoxy.
In some embodiments, X is F, Cl, Br, I, BF 4 、PF 6 、AsF 6 、SbF 6 、ClO 4 、CF 3 COO、OTf、OTs；
Each R 1 And R 2 Independently H, C 1-8 Alkyl radical, C 3-6 Cycloalkyl radical, C 6-10 Aryl or heteroaryl of 5 to 10 atoms, wherein said C 1-8 Alkyl radical, C 3-6 Cycloalkyl radical, C 6-10 Aryl and heteroaryl of 5 to 10 atoms are independently unsubstituted OR substituted by 1,2,3,4 OR 5 substituents selected from halogen, oxo, -CN, -OR a 、-NR a R b 、-C(＝O)R a 、-C(＝O)OR a 、C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Haloalkyl and C 1-4 Substituted by a substituent of alkoxy;
or R 1 、R 2 And are connected with themTogether form C 3-6 Cycloalkyl or heterocyclyl consisting of 5 to 10 atoms, wherein said C is 3-6 Cycloalkyl and heterocyclyl consisting of 5 to 10 atoms are independently unsubstituted or substituted by 1,2,3,4 or 5 substituents selected from halogen, oxo, -CN, -OH, -NH 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-C(＝O)ONH 2 、C 1-4 Alkyl radical, C 1-4 Haloalkyl and C 1-4 Substituted by a substituent of alkoxy.
In some embodiments, R 3 is-CN, -NH 2 、C 1-8 Alkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylamino radical, C 3-8 Cycloalkyl, heterocyclic radical consisting of 5-16 atoms, C 6-10 Aryl or heteroaryl of 5 to 16 atoms, wherein said C 1-8 Alkyl radical, C 3-8 Cycloalkyl, heterocyclic radical consisting of 5-16 atoms, C 6-10 Aryl and heteroaryl of 5 to 16 atoms are independently unsubstituted OR substituted by 1,2,3,4 OR 5 substituents selected from halogen, oxo, -CN, -OR c 、-NR c R d 、-C(＝O)OR c 、-C(＝O)OR c R d 、-NR c C(O)R d 、C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 6-10 Aryl and heteroaryl of 5 to 10 atoms;
each R 4 And R 5 Independently is-CN, -OR e 、-NR e R f 、-C(＝O)R e 、-C(＝O)OR e 、-S(＝O) 2 R e 、C 1-4 Alkyl radical, C 6-10 Aryl or heteroaryl of 5 to 10 atoms, wherein said C 1-4 Alkyl radical, C 6-10 Aryl and 5-10 atoms consisting of heteroaryl, independently unsubstituted or substituted by 1,2,3,4 or 5 atoms selected from halogen, oxo, -CN, -OH, -NH 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-C(＝O)ONH 2 、C 1-4 Alkyl radical, C 1-4 Haloalkyl and C 1-4 Substituted with a substituent of alkoxy;
or R 4 、R 5 And are connected to themWherein the 5-10 atom heterocyclyl groups are independently unsubstituted or substituted by 1,2,3,4 or 5 atoms selected from halogen, oxo, -CN, -OH, -NH 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-OC(O)CH 3 、C 1-4 Alkyl radical, C 1-4 Haloalkyl and C 1-4 Substituted by a substituent of alkoxy;
R a 、R b 、R c 、R d 、R e and R f Independently is H, -OH, -NH 2 、C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 6-10 Aryl or heteroaryl of 5 to 10 atoms, wherein said C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 6-10 Aryl and 5-10-atom heteroaryl are independently unsubstituted or substituted by 1,2,3,4 or 5 substituents selected from halogen, oxo, -CN, -OH, -NH 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、C 1-4 Alkyl radical, C 1-4 Haloalkyl and C 1-4 Alkoxy groups.
Each R 1 And R 2 Independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptane, n-octane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptane, n-octane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl are independently unsubstituted or substituted by 1, 2. 3,4 OR 5 groups selected from F, Cl, Br, I, oxo, -CN, -OR a 、-NR a R b 、-C(＝O)R a 、-C(＝O)OR a Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CF 3 Methoxy, ethoxy, n-propoxy and isopropoxy;
or R 1 、R 2 And the atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, or morpholinyl group, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, and morpholinyl groups are independently unsubstituted or substituted with 1,2,3,4, or 5 groups selected from F, Cl, Br, I, oxo, -CN, -OH, -NH 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-C(＝O)ONH 2 Methyl, ethyl, n-propyl, isopropyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CF 3 Methoxy, ethoxy, n-propoxy and isopropoxy.
In some embodiments, R 3 is-CN, -NH 2 Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptane, n-octane, methoxy, ethoxy, n-propoxy, isopropoxy, methylamino, ethylamino, n-propylamino, isopropylamino, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or pyridazinyl
Wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and,N-hexyl, n-heptane, n-octane, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and pyridazinyl
Independently unsubstituted OR substituted by 1,2,3,4 OR 5 substituents selected from F, Cl, Br, I, oxo, -CN, -OR c 、-NR c R d 、-C(＝O)OR c 、-C(＝O)OR c R d 、-NR c C(O)R d Methyl, ethyl, n-propyl, isopropyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CF 3 Phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl;
each R 4 And R 5 Independently is-CN, -OR e 、-NR e R f 、-C(＝O)R e 、-C(＝O)OR e 、-S(＝O) 2 R e Methyl, ethyl, n-propyl, isopropyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein said methyl, ethyl, n-propyl, isopropyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl are independently unsubstituted or substituted with 1,2,3,4 or 5 substituents selected from the group consisting of F, Cl, Br, I, oxo, -CN, -OH, -NH, and 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-C(＝O)ONH 2 methyl, ethyl, n-propyl, isopropyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CF 3 Methoxy, ethoxy,N-propoxy and isopropoxy;
or R 4 、R 5 And the atoms to which they are attached form an azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, or morpholinyl group, wherein said azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, and morpholinyl groups are independently unsubstituted or substituted with 1,2,3,4, or 5 groups selected from F, Cl, Br, I, oxo, -CN, -OH, -NH 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-OC(O)CH 3 Methyl, ethyl, n-propyl, isopropyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CF 3 Methoxy, ethoxy, n-propoxy and isopropoxy;
R a 、R b 、R c 、R d 、R e and R f Independently is H, -OH, -NH 2 Methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein said methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl are independently unsubstituted or substituted with 1,2,3,4, or 5 substituents selected from F, Cl, Br, I, oxo, -CN, -OH, -NH, -OH 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 Methyl, ethyl, n-propyl, isopropyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CF 3 Methoxy, ethoxy, n-propoxy and isopropoxy.
In some embodiments, wherein the compound of formula (III) is selected from at least one of the following structures:
in some embodiments, wherein the base is potassium carbonate, sodium carbonate, ammonium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, cesium hydroxide, sodium tert-butoxide, potassium tert-butoxide, or lithium tert-butoxide.
In some embodiments, the organic solvent is dichloromethane, chloroform, carbon tetrachloride, acetonitrile, acetone, or tetrahydrofuran.
In some embodiments, wherein the reaction temperature is from 10 ℃ to 50 ℃; preferably, the reaction temperature is 15-35 ℃; the reaction time is 18-30 h; preferably, the reaction time is 20-26 h.
In some embodiments, the mass ratio of the compound represented by the formula (III) to the compound represented by the formula (II-a) is 1.0: 1.0-1.0: 3.0.
In some embodiments, the mass ratio of the compound represented by the formula (III) to the compound represented by the formula (II-b) is 1.0: 1.0-1.0: 3.0.
In some embodiments, the method for preparing the three-membered ring provided by the invention has the advantages of high yield, excellent enantioselectivity of the product, high atom economy and the like.
Detailed description of the invention
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs and all patent publications cited throughout the disclosure of the present invention are hereby incorporated by reference in their entirety.
The following definitions shall apply unless otherwise indicated. For the purposes of the present invention, the chemical elements are described in the periodic table of elements, CAS version and handbook of chemicals, 75, th ed, 1994. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltio: 1999, and "March's Advanced Organic Chemistry", by Michael B&Sons, New York, 2007, and therefore all the contents of the present invention are incorporated by reference.
Many different aspects and embodiments of the present disclosure will be described below, and each aspect and each embodiment is not limiting as to the scope of the present disclosure. The terms "aspect" and "embodiment" are intended to be non-limiting, regardless of whether the terms "aspect" or "embodiment" appear anywhere in the specification. As used herein, the transitional term "comprising" which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements.
In the context of the present invention, all numbers disclosed herein are approximate values. The numerical value of each number may vary by 1%, 2%, 5%, 7%, 8%, or 10%. Whenever a number is disclosed with a value of N, any number within the values of N +/-1%, N +/-2%, N +/-3%, N +/-5%, N +/-7%, N +/-8% or N +/-10% is explicitly disclosed, wherein "+/-" means plus or minus. Whenever a lower limit, DL, and an upper limit, DU, are disclosed in a range of values, any value falling within the disclosed range is expressly disclosed.
All reaction steps described in the present invention are carried out to a certain extent such as a raw material consumption of about more than 70%, more than 80%, more than 90%, more than 95%, or a post-treatment such as cooling, collection, extraction, filtration, separation, purification or a combination thereof after the detection that the raw material for the reaction has been consumed. The degree of reaction can be detected by a conventional method such as Thin Layer Chromatography (TLC), High Performance Liquid Chromatography (HPLC), Gas Chromatography (GC) and the like. The reaction solution may be worked up by a conventional method, for example, by evaporating under reduced pressure or by distilling the reaction solvent conventionally, collecting the crude product, and directly subjecting it to the next reaction; or directly filtering to obtain a crude product, and directly putting the crude product into the next reaction; or after standing, pouring out supernatant to obtain a crude product, and directly putting the crude product into the next reaction; or selecting proper organic solvent or their combination to make purification steps of extraction, distillation, crystallization, column chromatography, rinsing and pulping.
The addition processes and the reactions of the steps are all carried out under certain temperature conditions, and any temperature suitable for the addition processes or the reactions is included in the invention. Further, many similar modifications, equivalents, or equivalents of the temperature and temperature ranges set forth herein are deemed to be encompassed by the present invention. The invention provides the preferred temperature or temperature range of each dropping process and the preferred reaction temperature of each reaction.
The solvent used in each reaction step described in the present invention is not particularly limited, and any solvent that can dissolve the starting materials to some extent and does not inhibit the reaction is included in the present invention. Further, many equivalents, substitutions, or equivalents in the art to which this invention pertains, as well as different proportions of solvents, solvent combinations, and solvent combinations described herein, are deemed to be encompassed by the present invention. The invention provides a preferable solvent used in each reaction step.
"room temperature" in the present invention means a temperature of from about 10 ℃ to about 40 ℃. In some embodiments, "room temperature" refers to a temperature of from about 20 ℃ to about 30 ℃; in other embodiments, "room temperature" refers to 20 ℃, 22.5 ℃,25 ℃, 27.5 ℃, and the like.
The term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted". The terms "optionally," "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. In general, the term "optionally" whether or not preceded by the term "substituted" indicates that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein the substituent can be, but is not limited to, F, Cl, Br, I, CN, N 3 、OH、OR a 、NR b R c 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical C 3-6 Cycloalkyl radical, C 3-6 cycloalkyl-C 1-4 Alkylene, heterocyclic group consisting of 3 to 6 atoms, (heterocyclic group consisting of 3 to 6 atoms) -C 1-4 Alkylene radical, C 6-10 Aryl radical, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5 to 10 atoms or (heteroaryl of 5 to 10 atoms) -C 1-4 Alkylene, wherein R a 、R b And R c Have the definitions as described in the present invention.
The term "alkyl" or "alkyl group" as used herein, denotes a saturated straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms. Unless otherwise specified, alkyl groups contain 1 to 20 carbon atoms, some embodiments being alkyl groups containing 1 to 12 carbon atoms, other embodiments being alkyl groups containing 1 to 10 carbon atoms, other embodiments being alkyl groups containing 1 to 8 carbon atoms, other embodiments being alkyl groups containing 1 to 6 carbon atoms, other embodiments being alkyl groups containing 1 to 4 carbon atoms, and other embodiments being alkyl groups containing 1 to 3 carbon atoms.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH) 3 ) Ethyl (Et, -CH) 2 CH 3 ) N-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Isopropyl (i-Pr, -CH (CH) 3 ) 2 ) N-butyl (n-Bu, -CH) 2 CH 2 CH 2 CH 3 ) Isobutyl (i-Bu, -CH) 2 CH(CH 3 ) 2 ) Sec-butyl (s-Bu, -CH (CH) 3 )CH 2 CH 3 ) Tert-butyl (t-Bu, -C (CH) 3 ) 3 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) N-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH)) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentanRadical (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 ) N-heptyl, n-octyl, and the like, wherein the alkyl groups can be independently unsubstituted or substituted with one or more substituents described herein.
The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp 2 A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, allyl, and the like.
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond, wherein said alkynyl radical may optionally be substituted with one or more substituents as described herein. In some embodiments, alkynyl groups contain 2-8 carbon atoms; in other embodiments, alkynyl groups contain 2-6 carbon atoms; in still other embodiments, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH) 2 C.ident.CH), 1-propynyl (propynyl, -C.ident.C-CH) 3 ) 1-alkynylbutyl (-CH) 2 CH 2 C ≡ CH), 2-alkynylbutyl (-CH) 2 C≡CCH 3 ) 3-alkynylbutyl (-C [ identical to ] CCH 2 CH 3 ) And so on.
The term "alkyl" and its prefix "alkane", as used herein, are intended to encompass both straight and branched saturated carbon chains.
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 20 carbon atoms, some examples of which are alkoxy groups containing 1 to 10 carbon atoms, other examples of which are alkoxy groups containing 1 to 8 carbon atoms, other examples of which are alkoxy groups containing 1 to 6 carbon atoms, other examples of which are alkoxy groups containing 1 to 4 carbon atoms, and other examples of which are alkoxy groups containing 1 to 3 carbon atoms.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) 3 ) Ethoxy (EtO, -OCH) 2 CH 3 ) 1-propoxy (n-PrO, n-propoxy, -OCH) 2 CH 2 CH 3 ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) 3 ) 2 ) 1-butoxy (n-BuO, n-butoxy, -OCH) 2 CH 2 CH 2 CH 3 ) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH) 2 CH(CH 3 ) 2 ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ) 1-pentyloxy (n-pentyloxy, -OCH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyloxy (-OCH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyloxy (-OCH (CH)) 2 CH 3 ) 2 ) 2-methyl-2-butoxy (-OC (CH)) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butoxy (-OCH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-l-butoxy (-OCH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-l-butoxy (-OCH) 2 CH(CH 3 )CH 2 CH 3 ) And the like, wherein the alkoxy group may independently be unsubstituted or substituted with one or more substituents described herein.
The term "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino", meaning amino groups respectivelyIndependently by one or two alkyl groups having the definitions described herein. Wherein the alkylamino group may be optionally substituted with one or more substituents described herein. In some embodiments, alkylamino is one or two C 1-6 Alkylamino radicals in which the alkyl radical is bound to the nitrogen atom, i.e. C 1-6 An alkylamino group; in some embodiments, alkylamino is one or two C 1-4 Alkylamino radicals in which the alkyl radical is bound to the nitrogen atom, i.e. C 1-4 An alkylamino group. Examples of alkylamino groups include, but are not limited to, methylamino (N-methylamino), ethylamino (N-ethylamino), dimethylamino (N, N-dimethylamino), diethylamino (N, N-diethylamino), N-propylamino (N-N-propylamino), isopropylamino (N-isopropylamino), and the like.
The terms "haloalkyl", "haloalkenyl" or "haloalkoxy" denote alkyl, alkenyl or alkoxy groups substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy and the like.
The term "cycloalkyl" refers to a saturated, monocyclic, bicyclic, or tricyclic ring system containing 3-12 carbon atoms having one or more points of attachment to the rest of the molecule. The bicyclic ring system includes spirobicyclic rings and fused bicyclic rings. In some of these embodiments, cycloalkyl is a ring system containing 3 to 10 carbon atoms; in other embodiments, the cycloalkyl group is a ring system containing 3 to 8 carbon atoms; in still other embodiments, the cycloalkyl group is a ring system containing 3 to 6 carbon atoms; in other embodiments, the cycloalkyl group is a ring system containing 5 to 6 carbon atoms; examples of cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. And the cycloalkyl groups may independently be unsubstituted or substituted with one or more substituents as described herein.
The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic, or tricyclic ring system containing from 3 to 12 ring atoms,wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms, and the ring system has one or more attachment points to the rest of the molecule. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH 2 -a group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepanyl, thiazepanyl, homopiperazinyl, oxazepanyl, and the like
Radical, diaza
Radical, S-N-aza
A radical, indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1, 3-benzodioxolyl, 2-oxa-5-azabicyclo [2.2.1 ] yl]Hept-5-yl. In heterocyclic radicals of-CH 2 Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl, pyrimidinedione. Examples of heterocyclic sulfur atoms that are oxidized include, but are not limited to, sulfolane and 1, 1-dioxothiomorpholinyl. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.
In some embodiments, heterocyclyl is a 3-6 atom heterocyclyl and refers to saturated groups containing 3-6 ring atomsOr a partially unsaturated monocyclic ring, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise specified, a heterocyclic group of 3 to 6 atoms may be carbon-based or nitrogen-based, and-CH 2 -the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 3 to 6 atoms include, but are not limited to: oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl. In heterocyclic radicals of-CH 2 Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl and 3, 5-dioxopiperidinyl. Examples of heterocyclic sulfur atoms that are oxidized include, but are not limited to, sulfolane and 1, 1-dioxothiomorpholinyl. Said heterocyclyl group of 3 to 6 atoms may be optionally substituted by one or more substituents as described herein.
In some embodiments, heterocyclyl is a 5-6 atom heterocyclyl, meaning a saturated or partially unsaturated monocyclic ring containing 5-6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 5 to 6 atoms may be carbon-based or nitrogen-based, and-CH 2 -the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 5 to 6 atoms include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentanylA group selected from tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, and thiaxalinyl. In heterocyclic radicals of-CH 2 Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl and 3, 5-dioxopiperidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, 1, 1-dioxothiomorpholinyl. Said heterocyclyl group of 5 to 6 atoms may be optionally substituted by one or more substituents as described herein.
In other embodiments, heterocyclyl is a 5-atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 5 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a 5 atom heterocyclic group may be carbon-or nitrogen-based, and-CH 2 -the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of 5-atom heterocyclic groups include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl. In heterocyclic radicals of-CH 2 Examples of-groups substituted with-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl and oxo-1, 3-thiazolidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group. The 5-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.
In other embodiments, heterocyclyl is a 6-atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 6 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 6 atoms may be carbon-based or nitrogen-based, and-CH 2 -the group may optionally be replaced by-C (═ O) -. Sulfur of ringThe atoms may optionally be oxidized to S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 6 atoms include, but are not limited to: tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl. In heterocyclic radicals of-CH 2 Examples of-groups substituted with-C (═ O) -include, but are not limited to, 2-piperidinonyl and 3, 5-dioxopiperidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, 1, 1-dioxothiomorpholinyl. The 6-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.
The term "heteroatom" refers to O, S, N, P and Si, including any oxidation state form of N, S and P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).
The term "halogen" refers to F, Cl, Br or I.
The term "aryl" used alone or as a majority of "aralkyl", "aralkoxy", or "aryloxyalkyl" refers to monocyclic, bicyclic, and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 atoms forming a ring and one or more attachment points are attached to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring", e.g., aromatic rings may include phenyl, naphthyl and anthracenyl. The aryl group can be independently unsubstituted or substituted with one or more substituents described herein.
The term "heteroaryl" may be used alone or as a majority of "heteroarylalkyl" or "heteroarylalkoxy" and refers to monocyclic, bicyclic, and tricyclic ring systems containing 5 to 14 ring atoms, or 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms with one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is 5-12 atom composed of 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is 5-10 atom composed of 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is 5-6 atom composed of 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl consisting of 6 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N.
In other embodiments, heteroaryl includes, but is not limited to, the following monocyclic groups: 2-furyl group, 3-furyl group, N-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, N-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group, pyridazinyl group (e.g., 3-pyridazinyl group), 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, tetrazolyl group (e.g., 5H-tetrazolyl group, 2H-tetrazolyl group), triazolyl group (e.g., 2-triazolyl group, 5-triazolyl group, 4H-1,2, 4-triazolyl, 1H-1,2, 4-triazolyl, 1,2, 3-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bicyclic groups are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl). The heteroaryl group is optionally substituted with one or more substituents described herein.
The term "unsaturated" as used herein means that the group contains one or more unsaturations.
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.
"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.
"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.
"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.
Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
The term "enantiomeric excess (enantiomeric excess)" or "ee%" is used to describe. It represents the excess of one enantiomer over the other, usually expressed as a percentage.
Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.
Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
The racemates of any resulting final products or intermediates can be resolved into the optical enantiomers by known methods, by methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, Racemates and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2) nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
The compounds of the present disclosure may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention contemplates that all stereoisomeric forms of the compounds of formula (I), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, and mixtures thereof, such as racemic mixtures, are integral to the invention.
In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.
General synthetic procedure
To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.
In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (II), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical plant, Guangdong Guanghua chemical plant, Guangzhou chemical plant, Tianjin Haojiuyu Chemicals Co., Ltd, Tianjin Shuichun chemical plant, Wuhan Xin Huayuan science and technology development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao maritime chemical plant.
The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. Anhydrous acetonitrile, dichloromethane and chloroform were obtained by reflux drying with calcium hydride. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.
The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.
The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants.
NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer, CDC1 3 、DMSO-d 6 、CD 3 OD or acetone-d 6 TMS (0ppm) or chloroform (7.26ppm) were used as reference standards for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in hertz (Hz).
The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-M (column type)Number: zorbax SB-C18,2.1X30mm,3.5 microns, 6min, flow rate of 0.6 mL/min. Mobile phase: 5% -95% (CH containing 0.1% formic acid) 3 CN) in (H containing 0.1% formic acid) 2 O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.
The purity of the compound was determined by High Performance Liquid Chromatography (HPLC), using Agilent 1260HPLC (column model: Agilent zorbax Eclipse Plus C18) and detected by DAD detector, and finally calculated by area normalization to obtain the purity of the compound.
The following acronyms are used throughout the invention:
| MeOH | methanol | CDCl 3 | Deuterated chloroform |
| DCM | Methylene dichloride | K 2 CO 3 | Potassium carbonate |
| PE | Petroleum ether | NaO t Bu | Potassium tert-butoxide |
| EtOAc | Ethyl acetate | KOH | Potassium hydroxide |
Detailed Description
The following examples may further illustrate the present invention, however, these examples should not be construed as limiting the scope of the present invention. When the structure of the compound of the present invention is inconsistent with the name, the structure of the compound is taken as the standard.
Examples
Example 1
P-toluenesulfonamide (41.1mg, 0.24mmol), K was first isolated 2 CO 3 (27.6mg,0.20mmol) and the compound R-1(86.8mg,0.20mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, DCM (2.0mL) was added under a nitrogen atmosphere, and the reaction was performed at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was subjected to dry-method sampling and column chromatography purification (petroleum ether: ethyl acetate (v/v) ═ 19:1) to give the product P-1(53.1mg, yield 88%).
1 H NMR(400MHz,CDCl 3 )δ7.86–7.81(m,2H),7.34(d,J＝8.1Hz,2H),7.32–7.22(m,2H),7.22–7.16(m,1H),7.15–7.09(m,2H),2.78(tt,J＝7.5,4.7Hz,1H),2.65–2.56(m,3H),2.45(s,3H),2.06(d,J＝4.6Hz,1H),1.88(dddd,J＝13.9,8.8,7.4,4.9Hz,1H),1.67(dtd,J＝14.1,8.0,6.4Hz,1H).
13 C NMR(101MHz,CDCl 3 )δ144.64,140.80,135.10,129.78,128.57,128.42,128.12,126.23,39.84,34.02,33.25,33.09,21.77；
HRMS-ESI(m/z)[M+H] + calc’d for C 17 H 20 NO 2 S + ,302.1209,found 302.1206.
Example 2
Para-cyanobenzenesulfonamide (43.7mg, 0.24mmol), K 2 CO 3 (27.6mg,0.20mmol) and the compound R-1(86.8mg,0.20mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, DCM (2.0mL) was added under a nitrogen atmosphere, and the reaction was performed at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the mixture was subjected to dry-method sampling and column chromatography purification (petroleum ether: ethyl acetate (v/v) ═ 19:1) to obtain the product P-2(40.5mg, yield 65%).
1 H NMR(400MHz,CDCl 3 )δ8.09–8.03(m,2H),7.87–7.81(m,2H),7.28(td,J＝7.7,7.1,1.1Hz,2H),7.23–7.17(m,1H),7.13(dd,J＝7.0,1.8Hz,2H),2.91(tt,J＝7.3,4.9Hz,1H),2.72–2.59(m,3H),2.12(d,J＝4.7Hz,1H),1.91(dddd,J＝13.9,8.7,7.5,5.1Hz,1H),1.73(dtd,J＝14.1,7.9,6.4Hz,1H)；
13 C NMR(101MHz,CDCl 3 )δ142.59,140.38,132.96,128.68,128.68,128.41,126.42,117.38,117.29,40.52,34.84,33.08,33.02；
HRMS-ESI(m/z)[M+H] + calc’d for C 17 H 17 N 2 O 2 S + ,313.1005,found 313.1010.
Example 3
First, p-methoxybenzenesulphonamide (44.9mg, 0.24mmol), K 2 CO 3 (27.6mg,0.20mmol) and the compound R-1(86.8mg,0.20mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, DCM (2.0mL) was added under a nitrogen atmosphere, and the reaction was performed at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was subjected to dry-type chromatography (petroleum ether: ethyl acetate (v/v) ═ 19:1) to obtain product P-3(43.8mg, yield 69%).
1 H NMR(600MHz,CDCl 3 )δ7.88(d,J＝8.6Hz,2H),7.27(t,J＝7.5Hz,2H),7.19(t,J＝7.4Hz,1H),7.12(d,J＝7.5Hz,2H),7.00(d,J＝8.5Hz,2H),3.88(s,3H),2.75(td,J＝7.4,3.7Hz,1H),2.66–2.55(m,3H),2.04(d,J＝4.5Hz,1H),1.88(dddd,J＝13.8,8.8,7.3,4.9Hz,1H),1.73–1.63(m,1H)；
13 C NMR(151MHz,CDCl 3 )δ163.76,140.85,130.32,129.65,128.60,128.46,126.26,114.38,55.80,39.82,33.97,33.27,33.14；
HRMS-ESI(m/z)[M+H] + calc’d for C 17 H 20 NO 3 S + ,318.1158,found 318.1153.
Example 4
P-acetamidobenzenesulfonamide (51.4mg, 0.24mmol), K 2 CO 3 (27.6mg,0.20mmol) and the compound R-1(86.8mg,0.20mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, DCM (2.0mL) was added under a nitrogen atmosphere, and the reaction was performed at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was purified by column chromatography (petroleum ether: ethyl acetate (v/v) ═ 9:1) to give the product P-4(46.3mg, yield 67%).
1 H NMR(400MHz,CDCl 3 )δ7.99(s,1H),7.87(dd,J＝9.0,2.5Hz,2H),7.77–7.70(m,2H),7.31–7.25(m,2H),7.23–7.17(m,1H),7.16–7.10(m,2H),2.77(td,J＝7.1,3.7Hz,1H),2.67–2.53(m,3H),2.22(s,3H),2.08(d,J＝4.6Hz,1H),1.99–1.85(m,1H),1.76–1.59(m,1H)；
13 C NMR(101MHz,CDCl 3 )δ169.12,143.11,140.68,132.28,129.38,128.62,128.44,126.30,119.32,40.02,34.12,33.21,33.09,24.83；
HRMS-ESI(m/z)[M+H] + calc’d for C 18 H 21 N 2 O 3 S + ,345.1267,found 345.1264.
Example 5
First, 2-Ethyl formate benzenesulfonamide (55.0mg, 0.24mmol), K 2 CO 3 (27.6mg,0.20mmol) and a compoundR-1(86.8mg,0.20mmol) was added to the reaction tube, the tube was evacuated through a vacuum line three times, DCM (2.0mL) was added under nitrogen atmosphere, and the reaction was carried out at room temperature for 24 h. After the reaction is finished, the solvent is removed by rotary evaporation, and the product is purified by column chromatography (petroleum ether: ethyl acetate (v/v) ═ 9:1) to obtain the product P-5(52.7mg, 73% yield).
1 H NMR(600MHz,CDCl 3 )δ8.09(dd,J＝7.9,1.3Hz,1H),7.65(td,J＝7.5,1.3Hz,1H),7.61(td,J＝7.7,1.5Hz,1H),7.57(dd,J＝7.5,1.4Hz,1H),7.26(t,J＝7.5Hz,2H),7.21–7.16(m,1H),7.15–7.11(m,2H),4.41(q,J＝7.2Hz,2H),3.00–2.88(m,1H),2.75(d,J＝7.0Hz,1H),2.66(t,J＝7.8Hz,2H),2.14(d,J＝4.7Hz,1H),1.88(dtd,J＝13.5,8.2,5.2Hz,1H),1.77(dq,J＝14.6,7.5Hz,1H),1.39(t,J＝7.1Hz,3H)；
13 C NMR(151MHz,CDCl 3 )δ167.50,140.88,135.97,133.97,133.34,130.51,129.95,128.76,128.57,128.45,126.21,62.51,40.48,35.11,33.39,32.99,14.13；
HRMS-ESI(m/z)[M+H] + calc’d for C 19 H 22 NO 4 S + ,360.1264,found 360.1259.
Example 6
Firstly, 2-thiophenesulfonamide (36.0mg, 0.24mmol), K 2 CO 3 (27.6mg,0.20mmol) and the compound R-1(86.8mg,0.20mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, DCM (2.0mL) was added under a nitrogen atmosphere, and the reaction was performed at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was purified by column chromatography (petroleum ether: ethyl acetate (v/v) ═ 9:1) to give the product P-6(41.4mg, yield 71%).
1 H NMR(400MHz,CDCl 3 )δ7.67(ddd,J＝10.6,4.4,1.4Hz,2H),7.24(dd,J＝8.2,6.7Hz,2H),7.18–7.13(m,1H),7.11(dt,J＝8.7,2.6Hz,3H),2.78(tt,J＝7.4,4.8Hz,1H),2.66–2.54(m,3H),2.11(d,J＝4.6Hz,1H),1.94–1.82(m,1H),1.68(dtd,J＝14.2,8.0,6.5Hz,1H)；
13 C NMR(101MHz,CDCl 3 )δ140.70,138.05,133.99,133.62,128.62,128.46,127.56,126.29,40.73,34.65,33.21,33.03；
HRMS-ESI(m/z)[M+H] + calc’d for C 14 H 16 NO 2 S 2 + ,294.0617,found 294.0615.
Example 7
First, phenylmethanesulfonamide (41.1mg, 0.24mmol), K 2 CO 3 (27.6mg,0.20mmol) and the compound R-1(86.8mg,0.20mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, DCM (2.0mL) was added under a nitrogen atmosphere, and the reaction was performed at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was purified by column chromatography (petroleum ether: ethyl acetate (v/v) ═ 19:1) to give the product P-7(45.7mg, yield 76%).
1 H NMR(600MHz,CDCl 3 )δ7.46–7.43(m,2H),7.41–7.37(m,3H),7.29(t,J＝7.5Hz,2H),7.20(t,J＝7.4Hz,1H),7.16(d,J＝7.5Hz,2H),4.46–4.25(m,2H),2.67(qd,J＝13.4,12.9,6.4Hz,3H),2.34(d,J＝6.9Hz,1H),1.90(d,J＝4.7Hz,1H),1.73(q,J＝7.3Hz,2H)；
13 C NMR(151MHz,CDCl 3 )δ140.75,131.02,131.01,129.00,128.88,128.64,128.50,126.31,58.70,38.90,33.93,32.96,32.82；
HRMS-ESI(m/z)[M+H] + calc’d for C 17 H 20 NO 2 S + ,302.1209,found 302.1210.
Example 8
First, methanesulfonamide (22.8mg, 0.24mmol), K 2 CO 3 (27.6mg,0.20mmol) and the compound R-1(86.8mg,0.20mmol) were added to a reaction tube, and air was purged three times through a vacuum lineDCM (2.0mL) was added under nitrogen and the reaction was carried out at room temperature for 48 h. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was subjected to dry-type chromatography (petroleum ether: ethyl acetate (v/v) ═ 19:1) to obtain the product P-8(41.5mg, yield 92%).
1 H NMR(400MHz,CDCl 3 )δ7.33–7.28(m,2H),7.21(dt,J＝5.9,1.7Hz,3H),3.00(s,3H),2.79(dtd,J＝9.3,7.9,7.2,5.4Hz,3H),2.58(d,J＝7.1Hz,1H),2.08(d,J＝4.6Hz,1H),1.94(dddd,J＝13.9,8.8,7.0,5.1Hz,1H),1.87–1.74(m,1H).
13 C NMR(101MHz,CDCl 3 )δ140.61,128.69,128.51,126.38,39.54,39.17,33.56,33.23,33.19；
HRMS-ESI(m/z)[M+H] + calc’d for C 11 H 16 NO 2 S + ,226.0896,found 226.0893.
Example 9
1-methylcyclopropanesulfonamide (42.0mg, 0.24mmol), K was first introduced 2 CO 3 (27.6mg,0.20mmol) and the compound R-1(86.8mg,0.20mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, DCM (2.0mL) was added under a nitrogen atmosphere, and the reaction was performed at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was subjected to dry-method sampling and column chromatography purification (petroleum ether: ethyl acetate (v/v) ═ 19:1) to give the product P-9(40.7mg, yield 77%).
1 H NMR(400MHz,CDCl 3 )δ7.29(dd,J＝8.1,6.9Hz,2H),7.24–7.17(m,3H),2.89–2.67(m,3H),2.55(d,J＝6.9Hz,1H),2.07(d,J＝4.6Hz,1H),1.95–1.83(m,2H),1.65(s,3H),1.43(q,J＝3.1,2.6Hz,2H),0.84(td,J＝4.5,2.2Hz,2H)；
13 C NMR(101MHz,CDCl 3 )δ140.89,128.63,128.46,126.29,38.47,35.32,33.52,33.40,33.10,18.64,12.84,12.75；
HRMS-ESI(m/z)[M+H] + calc’d for C 14 H 20 NO 2 S + ,266.1209,found 266.1205.
Example 10
N, N-dimethylsulfonamide (26.9mg, 0.24mmol), K was first added 2 CO 3 (27.6mg,0.20mmol) and the compound R-1(86.8mg,0.20mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, DCM (2.0mL) was added under a nitrogen atmosphere, and the reaction was performed at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was purified by column chromatography (petroleum ether: ethyl acetate (v/v) ═ 9:1) to give the product P-10(38.3mg, yield 75%).
1 H NMR(600MHz,CDCl 3 )δ7.29(t,J＝7.5Hz,2H),7.21(d,J＝7.2Hz,3H),2.91(s,6H),2.78(ddt,J＝30.0,14.5,7.5Hz,2H),2.64(p,J＝6.2,5.7Hz,1H),2.50(d,J＝6.9Hz,1H),2.02(d,J＝3.5Hz,1H),1.85(hept,J＝7.1Hz,2H)；
13 C NMR(151MHz,CDCl 3 )δ140.93,128.64,128.49,126.30,38.65,38.18,33.91,33.41,32.96；
HRMS-ESI(m/z)[M+H] + calc’d for C 12 H 19 N 2 O 2 S + ,255.1162,found 255.1157.
Example 11
First, sulfamide (30.0mg, 0.24mmol), K 2 CO 3 (27.6mg,0.20mmol) and the compound R-1(86.8mg,0.20mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, DCM (2.0mL) was added under a nitrogen atmosphere, and the reaction was performed at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the mixture was subjected to dry-method sampling and column chromatography purification (petroleum ether: ethyl acetate (v/v) ═ 9:1) to obtain the product P-11(23.9mg, yield 67%).
1 H NMR(600MHz,CDCl 3 )δ7.29(td,J＝7.5,5.1Hz,4H),7.24–7.19(m,6H),2.90–2.75(m,6H),2.65(d,J＝7.0Hz,2H),2.17(t,J＝4.2Hz,2H),1.99–1.89(m,2H),1.88–1.79(m,2H)；
13 C NMR(151MHz,CDCl 3 )δ140.87,140.80,128.67,128.66,128.61,128.57,126.34,126.32,40.24,39.97,34.80,34.52,33.41,33.34,33.07,33.02；
HRMS-ESI(m/z)[M+H] + calc’d for C 20 H 25 N 2 O 2 S + ,357.1631,found 357.1626.
Example 12
Ethyl carbamate (21.4mg, 0.24mmol), KOH (11.2mg,0.20mmol) and compound R-2(82.4mg,0.20mmol) were added to the reaction tube, the tube was evacuated three times through a vacuum line, DCM (2.0mL) was added under nitrogen atmosphere, and the reaction was carried out at room temperature for 24 h. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was purified by column chromatography (petroleum ether: ethyl acetate (v/v) ═ 9:1) to give the product P-12(24.0mg, yield 61%).
1 H NMR(600MHz,CDCl 3 )δ4.13(q,J＝7.0Hz,2H),2.27(dd,J＝6.2,2.8Hz,1H),2.21(dq,J＝8.7,5.0,4.1Hz,1H),2.01(q,J＝2.7,2.0Hz,1H),1.91(d,J＝11.1Hz,1H),1.79–1.60(m,4H),1.34–1.01(m,9H)； 13 C NMR(151MHz,CDCl 3 )δ164.13,62.47,43.34,40.27,30.57,30.49,29.73,26.39,25.86,25.72,14.45；
HRMS-ESI(m/z)[M+H] + calc’d for C 11 H 20 NO 2 + ,198.1489,found 198.1487.
Example 13
Benzyl carbamate (36.3mg, 0.24mmol), KOH (11.2mg,0.20mmol) and compound R-2(82.4mg,0.20mmol) were added to the reaction tube, the tube was evacuated three times through a vacuum line, DCM (2.0mL) was added under nitrogen atmosphere, and the reaction was carried out at room temperature for 24 h. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was purified by column chromatography (petroleum ether: ethyl acetate (v/v) ═ 9:1) to give the product P-13(36.3mg, yield 70%).
1 H NMR(400MHz,CDCl 3 )δ7.37–7.29(m,5H),5.13(s,2H),2.30(d,J＝6.2Hz,1H),2.25(td,J＝6.2,3.6Hz,1H),2.04(d,J＝3.8Hz,1H),1.95–1.89(m,1H),1.78–1.61(m,4H),1.28–1.01(m,6H)；
13 C NMR(101MHz,CDCl 3 )δ163.85,136.15,128.64,128.29,128.05,68.06,43.48,40.25,30.70,30.46,29.72,26.35,25.83,25.69；
HRMS-ESI(m/z)[M+H] + calc’d for C 16 H 22 NO 2 + ,260.1645,found 260.1642.
Example 14
Benzamide (29.1mg, 0.24mmol), KOH (11.2mg,0.20mmol) and compound R-2(82.4mg,0.20mmol) were added to the reaction tube, the tube was evacuated through a vacuum line three times, DCM (2.0mL) was added under nitrogen atmosphere, and the reaction was carried out at room temperature for 24 h. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was subjected to dry-type chromatography and purified by column chromatography (petroleum ether: ethyl acetate (v/v) ═ 9:1) to obtain the product P-14(23.6mg, yield 51%).
1 H NMR(400MHz,CDCl 3 )δ8.07–7.97(m,2H),7.57–7.50(m,1H),7.44(dd,J＝8.3,6.9Hz,2H),2.44(td,J＝6.3,3.7Hz,1H),2.39(d,J＝6.1Hz,1H),2.29(d,J＝3.7Hz,1H),1.94–1.63(m,5H),1.42(dddt,J＝14.5,9.7,6.3,3.1Hz,1H),1.33–1.02(m,5H)；
13 C NMR(101MHz,CDCl 3 )δ179.77,133.50,132.67,129.22,128.45,42.83,39.73,30.84,30.80,29.25,26.43,25.94,25.91；
HRMS-ESI(m/z)[M+H] + calc’d for C 15 H 20 NO + ,230.1539,found 230.1537.
Example 15
Benzyl carbamate (36.3mg, 0.24mmol), KOH (11.2mg,0.20mmol) and compound R-3(76.9mg,0.20mmol) were added to the reaction tube, the tube was evacuated three times through a vacuum line, DCM (2.0mL) was added under nitrogen atmosphere, and the reaction was carried out at room temperature for 24 h. After the reaction was completed, the solvent was removed by rotary evaporation, and the mixture was subjected to dry-method sampling and column chromatography purification (petroleum ether: ethyl acetate (v/v) ═ 9:1) to give the product P-15(30.8mg, yield 67%).
1 H NMR(400MHz,CDCl 3 )δ7.41–7.28(m,5H),5.12(s,2H),2.65(dd,J＝3.0,1.4Hz,2H),2.00–1.89(m,2H),1.85–1.73(m,2H),1.48–1.35(m,2H),1.31–1.16(m,2H)；
13 C NMR(101MHz,CDCl 3 )δ164.13,136.22,128.63,128.32,128.30,67.97,37.25,23.80,19.89；
HRMS-ESI(m/z)[M+H] + calc’d for C 14 H 18 NO 2 + ,232.1332,found 232.1329.
Example 16
Benzyl carbamate (18.1mg, 0.12mmol), KOH (5.6mg,0.10mmol) and compound R-4(41.4mg,0.10mmol) were added to the reaction tube, the tube was evacuated three times through a vacuum line, DCM (2.0mL) was added under nitrogen atmosphere, and the reaction was carried out at room temperature for 24 h. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was subjected to dry-type chromatography (petroleum ether: ethyl acetate (v/v) ═ 9:1) to obtain the product P-16(17.5mg, yield 67%).
1 H NMR(400MHz,CDCl 3 )δ7.40–7.28(m,5H),5.12(s,2H),2.49–2.43(m,2H),1.61–1.39(m,8H),0.98(t,J＝7.1Hz,6H).
13 C NMR(101MHz,CDCl 3 )δ164.17,136.33,128.61,128.21,127.97,67.90,42.74,29.85,20.82,13.98；HRMS-ESI(m/z)[M+H] + calc’d for C 16 H 24 NO 2 + ,262.1802,found 262.1798.
Example 17
Firstly, NaO is added t Bu (19.2mg,0.20mmol) and compound R-1(86.8mg,0.20mmol) were added to a reaction tube, and the tube was evacuated through a vacuum line three times, and n-hexylamine (24.3mg, 0.24mmol) and DCM (2.0mL) were added under a nitrogen atmosphere and reacted at room temperature for 24 h. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was purified by column chromatography (petroleum ether: ethyl acetate (v/v) ═ 9:1-2:1) to obtain P-17(32.0mg, yield 69%).
1 H NMR(600MHz,CDCl 3 )δ7.27(t,J＝7.5Hz,2H),7.22–7.16(m,3H),2.80(ddd,J＝15.1,9.5,6.0Hz,1H),2.71(ddd,J＝13.4,9.4,6.5Hz,1H),2.26(ddd,J＝11.3,8.7,6.5Hz,1H),2.12(ddd,J＝11.3,8.6,5.7Hz,1H),1.74(ddt,J＝15.2,9.1,5.9Hz,1H),1.69–1.62(m,1H),1.60–1.49(m,3H),1.39–1.24(m,7H),1.19(d,J＝6.4Hz,1H),0.89(t,J＝6.8Hz,3H)；
13 C NMR(151MHz,CDCl 3 )δ142.10,128.54,128.43,125.87,61.73,39.13,35.02,34.00,33.98,31.99,30.00,27.24,22.73,14.18；
HRMS-ESI(m/z)[M+H] + calc’d for C 16 H 26 N + ,232.2060,found 232.2057.
Example 18
Firstly, NaO is added t Bu (19.2mg,0.20mmol) and the compound R-1(86.8mg,0.20mmol) were charged into a reaction tube, and purging was performed three times through a vacuum line, and under a nitrogen atmosphere, cyclohexylamine (23.8mg, 0.24mmol) and DCM (2.0mL) were added and reacted at room temperature for 24 hours. After the reaction is finished, the solvent is removed by rotary evaporation, dry-method sample loading is carried out, and column chromatography purification is carried out (petroleum ether: ethyl acetate (v/v) ═ 9:1-2:1)) The product P-18(24.1mg, 53% yield) was obtained.
1 H NMR(600MHz,CDCl 3 )δ7.27(t,J＝7.6Hz,2H),7.22–7.16(m,3H),2.83(ddd,J＝13.8,10.2,5.7Hz,1H),2.70(ddd,J＝13.9,10.1,6.0Hz,1H),1.89–1.71(m,5H),1.64–1.55(m,2H),1.51(d,J＝3.4Hz,1H),1.42–1.28(m,3H),1.25(d,J＝6.4Hz,1H),1.22–1.11(m,3H),1.04(tt,J＝10.7,3.9Hz,1H)；
13 C NMR(151MHz,CDCl 3 )δ142.17,128.49,128.43,125.85,69.06,38.20,35.22,34.24,33.23,32.59,32.52,26.23,25.15,25.11；
HRMS-ESI(m/z)[M+H] + calc’d for C 16 H 24 N + ,230.1903,found 230.1900.
Example 19
Firstly, NaO is added t Bu (9.6mg,0.10mmol) and the compound R-1(43.8mg,0.10mmol) were charged into a reaction tube, and air was purged three times through a vacuum line, isopropylamine (7.1mg, 0.12mmol) and DCM (1.0mL) were added under a nitrogen atmosphere, and reacted at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the mixture was subjected to dry-method sampling and column chromatography purification (petroleum ether: ethyl acetate (v/v) ═ 9:1-2:1) to obtain the product P-19(12.0mg, yield 63%).
1 H NMR(600MHz,CDCl 3 )δ7.26(dd,J＝6.5,3.8Hz,2H),7.23–7.15(m,3H),2.83(tt,J＝8.7,4.2Hz,1H),2.75–2.65(m,1H),1.79(dq,J＝14.8,4.8Hz,1H),1.66–1.58(m,1H),1.52(d,J＝3.9Hz,1H),1.38(ddd,J＝18.0,9.1,4.2Hz,2H),1.24(td,J＝5.8,2.9Hz,1H),1.13(ddt,J＝16.3,5.8,2.4Hz,6H)；
13 C NMR(151MHz,CDCl 3 )δ142.12,128.52,128.47,125.90,61.00,38.88,35.16,34.21,33.20,22.52,21.98；HRMS-ESI(m/z)[M+H] + calc’d for C 13 H 20 N + ,190.1590,found 190.1589.
Example 20
P-toluenesulfonamide (41.1mg, 0.24mmol), K was first isolated 2 CO 3 (27.6mg,0.20mmol) and the compound R-5(66.0mg,0.20mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, DCM (2.0mL) was added under a nitrogen atmosphere, and the reaction was performed at room temperature for 48 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was subjected to dry-type chromatography (petroleum ether: ethyl acetate (v/v) ═ 19:1) to give the product P-20(34.6mg, yield 88%).
1 H NMR(600MHz,CDCl 3 )δ7.82(dd,J＝8.3,1.8Hz,2H),7.34(d,J＝7.9Hz,2H),2.44(s,3H),2.36(bs,4H)；
13 C NMR(151MHz,CDCl 3 )δ144.78,134.97,129.85,128.10,27.53,21.75；
HRMS-ESI(m/z)[M+H] + calc’d for C 9 H 12 NO 2 S + ,198.0583,found 198.0582.
Example 21
P-toluenesulfonamide (41.1mg, 0.24mmol), K was first isolated 2 CO 3 (27.6mg,0.20mmol) and the compound R-6(68.8mg,0.20mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, and DCM (2.0mL) was added under a nitrogen atmosphere to react at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was purified by column chromatography (petroleum ether: ethyl acetate (v/v) ═ 19:1) to obtain the product P-21(40.1mg, yield 95%).
1 H NMR(600MHz,CDCl 3 )δ7.85–7.79(m,2H),7.33(d,J＝8.0Hz,2H),2.82(ttd,J＝10.1,5.6,1.4Hz,1H),2.61(dd,J＝7.0,1.4Hz,1H),2.44(s,3H),2.02(d,J＝4.6Hz,1H),1.25(dd,J＝5.6,1.2Hz,3H)；
13 C NMR(151MHz,CDCl 3 )δ144.52,135.49,129.81,127.92,35.97,34.86,21.75,16.90；
HRMS-ESI(m/z)[M+H] + calc’d for C 10 H 14 NO 2 S + ,212.0740,found 212.0737.
Example 22
P-toluenesulfonamide (41.1mg, 0.24mmol), K was first isolated 2 CO 3 (27.6mg,0.20mmol) and the compound R-7(81.2mg,0.20mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, DCM (2.0mL) was added under a nitrogen atmosphere, and the reaction was performed at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was subjected to dry-type chromatography (petroleum ether: ethyl acetate (v/v) ═ 19:1) to obtain the product P-22(29.6mg, yield 54%).
1 H NMR(600MHz,CDCl 3 )δ7.87(d,J＝8.1Hz,2H),7.33(d,J＝7.9Hz,2H),7.31–7.27(m,3H),7.22(dd,J＝7.5,2.0Hz,2H),3.78(dd,J＝7.2,4.5Hz,1H),2.99(d,J＝7.2Hz,1H),2.43(s,3H),2.39(d,J＝4.4Hz,1H)； 13 C NMR(151MHz,CDCl 3 )δ144.78,135.20,135.15,129.89,128.70,128.44,128.09,126.70,41.19,36.08,21.80；
HRMS-ESI(m/z)[M+H] + calc’d for C 15 H 16 NO 2 S + ,274.0896,found 274.0893.
Example 23
P-toluenesulfonamide (20.5mg, 0.12mmol), K 2 CO 3 (13.8mg,0.10mmol) and the compound R-8(41.2mg,0.10mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, DCM (1.0mL) was added under a nitrogen atmosphere, and the reaction was performed at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was purified by column chromatography (petroleum ether: ethyl acetate (v/v) ═ 19:1) to obtain the product P-23(21.5mg, yield 77%).
1 H NMR(400MHz,CDCl 3 )δ7.90–7.76(m,2H),7.33(d,J＝8.0Hz,2H),5.72(ddt,J＝16.9,10.2,6.7Hz,1H),4.99–4.88(m,2H),2.71(tt,J＝7.3,4.7Hz,1H),2.63(d,J＝7.0Hz,1H),2.44(s,3H),2.05(d,J＝4.6Hz,1H),1.94(q,J＝6.9Hz,2H),1.55(dtd,J＝13.4,7.2,6.6,4.7Hz,1H),1.40–1.17(m,5H)；
13 C NMR(101MHz,CDCl 3 )δ144.55,138.59,135.28,129.75,128.11,114.66,40.49,33.88,33.60,31.28,28.35,26.36,21.76；
HRMS-ESI(m/z)[M+H] + calc’d for C 15 H 22 NO 2 S + ,280.1366,found 280.1362.
Example 24
Para-toluenesulfonamide (20.5mg, 0.12mmol), K 2 CO 3 (13.8mg,0.10mmol) and the compound R-9(47.9mg,0.10mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, DCM (1.0mL) was added under a nitrogen atmosphere, and the reaction was performed at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the mixture was subjected to dry-method sampling and column chromatography purification (petroleum ether: ethyl acetate (v/v) ═ 19:1) to give the product P-24(29.6mg, yield 85%).
1 H NMR(600MHz,CDCl 3 )δ7.83(d,J＝8.3Hz,2H),7.34(d,J＝7.9Hz,2H),3.32(t,J＝6.8Hz,2H),2.71(tt,J＝7.3,4.5Hz,1H),2.64(d,J＝6.9Hz,1H),2.45(s,3H),2.06(d,J＝4.5Hz,1H),1.75(p,J＝7.1Hz,2H),1.65–1.56(m,1H),1.43–1.20(m,5H)；
13 C NMR(151MHz,CDCl 3 )δ144.68,135.27,129.79,128.16,40.27,33.93,33.59,32.65,31.23,27.65,26.13,21.79；
HRMS-ESI(m/z)[M+H] + calc’d for C 14 H 21 BrNO 2 S + ,346.0471,found 346.0469.
Example 25
P-toluenesulfonamide (20.5mg, 0.12mmol), K 2 CO 3 (13.8mg,0.10mmol) and compound R-10(49.2mg,0.10mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, and DCM (1.0mL) was added under a nitrogen atmosphere and reacted at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the mixture was subjected to dry-method sampling and column chromatography purification (petroleum ether: ethyl acetate (v/v) ═ 9:1) to obtain the product P-25(23.5mg, yield 65%).
1 H NMR(600MHz,CDCl 3 )δ8.02–7.98(m,2H),7.85–7.81(m,2H),7.56(td,J＝7.3,1.4Hz,1H),7.44(t,J＝7.8Hz,2H),7.33(d,J＝7.9Hz,2H),4.33–4.21(m,2H),2.81(tt,J＝7.8,4.5Hz,1H),2.66(d,J＝6.9Hz,1H),2.41(s,3H),2.11(d,J＝4.5Hz,1H),1.83–1.71(m,3H),1.51–1.43(m,1H)；
13 C NMR(151MHz,CDCl 3 )δ166.58,144.75,135.14,133.13,130.29,129.85,129.67,128.52,128.15,64.08,39.75,34.01,28.14,26.26,21.75；
HRMS-ESI(m/z)[M+H] + calc’d for C 19 H 22 NO 4 S + ,360.1264,found 360.1259.
Example 26
P-toluenesulfonamide (20.5mg, 0.12mmol), K 2 CO 3 (13.8mg,0.10mmol) and the compound R-11(37.0mg,0.10mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, DCM (1.0mL) was added under a nitrogen atmosphere, and the reaction was performed at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the mixture was subjected to dry-method sampling and column chromatography purification (petroleum ether: ethyl acetate (v/v) ═ 19:1) to give the product P-26(20.3mg, yield 86%).
1 H NMR(600MHz,CDCl 3 )δ7.83–7.79(m,2H),7.32(d,J＝7.9Hz,2H),3.33(s,2H),2.44(s,3H),1.97–1.91(m,2H),1.66–1.53(m,3H),1.44–1.34(m,1H)；
13 C NMR(151MHz,CDCl 3 )δ144.19,136.19,129.71,127.73,46.87,27.08,21.75,19.66；
HRMS-ESI(m/z)[M+H] + calc’d for C 12 H 16 NO 2 S + ,238.0896,found 238.0893.
Example 27
P-toluenesulfonamide (20.5mg, 0.12mmol), K 2 CO 3 (13.8mg,0.10mmol) and the compound R-12(45.0mg,0.10mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, DCM (2.0mL) was added under a nitrogen atmosphere, and the reaction was performed at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was subjected to dry-type chromatography (petroleum ether: ethyl acetate (v/v) ═ 19:1) to obtain the product P-27(22.2mg, yield 70%).
1 H NMR(600MHz,CDCl 3 )δ7.82(d,J＝7.9Hz,2H),7.32(d,J＝7.9Hz,2H),2.96(s,2H),2.44(s,3H),2.08–2.01(m,2H),1.77(s,2H),1.59(q,J＝7.0,6.3Hz,2H),1.45(d,J＝8.3Hz,2H),1.38(d,J＝10.2Hz,1H),1.31(dd,J＝14.5,10.4Hz,2H),1.14(d,J＝7.7Hz,2H),1.04–0.99(m,1H)；
13 C NMR(151MHz,CDCl 3 )δ144.03,136.30,129.70,127.62,42.19,39.47,38.72,33.58,29.36,25.62,21.75；HRMS-ESI(m/z)[M+H] + calc’d for C 18 H 24 NO 2 S + ,318.1522,found 318.1518.
Example 28
P-toluenesulfonamide (20.5mg, 0.12mmol), K 2 CO 3 (13.8mg,0.10mmol) and the compound R-4(41.4mg,0.10mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, DCM (2.0mL) was added under a nitrogen atmosphere, and the reaction was performed at room temperature for 24 hours. After the reaction is finished, removing by rotary evaporationSolvent, dry loading and column chromatography purification (petroleum ether: ethyl acetate (v/v) ═ 19:1) gave product P-28(21.5mg, 76% yield).
1 H NMR(400MHz,CDCl 3 )δ7.87–7.79(m,2H),7.31(dd,J＝8.0,5.4Hz,2H),2.78(ddt,J＝8.8,7.2,3.6Hz,1H),2.64(p,J＝4.6Hz,1H),2.44(d,J＝3.4Hz,3H),1.75(ddt,J＝14.3,8.8,5.5Hz,1H),1.69–1.60(m,1H),1.50–1.22(m,6H),0.89(dt,J＝11.0,7.3Hz,6H)；
13 C NMR(101MHz,CDCl 3 )δ144.31,143.86,138.17,135.60,129.63,129.55,128.16,127.55,49.80,45.15,32.03,28.92,21.77,21.73,20.90,20.73,13.90,13.86；
HRMS-ESI(m/z)[M+H] + calc’d for C 15 H 24 NO 2 S + ,282.1522,found 282.1519.
Example 29
Malononitrile (15.9mg, 0.24mmol), K 2 CO 3 (27.6mg,0.20mmol) and the compound R-1(86.8mg,0.20mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, DCM (2.0mL) was added under a nitrogen atmosphere, and the reaction was performed at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was subjected to dry-type chromatography purification (petroleum ether: ethyl acetate (v/v) ═ 19:1-9:1) to give the product P-29(32.2mg, yield 82%).
1 H NMR(400MHz,CDCl 3 )δ7.34(td,J＝7.2,1.3Hz,2H),7.30–7.23(m,1H),7.24–7.20(m,2H),2.88(dp,J＝21.6,6.9Hz,2H),2.04–1.91(m,3H),1.88(dd,J＝8.6,5.5Hz,1H),1.48(dd,J＝7.5,5.6Hz,1H)；
13 C NMR(101MHz,CDCl 3 )δ139.63,128.90,128.58,126.79,115.52,113.87,34.24,32.00,30.70,24.77,3.93；HRMS-ESI(m/z)[M+H] + calc’d for C 13 H 13 N 2 + ,197.1073,found 197.1078.
Example 30
First dibenzoylmethane (53.8mg, 0.24mmol), K 2 CO 3 (27.6mg,0.20mmol) and the compound R-1(86.8mg,0.20mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, DCM (2.0mL) was added under a nitrogen atmosphere, and the reaction was performed at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the mixture was subjected to dry-method sampling and column chromatography purification (petroleum ether: ethyl acetate (v/v) ═ 19:1) to obtain the product P-30(50.5mg, yield 71%).
1 H NMR(400MHz,CDCl 3 )δ7.94–7.86(m,4H),7.54–7.47(m,2H),7.39(dd,J＝8.4,7.0Hz,4H),7.25–7.17(m,4H),7.16–7.10(m,1H),2.89–2.79(m,4H),2.51(p,J＝6.5Hz,1H),1.97(q,J＝7.2Hz,2H)；
13 C NMR(101MHz,CDCl 3 )δ195.03,141.36,137.46,133.01,128.60,128.55,128.28,126.14,35.34,35.18,34.72,27.56；
HRMS-ESI(m/z)[M+H] + calc’d for C 25 H 23 O 2 + ,355.1693,found 355.1688.
Example 31
Diethyl malonate (38.4mg, 0.24mmol), K 2 CO 3 (27.6mg,0.20mmol) and the compound R-1(86.8mg,0.20mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, DCM (2.0mL) was added under a nitrogen atmosphere, and the reaction was performed at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was subjected to dry-type chromatography (petroleum ether: ethyl acetate (v/v) ═ 19:1) to obtain the product P-31(41.6mg, yield 72%).
1 H NMR(400MHz,CDCl 3 )δ7.28(ddd,J＝7.6,6.3,1.4Hz,2H),7.21–7.14(m,3H),4.34–4.09(m,4H),2.82–2.66(m,2H),1.93(dtd,J＝9.0,8.2,7.1Hz,1H),1.78(ddt,J＝13.2,8.9,6.5Hz,1H),1.59–1.48(m,1H),1.41–1.32(m,2H),1.27(dt,J＝10.4,7.1Hz,6H)；
13 C NMR(101MHz,CDCl 3 )δ170.57,168.42,141.53,128.55,128.52,126.09,61.53,61.50,35.29,34.36,30.85,27.91,21.04,14.32,14.20；
HRMS-ESI(m/z)[M+H] + calc’d for C 17 H 23 O 4 + ,291.1591,found 291.1587.
Example 32
Methyl cyanoacetate (23.8mg, 0.24mmol), K 2 CO 3 (27.6mg,0.20mmol) and the compound R-1(86.8mg,0.20mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, DCM (2.0mL) was added under a nitrogen atmosphere, and the reaction was performed at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the mixture was subjected to dry-method sampling and column chromatography purification (petroleum ether: ethyl acetate (v/v) ═ 19:1-9:1) to obtain the product P-32(39.3mg, yield 86%).
1 H NMR(600MHz,CDCl 3 )δ7.30(t,J＝7.5Hz,2H),7.24–7.18(m,3H),3.81(s,3H),2.86(dt,J＝14.3,7.3Hz,1H),2.79(dt,J＝14.2,7.5Hz,1H),1.98–1.87(m,3H),1.82(dd,J＝8.6,4.6Hz,1H),1.35(dd,J＝7.4,4.7Hz,1H).
13 C NMR(151MHz,CDCl 3 )δ168.43,140.49,128.68,128.60,126.43,117.31,53.59,34.72,32.32,31.14,25.41,19.40；
HRMS-ESI(m/z)[M+H] + calc’d for C 14 H 16 NO 2 + ,230.1176,found 230.1174.
Example 33
2- (phenylsulfonyl) acetonitrile (43.5mg, 0.24mmol), K 2 CO 3 (27.6mg,0.20mmol) and Compound R-1(86.8mg,0.20mmol) were added to a reaction tubeAfter purging three times through a vacuum line, DCM (2.0mL) was added under nitrogen atmosphere, and the reaction was carried out at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was purified by column chromatography (petroleum ether: ethyl acetate (v/v) ═ 9:1) to give the product P-33(55.0mg, yield 88%).
1 H NMR(400MHz,CDCl 3 )δ7.97(d,J＝7.5Hz,2H),7.75(t,J＝7.5Hz,1H),7.64(t,J＝7.7Hz,2H),7.29(t,J＝7.4Hz,2H),7.21(t,J＝7.3Hz,1H),7.15(d,J＝6.9Hz,2H),2.76–2.58(m,2H),2.28–2.17(m,1H),2.08–1.91(m,2H),1.78(dtd,J＝14.2,8.4,5.7Hz,1H),1.40(dd,J＝7.9,5.7Hz,1H)；
13 C NMR(101MHz,CDCl 3 )δ140.03,137.41,134.96,129.76,128.88,128.72,128.51,126.54,114.96,38.42,34.44,31.97,27.72,22.40；
HRMS-ESI(m/z)[M+Na] + calc’d for C 18 H 17 NNaO 2 S + ,334.0872,found 334.0867.
Example 34
Firstly, 10-oxo-10, 11-dihydro-5H-diphenyl [ b, f)]Azepine-5-carboxamide (30.3mg, 0.12mmol), K 2 CO 3 (13.8mg,0.10mmol) and the compound R-1(43.4mg,0.10mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, DCM (2.0mL) was added under a nitrogen atmosphere, and the reaction was performed at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was subjected to dry-type chromatography purification (petroleum ether: ethyl acetate (v/v) ═ 19:1-4:1) to give the product P-34(21.5mg, yield 56%).
1 H NMR(600MHz,CDCl 3 )δ8.10(d,J＝7.2Hz,1H),7.38(q,J＝7.6Hz,1H),7.29(d,J＝6.1Hz,2H),7.19(dt,J＝14.1,7.2Hz,3H),7.12(d,J＝7.5Hz,2H),6.99(q,J＝10.9,8.5Hz,4H),6.92(q,J＝7.3Hz,1H),6.39(d,J＝16.3Hz,1H),2.63(t,J＝7.5Hz,1H),2.55(dt,J＝14.5,6.8Hz,1H),2.06(s,1H),1.70(s,1H),1.10(s,2H),0.85(dq,J＝14.5,7.4Hz,1H)；
13 C NMR(151MHz,CDCl 3 )δ191.92,147.39,144.70,142.14,133.64,131.57,131.46,128.52,128.37,128.30,128.09,125.85,125.34,124.37,123.96,119.86,119.61,119.17,42.39,35.64,31.60,27.40；
HRMS-ESI(m/z)[M+H] + calc’d for C 25 H 23 N 2 O 2 + ,383.1754,found 383.1761.
Example 35
5-aminomethyl-2-chloropyridine (17.1mg, 0.12mmol), K was first introduced 2 CO 3 (13.8mg,0.10mmol) and the compound R-6(34.4mg,0.10mmol) were added to a reaction tube, and purging was performed three times through a vacuum line, DCM (2.0mL) was added under a nitrogen atmosphere, and the reaction was performed at room temperature for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the mixture was subjected to dry-method loading and column chromatography purification (dichloromethane: methanol (v/v) ═ 1:0-191) to obtain the product P-35(11.7mg, yield 64%).
1 H NMR(600MHz,CDCl 3 )δ8.33(d,J＝2.5Hz,1H),7.71(dd,J＝8.2,2.5Hz,1H),7.31(d,J＝8.1Hz,1H),3.41(q,J＝14.0Hz,2H),1.62(d,J＝3.6Hz,1H),1.58–1.52(m,1H),1.40(d,J＝6.3Hz,1H),1.20(d,J＝5.5Hz,3H)；
13 C NMR(151MHz,CDCl 3 )δ150.27,149.08,138.56,134.07,124.18,61.22,35.43,35.13,18.28；
HRMS-ESI(m/z)[M+H] + calc’d for C 9 H 12 ClN 2 + ,183.0684,found 183.0679.
While the methods of the present invention have been described in terms of several embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other variations and combinations of the techniques described herein, may be made to implement and use the techniques of the present invention without departing from the spirit and scope of the invention. Those skilled in the art can modify the reaction parameters appropriately to achieve the desired results in view of the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (10)
1. A process for the preparation of a three-membered ring, which comprises: in the presence of alkali, reacting a compound shown as a formula (III) with a compound shown as a formula (II-a) or (II-b) in an organic solvent to obtain a corresponding compound shown as a formula (I-a) or (I-b);
wherein the content of the first and second substances,
x is halogen, BF 4 、PF 6 、AsF 6 、SbF 6 、ClO 4 、CF 3 COO、OTf、OTs；
L is a bond, - (CH) 2 ) q -, -C (═ O) -, or-S (═ O) 2 -；
q is 0,1, 2,3,4 or 5;
each R 1 And R 2 Independently H, C 1-12 Alkyl radical, C 3-8 Cycloalkyl radical, C 6-10 Aryl or heteroaryl of 5 to 12 atoms, wherein said C 1-12 Alkyl radical, C 3-8 Cycloalkyl radical, C 6-10 Aryl and heteroaryl of 5 to 12 atoms are independently unsubstituted OR substituted by 1,2,3,4 OR 5 substituents selected from halogen, oxo, -CN, -OR a 、-NR a R b 、-C(＝O)R a 、-C(＝O)OR a 、C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Haloalkyl and C 1-6 Substituted by a substituent of alkoxy;
or R 1 、R 2 Together with the atoms to which they are attached form C 3-8 Cycloalkyl or heterocyclyl consisting of 5 to 12 atoms, wherein said C is 3-8 Cycloalkyl and heterocyclyl consisting of 5 to 12 atoms are independently unsubstituted or substituted by 1,2,3,4 or 5 substituents selected from halogen, oxo, -CN, -OH, -NH 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-C(＝O)ONH 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl and C 1-6 Substituted by a substituent of alkoxy;
R 3 is-CN, -NH 2 、C 1-12 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, C 3-12 Cycloalkyl, heterocyclic group consisting of 5 to 20 atoms, C 6-10 Aryl or heteroaryl of 5 to 20 atoms, wherein said C 1-12 Alkyl radical, C 3-12 Cycloalkyl, heterocyclic group consisting of 5 to 20 atoms, C 6-10 Aryl and heteroaryl of 5 to 20 atoms are independently unsubstituted OR substituted by 1,2,3,4 OR 5 substituents selected from halogen, oxo, -CN, -OR c 、-NR c R d 、-C(＝O)OR c 、-C(＝O)OR c R d 、-NR c C(O)R d 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 6-10 Aryl and heteroaryl of 5 to 12 atoms;
each R 4 And R 5 Independently is-CN, -OR e 、-NR e R f 、-C(＝O)R e 、-C(＝O)OR e 、-S(＝O) 2 R e 、C 1-6 Alkyl radical, C 6-10 Aryl or heteroaryl of 5 to 12 atoms, wherein said C 1-6 Alkyl radical, C 6-10 Aryl and 5-12-atom heteroaryl are independently unsubstituted or substituted by 1,2,3,4 or 5 substituents selected from halogen, oxo, -CN, -OH, -NH 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-C(＝O)ONH 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl and C 1-6 Substituted by a substituent of alkoxy;
or R 4 、R 5 And together with the atoms to which they are attached form a 5-12 atom heterocyclic group, wherein said 5-12 atom heterocyclic group is unsubstituted or substituted with 1,2,3,4 or 5 substituents selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-OC(＝O)CH 3 、C 1-6 Alkyl radical, C 1-6 Haloalkyl and C 1-6 Substituted by a substituent of alkoxy;
R a 、R b 、R c 、R d 、R e and R f Independently is H, -OH, -NH 2 、C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 6-10 Aryl or heteroaryl of 5 to 12 atoms, wherein said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 6-10 Aryl and 5-12-atom heteroaryl are independently unsubstituted or substituted by 1,2,3,4 or 5 substituents selected from halogen, oxo, -CN, -OH, -NH 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、C 1-6 Alkyl radical, C 1-6 Haloalkyl and C 1-6 Substituted by a substituent of alkoxy.
2. The production method according to claim 1, wherein:
x is F, Cl, Br, I, BF 4 、PF 6 、AsF 6 、SbF 6 、ClO 4 、CF 3 COO、OTf、OTs；
Each R 1 And R 2 Independently H, C 1-8 Alkyl radical, C 3-6 Cycloalkyl radical, C 6-10 Aryl or heteroaryl of 5 to 10 atoms, wherein said C 1-8 Alkyl radical, C 3-6 Cycloalkyl radical, C 6-10 Aryl and heteroaryl of 5 to 10 atoms are independently unsubstituted OR substituted by 1,2,3,4 OR 5 substituents selected from halogen, oxo, -CN, -OR a 、-NR a R b 、-C(＝O)R a 、-C(＝O)OR a 、C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Haloalkyl and C 1-4 Substituted by a substituent of alkoxy;
or R 1 、R 2 Together with the atoms to which they are attached form C 3-6 Cycloalkyl or heterocyclyl consisting of 5 to 10 atoms, wherein said C is 3-6 Cycloalkyl and heterocyclyl consisting of 5 to 10 atoms are independently unsubstituted or substituted by 1,2,3,4 or 5 substituents selected from halogen, oxo, -CN, -OH, -NH 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-C(＝O)ONH 2 、C 1-4 Alkyl radical, C 1-4 Haloalkyl and C 1-4 Substituted by a substituent of alkoxy.
3. The production method according to claim 1, wherein:
R 3 is-CN, -NH 2 、C 1-8 Alkyl radical, C 1-4 Alkoxy radical, C 1-4 Alkylamino radical, C 3-8 Cycloalkyl, heterocyclic radical consisting of 5-16 atoms, C 6-10 Aryl or heteroaryl of 5 to 16 atoms, wherein said C 1-8 Alkyl radical, C 3-8 Cycloalkyl, heterocyclic radical consisting of 5-16 atoms, C 6-10 Aryl and heteroaryl of 5 to 16 atoms are independently unsubstituted OR substituted by 1,2,3,4 OR 5 substituents selected from halogen, oxo, -CN, -OR c 、-NR c R d 、-C(＝O)OR c 、-C(＝O)OR c R d 、-NR c C(O)R d 、C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 6-10 Aryl and heteroaryl of 5 to 10 atoms;
each R 4 And R 5 Independently is-CN, -OR e 、-NR e R f 、-C(＝O)R e 、-C(＝O)OR e 、-S(＝O) 2 R e 、C 1-4 Alkyl radical, C 6-10 Aryl or heteroaryl of 5 to 10 atoms, wherein said C 1-4 Alkyl radical, C 6-10 Aryl and 5-10 atoms consisting of heteroaryl, independently unsubstituted or substituted by 1,2,3,4 or 5 atoms selected from halogen, oxo, -CN, -OH, -NH 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-C(＝O)ONH 2 、C 1-4 Alkyl radical, C 1-4 Haloalkyl and C 1-4 Substituted by a substituent of alkoxy;
or R 4 、R 5 And the atoms to which they are attached form a 5-10 atom heterocyclyl group, wherein the 5-10 atom heterocyclyl group is independently unsubstituted or substituted with 1,2,3,4 or 5 substituents selected from the group consisting of halogen, oxo, -CN, -OH, -NH 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-OC(＝O)CH 3 、C 1-4 Alkyl radical, C 1-4 Haloalkyl and C 1-4 Substituted by a substituent of alkoxy;
R a 、R b 、R c 、R d 、R e and R f Independently is H, -OH, -NH 2 、C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 6-10 Aryl or heteroaryl of 5 to 10 atoms, wherein said C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 6-10 Aryl and 5-10-atom heteroaryl are independently unsubstituted or substituted by 1,2,3,4 or 5 substituents selected from halogen, oxo, -CN, -OH, -NH 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、C 1-4 Alkyl radical, C 1-4 Haloalkyl and C 1-4 Substituted by a substituent of alkoxy.
4. The production method according to claim 1, wherein:
each R 1 And R 2 Independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptane, n-octane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptane, n-octane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl are independently unsubstituted or substituted by 1, 2. 3,4 OR 5 groups selected from F, Cl, Br, I, oxo, -CN, -OR a 、-NR a R b 、-C(＝O)R a 、-C(＝O)OR a Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethylAlkenyl, propenyl, allyl, ethynyl, propargyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CF 3 Methoxy, ethoxy, n-propoxy and isopropoxy;
or R 1 、R 2 And the atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, or morpholinyl group, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, and morpholinyl groups are independently unsubstituted or substituted with 1,2,3,4, or 5 groups selected from F, Cl, Br, I, oxo, -CN, -OH, -NH 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-C(＝O)ONH 2 Methyl, ethyl, n-propyl, isopropyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CF 3 Methoxy, ethoxy, n-propoxy and isopropoxy.
5. The production method according to claim 1, wherein:
R 3 is-CN, -NH 2 Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptane, n-octane, methoxy, ethoxy, n-propoxy, isopropoxy, methylamino, ethylamino, n-propylamino, isopropylamino, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or pyridazinyl
Wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and tert-butyl,N-pentyl, n-hexyl, n-heptane, n-octane, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and
independently unsubstituted OR substituted by 1,2,3,4 OR 5 substituents selected from F, Cl, Br, I, oxo, -CN, -OR c 、-NR c R d 、-C(＝O)OR c 、-C(＝O)OR c R d 、-NR c C(O)R d Methyl, ethyl, n-propyl, isopropyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CF 3 Phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl;
each R 4 And R 5 Independently is-CN, -OR e 、-NR e R f 、-C(＝O)R e 、-C(＝O)OR e 、-S(＝O) 2 R e Methyl, ethyl, n-propyl, isopropyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein said methyl, ethyl, n-propyl, isopropyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl are independently unsubstituted or substituted with 1,2,3,4 or 5 substituents selected from the group consisting of F, Cl, Br, I, oxo, -CN, -OH, -NH, and 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-C(＝O)ONH 2 methyl, ethyl, n-propyl, isopropyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CF 3 Methoxy, ethoxy, n-propoxy and isopropoxy;
or R 4 、R 5 And the atoms to which they are attached form an azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, or morpholinyl group, wherein said azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, and morpholinyl groups are independently unsubstituted or substituted with 1,2,3,4, or 5 groups selected from F, Cl, Br, I, oxo, -CN, -OH, -NH 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-OC(O)CH 3 Methyl, ethyl, n-propyl, isopropyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CF 3 Methoxy, ethoxy, n-propoxy and isopropoxy;
R a 、R b 、R c 、R d 、R e and R f Independently is H, -OH, -NH 2 Methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein said methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl are independently unsubstituted or substituted with 1,2,3,4, or 5 substituents selected from F, Cl, Br, I, oxo, -CN, -OH, -NH, -OH 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 Methyl, ethyl, n-propyl, isopropyl, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CF 3 Methoxy, ethoxy, n-propoxy and isopropoxy.
6. The process according to claim 1, wherein the compound represented by the formula (III) is selected from at least one of the following structures:
7. the method according to claim 1, wherein the base is potassium carbonate, sodium carbonate, ammonium carbonate, sodium hydrogen carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, cesium hydroxide, sodium tert-butoxide, potassium tert-butoxide or lithium tert-butoxide.
8. The method according to claim 1, wherein the organic solvent is dichloromethane, chloroform, carbon tetrachloride, acetonitrile, acetone or tetrahydrofuran.
9. The method according to claim 1, wherein the reaction temperature is 10 ℃ to 50 ℃; the reaction time is 18-30 h.
10. The method of claim 1, wherein:
the mass ratio of the compound shown in the formula (III) to the compound shown in the formula (II-a) is 1.0: 1.0-1.0: 3.0;
the mass ratio of the compound shown in the formula (III) to the compound shown in the formula (II-b) is 1.0: 1.0-1.0: 3.0.
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