Compound and preparation method thereof

Abstract

The invention provides a compound and a preparation method thereof. According to the embodiment of the invention, the compound is a compound as shown in a formula (I), and a stereoisomer, a tautomer, a solvate and a pharmaceutically acceptable salt thereof: # imgabs0 #, in which R1 is selected from at least one of hydrogen, halogen,-CN,-OH,-SH,-NO2, C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxy, Boc, Fmoc and Trt; and R2 is selected from at least one of hydrogen, halogen,-CN,-OH,-SH,-NO2, C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxy and Boc. The compound can be used as a molecular probe of < 19 > F-NMR, has the advantages of strong signal, high environmental sensitivity and the like, and is suitable for protein and polypeptide conformation dynamics research and drug screening.

Description

Technical Field

[0001] The present invention relates to the technical field of organic compound preparation, specifically, to compounds, and more specifically, to a method for preparing compounds. Background Art

[0002] 19 F nuclear magnetic resonance (NMR) spectroscopy is a powerful tool for studying protein dynamics and drug screening. 19 F has a spin quantum number of 1 / 2 and is the second most sensitive stable NMR-active nucleus, with a sensitivity of 83.4% that of 1H. 19 F is an isotope with 100% natural abundance and is not found in most organisms. 19 F, and therefore will not be interfered by background signals. The 19F resonance is highly sensitive to the chemical environment, with a chemical shift range spanning hundreds of ppm. 19 The unique advantages of F-NMR have led to its wide application in membrane protein dynamics, protein aggregation, intracellular protein behavior, drug screening, etc.

[0003] Currently, many fluorinated amino acids have been developed for use as 19 F-NMR probes include monofluorophenylalanine, monofluorotyrosine, monofluorotryptophan, trifluoromethylphenylalanine and trifluoromethylleucine. Fluorine atoms have the highest electronegativity. When fluorine atoms are introduced into organic compounds, the electron cloud density distribution and pH of the compounds will change. The unique structural effect of fluorine in aromatic compounds and benzene rings will make the electronic effect of monofluoro-substituted aromatic compounds less significant, and the chemical shift of fluorine can be further amplified. Therefore, fluorine-labeled aromatic amino acids, especially fluorine-labeled phenylalanine and fluorine-labeled tyrosine, are widely used in protein 19 F-NMR study. Compared with monofluorinated compounds, trifluoromethyl aromatic compounds increase the signal concentration of equivalent fluorine in the molecule and have stronger 19 F-NMR signal. It is worth mentioning that the trifluoromethyl group exhibits a faster longitudinal relaxation rate and a slower transverse relaxation rate due to its rapid rotation, resulting in higher sensitivity. For this reason, trifluoromethylphenylalanine is used as 19 F-NMR probes have been widely used. For example, Manglik et al. first realized the site-specific insertion of para-trifluoromethylphenylalanine into proteins in prokaryotes by genetic codon expansion; Wang et al. further realized the insertion of meta-trifluoromethylphenylalanine into membrane proteins in an insect cell expression system and successfully used it to study the allosteric regulation mechanism of cannabinoid receptor CB1. However, trifluoromethylated tryptophan has not yet been developed.

[0004] Therefore, it is urgent to prepare a type of trifluoromethyl tryptophan. The trifluoromethyl tryptophan can be used as19 F-NMR probe has the advantages of strong signal and high environmental sensitivity, and is suitable for protein and peptide conformational dynamics. 19 F-NMR studies and drug screening. Summary of the invention

[0005] The present invention aims to solve at least one of the technical problems existing in the prior art to a certain extent. To this end, the present invention provides a compound.

[0006] The present invention is accomplished based on the following findings of the inventors:

[0007] 19 F nuclear magnetic resonance (NMR) spectroscopy is a powerful tool for studying protein dynamics and drug screening. Natural proteins do not contain fluorine. In order to introduce fluorine into proteins, 19 F labeling, the existing technology has developed a variety of methods, and many fluorinated amino acids have been developed for use 19 F-NMR probes include monofluorophenylalanine, monofluorotyrosine, monofluorotryptophan, trifluoromethylphenylalanine, and trifluoromethylleucine, but there is no trifluoromethylated tryptophan. 19 F-NMR probe was developed. In order to overcome this problem, the inventors developed a type of trifluoromethyl tryptophan and its preparation process. According to the embodiments of the present invention, trifluoromethyl tryptophan can be used as 19 F-NMR probe has the advantages of strong signal and high environmental sensitivity, and is suitable for protein and peptide conformational dynamics. 19 F-NMR studies and drug screening.

[0008] The first aspect of the present invention discloses a compound. According to an embodiment of the present invention, the compound is a compound represented by formula (I), and its stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts:

[0009]

[0010] Wherein, R1 is selected from hydrogen, halogen, -CN, -OH, -SH, -NO2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C1-C 10 At least one of alkoxy, Boc, Fmoc and Trt;

[0011] R2 is selected from hydrogen, halogen, -CN, -OH, -SH, -NO2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C1-C 10 At least one of alkoxy and Boc. The compounds according to the embodiments of the present invention can be used as 19F-NMR probe has the advantages of strong signal and high environmental sensitivity, and is suitable for protein and peptide conformational dynamics. 19 F-NMR studies and drug screening.

[0012] The second aspect of the present invention discloses a method for preparing a compound. According to an embodiment of the present invention, the preparation route of the method is as follows:

[0013]

[0014] The method comprises the following steps:

[0015] Step 1) Compound I-1 undergoes a condensation reaction with HCl HNMe (OMe) to obtain compound II;

[0016] Step 2) Compound II undergoes a substitution reaction with Boc2O to obtain compound III;

[0017] Step 3) Compound III undergoes reduction reaction to obtain compound IV;

[0018] Step 4) Compound IV and A ring addition reaction occurs to obtain compound V;

[0019] Step 5) Compound V prepared in step 4) undergoes a deprotection reaction to obtain product VI. The preparation method according to the embodiment of the present invention provides a general method for preparing trifluoromethyltryptophan and can prepare the product in gram quantities.

[0020] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The above and / or additional aspects and advantages of the present invention will become apparent and easily understood from the description of the embodiments in conjunction with the following drawings, in which:

[0022] Figure 1 is the reaction product shown in step 1 in Example 1 1 HNMR results.

[0023] Figure 2 The reaction product of step 2 in Example 1 1 HNMR results.

[0024] Figure 3 The reaction product of step 3 in Example 1 1 HNMR results.

[0025] Figure 4 For the final product of Example 1 1HNMR results.

[0026] Figure 5 For the final product of Example 3 1 HNMR results. DETAILED DESCRIPTION

[0027] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0028] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include one or more of the features. Further, in the description of the present invention, unless otherwise specified, the meaning of "plurality" is two or more.

[0029] The endpoints and any values ​​of the ranges disclosed in the present invention are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be considered as specifically disclosed in this article.

[0030] In order to make the present invention more easily understood, certain technical and scientific terms are specifically defined below. Unless otherwise clearly defined elsewhere in the present invention, all other technical and scientific terms used in the present invention have the meanings commonly understood by those skilled in the art to which the present invention belongs.

[0031] In the present invention, the terms "comprise" or "include" are open expressions, that is, including the contents specified in the present invention, but not excluding other contents.

[0032] In the present invention, the terms "optionally", "optional" or "optionally" generally mean that the subsequently described event or situation can but does not necessarily occur, and the description includes cases where the event or situation occurs and cases where it does not occur.

[0033] The numerical ranges recorded in the specification and claims of this application, when the numerical range is understood as an "integer", should be understood as recording the two endpoints of the range and each integer in the range. For example, "an integer from 1 to 6" should be understood as recording each integer of 0, 1, 2, 3, 4, 5 and 6. "An integer from 0 to 9" should be understood as recording each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9. When the numerical range is understood as a "number", it should be understood as recording the two endpoints of the range and each integer in the range and each decimal in the range. For example, "a number from 1 to 10" should be understood as not only recording each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least recording the sum of each integer therein and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, respectively.

[0034] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0035] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt of a non-toxic acid or base, including salts of inorganic acids and bases, organic acids and bases. Salts derived from inorganic bases include, but are not limited to, metal salts formed by Al, Ca, Li, Mg, K, Na and Zn; salts derived from organic bases include, but are not limited to, salts of primary, secondary or tertiary amines, including naturally occurring substituted or unsubstituted amines, cyclic amines and basic ion exchange resins, such as ammonium, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, benzylpenicillin, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine or organic salts formed by polyamine resins; Salts derived from inorganic and organic acids include, but are not limited to, organic salts formed from sulfuric, phosphoric, nitric, hydrobromic, hydrochloric, formic, acetic, propionic, benzenesulfonic, benzoic, phenylacetic, salicylic, alginic, anthranilic, camphoric, citric, ethylenesulfonic, formic, fumaric, furoic, gluconic, glucuronic, glutamic, glycolic, isethionic, lactic, maleic, malic, mandelic, mucic, pamoic, pantothenic, stearic, succinic, sulfanilic, tartaric, p-toluenesulfonic, malonic, 2-hydroxypropionic, oxalic, glycolic, glucuronic, galacturonic, citric, lysine, arginine, aspartic, cinnamic, p-toluenesulfonic, methanesulfonic, ethanesulfonic, or trifluoromethanesulfonic acids.

[0036] In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. These may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be useful in the identification, characterization or purification of the compounds of the present invention.

[0037] The term "stereoisomer" refers to isomers produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformers. The stereochemical definitions and conventions used in the present invention are generally defined in accordance with SP 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.

[0038] Depending on the choice of raw materials and methods, the compounds of the present invention may exist in the form of one of the possible isomers or a mixture thereof, for example as a pure optical isomer, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. When describing optically active compounds, prefixes D and L or R and S are used to represent the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are symbols for the rotation of plane polarized light caused by the specified compound, where (–) or L indicates that the compound is left-handed. Compounds prefixed with (+) or D are right-handed. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of the isomers are generally referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. Many geometric isomers of olefins, C=N double bonds, etc. may also exist in the compounds described herein, and all such stable isomers are contemplated in the present invention. When the compounds described herein contain olefinic double bonds, unless otherwise specified, such double bonds include both E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis- or trans- configuration.

[0039] When the bonds to the chiral carbon in the formula of the present invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the enantiomerically pure compounds and mixtures thereof produced therefrom are included within the scope of the general formula. The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by a wedge-shaped bond and a dashed bond.

[0040] Optically active (R)-or (S)-isomers can be prepared using chiral preparations or chiral preparations, or can be split using conventional techniques. The compounds of the present invention containing asymmetrically substituted carbon atoms can be separated in optically active form or racemic form. The splitting of the racemic mixture of a compound can be carried out by any of many methods known in the art. Exemplary methods include fractional recrystallization using chiral splitting acid, which is an optically active salified organic acid. Suitable splitting agents for fractional recrystallization methods are, for example, optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include α-methyl-benzylamine (e.g., S and R forms or diastereomeric pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. The resolution of the racemic mixture can also be carried out by eluting on a column filled with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High performance liquid chromatography (HPLC) can also be used to carry out supercritical fluid chromatography (SFC). The selection of specific methods and elution conditions, the selection of chromatographic columns can be selected by those skilled in the art according to the structure of the compound and the test results. Further, optically pure starting materials or reagents of known configuration can also be used to obtain any enantiomer or diastereomer of the compound described in the present invention through stereoorganic preparation.

[0041] The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0042] The term "solvate" means that the compound of the present invention or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent forces between molecules. When the solvent is water, it is a hydrate.

[0043] The term "C1-C 10 “Alkyl” is understood to mean a straight-chain or branched, saturated, monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkyl radical is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-methylpentyl ... ,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers. In particular, the radical has 1, 2, 3, 4, 5, 6 carbon atoms ("C1-C6 alkyl"), such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, more particularly, the radical has 1, 2 or 3 carbon atoms ("C1-C3 alkyl"), such as methyl, ethyl, n-propyl or isopropyl.

[0044] The term "C3-C 10 "Cycloalkyl" is understood to mean a saturated, monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 10 carbon atoms, including fused or bridged polycyclic ring systems. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon radical such as a decalin ring. In particular, the radical has 3 to 6 carbon atoms ("C3-C6 cycloalkyl"), for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0045] The term "C1-C 10 "Alkoxy" is understood to mean -O-(C1-C 10 Alkyl), where "C1-C 10 "C1-C6 alkyl" has the above definition. In particular, the group is -O-(C1-C6 alkyl), wherein "C1-C6 alkyl" has the above definition.

[0046] The present invention provides a compound and a preparation method thereof, which are described in detail below.

[0047] Compound

[0048] The first aspect of the present invention discloses a compound. According to an embodiment of the present invention, the compound is a compound represented by formula (I), and its stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts:

[0049]

[0050] Wherein, R1 is selected from hydrogen, halogen, -CN, -OH, -SH, -NO2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C1-C 10 At least one of alkoxy, Boc, Fmoc and Trt; R2 is selected from hydrogen, halogen, -CN, -OH, -SH, -NO2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C1-C 10 At least one of alkoxy and Boc. The trifluoromethyl tryptophan according to the embodiment of the present invention can be used as 19 F-NMR probe has the advantages of strong signal and high environmental sensitivity, and is suitable for protein and peptide conformational dynamics. 19 F-NMR studies and drug screening.

[0051] According to an embodiment of the present invention, R1 is selected from at least one of hydrogen, halogen, -CN, -OH, -SH, -NO2, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, Boc (tert-butyloxycarbonyl), Fmoc (tert-methyloxycarbonyl) and Trt (trityl); R2 is selected from at least one of hydrogen, halogen, -CN, -OH, -SH, -NO2, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and Boc.

[0052] According to an embodiment of the present invention, R1 is selected from at least one of hydrogen, Boc, Fmoc and Trt; R2 is selected from at least one of hydrogen and Boc.

[0053] According to an embodiment of the present invention, the compound is

[0054] A method for preparing a compound

[0055] The second aspect of the present invention discloses a method for preparing a compound. According to an embodiment of the present invention, the preparation route of the method is as follows:

[0056]

[0057] The method comprises the following steps:

[0058] Step 1) Compound I-1 (R1-L-Glu-OtBu) undergoes condensation reaction with HCl HNMe(OMe) (dimethylhydroxylamine hydrochloride) to obtain compound II;

[0059] Step 2) Compound II undergoes a substitution reaction with Boc2O to obtain compound III;

[0060] Step 3) Compound III undergoes reduction reaction to obtain compound IV;

[0061] Step 4) Compound IV and A ring addition reaction occurs to obtain compound V;

[0062] Step 5) Compound V prepared in step 4) undergoes a deprotection reaction to obtain product VI. The preparation method according to the embodiment of the present invention provides a general method for preparing trifluoromethyltryptophan and can prepare the product in gram quantities.

[0063] According to an embodiment of the present invention, in compound I-1, compound II, compound III, compound IV, and compound V, R1 is Boc, and R2 is H; in compound VI, R1 is H, and R2 is H.

[0064] According to an embodiment of the present invention, the solvent for the condensation reaction in step 1) includes DCM (dichloromethane).

[0065] According to an embodiment of the present invention, the solvent for the substitution reaction in step 2) includes DMF (dimethylformamide).

[0066] According to an embodiment of the present invention, the solvent of the reduction reaction in step 3) includes THF (tetrahydrofuran), and the reducing agent of the reduction reaction in step 3) includes DIBAL-H (diisobutylaluminum hydride).

[0067] According to an embodiment of the present invention, the solvent for the ring-addition reaction in step 4) includes DMF (dimethylformamide).

[0068] According to an embodiment of the present invention, the solvent for the deprotection reaction in step 5) includes DCM (dichloromethane); the catalyst for the deprotection reaction in step 5) includes TFA (trifluoroacetic acid).

[0069] According to an embodiment of the present invention, compound I-2 (Boc-L-Glu-OtBu) is used as a raw material, and a multi-step chemical reaction of the side chain carboxyl group is first converted into an aldehyde through Weinreb amide, and then reacted with trifluoromethyl o-iodoaniline under palladium catalysis conditions, thereby achieving the preparation of trifluoromethyltryptophan.

[0070] According to an embodiment of the present invention, the preparation route is as follows:

[0071]

[0072] The method comprises the following steps:

[0073] Step 1) In dichloromethane (DCM) solvent, the side chain carboxyl group of compound I-2 (Boc-L-glutamic acid-1-tert-butyl ester) undergoes condensation reaction with HCl HNMe (OMe) to obtain compound II;

[0074] Step 2) In N,N-dimethylformamide (DMF) solution, using 4-dimethylaminopyridine (DMAP) as a catalyst, compound II and di-tert-butyl dicarbonate (Boc2O) undergo a substitution reaction to obtain compound III;

[0075] Step 3) Compound III prepared in step 2) is used as a reducing agent to prepare compound IV;

[0076] Step 4) In N,N-dimethylformamide (DMF) solution, with palladium as catalyst, compound IV and trifluoromethyl-substituted o-iodoaniline undergo ring-enlargement reaction to obtain compound V;

[0077] Step 5) The compound V prepared in step 4) is treated with trifluoroacetic acid (TFA) and dichloromethane (DCM) to remove the Boc and tBu protecting groups to obtain product VI.

[0078] According to an embodiment of the present invention, in the step 4), the palladium catalyst is selected from at least one of the following: palladium acetate, palladium trifluoroacetate and palladium chloride.

[0079] According to an embodiment of the present invention, the trifluoromethyl group in step 4) is suitable for substituting any position on the benzene ring.

[0080] According to an embodiment of the present invention, the protecting group removal reagent in step 5) includes at least one of TFA and DCM.

[0081] According to an embodiment of the present invention, in the step 1), the molar ratio of the compound I-2 (Boc-L-glutamic acid-1-tert-butyl ester), the HCl HNMe (OMe), the benzotriazol-1-yl-oxytripyrrolidinophosphine hexafluorophosphate (PyBOP) and the triethylamine (Et3N) is 1:(1-2):(1-2):(2-4);

[0082] In the step 2), the molar ratio of the compound II, the Boc2O and the DMAP is 1:(1-2):

[0083] (0.1~0.2);

[0084] In the step 3), the molar ratio of the compound III to the DIBAL-H is 1:(1-2);

[0085] In the step 4), the molar ratio of the compound IV, the 4-amino-3-iodotrifluorotoluene, the 1,4-diazabicyclooctane (DABCO) and the palladium catalyst (Pd(OAc)2) is 1:(1-2):(2-4):(0.01-0.1); in the step 5), the volume ratio of the TFA and the DCM in the deprotection reagent is preferably 1:1. According to an embodiment of the present invention, the benzotriazole-1-yl-oxytripyrrolidinophosphorus hexafluorophosphate is used as a condensation agent and the triethylamine is used as a base to promote the condensation reaction to generate compound II; 1,4-diazabicyclooctane (DABCO) is used as a reaction to provide an alkaline environment to promote the generation of compound V.

[0086] According to an embodiment of the present invention,

[0087] In the step 1), the reaction conditions for preparing compound I-2 are as follows: react in DCM at room temperature for 2 hours;

[0088] In the step 2), the reaction conditions for preparing compound II are as follows: reacting in DMF at room temperature for 2 hours;

[0089] In the step 3), the reaction conditions for preparing compound III are as follows: reacting at -78°C for 1 hour under nitrogen protection;

[0090] In the step 4), the reaction conditions for preparing compound IV are as follows: reacting at 85°C to room temperature for 6 hours under nitrogen protection;

[0091] In the step 5), the deprotection treatment conditions are as follows: treatment at room temperature for 2 hours.

[0092] According to an embodiment of the present invention, the amount of the compound I-2 and the HCl HNMe (OMe) substance is 3-20 mL / mmol, for example, it can be 3 mL / mmol, 4 mL / mmol, 5 mL / mmol, 6 mL / mmol, 7 mL / mmol, 8 mL / mmol, 9 mL / mmol, 10 mL / mmol, 11 mL / mmol, 12 mL / mmol, 13 mL / mmol, 14 mL / mmol, 15 mL / mmol, 16 mL / mmol, 17 mL / mmol, 18 mL / mmol, 19 mL / mmol, 20 mL / mmol or a range of 4-20 mL / mmol, 5-20 mL / mmol, preferably 5 mL / mmol.

[0093] The scheme of the present invention will be explained below in conjunction with the embodiments. It will be appreciated by those skilled in the art that the following embodiments are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. Where specific techniques or conditions are not indicated in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used are not indicated by the manufacturer and are all conventional products that can be obtained commercially.

[0094] Example 1: Preparation of 5-trifluoromethyl-tryptophan (Compound VI)

[0095] The preparation experimental method process in this embodiment is as follows:

[0096] Step 1:

[0097] The reaction route is as follows:

[0098]

[0099] Under ice-water bath conditions, 24.3g of compound I-2 (Boc-L-Glu-OtBu) (80mmol) was dissolved in 242mL DCM, and then 12.3mL triethylamine (88mmol) and 45.8g PyBOP (88mmol) were added in proportion. After stirring for 10 minutes, 8.6g HClHNMe(OMe) (88mmol) and 12.3mL Et3N (88mmol) were added. The reaction was taken out of the ice-water bath and continued to stir the reaction at room temperature for 1.5 hours. After the reaction was completed, the reaction solution was washed with 10% citric acid (1X 250mL), the aqueous phase was extracted with DCM (3X 100mL), and the organic phases were combined; thereafter, the organic phase was washed with sodium bicarbonate (NaHCO3) (2X 250mL) and saturated brine (2X250mL) in turn, and finally, the organic phase was dried with magnesium sulfate (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (1:1 petroleum ether / ethyl acetate) to give 26.3 g (95% yield) of the desired product as a colorless oil that solidified into a white solid upon storage at 20°C. 1 HNMR results are shown in Figure 1 .

[0100] 1 HNMR (400MHz,CDCl3),C 16 H 30 N2O6, δ4.19(td,J=8.5,4.9Hz,1H),3.68(s,3H),3.18(s,3H),2.51(dddd,J=22.4,16.2,11.5,6.7Hz,2H),2.16(s,2H),1.47(s,9H),1.44(s,9H).

[0101]

[0102] Step 2:

[0103] The reaction route is as follows:

[0104] 24.2g of compound II (70mmol) was dissolved in DMF (35mL), and 1.7g of DMAP (14mmol) and 35mL of DMF solution containing 30.6g of Boc2O (140mmol) were added in sequence, and stirred for 2 hours under reduced pressure at room temperature. After the reaction was completed, DMF was removed by rotary evaporation under reduced pressure, 200mL of ether was added to dilute the mixture, and washed with water (H2O) (4×200mL) and brine (100mL) in sequence. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (1:1 Hex / EtOAc) to obtain 17.0g (54% yield) of a viscous light yellow oil. 1 HNMR results are shown in Figure 2 .

[0105] 1 HNMR (400MHz,CDCl3),C 21 H 38 N2O8, δ4.85–4.77(m,1H),3.67(s,3H),3.17(s,3H),2.58–2.38(m,3H),2.20–2.01(m,1H),1.50(s,18H),1.45(s,9H).

[0106]

[0107] Step 3:

[0108] The reaction route is as follows:

[0109] Under nitrogen protection, 20 mL of anhydrous tetrahydrofuran (THF) was added to a reaction tube containing 17.0 g of compound III (38.1 mmol) to fully dissolve. The reaction was placed in a mixture of acetone and dry ice and cooled to -78°C. Then, 41.9 mL of DIBAL-H (1.0 M, 41.9 mmol) in THF was slowly added dropwise under nitrogen protection, and the reaction was maintained at -78°C for 1 hour. After the reaction was completed, 6 mL of methanol (MeOH) was added to quench the reaction and return to room temperature. After the reaction solution was diluted with Et2O (100 mL), 100 mL of saturated potassium sodium tartrate solution was added, and stirring was continued at room temperature for 45 minutes. DCM (2×200 mL) was then added for extraction, and the organic phase was dried with MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (5:1 Hex / EtOAc) to give 8.1 g (54.5% yield) of a white solid. 1 HNMR results are shown in Figure 3 .

[0110] 1 HNMR (400MHz,CDCl3),C 16 H 30 N2O6, δ9.69(t,J=1.3Hz,1H),4.67(dd,J=9.4,5.2Hz,1H),2.56–2.32(m,3H),2.13–2.01(m,1H),1.43(s,18H),1.38(s,9H).

[0111]

[0112] Step 4:

[0113] The reaction route is as follows:

[0114] Under nitrogen protection, 4-amino-3-iodobenzotrifluoride (22mmol), compound IV (20mmol), 6.7g DABCO (60mmol), 20mL anhydrous DMF and 227mg palladium acetate (1.0mmol) were added in sequence, and the reaction was carried out at 85°C for 6 hours. After the reaction was completed, DMF was removed by rotary evaporation under reduced pressure, H2O (200mL) was added to dilute the mixture, and ethyl acetate (2×200mL) was used for extraction. The organic phase was washed with brine (2×200mL), then dried with sodium sulfate (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography to obtain the desired product V.

[0115]

[0116] Step 5:

[0117] The reaction route is as follows:

[0118] The compound V obtained in step 4 was dissolved in 100 mL of a mixed solution of DCM and TFA (DCM:TFA=1:1), and the reaction was stirred at room temperature for 2 hours to remove the protective group. After the reaction was completed, the organic solvent was removed by rotary evaporation under reduced pressure. The reaction mixture was diluted with water and purified by high performance liquid chromatography (HPLC) to obtain the target product VI. 1 HNMR results are shown in Figure 4 .

[0119] 1 H NMR (400 MHz, D2O), C 11 H 12 N2O2, δ7.80(d,J=1.6Hz,1H),7.40(d,J=8.6Hz,1H),7.31(dd,J=8.6,1.7Hz, 1H),7.21(s,1H),4.16(dd,J=7.1,5.4Hz,1H),3.25(dd,J=14.0,6.3Hz,2H).

[0120] Example 2: Preparation of 4-trifluoromethyl-tryptophan (4CF3W)

[0121] This implementation case adopts the same implementation as Example 1, except that the 4-amino-3-iodobenzotrifluoromethane used in step 4 is replaced by 2-iodo-3-trifluoromethylaniline, and the reaction route of step 4 is as follows: The reaction route of step 5 is as follows: The rest of the process is basically the same.

[0122] Example 3: Preparation of 6-trifluoromethyl-tryptophan (6CF3W)

[0123] This implementation case adopts the same implementation method as Example 1, with the only difference being that the 4-amino-3-iodobenzotrifluoride used in step 4 replaces 3-amino-4-iodobenzotrifluoride, and the reaction route of step 4 is as follows:

[0124] The reaction route of step 5 is as follows: The other processes are basically the same, 6-trifluoromethyl-tryptophan 1 HNMR results are shown in Figure 5 .

[0125] 1 HNMR,C 11 H 12N2O2, (400MHz, D2O) δ7.69–7.60(m,2H),7.37–7.23(m,2H),4.15(dd,J=7.2,5.4Hz,1H),3.30(qd,J=15.4,6.3Hz,3H).

[0126] Example 4: Preparation of 7-trifluoromethyl-tryptophan (7CF3W)

[0127] This implementation case adopts the same implementation as Example 1, except that the 4-amino-3-iodobenzotrifluoromethane used in step 4 is replaced by 2-iodo-6-(trifluoromethyl)aniline, and the reaction route of step 4 is as follows:

[0128]

[0129] The reaction route of step 5 is as follows: The rest of the process is basically the same.

[0130] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, unless they are contradictory.

[0131] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A compound, characterized in that The compound is a compound represented by formula (I), and its stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts: Wherein, R1 is selected from hydrogen, halogen, -CN, -OH, -SH, -NO2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C1-C 10 At least one of alkoxy, Boc, Fmoc and Trt; R2 is selected from hydrogen, halogen, -CN, -OH, -SH, -NO2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, C1-C 10 At least one of alkoxy and Boc.

2. The compound according to claim 1, characterized in that R1 is selected from at least one of hydrogen, halogen, -CN, -OH, -SH, -NO2, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, Boc, Fmoc and Trt; R2 is selected from at least one of hydrogen, halogen, -CN, -OH, -SH, -NO2, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and Boc.

3. The compound according to claim 1, characterized in that R1 is selected from at least one of hydrogen, Boc, Fmoc and Trt; R2 is selected from at least one of hydrogen and Boc.

4. The compound according to claim 1, characterized in that The compound is 5. A method for preparing a compound, characterized in that: The preparation route is as follows: The method comprises the following steps: Step 1) Compound I-1 undergoes a condensation reaction with HCl HNMe (OMe) to obtain compound II; Step 2) Compound II undergoes a substitution reaction with Boc2O to obtain compound III; Step 3) Compound III undergoes reduction reaction to obtain compound IV; Step 4) Compound IV and A ring addition reaction occurs to obtain compound V; Step 5) Compound V prepared in step 4) undergoes a deprotection reaction to obtain product VI.

6. The method according to claim 5, characterized in that In compound I-1, compound II, compound III, compound IV, and compound V, R1 is Boc and R2 is H; in compound VI, R1 is H and R2 is H; Optionally, the solvent for the condensation reaction in step 1) includes DCM; Optionally, the solvent for the substitution reaction in step 2) comprises DMF; Optionally, the solvent for the reduction reaction in step 3) includes THF, and the reducing agent for the reduction reaction in step 3) includes DIBAL-H; Optionally, the solvent for the ring-addition reaction in step 4) comprises DMF; Optionally, the solvent for the deprotection reaction in step 5) includes DCM; the catalyst for the deprotection reaction in step 5) includes TFA.

7. The method according to claim 6, characterized in that The preparation route is as follows: The method comprises the following steps: Step 1) In a dichloromethane solvent, the side chain carboxyl group of compound I-2 undergoes a condensation reaction with HCl HNMe (OMe) to obtain compound II; Step 2) In a DMF solution, with DMAP as a catalyst, compound II and Boc2O undergo a substitution reaction to obtain compound III; Step 3) Compound Ⅳ is prepared by using compound III prepared in step 2) with DIBAL-H as a reducing agent; Step 4) In a DMF solution, using metal palladium as a catalyst, compound IV and trifluoromethyl-substituted o-iodoaniline undergo a ring-enlargement reaction to obtain compound V; Step 5) Compound V prepared in step 4) is treated with TFA and DCM to remove Boc and tBu protecting groups to obtain product VI.

8. The method according to claim 7, characterized in that In the step 4), the palladium catalyst is selected from at least one of the following: palladium acetate, palladium trifluoroacetate and palladium chloride.

9. The method according to claim 7, characterized in that: The trifluoromethyl group in step 4) is suitable for substituting any position on the benzene ring.

10. The method according to claim 7, characterized in that The deprotecting agent in step 5) includes at least one of TFA and DCM.

11. The method according to claim 7, characterized in that In the step 1), the molar ratio of the compound I-2, the HClHNMe (OMe), benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate and triethylamine is 1: (1～2)：(1～2)：(2～4)； In the step 2), the molar ratio of the compound II, the Boc2O and the DMAP is 1:(1-2):(0.1-0.2); In the step 3), the molar ratio of the compound III to the DIBAL-H is 1:(1-2); In the step 4), the molar ratio of the compound IV, the 4-amino-3-iodobenzotrifluoride, the DABCO and the palladium catalyst is 1:(1-2):(2-4):(0.01-0.1); In the step 5), the volume ratio of the TFA and the DCM in the deprotection reagent is preferably 1:

1.

12. The method according to claim 7, characterized in that In the step 1), the reaction conditions for preparing compound I-2 are as follows: react in DCM at room temperature for 2 hours; In the step 2), the reaction conditions for preparing compound II are as follows: reacting in DMF at room temperature for 2 hours; In the step 3), the reaction conditions for preparing compound III are as follows: reacting at -78°C for 1 hour under nitrogen protection; In the step 4), the reaction conditions for preparing compound IV are as follows: reacting at 85°C to room temperature for 6 hours under nitrogen protection; In the step 5), the deprotection treatment conditions are as follows: treatment at room temperature for 2 hours.

13. The method according to claim 7, characterized in that The amount of the compound I-2 and the HCl HNMe (OMe) substance is 3-20 mL / mmol, preferably 5 mL / mmol.

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