Synthesis method of 1, 5-disubstituted-3-oxabicyclo [3.1. 1] heptane

Abstract

The invention provides a synthesis method of 1, 5-disubstituted-3-oxabicyclo [3.1. 1] heptane, and belongs to the field of pharmacy. The method comprises the following steps: reacting a compound V with a catalyst to obtain a compound I, namely 1, 5-disubstituted-3-oxabicyclo [3.1. 1] heptane, and the catalyst is a Lewis acid catalyst. Compared with methods recorded in existing literatures, the method for synthesizing the 3-oxabicyclo [3.1. 1] heptane compound has the advantages that the product yield and purity are obviously improved, the universality is good, the functional group compatibility is strong, the reaction condition is mild, the yield is higher, the method is suitable for industrial large-scale production, the obtained product can be used as a high-value intermediate to continue functional group conversion, and the method is suitable for industrial large-scale production. The application prospect is wide. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of pharmaceuticals, and particularly relates to a method for synthesizing 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane. Background Art

[0002] In the past decade, scientists have tried to replace the benzene ring units in bioactive compounds with saturated three-dimensional rigid bioisosteres to obtain novel drug structures with improved properties that can break patent restrictions, which has attracted widespread attention from medicinal chemists and organic chemists. For example, bicyclo[1.1.1]pentane, as a bioisostere of phenyl, tert-butyl, and alkynyl groups in bioactive molecules, can significantly improve the performance of drugs in terms of permeability, water solubility, lipophilicity, and metabolic stability; researchers inserted oxygen atoms into the bicyclo[1.1.1]pentane structure to obtain a new generation of saturated benzene analogs 2-oxabicyclo[2.1.1]hexane compounds (Angew.Chem.Int.Ed.2020,7161), which have higher water solubility and lower lipophilicity than bicyclo[1.1.1]pentane and the corresponding meta / para disubstituted benzenes, and are also chemically and metabolically stable.

[0003] Bicyclo[3.1.1]heptane was used to study the replacement of meta-substituted benzene fragments of biologically active compounds (Nature, 2022, 721). Subsequently, researchers introduced nitrogen atoms into bicyclo[3.1.1]heptane and developed 3-azabicyclo[3.1.1]heptane compounds (Angew.Chem.Int.Ed.2023, e202304246). Both bicyclo[3.1.1]heptane compounds with bridge ring characteristics showed excellent pharmacological properties. Therefore, by introducing oxygen atoms into bicyclo[3.1.1]heptane, a new type of benzene bioisostere molecular building block, namely 3-oxabicyclo[3.1.1]heptane, can be obtained. 3-Oxabicyclo[3.1.1]heptane compounds are an important class of intermediates and are widely used in the field of medicine. For example, 3-oxabicyclo[3.1.1]heptane compounds are used as important molecular building blocks in Gilead Sciences' published patent application WO2022 / 225941A1 for the synthesis of glucagon-like peptide-1 receptor (GLP-1R) agonists. GLP-1R is one of the most effective targets for the treatment of type 2 diabetes. In patent application WO2024 / 015497A1, 3-oxabicyclo[3.1.1]heptane compounds are used for the synthesis of tyrosine kinase 2 (TYK2) inhibitors. In patent application WO2022 / 104079A1, 1,5-disubstituted 3-oxabicyclo[3.1.1]heptane compounds are used for the synthesis of Bruton's tyrosine kinase (BTK) inhibitor compounds, and the active IC in the in vitro BTK kinase assay is .50 <1nM. Since BTK small molecule inhibitors are very specific, they can be used to treat B-cell malignant blood tumors. 3-Oxabicyclo[3.1.1]heptane compounds have great application potential in drug development. Therefore, it is of certain significance to study the synthesis method of 3-Oxabicyclo[3.1.1]heptane compounds.

[0004]

[0005] However, there are few reports on the synthesis of 3-oxabicyclo[3.1.1]heptane compounds. The literature (J.Chem.Soc.C, 1969, 2346-2348) reported a method for synthesizing 1,5-bishydroxymethyl-3-oxabicyclo[3.1.1]heptane: using a dichloro compound as a raw material, cyclizing under sodium ethoxide conditions, and then reducing the two ester groups simultaneously to obtain a spirocyclic diol, and finally rearranging in 6N sulfuric acid and 20% hydrochloric acid to synthesize a 3-oxabicyclo[3.1.1]heptane diol compound. However, this method has the following problems: the reagent used for the third step rearrangement reaction is the reflux of a protonic acid aqueous solution, which is not suitable for substrates with poor water solubility, and the reaction conditions of the protonic acid aqueous solution are relatively harsh, and the functional group tolerance is poor, and it is not suitable for acid-sensitive substrates (such as those containing a tert-butyloxycarbonyl protecting group, a cyano group, an ester group, an amide group, etc.); the feed amount in the literature is only 0.5 g, and the reaction scale is small; the obtained product has two identical hydroxymethyl functional groups and cannot be used as a high-value intermediate for efficient and selective functional group transformation.

[0006]

[0007] The literature (Adv. Synth. Catal. 2014, 356, 3363–3369) reported a method for synthesizing 3-oxabicyclo[3.1.1]heptane with three functional groups. In this route, α,β-unsaturated aldehyde is used as raw material, and the allylic alcohol intermediate is obtained through the Morita-Baylis-Hillman reaction, and then the polysubstituted olefin intermediate is obtained through phosphorus tribromide bromination and etherification reaction, and finally a cycloaddition reaction occurs under sealed tube high temperature conditions to synthesize trisubstituted 3-oxabicyclo[3.1.1]heptane. However, it has the following problems: it needs to use a complex polysubstituted olefin pre-synthesized through three steps as raw material, and the key step of the cyclization reaction occurs under sealed tube high temperature conditions, which is not easy to scale up; the cycloaddition reaction is greatly affected by the substituent, and the distyryl group is an indispensable group, which limits the versatility of the method.

[0008]

[0009] The literature (Org. Lett. 2012, 14, 3214) reports a method for synthesizing 3-oxabicyclo[3.1.1]heptane with four substituents. First, an alkynyl compound reacts with an aldehyde under the action of a strong base to obtain a secondary alcohol, which is then alkylated to synthesize a diene ether, and finally an intramolecular ketene imine and olefin [2+2] cycloaddition is performed to obtain the oxabicyclo[3.1.1]heptane product. However, it has the following problems: complex diene and alkynylamine intermediates are synthesized through two-step reactions; the formation of the product depends on fixed substituent groups and cannot be replaced, which limits the versatility of the method. For example, when the inner olefin of the diene intermediate is replaced by the terminal olefin, the 3-oxabicyclo[3.1.1]heptane skeleton cannot be formed.

[0010] Summary of the invention

[0011] In order to overcome the defects of the prior art, the object of the present invention is to provide a method for preparing 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane with mild reaction conditions, higher yield and suitable for industrial scale-up production.

[0012] The present invention provides a method for preparing 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane, the method comprising the following steps:

[0013]

[0014] Reacting compound V with a catalyst to obtain compound I, i.e., 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane, wherein the catalyst is a Lewis acid catalyst;

[0015] R 3 Selected from hydrogen, cyano, unsubstituted or substituted with one or more R b0 Substituted 3-8 membered saturated cycloalkyl, unsubstituted or substituted with one or more R b1 substituted 3-8 membered saturated nitrogen heterocyclic group, unsubstituted or substituted with one or more R b0 substituted 5-6 membered heteroaryl, unsubstituted or substituted with one or more R b0 Substituted phenyl;

[0016] R b0 Selected from C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, R b1 Selected from amino protecting groups, C 1-6 Alkyl, halogen substituted C 1-6 alkyl.

[0017] Furthermore, the R 3Selected from hydrogen, cyano, unsubstituted or substituted with one or more R b0 Substituted 3-6 membered saturated cycloalkyl, unsubstituted or substituted with one or more R b1 Substituted 3-6 membered saturated nitrogen heterocyclic group, unsubstituted or substituted with one or more R b0 substituted 5-6 membered heteroaryl, unsubstituted or substituted with one or more R b0 Substituted phenyl;

[0018] R b0 Selected from C 1-3 Alkyl, halogen substituted C 1-3 Alkyl, R b1 Selected from amino protecting groups, C 1-3 Alkyl, halogen substituted C 1-3 alkyl.

[0019] Further, the 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane is selected from one of the following compounds:

[0020]

[0021] Furthermore, the molar ratio of the compound V to the catalyst is 1:0.1-1.5; the catalyst is a boron trifluoride ether complex; the solvent of the reaction is an organic solvent; the reaction temperature is -10-10°C, and the reaction time is 0.5-3 hours;

[0022] Preferably, the molar ratio of the compound V to the catalyst is 1:0.2-1; the solvent of the reaction is tetrahydrofuran, diethyl ether or a mixed solution of the two; the reaction temperature is 0°C and the reaction time is 1-2 hours.

[0023] Furthermore, the preparation of the compound V comprises the following steps:

[0024]

[0025] Reacting compound IV with a reducing agent to obtain compound V;

[0026] R 1 , R 2 Each independently selected from hydrogen, cyano, unsubstituted or substituted with one or more R a0 Substituted 3-8 membered saturated cycloalkyl, unsubstituted or substituted with one or more R a1 substituted 3-8 membered saturated heterocyclic group, unsubstituted or substituted with one or more R a0 substituted 5-6 membered heteroaryl, unsubstituted or substituted with one or more R a0 Substituted phenyl, COOR a2 ; and R 1, R 2 Not at the same time hydrogen;

[0027] R a0 Selected from C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, R a1 Selected from protecting groups, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, R a2 Selected from C 1-6 alkyl.

[0028] Furthermore, when R 1 is selected from unsubstituted or substituted with one or more R a0 substituted 5-6 membered heteroaryl, unsubstituted or substituted with one or more R a0 Substituted phenyl, R 2 Selected from COOR a2 , R a0 Selected from C 1-3 Alkyl, halogen substituted C 1-3 Alkyl, R a2 C 1-3 Alkyl, R 3 With R 1 At the same time, the preparation of the compound V comprises the following steps: reacting compound IV with reducing agent A to obtain compound V, wherein the molar ratio of compound IV to reducing agent A is 1:1-2; reducing agent A is a negative hydrogen reducing agent, and the solvent of the reaction is an organic solvent; the reaction temperature is -10 to 10°C, and the reaction time is 20 to 40 minutes;

[0029] When R 1 is selected from unsubstituted or substituted with one or more R a0 Substituted 3-6 membered saturated cycloalkyl, unsubstituted or substituted with one or more R a1 Substituted 4-6 membered saturated nitrogen heterocyclic group, R a0 Selected from C 1-3 Alkyl, halogen substituted C 1-3 Alkyl, R a1 is an amino protecting group, R 2 is cyano, R 3 With R 1 The same, the preparation of the compound V comprises the following steps: reacting compound IV with a reducing agent B to obtain an intermediate A, and reacting intermediate A with a reducing agent C to obtain compound V, wherein the structure of intermediate A is The molar ratio of the compound IV and the reducing agent B is 1:1-2.5; the reducing agent B is a Lewis acid reducing agent; the solvent for the reaction of the compound IV and the reducing agent B is an organic solvent; the temperature for the reaction of the compound IV and the reducing agent B is -10 to 10°C, and the reaction time of the compound IV and the reducing agent B is 1 to 3 hours; the molar ratio of the intermediate A and the reducing agent C is 1:0.5-1.5; the reducing agent C is a negative hydrogen reducing agent; the solvent for the reaction of the intermediate A and the reducing agent C is an organic solvent; the temperature for the reaction of the intermediate A and the reducing agent C is -10 to 10°C, and the reaction time of the intermediate A and the reducing agent C is 0.5 to 1.5 hours;

[0030] When R 1 is cyano, R 2 Selected from COOR a2 , R a2 C 1-3 Alkyl, R 3 With R 1 At the same time, the preparation of the compound V comprises the following steps: reacting compound IV with a reducing agent D to obtain compound V, wherein the molar ratio of compound IV to reducing agent D is 1:1-3; the reducing agent D is a borohydride salt, and the solvent of the reaction is an organic solvent; the reaction temperature is 10 to 40° C., and the reaction time is 5 to 20 hours;

[0031] When R 1 , R 2 Each independently selected from COOR a2 , R a2 C 1-3 Alkyl, R 3 When is hydrogen, the preparation of the compound V comprises the following steps: subjecting the compound IV to a deacidification reaction to obtain an intermediate B, and reacting the intermediate B with a reducing agent E to obtain a compound V, wherein the structure of the intermediate B is The solvent of the deacidification reaction is an organic solvent; the temperature of the deacidification reaction is 150-170°C, and the time is 22-25 hours; the molar ratio of the intermediate B to the reducing agent E is 1:1-1.5; the reducing agent E is a negative hydrogen reducing agent; the solvent for the reaction of the intermediate B and the reducing agent E is an organic solvent; the temperature of the reaction of the intermediate B and the reducing agent E is -10-40°C, and the time for the reaction of the intermediate B and the reducing agent E is 1-3 hours.

[0032] Furthermore, when R 1 is selected from unsubstituted or substituted with one or more R a0 substituted 5-6 membered heteroaryl, unsubstituted or substituted with one or more R a0 Substituted phenyl, R 2 Selected from COOR a2 , Ra0 Selected from C 1-3 Alkyl, halogen substituted C 1-3 Alkyl, R a2 C 1-3 Alkyl, R 3 With R 1 When the reaction conditions are the same, the molar ratio of the compound IV to the reducing agent A is 1:1.5; the reducing agent A is lithium aluminum hydride, and the solvent of the reaction is an ether solvent; the reaction temperature is 0°C and the reaction time is 30 minutes;

[0033] When R 1 is selected from unsubstituted or substituted with one or more R a0 Substituted 3-6 membered saturated cycloalkyl, unsubstituted or substituted with one or more R a1 Substituted 4-6 membered saturated nitrogen heterocyclic group, R a0 Selected from C 1-3 Alkyl, halogen substituted C 1-3 Alkyl, R a1 is an amino protecting group, R 2 Selected from cyano, R 3 With R 1 The same, the molar ratio of the compound IV and the reducing agent B is 1:1.2-2; the reducing agent B is diisobutylaluminum hydride; the solvent for the reaction of the compound IV and the reducing agent B is dichloromethane; the temperature for the reaction of the compound IV and the reducing agent B is 0°C, and the reaction time of the compound IV and the reducing agent B is 2 hours; the molar ratio of the intermediate and the reducing agent C is 1:1; the reducing agent C is lithium aluminum hydride; the solvent for the reaction of the intermediate A and the reducing agent C is ether; the temperature for the reaction of the intermediate and the reducing agent C is 0°C, and the reaction time of the intermediate and the reducing agent C is 1 hour;

[0034] When R 1 is cyano, R 2 Selected from COOR a2 , R a2 C 1-3 Alkyl, R 3 With R 1 When the reaction conditions are the same, the molar ratio of the compound IV to the reducing agent D is 1:2; the reducing agent D is sodium borohydride, and the solvent of the reaction is methanol; the reaction temperature is 20 to 30° C., and the reaction time is 7 to 17 hours;

[0035] When R 1 , R 2 Each independently selected from COOR a2 , R a2 C 1-3 Alkyl, R 3 When it is hydrogen, the deacidification reaction is carried out in Na +In the presence of + The molar ratio of the intermediate B and the reducing agent E is 1:0.5-1.5; the solvent of the deacidification reaction is dimethyl sulfoxide; the temperature of the deacidification reaction is 160°C and the time is 24 hours; the molar ratio of the intermediate B and the reducing agent E is 1:1.1; the reducing agent E is lithium aluminum hydride; the solvent for the reaction of the intermediate B and the reducing agent E is ether; the temperature of the reaction of the intermediate B and the reducing agent E is 0-30°C, and the time of the reaction of the intermediate B and the reducing agent E is 2 hours.

[0036] Further, the compound IV and Na + The molar ratio is 1:1.

[0037] Furthermore, the preparation of compound IV comprises the following steps:

[0038]

[0039] Reacting compound II, compound III and a base to obtain compound IV;

[0040] X 1 Selected from halogen, X 2 Selected from halogen.

[0041] Furthermore, X 1 is selected from chlorine, bromine or iodine, X 2 Selected from chlorine, bromine or iodine; the molar ratio of compound II, compound III and base is 1:0.5-2.5:1.5-3.5; the base is an organic base or an inorganic base; the solvent of the reaction is an organic solvent; the reaction temperature is 10-130°C and the reaction time is 5-20 hours;

[0042] Preferably, the molar ratio of compound II, compound III and base is 1:1-2.2:2-3; the base is sodium hydride, potassium carbonate, lithium hexamethyldisilazide, sodium hexamethyldisilazide or potassium hexamethyldisilazide; the solvent of the reaction is tetrahydrofuran, N,N-dimethylformamide or a mixed solution of the two; the reaction temperature is 20-120°C and the reaction time is 7-17 hours.

[0043] The present invention also provides a method for preparing compound A, the method comprising the following steps:

[0044]

[0045] (1) preparing 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane of formula I according to the above method;

[0046] (2) reacting 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane represented by formula I with compound 279 in the presence of a catalyst to obtain compound A, wherein the catalyst is Furthermore, in step (2), the solvent of the reaction is an organic solvent; the temperature of the reaction is 40 to 60° C., and the reaction time is 14 to 18 hours.

[0047] Furthermore, in step (2), the solvent of the reaction is toluene; the temperature of the reaction is 50° C., and the reaction time is 16 hours.

[0048] Definitions of terms used in the present invention: Unless otherwise specified, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms that are not specifically defined in the present invention, the meanings that can be given to them by those skilled in the art should be given according to the disclosure and context. Among them:

[0049] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. 1-6 Alkyl refers to straight or branched chain alkyl groups containing 1, 2, 3, 4, 5 or 6 carbon atoms, and so on.

[0050] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. The alkyl group may be straight or branched, and the alkyl group may be optionally substituted with one or more substituents as defined herein. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl).

[0051] "Aryl" refers to an all-carbon monocyclic group with a conjugated π electron system, such as phenyl. The aryl group does not contain heteroatoms, such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be on a carbon atom on the ring with a conjugated π electron system.

[0052] "Heteroaryl" refers to a heteroaromatic group containing one to multiple heteroatoms. The heteroatoms referred to here include, but are not limited to, oxygen, sulfur, and nitrogen. For example, furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc.

[0053] The "5-6 membered heteroaryl group" refers to a heteroaryl group having 5 or 6 ring atoms.

[0054] The 3- to 6-membered saturated cycloalkyl group refers to a saturated cycloalkyl group having 3, 4, 5 or 6 ring atoms.

[0055] The 3- to 6-membered saturated nitrogen heterocyclic group refers to a saturated nitrogen heterocyclic group having 3, 4, 5 or 6 ring atoms.

[0056] "Halogen-substituted C1-3 "Alkyl" refers to C 1-3 A group in which one or more hydrogen atoms in an alkyl group are replaced by halogen atoms. For example, trifluoromethyl.

[0057] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0058] Amino protecting groups refer to chemical groups added to amino groups in order to protect them from the effects of reaction conditions in organic synthesis. These protecting groups can be removed by appropriate conditions after the reaction is completed, thereby restoring the activity of the amino group. The introduction and removal of amino protecting groups can selectively protect the amino functional group without affecting the reactions of other functional groups. For example, tert-butyloxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, trifluoroacetyl, etc.

[0059] “Ether solvents” include diethyl ether, tetrahydrofuran or dioxane.

[0060] Compared with the prior art, the present invention has achieved the following beneficial effects:

[0061] (1) The rearrangement ring-closing step of the present invention uses boron trifluoride etherate complex as a catalyst, the conditions are mild, the functional group tolerance is high, and the method has a wide range of applicability. Compared with the method described in the literature (J. Chem. Soc. C, 1969, 2346-2348), the product yield and purity of the method of the present invention using boron trifluoride etherate complex as a catalyst for synthesizing 3-oxabicyclo[3.1.1]heptane compounds are significantly improved.

[0062] (2) The present invention uses aromatic or alkyl esters or nitriles as raw materials and introduces a variety of functional groups, and the method has good versatility.

[0063] (3) The 3-oxabicyclo[3.1.1]heptane compounds synthesized by the present invention can be further converted into other valuable pharmaceutical intermediates, providing a convenient method for the synthesis of more complex compounds containing a 3-oxabicyclo[3.1.1]heptane skeleton.

[0064] (4) The 3-oxabicyclo[3.1.1]heptane compounds synthesized by the present invention can produce more than 50 g of product in one batch, with a total yield of up to 61.6%, which has the potential for kilogram-scale synthesis.

[0065] Experimental results show that the present invention uses aromatic or alkyl esters or nitrile as raw materials to prepare 3-oxabicyclo[3.1.1]heptane compounds. Compared with the method for preparing 3-oxabicyclo[3.1.1]heptane compounds in the prior art, the present invention has good versatility, strong functional group compatibility, mild reaction conditions, and higher yield, and is suitable for industrial scale-up production. The obtained product can be used as a high-value intermediate to further undergo functional group transformation.

[0066] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0067] The above contents of the present invention are further described in detail below through specific implementation methods in the form of examples. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Figure 1 is compound I-1 (A) 1 H NMR spectrum and (B) 19 F NMR spectrum.

[0069] Figure 2 For compound I-2 1 H NMR spectrum.

[0070] Figure 3 For compound I-3 1 H NMR spectrum.

[0071] Figure 4 For compound I-4 1 H NMR spectrum.

[0072] Figure 5 For compound I-5 1 H NMR spectrum.

[0073] Figure 6 For compound I-6 1 H NMR spectrum.

[0074] Figure 7 For compound I-7 1 H NMR spectrum. DETAILED DESCRIPTION

[0075] The raw materials and equipment used in the present invention are all known products, which are obtained by purchasing commercially available products.

[0076] The "room temperature" referred to in the present invention is 25±5°C.

[0077] The term "overnight" as used in the present invention refers to a reaction time of 12±5 hours.

[0078] 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane was prepared according to the following synthetic route:

[0079]

[0080] Example 1-7 is a method for preparing 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane.

[0081] Example 1

[0082]

[0083] Step 1:

[0084] Add dry N,N-dimethylformamide (1600mL) to a 5000mL reaction bottle, add III-1 (133.27g, 573.945mmol, 1equiv), cool to 0℃, slowly add sodium hydride (49.13g, 1228.242mmol, 2.14equiv, 60% content), compound II (140g, 573.945mmol, 1equiv). React at room temperature overnight, LCMS monitors the reaction completion; pour the reaction solution into 2000mL ice water, extract with ethyl acetate, collect and combine the organic phases, wash with saturated sodium chloride, dry, and concentrate; column chromatography (ethyl acetate: petroleum ether = 0%-20%, ultraviolet, potassium permanganate color development), collect the target fraction, and concentrate to obtain yellow liquid IV-1, 121.6g. Yield: 67.41%.

[0085] Step 2:

[0086] Add compound IV-1 (121.1 g, 385.296 mmol, 1 equiv), ether (500 mL), and tetrahydrofuran (500 mL) to a 2000 mL reaction bottle; cool to 0°C, slowly add lithium aluminum hydride (22.08 g, 581.797 mmol, 1.51 equiv), react at 0°C for 30 min, and monitor the reaction completion by LCMS. Cool to 0°C, add 22 mL of water, 22 mL of 15% NaOH aqueous solution, 66 mL of water, and then add anhydrous sodium sulfate, filter, collect the filtrate, column chromatography (ethyl acetate: petroleum ether = 20%-50%, potassium permanganate color development), collect the target fraction, and concentrate to obtain a white solid V-1, 79.4 g, yield: 72.72%.

[0087] Step 3:

[0088] Add V-1 (67.7 g, 248.653 mmol, 1 equiv) and ether (500 mL) to a 1000 mL three-necked flask, cool to 0°C, slowly drop boron trifluoride ether (36.04 g, 119.353 mmol, 0.48 equiv, the mass fraction of boron trifluoride in boron trifluoride ether is 48%), react at 0°C for 1 h, monitor by LCMS and TLC, and the reaction is complete. Saturated sodium bicarbonate aqueous solution (600 mL) is slowly added to the reaction solution, extracted with ether, collected and combined the organic phase, washed with saturated sodium chloride, dried and concentrated by column chromatography (ethyl acetate: petroleum ether = 15%-40%, ultraviolet, potassium permanganate color development), collect the target fraction, and concentrate to obtain a white solid I-1, 64.1 g, yield: 94.45%. Purity: 99.75%. 1 H NMR (400MHz, Chloroform-d) δ7.60–7.52(m,2H),7.22(dd,J=7.7,0.9Hz,2H),3.93(s,2H),3.87(s,2H),3.52(s,2H),2.16–1.99(m,4H); 19 F NMR (377MHz, Chloroform-d) delta-62.41.

[0089] The total yield of 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane prepared according to the above route was 46.3%. 1 H NMR spectra and 19 F NMR spectrum Figure 1 shown.

[0090] Example 2

[0091]

[0092] Step 1:

[0093] Add dry N,N-dimethylformamide (400 mL) to a 1000 mL reaction bottle, add III-2 (33.66 g, 204.980 mmol, 1.00 equiv), cool to 0 ° C, slowly add sodium hydride (17.46 g, 436.607 mmol, 2.13 equiv, 60% content), compound II (50 g, 204.980 mmol, 1 equiv), react at room temperature overnight, and monitor the reaction completion by LCMS. Pour the reaction solution into 500 mL of ice water, extract with ethyl acetate, collect and combine the organic phases, wash with saturated sodium chloride, dry, and concentrate; column chromatography (ethyl acetate: petroleum ether = 0-20%, potassium permanganate color development), collect the target fraction, and obtain yellow liquid IV-2, 37 g, yield: 73.28%.

[0094] Step 2:

[0095] Add IV-2 (31 g, 125.860 mmol, 1 equiv) and ether (400 mL) to a 500 mL reaction bottle, cool to 0°C, slowly add lithium aluminum hydride (7.21 g, 190.049 mmol, 1.5 equiv), react at 0°C for 30 min, and monitor the reaction completion by LCMS. At 0°C, add 7.2 mL of water, 7.2 mL of 15% sodium hydroxide aqueous solution, 21.6 mL of water, and 36 g of anhydrous sodium sulfate to the reaction solution, filter, concentrate, and perform column chromatography (ethyl acetate: petroleum ether = 20%-40%, potassium permanganate color development), collect the target fraction, and concentrate to obtain V-2, 23.5 g, with a yield of 91.41%.

[0096] Step 3:

[0097] Method 1: Add ether (125 mL), V-2 (25 g, 122.388 mmol, 1 equiv) to a 500 mL reaction bottle, cool to 0°C, slowly drop boron trifluoride ether (17.74 g, 122.388 mmol, 1 equiv, 48%), react at 0°C for 1 h, and monitor the reaction completion by LCMS and TLC. Saturated sodium bicarbonate aqueous solution (125 mL) is slowly added to the reaction solution, extracted with ether, collected and combined the organic phases, washed with saturated sodium chloride, dried, concentrated, column chromatographed (ethyl acetate: petroleum ether = 15%-20%, potassium permanganate coloring), concentrated to obtain a light yellow oil I-2, 23.3 g, yield: 91.27%. Purity: 97.93%. 1 H NMR(300MHz,DMSO-d6)δ7.36–7.28(m,2H),7.25–7.18(m,1H),7.16–7.09(m,2H),4.58 (t,J=5.4Hz,1H),3.74(d,J=8.4Hz,4H),3.27(d,J=5.5Hz,2H),1.91(d,J=2.0Hz,4H).

[0098] The total yield of 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane prepared according to method 1 was 61.1%.

[0099] Method 2: Add V-2 (500 mg, 2.448 mmol, 1 equiv) and anhydrous ether (8 mL) to a 40 mL sample bottle, cool to 0°C, add boron trifluoride ether (347.41 mg, 1.175 mmol, 0.48 equiv, 48%), stir at 0°C for 1 h, monitor the complete reaction by LCMS and TLC, slowly add 10 mL of saturated sodium bicarbonate solution to the reaction solution at 0°C, extract with ether, collect and combine the organic phases, wash with saturated sodium chloride, dry, concentrate, column chromatography (ethyl acetate: petroleum ether = 15%-25%, potassium permanganate color development), concentrate to obtain a light yellow oil Ⅰ-2, 423 mg, yield: 83.50%. Purity: 98.70%. 1 H NMR(300MHz,DMSO-d6)δ7.36–7.28(m,2H),7.25–7.18(m,1H),7.16–7.09(m,2H),4.58 (t, J=5.4Hz, 1H), 3.74 (d, J=8.4Hz, 4H), 3.27 (d, J=5.5Hz, 2H), 1.91 (d, J=2.0Hz, 4H).

[0100] The total yield of 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane prepared according to method 2 was 51.7%. 1 H NMR spectrum Figure 2 shown.

[0101] Example 3

[0102]

[0103] Step 1:

[0104] Add tetrahydrofuran (800 mL), II (90 g, 368.964 mmol, 1 equiv), III-3 (29.93 g, 368.964 mmol, 1 equiv) to a 2000 mL reaction bottle, cool to 0°C, dropwise add a tetrahydrofuran solution of sodium hexamethyldisilazide (555 mL, 2 mol / L, 3 equiv), react overnight at room temperature, and monitor the reaction completion by GCMS. Cool to 0°C, add water (1000 mL), extract with ethyl acetate, collect and combine the organic phases, wash with saturated sodium chloride, dry, concentrate, column chromatography (ethyl acetate: petroleum ether = 8%-20%, potassium permanganate color development), collect the target fraction, and concentrate to obtain a yellow liquid IV-3, 54.6 g, yield: 90.69%.

[0105] Step 2:

[0106] Add dichloromethane (200 mL), IV-3 (10 g, 61.267 mmol, 1 equiv) to a 500 mL reaction bottle, cool to -78 °C, slowly add diisobutylaluminum hydride (1 mol / L n-hexane solution, 73.6 mL, 1.2 equiv), slowly heat to 0 °C, and stir for 2 h. LCMS monitors the reaction to be complete. Cool to 0 °C, add 2.9 mL of water, 2.9 mL of 15% NaOH aqueous solution, 7.3 mL of water, stir at room temperature for 15 min, then add anhydrous sodium sulfate, filter, collect the filtrate, column chromatography (ethyl acetate: petroleum ether = 7.5%-21%, potassium permanganate color development), collect the target fraction, and concentrate to obtain a light yellow liquid IV'-3, 7.4 g, yield: 72.66%.

[0107] Step 3:

[0108] Add IV'-3 (7.3 g, 43.918 mmol, 1 equiv) and ether (140 mL) to a 500 mL reaction bottle, cool to 0°C, and slowly add lithium aluminum hydride (1.67 g, 43.918 mmol, 1 equiv). React at 0°C for 1 h, and the reaction is complete after LCMS monitoring. Cool to 0°C, add 1.6 mL of water, 1.6 mL of 15% NaOH aqueous solution, 4.8 mL of water, and then add anhydrous sodium sulfate, filter, collect the filtrate, and concentrate to obtain an off-white oil V-3, 6.9 g, yield: 88.27%.

[0109] Step 4:

[0110] Add V-3 (6.9 g, 41.014 mmol, 1 equiv) and ether (70 mL) to a 250 mL reaction bottle, cool to 0°C, slowly add boron trifluoride ether (5.82 g, 19.687 mmol, 0.48 equiv, 48%), react at 0°C for 1 h, and monitor the reaction with LCMS until it is complete. Saturated sodium bicarbonate aqueous solution (100 mL) was slowly added to the reaction solution, extracted with ether, collected and combined the organic phases, washed with saturated sodium chloride, dried, concentrated, and subjected to column chromatography (ethyl acetate: petroleum ether = 8%-15%, potassium permanganate color development), collected the target fractions, and concentrated to obtain a colorless oil I-3, 5.4 g, with a yield of 77.66%. Purity: 99.23%. 1 H NMR (400MHz, Chloroform-d) δ3.64(d,J=1.4Hz,4H),3.24(s,2H),1.26(d,J=1.3Hz,4H),0.48(tt,J=8.3,5.2Hz,1H),0.25–0.12(m,2H),0.05(s,2H).

[0111] The total yield of 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane prepared according to the above route was 45.2%. 1 H NMR spectrum Figure 3 shown.

[0112] Example 4

[0113]

[0114] Step 1:

[0115] Add tetrahydrofuran (200 mL), Ⅱ (28.3 g, 116.019 mmol, 1 equiv), Ⅲ-4 (22.77 g, 116.019 mmol, 1 equiv) to a 5000 mL reaction bottle, cool to 0°C, dropwise add a tetrahydrofuran solution of sodium hexamethyldisilazide (30.8 mL, 12.300 mmol, 3 equiv), react at room temperature overnight, and monitor the reaction to be complete by LCMS. Concentrate to remove most of the THF, add water (250 mL), extract with ethyl acetate, collect and combine the organic phases, wash with saturated sodium chloride, dry, concentrate, column chromatography (ethyl acetate: petroleum ether = 27.3%-50%, potassium permanganate color development), collect the target fraction, and concentrate to obtain a yellow liquid Ⅳ-4, 29.5 g, yield: 91.35%.

[0116] Step 2:

[0117] Add dichloromethane (200 mL), IV-4 (21.8 g, 78.318 mmol, 1 equiv) to a 500 mL reaction bottle, cool to -78 °C, slowly add diisobutylaluminum hydride (1 mol / L n-hexane solution, 156 mL, 2.0 equiv), slowly warm to 0 °C, and stir for 2 h. LCMS monitors the reaction to be complete. Cool to 0 °C, add 5.8 mL of water, 5.8 mL of 15% sodium hydroxide aqueous solution, 10 mL of water, stir at room temperature for 15 min, then add anhydrous sodium sulfate, filter, collect the filtrate, column chromatography (ethyl acetate: petroleum ether = 7.5%-21%, potassium permanganate color development), collect the target fraction, and concentrate to obtain a light yellow liquid IV'-4, 7.4 g, yield: 33.58%.

[0118] Step 3:

[0119] Add IV'-4 (9.5 g, 33.766 mmol, 1 equiv) and ether (250 mL) to a 500 mL reaction bottle, cool to 0°C, and slowly add lithium aluminum hydride (1.28 g, 33.729 mmol, 1 equiv). React at 0°C for 1 h, and the reaction is complete after LCMS monitoring. Cool to 0°C, add 1.2 mL of water, 1.2 mL of 15% sodium hydroxide solution, and then add 3.6 mL of water, and then add anhydrous sodium sulfate, filter, collect the filtrate, and concentrate to obtain an off-white oil V-4, 8.778 g, yield: 91.74%.

[0120] Step 4:

[0121] Add V-4 (8.7 g, 30.702 mmol, 1 equiv) and ether (80 mL) to a 250 mL reaction bottle, cool to 0°C, slowly add boron trifluoride ether (1.82 g, 6.140 mmol, 0.2 equiv, 48%), react at 0°C for 1 h, monitor by LCMS, and the reaction is complete. Saturated sodium bicarbonate aqueous solution (100 mL) is slowly added to the reaction solution, extracted with ether, the organic phase is collected and combined, washed with saturated sodium chloride, dried, concentrated, column chromatography (ethyl acetate: petroleum ether = 30%-35%, potassium permanganate color development), the target fraction is collected, and concentrated to obtain a colorless oil I-4, 6.79 g, yield: 78.05%. Purity: 95.24%. 1 H NMR(400MHz,Chloroform-d)δ3.90–3.82(m,4H),3.70(dd,J=8.7,5.7Hz,2H),3.65(s,2H),3. 47(s,2H),2.38(tt,J=8.5,5.7Hz,1H),1.76(d,J=2.6Hz,3H),1.59–1.51(m,2H),1.44(s,9H).

[0122] The total yield of 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane prepared according to the above route was 21.9%. 1 H NMR spectrum Figure 4 shown.

[0123] Example 5

[0124]

[0125] Step 1:

[0126] Add tetrahydrofuran (500 mL), II (58.51 g, 239.868 mmol, 1 equiv), III-5 (53.8 g, 239.853 mmol, 1 equiv) to a 1000 mL reaction bottle, cool to 0°C, dropwise add a tetrahydrofuran solution of sodium hexamethyldisilazide (361 mL, 2 mol / L, 12.300 mmol, 3 equiv), react at room temperature overnight, and monitor the reaction to be complete by LCMS. Concentrate to remove most of the THF, add water (350 mL), extract with ethyl acetate, collect and combine the organic phases, wash with saturated sodium chloride, dry, concentrate, column chromatography (ethyl acetate: petroleum ether = 28%-50%, potassium permanganate color development), collect the target fraction, and concentrate to obtain a yellow liquid IV-5, 71.8 g, yield: 97.7%.

[0127] Step 2:

[0128] Add dichloromethane (700 mL) and IV-5 (71.8 g, 234.330 mmol1 equiv) to a 1000 mL reaction bottle, cool to -78 °C, slowly add diisobutylaluminum hydride (1 mol / L n-hexane solution, 470 mL, 0.046 mmol, 1.2 equiv), slowly heat to 0 °C, and stir for 2 h. LCMS monitors the reaction to be complete. Cool to 0 °C, slowly add 18 mL of water, 18 mL of 15% sodium hydroxide aqueous solution, 40 mL of water, stir at room temperature for 15 min, then add anhydrous sodium sulfate, filter, collect the filtrate, column chromatography (ethyl acetate: petroleum ether = 30%-50%, potassium permanganate color development), collect the target fraction, and concentrate to obtain a light yellow liquid IV'-5, 27.7 g, yield: 34.38%.

[0129] Step 3:

[0130] Add IV'-5 (27.7 g, 80.574 mmol, 1 equiv) and ether (400 mL) to a 1000 mL reaction bottle, cool to 0°C, and slowly add lithium aluminum hydride (3.06 g, 80.574 mmol, 1 equiv). React at 0°C for 1 h, and the reaction is complete after LCMS monitoring. Cool to 0°C, add 3 mL of water, 3 mL of 15% sodium hydroxide aqueous solution, and then add 9 mL of water, and then add anhydrous sodium sulfate, filter, collect the filtrate, and concentrate to obtain an off-white solid V-5, 16.2 g, yield: 64.56%.

[0131] Step 4:

[0132] Add V-5 (16.2 g, 52.019 mmol, 1 equiv) and ether (150 mL) to a 250 mL reaction bottle, cool to 0°C, slowly add boron trifluoride ether (3.08 g, 10.404 mmol, 0.2 equiv, 48%), react at 0°C for 1 h, and monitor the reaction with LCMS until it is complete. Saturated sodium bicarbonate aqueous solution (200 mL) was slowly added to the reaction solution, extracted with ether, collected and combined the organic phases, washed with saturated sodium chloride, dried, concentrated, and subjected to column chromatography (ethyl acetate: petroleum ether = 26.9%-40%, potassium permanganate color development), collected the target fractions, and concentrated to obtain a colorless oil I-5, 13.2 g, yield: 77.99%. Purity: 95.71%. 1 H NMR(400MHz,Chloroform-d)δ4.15(d,J=13.0Hz,2H),3.77(d,J=11.6Hz,4H),3.43(s,2H),2.58(t,J=12.8H z,2H),1.64–1.54(m,5H),1.53–1.47(m,2H),1.45(s,9H),1.36–1.24(m,1H),1.11(qd,J=12.5,4.3Hz,2H).

[0133] The total yield of 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane prepared according to the above route was 16.9%. 1 H NMR spectrum Figure 5 shown.

[0134] Example 6

[0135]

[0136] Step 1:

[0137] Add compound II (10 g, 40.996 mmol, 1 equiv) in N, N-dimethylformamide (200 mL) to a 500 mL reaction bottle, add III-6 (4.64 g, 40.996 mmol, 1 equiv), slowly add potassium carbonate (11.33 g, 81.992 mmol, 2 equiv), react at room temperature overnight, and monitor the reaction to be complete by GCMS. Slowly add water (80 mL) to quench the reaction, extract with ethyl acetate, collect and combine the organic phases, wash with saturated sodium chloride, dry, and concentrate; column chromatography (ethyl acetate: petroleum ether = 15%-16%, potassium permanganate color development), collect the target fractions, and obtain a light yellow solid IV-6, 2 g, with a yield of 24.99%.

[0138] Step 2:

[0139] Add IV-6 (200 mg, 1.024 mmol, 1 equiv) and methanol (3 mL) to an 8 mL reaction bottle, cool to 0°C, add sodium borohydride (77.51 mg, 2.048 mmol, 2 equiv) in batches, stir and react at room temperature overnight after addition, and monitor the reaction to be complete with GCMS. Cool the reaction system to 0°C, slowly drop saturated sodium bicarbonate solution (4 mL) to quench the reaction, stir at room temperature for 4 h, filter, concentrate the filtrate under reduced pressure to remove methanol, add ethyl acetate for extraction, collect and combine the organic phases, wash with saturated sodium chloride, dry, and concentrate to obtain a white solid V-6, 130 mg, yield: 72.15%.

[0140] Step 3:

[0141] Add tetrahydrofuran (3 mL) to an 8 mL reaction bottle, cool to 0°C, add V-6 (130 mg, 0.849 mmol, 1 equiv), slowly drop boron trifluoride ether (123.01 mg, 0.408 mmol, 0.48 equiv, 48%), react at 0°C for 1 h, and monitor the reaction completion by LCMS. Saturated sodium bicarbonate aqueous solution (2 mL) was slowly added to the reaction solution, extracted with ethyl acetate, collected and combined the organic phases, washed with saturated sodium chloride, dried, and concentrated to obtain a white solid I-6, 100 mg, yield: 76.92%. 1 H NMR (400MHz, Chloroform-d) δ4.04(s,2H),3.82(s,2H),3.46(s,2H),2.37-2.42(m,2H),2.00-2.05(m,2H),1.65(brs,1H).

[0142] The total yield of 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane prepared according to the above route was 13.9%. 1 H NMR spectrum Figure 6 shown.

[0143] Example 7

[0144]

[0145] Step 1:

[0146] Add N,N-dimethylformamide (270 mL) to a 1L three-necked flask, cool to 0°C, slowly add sodium hydride (14.76 g, 2 equiv) at 0°C, drop compound III-7 (62.05 g, 2.1 equiv), return to room temperature for reaction, then heat to 60°C, slowly drop compound II (45 g, 1 equiv), slowly heat to 120°C after addition, and react at 120°C overnight. Monitor by LCMS. The reaction solution was cooled to room temperature, introduced into ice water, a small amount of ammonium chloride was added, 400 mL of ethyl acetate was added for extraction, and 200 ml of water was added for backwashing. The organic phase was retained and dried, and 60 g of crude product was obtained by spin drying. The product was purified by column chromatography (petroleum ether: ethyl acetate = 5%-6%), (TLC: petroleum ether / ethyl acetate = 5 / 1, potassium permanganate for color development), and light yellow transparent liquid compound Ⅵ-7 (22.93 g, yield 85.6%) was obtained by spin drying.

[0147] Step 2:

[0148] Compound IV-7 (5.49 g, 22.661 mmol, 1 equiv) was dissolved in dimethyl sulfoxide (21.6 mL), sodium chloride (1.32 g, 22.587 mmol, 1 equiv) was added at room temperature, and then water (1 mL, 55.509 mmol, 2.45 equiv) was added, and the temperature was slowly raised to 160°C, and the reaction was carried out for 24 hours, and GCMS was monitored. After cooling to room temperature, the reaction solution was added dropwise to 30 mL of ice water, and extracted three times with 100 mL of ethyl acetate: petroleum ether = 1:2 solution, dried over anhydrous sodium sulfate, concentrated, and column chromatography (petroleum ether: ethyl acetate = 10%-15%) was performed to obtain compound IV'-7 (3 g, yield 67.1%).

[0149] Step 3:

[0150] Add anhydrous ether (30 mL) to a 100 mL three-necked flask, cool to 0 ° C, control the temperature at -10 ° C -0 ° C, add lithium aluminum hydride (686.72 mg, 18.095 mmol, 1.1 equiv) in batches, slowly drop compound IV'-7 ether solution (2.8 g dissolved in 30 mL anhydrous ether), slowly return to room temperature after the addition is complete, react at room temperature for 2 hours, monitor the reaction by TLC, cool to about 0 ° C, slowly add water (1.54 g, 5 eq), stir for half an hour, add anhydrous sodium sulfate to dry, filter, and concentrate to obtain compound V-7 (1.6 g, yield 72.1%).

[0151] Step 4:

[0152] Compound V-7 (2.1 g, 16.384 mmol, 1 equiv) and anhydrous ether (30 mL) in a 100 mL three-necked flask were cooled to 0°C, and boron trifluoride ether (2.33 g, 16.384 mmol, 1 equiv) was added. The reaction was maintained at 0°C for two hours. The reaction was complete when monitored by TLC. 20 mL of saturated NaHCO was slowly added at 0°C. 3 The aqueous solution was quenched and separated. The aqueous phase was extracted with diethyl ether three times (50 mL each time). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (n-pentane: ethyl acetate = 50%-54%). Potassium permanganate was used for color development to obtain compound Ⅰ-7 (1.05 g, yield 48.0%). 1 H NMR(300MHz,Chloroform-d)δ3.95(d,J=2.2Hz,2H),3.88(s,2H),3.41(s,2H),2 .38-2.32(m,1H),1.93(td,J=6.2,2.5Hz,2H),1.80(brs,1H),1.68–1.54(m,2H).

[0153] The total yield of 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane prepared according to the above route was 19.8%. 1 H NMR spectrum Figure 7 shown.

[0154] Taking Example 8 as an example, it is explained that the 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane prepared by the present invention is an important pharmaceutical intermediate and can be used to further prepare known tyrosine kinase 2 (TYK2) inhibitors.

[0155] Example 8

[0156] According to the method described in the first paragraph on page 359 of the specification of patent application WO2024 / 015497A1, the TYK2 inhibitor (i.e., compound 324 on page 448 of WO2024 / 015497A1) was prepared using the following route, using compound 279 described on page 222 of WO2024 / 015497A1 and compound Ⅰ-7 obtained in Example 7 of the present invention as raw materials.

[0157]

[0158] The following is a comparative example of preparing compound I-2 according to the method described in the literature (J. Chem. Soc. C, 1969, 2346-2348).

[0159] Comparative Example 1

[0160]

[0161] V-2 (500 mg, 2.448 mmol, 1 equiv) and hydrochloric acid (20%, 40 mL) were added to a 250 mL single-mouth bottle, and refluxed at 100°C for 4 h. The reaction was monitored by LCMS. At 0°C, 15% aqueous sodium hydroxide solution (60 mL) was slowly added to the reaction solution, extracted with ether, and the organic phase was collected and combined, washed with saturated sodium chloride, dried, concentrated, and chromatographed on a column (ethyl acetate: petroleum ether = 15%-23%, potassium permanganate color development). The mixture was concentrated to obtain Ⅰ-2 as a light yellow oil, 381 mg, with a yield of 75.25%. Purity: 95.05%. 1 HNMR(300MHz,DMSO-d6)δ7.36–7.28(m,2H),7.25–7.18(m,1H),7.16–7.09(m,2H),4.5 8(t,J=5.4Hz,1H), 3.74(d,J=8.4Hz,4H), 3.27(d,J=5.5Hz,2H), 1.91(d,J=2.0Hz,4H).

[0162] Comparative Example 2

[0163]

[0164] Add V-2 (500 mg, 2.448 mmol, 1 equiv) and sulfuric acid (6N, 40 mL) to a 250 mL single-mouth bottle, reflux at 100 ° C for 4 h, and monitor the complete reaction by LCMS. At 0 ° C, slowly add 15% sodium hydroxide aqueous solution (64 mL) to the reaction solution, extract with ether, collect and combine the organic phases, wash with saturated sodium chloride, dry, concentrate the column, column chromatography (ethyl acetate: petroleum ether = 15%-22%, potassium permanganate color development), and concentrate to obtain a light yellow oil I-2, 386 mg, yield: 75.65%. Purity: 94.27%. 1 HNMR(300MHz,DMSO-d6)δ7.36–7.28(m,2H),7.25–7.18(m,1H),7.16–7.09(m,2H),4.5 8(t,J=5.4Hz,1H), 3.74(d,J=8.4Hz,4H), 3.27(d,J=5.5Hz,2H), 1.91(d,J=2.0Hz,4H).

[0165] Combining the comparative examples 1, 2 and the method 2 of step 3 of the embodiment 2 of the present invention, it can be seen that under the same reaction scale of 500 mg, the yield of the product I-2 obtained by the method 2 of step 3 of the embodiment 2 of the present invention is 83.50%, which is significantly higher than 75.25% and 75.65% of the comparative examples 1 and 2; the purity of the product I-2 obtained by the method 2 of step 3 of the embodiment 2 of the present invention is 98.70%, which is significantly higher than 95.05% and 94.27% of the comparative examples 1 and 2. That is to say, compared with the method described in the literature (J. Chem. Soc. C, 1969, 2346-2348), the product yield and purity of the method of the present invention for synthesizing 3-oxabicyclo[3.1.1]heptane compounds using boron trifluoride etherate as a catalyst are significantly improved.

[0166] In summary, the present invention provides a 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane and a method for synthesizing the same. Compared with the method for preparing 3-oxabicyclo[3.1.1]heptane compounds in the prior art, the method of the present invention not only significantly improves the product yield and purity, but also has good versatility, strong functional group compatibility, mild reaction conditions, and higher yield, and is suitable for industrial scale-up production. The obtained product can be used as a high-value intermediate to further undergo functional group transformation.

Claims

1. A method for preparing 1,5-disubstituted-3-oxabicyclo[ 3.1.1] Heptane method, characterized in that The method comprises the following steps: Reacting compound V with a catalyst to obtain compound I, i.e., 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane, wherein the catalyst is a Lewis acid catalyst; R 3 Selected from hydrogen, cyano, unsubstituted or substituted with one or more R b0 Substituted 3-8 membered saturated cycloalkyl, unsubstituted or substituted with one or more R b1 substituted 3-8 membered saturated nitrogen heterocyclic group, unsubstituted or substituted with one or more R b0 substituted 5-6 membered heteroaryl, unsubstituted or substituted with one or more R b0 Substituted phenyl; R b0 Selected from C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, R b1 Selected from amino protecting groups, C 1-6 Alkyl, halogen substituted C 1-6 alkyl.

2. The method according to claim 1, characterized in that the R 3 Selected from hydrogen, cyano, unsubstituted or substituted with one or more R b0 Substituted 3-6 membered saturated cycloalkyl, unsubstituted or substituted with one or more R b1 Substituted 3-6 membered saturated nitrogen heterocyclic group, unsubstituted or substituted with one or more R b0 substituted 5-6 membered heteroaryl, unsubstituted or substituted with one or more R b0 Substituted phenyl; R b0 Selected from C 1-3 Alkyl, halogen substituted C 1-3 Alkyl, R b1 Selected from amino protecting groups, C 1-3 Alkyl, halogen substituted C 1-3 alkyl.

3. The method according to claim 2, characterized in that the 1,5-disubstituted-3-oxabicyclo[ 3.1.1] Heptane is selected from one of the following compounds:

4. The method according to claim 1, characterized in that The molar ratio of the compound V to the catalyst is 1:0.1-1.5; the catalyst is a boron trifluoride ether complex; the solvent of the reaction is an organic solvent; the temperature of the reaction is -10-10°C, and the time is 0.5-3 hours; Preferably, the molar ratio of the compound V to the catalyst is 1:0.2-1; the solvent of the reaction is tetrahydrofuran, diethyl ether or a mixed solution of the two; the reaction temperature is 0°C and the reaction time is 1-2 hours.

5. The method according to any one of claims 1 to 4, characterized in that: The preparation of the compound V comprises the following steps: Reacting compound IV with a reducing agent to obtain compound V; R1 and R2 are each independently selected from hydrogen, cyano, unsubstituted or substituted with one or more R a0 Substituted 3-8 membered saturated cycloalkyl, unsubstituted or substituted with one or more R a1 substituted 3-8 membered saturated heterocyclic group, unsubstituted or substituted with one or more R a0 substituted 5-6 membered heteroaryl, unsubstituted or substituted with one or more R a0 Substituted phenyl, COOR a2 ; and R1 and R2 are not hydrogen at the same time; R a0 Selected from C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, R a1 Selected from protecting groups, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, R a2 Selected from C 1-6 alkyl.

6. The method according to claim 5, characterized in that When R1 is selected from unsubstituted or substituted with one or more R a0 substituted 5-6 membered heteroaryl, unsubstituted or substituted with one or more R a0 Substituted phenyl, R2 is selected from COOR a2 , R a0 Selected from C 1-3 Alkyl, halogen substituted C 1-3 Alkyl, R a2 C 1-3 alkyl, R3 and R1 are the same, the preparation of the compound V comprises the following steps: reacting compound IV with reducing agent A to obtain compound V, wherein the molar ratio of compound IV to reducing agent A is 1:1-2; reducing agent A is a negative hydrogen reducing agent, and the solvent of the reaction is an organic solvent; the reaction temperature is -10 to 10°C, and the reaction time is 20 to 40 minutes; When R1 is selected from unsubstituted or substituted with one or more R a0 Substituted 3-6 membered saturated cycloalkyl, unsubstituted or substituted with one or more R a1 Substituted 4-6 membered saturated nitrogen heterocyclic group, R a0 Selected from C 1-3 Alkyl, halogen substituted C 1-3 Alkyl, R a1 When R2 is an amino protecting group, R3 is the same as R1, the preparation of the compound V comprises the following steps: reacting the compound IV with a reducing agent B to obtain an intermediate A, and reacting the intermediate A with a reducing agent C to obtain a compound V, wherein the structure of the intermediate A is The molar ratio of the compound IV and the reducing agent B is 1:1-2.5; the reducing agent B is a Lewis acid reducing agent; the solvent for the reaction of the compound IV and the reducing agent B is an organic solvent; the temperature for the reaction of the compound IV and the reducing agent B is -10 to 10°C, and the reaction time of the compound IV and the reducing agent B is 1 to 3 hours; the molar ratio of the intermediate A and the reducing agent C is 1:0.5-1.5; the reducing agent C is a negative hydrogen reducing agent; the solvent for the reaction of the intermediate A and the reducing agent C is an organic solvent; the temperature for the reaction of the intermediate A and the reducing agent C is -10 to 10°C, and the reaction time of the intermediate A and the reducing agent C is 0.5 to 1.5 hours; When R1 is cyano, R2 is selected from COOR a2 , R a2 C 1-3 alkyl, R3 and R1 are the same, the preparation of the compound V comprises the following steps: reacting compound IV with a reducing agent D to obtain compound V, wherein the molar ratio of compound IV to reducing agent D is 1:1-3; the reducing agent D is a borohydride salt, and the solvent of the reaction is an organic solvent; the reaction temperature is 10-40°C, and the reaction time is 5-20 hours; When R1 and R2 are independently selected from COOR a2 , R a2 C 1-3 When R3 is hydrogen, the preparation of the compound V comprises the following steps: subjecting the compound IV to a deacidification reaction to obtain an intermediate B, and reacting the intermediate B with a reducing agent E to obtain a compound V, wherein the structure of the intermediate B is The solvent of the deacidification reaction is an organic solvent; the temperature of the deacidification reaction is 150-170°C, and the time is 22-25 hours; the molar ratio of the intermediate B to the reducing agent E is 1:1-1.5; the reducing agent E is a negative hydrogen reducing agent; the solvent for the reaction of the intermediate B and the reducing agent E is an organic solvent; the temperature of the reaction of the intermediate B and the reducing agent E is -10-40°C, and the time for the reaction of the intermediate B and the reducing agent E is 1-3 hours.

7. The method according to claim 6, characterized in that When R1 is selected from unsubstituted or substituted with one or more R a0 substituted 5-6 membered heteroaryl, unsubstituted or substituted with one or more R a0 Substituted phenyl, R2 is selected from COOR a2 , R a0 Selected from C 1-3 Alkyl, halogen substituted C 1-3 Alkyl, R a2 C 1-3 alkyl, when R3 is the same as R1, the molar ratio of the compound IV to the reducing agent A is 1:1.5; the reducing agent A is lithium aluminum hydride, and the solvent of the reaction is an ether solvent; the reaction temperature is 0°C and the reaction time is 30 minutes; When R1 is selected from unsubstituted or substituted with one or more R a0 Substituted 3-6 membered saturated cycloalkyl, unsubstituted or substituted with one or more R a1 Substituted 4-6 membered saturated nitrogen heterocyclic group, R a0 Selected from C 1-3 Alkyl, halogen substituted C 1-3 Alkyl, R a1 is an amino protecting group, R2 is selected from cyano, and when R3 is the same as R1, the molar ratio of the compound IV to the reducing agent B is 1:1.2-2; the reducing agent B is diisobutylaluminum hydride; the solvent for the reaction of the compound IV and the reducing agent B is dichloromethane; the temperature for the reaction of the compound IV and the reducing agent B is 0°C, and the reaction time of the compound IV and the reducing agent B is 2 hours; the molar ratio of the intermediate to the reducing agent C is 1:1; the reducing agent C is lithium aluminum hydride; the solvent for the reaction of the intermediate A and the reducing agent C is ether; the temperature for the reaction of the intermediate and the reducing agent C is 0°C, and the reaction time of the intermediate and the reducing agent C is 1 hour; When R1 is cyano, R2 is selected from COOR a2 , R a2 C 1-3 alkyl, when R3 is the same as R1, the molar ratio of the compound IV to the reducing agent D is 1:2; the reducing agent D is sodium borohydride, and the solvent of the reaction is methanol; the reaction temperature is 20 to 30°C, and the reaction time is 7 to 17 hours; When R1 and R2 are independently selected from COOR a2 , R a2 C 1-3 When R3 is hydrogen, the deacidification reaction is carried out in Na + In the presence of + The molar ratio of the intermediate B and the reducing agent E is 1:0.5-1.5; the solvent of the deacidification reaction is dimethyl sulfoxide; the temperature of the deacidification reaction is 160°C, and the time of the deacidification reaction is 24 hours; the molar ratio of the intermediate B and the reducing agent E is 1:1.1; the reducing agent E is lithium aluminum hydride; the solvent for the reaction of the intermediate B and the reducing agent E is ether; the temperature of the reaction of the intermediate B and the reducing agent E is 0-30°C, and the time of the reaction of the intermediate B and the reducing agent E is 2 hours.

8. The method according to claim 5, characterized in that The preparation of compound IV comprises the following steps: Reacting compound II, compound III and a base to obtain compound IV; X1 is selected from halogen, and X2 is selected from halogen.

9. The method according to claim 8, characterized in that X1 is selected from chlorine, bromine or iodine, and X2 is selected from chlorine, bromine or iodine; the molar ratio of the compound II, the compound III and the base is 1:0.5-2.5:1.5-3.5; the base is an organic base or an inorganic base; the solvent of the reaction is an organic solvent; the reaction temperature is 10-130°C, and the reaction time is 5-20 hours; Preferably, the molar ratio of compound II, compound III and base is 1:1-2.2:2-3; the base is sodium hydride, potassium carbonate, lithium hexamethyldisilazide, sodium hexamethyldisilazide or potassium hexamethyldisilazide; the solvent of the reaction is tetrahydrofuran, N,N-dimethylformamide or a mixed solution of the two; the reaction temperature is 20-120°C and the reaction time is 7-17 hours.

10. A method for preparing compound A, characterized in that: The method comprises the following steps: (1) preparing 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane of formula I according to the method described in any one of claims 1 to 9; (2) The 1,5-disubstituted-3-oxabicyclic ring [ 3.1.1] Heptane and compound 279 react under the action of a catalyst to obtain compound A, wherein the catalyst is

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