Synthesis method of 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane

Abstract

The present invention provides a method for synthesizing 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane, belonging to the field of pharmaceuticals. The method comprises the following steps: reacting compound V with a catalyst to obtain compound I, namely 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane, wherein the catalyst is a Lewis acid catalyst. Compared with the methods recorded in the existing literature, the method for synthesizing 3-oxabicyclo[3.1.1]heptane compounds in the present invention not only significantly improves the product yield and purity, but also has good generality, strong functional group compatibility, mild reaction conditions, and higher yields, is suitable for industrial scale-up production, and the obtained product can be used as a high-value intermediate for further functional group transformation, with broad application prospects.

Description

Technical Field

[0001] The present 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 attempted to replace the benzene ring unit in bioactive compounds with saturated three-dimensional rigid bioisosteres to obtain drug structures with improved properties and novel patent-breaking characteristics, thus attracting extensive attention from medicinal 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 an oxygen atom into the bicyclo[1.1.1]pentane structure to obtain a new generation of saturated benzene analogues, 2-oxabicyclo[2.1.1]hexane compounds (Angew. Chem. Int. Ed. 2020, 7161), and these compounds have higher water solubility and lower lipophilicity than bicyclo[1.1.1]pentane and the corresponding meta / para-disubstituted benzenes, and are also stable chemically and metabolically.

[0003] Bicyclo[3.1.1]heptane has been used to study the replacement of the meta-substituted benzene fragment in bioactive compounds (Nature, 2022, 721). Subsequently, researchers introduced a nitrogen atom into bicyclo[3.1.1]heptane to develop 3-azabicyclo[3.1.1]heptane compounds (Angew. Chem. Int. Ed. 2023, e202304246), and both of these bicyclo[3.1.1]heptane compounds with bridged-ring characteristics exhibit excellent pharmacochemical properties. Therefore, introducing an oxygen atom into bicyclo[3.1.1]heptane can result in a novel benzene bioisostere molecular building block, namely 3-oxabicyclo[3.1.1]heptane. 3-Oxabicyclo[3.1.1]heptane compounds are an important class of intermediates and have wide applications in the pharmaceutical field. For example, as important molecular building blocks, 3-oxabicyclo[3.1.1]heptane compounds are used in the synthesis of glucagon-like peptide-1 receptor (GLP-1R) agonists in the patent application WO2022 / 225941A1 publicly disclosed by Gilead Sciences, and GLP-1R is one of the most effective targets for treating type 2 diabetes. In the patent application WO2024 / 015497A1, 3-oxabicyclo[3.1.1]heptane compounds are used in the synthesis of tyrosine kinase 2 (TYK2) inhibitors. In the patent application WO2022 / 104079A1, 1,5-disubstituted 3-oxabicyclo[3.1.1]heptane compounds are used in the synthesis of Bruton's tyrosine kinase (BTK) inhibitor compounds, and their activity IC in in vitro BTK kinase assays50 <1 nM. Since the BTK small molecule inhibitor has very good specificity, it can be used to treat B-cell malignant hematological tumor diseases. 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 synthesis method of 1,5-bis(hydroxymethyl)-3-oxabicyclo[3.1.1]heptane: using a dichloro compound as the raw material, cyclizing under the condition of sodium ethoxide, then reducing the two ester groups simultaneously to obtain a spiro diol, and finally undergoing a rearrangement reaction 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 in the third-step rearrangement reaction is refluxing with an aqueous solution of a protonic acid, which is not suitable for substrates with poor water solubility, and the reaction conditions of the aqueous solution of the protonic acid are relatively harsh, with poor functional group tolerance and not suitable for acid-sensitive substrates (such as those containing tert-butoxycarbonyl protecting groups, cyano groups, ester groups, amides, etc.); the literature feed amount 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 synthesis method of 3-oxabicyclo[3.1.1]heptane with 3 functional groups. In this route, using an α,β-unsaturated aldehyde as the raw material, an allyl alcohol intermediate is obtained through the Morita-Baylis-Hillman reaction, then brominated with phosphorus tribromide and etherified to obtain a polysubstituted olefin intermediate, and finally a cycloaddition reaction occurs under the conditions of a sealed tube and high temperature to synthesize a trisubstituted 3-oxabicyclo[3.1.1]heptane. However, it has the following problems: it is necessary to use a complex polysubstituted olefin pre-synthesized through three steps as the raw material, and the key step of the cyclization reaction occurs under the conditions of a sealed tube and high temperature, which is not easy to scale up; the cycloaddition reaction is greatly affected by substituents, and a stilbenyl group is an essential group, which limits the generality of the method.

[0008]

[0009] The literature (Org. Lett. 2012, 14, 3214) reported a synthetic method of 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, and then the ether of the diene is synthesized by alkylation. Finally, the oxabicyclo[3.1.1]heptane product is obtained through the intramolecular [2+2] cycloaddition of ketene imine and alkene. However, it has the following problems: synthesizing complex diene and alkynylamine intermediates through two-step reactions; the formation of the product depends on fixed substituents and cannot be replaced, which limits the generality of the method. For example, when the internal alkene of the diene intermediate is replaced by a terminal alkene, 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, and the method comprises the following steps:

[0013]

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

[0015] R 3 is selected from hydrogen, cyano, unsubstituted or substituted by one or more R b0 substituted 3-8 membered saturated cycloalkyl, unsubstituted or substituted by one or more R b1 substituted 3-8 membered saturated azacycloalkyl, unsubstituted or substituted by one or more R b0 substituted 5-6 membered heteroaryl, unsubstituted or substituted by one or more R b0 substituted phenyl;

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

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

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

[0019] Furthermore, 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 to 1.5; the catalyst is boron trifluoride diethyl ether complex; the solvent for the reaction is an organic solvent; the temperature of the reaction is -10 to 10 °C, and the time is 0.5 to 3 hours;

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

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

[0024]

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

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

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

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

[0029] When R 1 is selected from unsubstituted or one or more R a0 substituted 3-6-membered saturated cycloalkyl, unsubstituted or one or more R a1 substituted 4-6-membered saturated nitrogen heterocyclic group, R a0 is 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 is the same as R 1 , the preparation of the compound V includes 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 the compound V, wherein the structure of the intermediate A is The molar ratio of the compound IV to 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 reaction temperature 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 to the reducing agent C is 1:0.5 - 1.5; the reducing agent C is a hydride reducing agent; the solvent for the reaction of the intermediate A and the reducing agent C is an organic solvent; the reaction temperature 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 is selected from COOR a2 , R a2 is C 1-3 alkyl, and when R 3 is the same as R 1 , the preparation of the compound V includes the following steps: reacting the compound IV with the reducing agent D to obtain the compound V, wherein the molar ratio of the compound IV to the reducing agent D is 1:1 - 3; the reducing agent D is a borohydride salt, and the solvent for the reaction is an organic solvent; the reaction temperature is 10 to 40 °C, and the time is 5 to 20 hours;

[0031] When R 1 , R 2 are each independently selected from COOR a2 , R a2 is C 1-3 alkyl, and R 3 is hydrogen, the preparation of the compound V includes 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 the compound V, wherein the structure of the intermediate B is The solvent for the deacidification reaction is an organic solvent; the deacidification reaction temperature is 150 to 170 °C, and the time is 22 to 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 hydride reducing agent; the solvent for the reaction of the intermediate B and the reducing agent E is an organic solvent; the reaction temperature of the intermediate B and the reducing agent E is -10 to 40 °C, and the reaction time of the intermediate B and the reducing agent E is 1 to 3 hours.

[0032] Further, when R 1 is selected from a 5- or 6-membered heteroaryl group which is unsubstituted or substituted by one or more R a0 groups, or a phenyl group which is unsubstituted or substituted by one or more R a0 groups, and R 2 is selected from COOR a2 , Ra0 Selected from C 1-3 alkyl, halogen-substituted C 1-3 alkyl, R a2 is C 1-3 alkyl, R 3 is the same as R 1 the molar ratio of the compound IV to the reducing agent A is 1:1.5; the reducing agent A is lithium aluminum hydride, the solvent for the reaction is an ether solvent; the temperature of the reaction is 0 °C and the time is 30 minutes;

[0033] When R 1 is selected from unsubstituted or substituted by one or more R a0 substituted 3- to 6-membered saturated cycloalkyl, unsubstituted or substituted by one or more R a1 substituted 4- to 6-membered saturated azacyclic group, R a0 is selected from C 1-3 alkyl, halogen-substituted C 1-3 alkyl, R a1 is an amino protecting group, R 2 is selected from cyano, R 3 is the same as R 1 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 with the reducing agent B is dichloromethane; the temperature of the reaction of the compound IV with the reducing agent B is 0 °C and the time of the reaction of the compound IV with 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 with the reducing agent C is diethyl ether; the temperature of the reaction of the intermediate with the reducing agent C is 0 °C and the time of the reaction of the intermediate with the reducing agent C is 1 hour;

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

[0035] When R 1 , R 2 are each independently selected from COOR a2 , R a2 is C 1-3 alkyl, R 3 is hydrogen, the deacidification reaction is carried out in Na +in the presence of the compound IV and Na + The molar ratio of is 1:0.5 - 1.5; the solvent for 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 intermediate B to reducing agent E is 1:1.1; the reducing agent E is lithium aluminum hydride; the solvent for the reaction of intermediate B with reducing agent E is diethyl ether; the temperature of the reaction of intermediate B with reducing agent E is 0 - 30 °C, and the time of the reaction of intermediate B with reducing agent E is 2 hours.

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

[0037] Further, the preparation of the compound IV includes the following steps:

[0038]

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

[0040] X 1 is selected from halogen, X 2 is selected from halogen.

[0041] Further, X 1 is selected from chlorine, bromine or iodine, X 2 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 for the reaction is an organic solvent; the temperature of the reaction is 10 - 130 °C and the time is 5 - 20 hours;

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

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

[0044]

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

[0046] (2) React 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane represented by Formula I and Compound 279 under the action of a catalyst to obtain Compound A, and the catalyst is Further, in step (2), the solvent for the reaction is an organic solvent; the temperature of the reaction is 40 to 60 °C, and the time is 14 to 18 hours.

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

[0048] Definition of the terms used in the present invention: Unless otherwise specified, the initial definitions provided for the groups or terms herein apply to the group or term throughout the specification; for terms not specifically defined in the present invention, 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 contents in the hydrocarbon group are represented by a prefix. For example, the prefix C a～b Alkyl represents any alkyl group containing "a" to "b" carbon atoms. For example, C 1-6 Alkyl refers to a straight-chain or branched-chain alkyl group 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 can be straight-chain or branched-chain, and the alkyl group can be optionally substituted by one or more substituents as defined in the present invention. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl).

[0051] "Aryl" refers to a fully carbon monocyclic group having 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 of the ring having a conjugated π-electron system.

[0052] "Heteroaryl" refers to a heteroaromatic group containing one or more 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] "5-6-membered heteroaryl" refers to a heteroaryl having 5 or 6 ring atoms.

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

[0055] 3-6-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 hydrogens in the alkyl group are substituted by halogens. For example, trifluoromethyl.

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

[0058] An amino protecting group refers to a chemical group added to an amino group in organic synthesis to protect the amino group from the influence of reaction conditions. These protecting groups can be removed under 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-butoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, trifluoroacetyl, etc.

[0059] "Ether solvents" include diethyl ether, tetrahydrofuran or dioxane, etc.

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

[0061] (1) In the rearrangement and cyclization step of the present invention, boron trifluoride diethyl ether complex is used as a catalyst, with mild conditions, high functional group tolerance, and a wide application range of the method. Compared with the method described in the literature (J. Chem. Soc. C, 1969, 2346 - 2348), the product yield and purity of the method for catalytic synthesis of 3-oxabicyclo[3.1.1]heptane compounds using boron trifluoride diethyl ether complex as a catalyst in the present invention are significantly improved.

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

[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 the 3-oxabicyclo[3.1.1]heptane skeleton.

[0064] (4) For the 3-oxabicyclo[3.1.1]heptane compounds synthesized by the present invention, more than 50 g can be obtained in one batch at most, and the total yield can reach up to 61.6%, showing the potential for kilogram-scale synthesis.

[0065] The experimental results show that the present invention uses aryl or alkyl esters or nitriles as raw materials to prepare 3-oxabicyclo[3.1.1]heptane compounds. Compared with the methods for preparing 3-oxabicyclo[3.1.1]heptane compounds in the prior art, the present invention has good generality, strong functional group compatibility, mild reaction conditions, higher yields, is suitable for industrial scale-up production, and the obtained products can be used as high-value intermediates for further functional group transformation.

[0066] Obviously, based on the above content of the present invention, according to the common general technical knowledge and customary means in the art, without departing from the above basic technical idea of the present invention, various other forms of modifications, substitutions or changes can be made.

[0067] The following is a further detailed description of the above content of the present invention through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. Brief Description of the Drawings

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

[0069] Figure 2 is the 1 1H NMR spectrum of Compound I-2.

[0070] Figure 3 is the 1 1H NMR spectrum of Compound I-3.

[0071] Figure 4 is the 1 1H NMR spectrum of Compound I-4.

[0072] Figure 5 is the 1 1H NMR spectrum of Compound I-5.

[0073] Figure 6 is the 1 1H NMR spectrum of Compound I-6.

[0074] Figure 7 is the 1 1H NMR spectrum of Compound I-7. Detailed Description of the Embodiments

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

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

[0077] The "overnight" referred to in the present invention means reacting for 12 ± 5 hours.

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

[0079]

[0080] Examples 1-7 are methods for preparing 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane.

[0081] Example 1

[0082]

[0083] Step 1:

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

[0085] Step 2:

[0086] Add compound IV-1 (121.1 g, 385.296 mmol, 1 equiv), diethyl ether (500 mL), and tetrahydrofuran (500 mL) to a 2000 mL reaction flask; cool down to 0 °C, and 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 by LCMS until completion. Cool down to 0 °C, add 22 mL of water, 22 mL of 15% aqueous NaOH solution, 66 mL of water, then add anhydrous sodium sulfate, filter, collect the filtrate, perform column chromatography (ethyl acetate: petroleum ether = 20%-50%, visualized by potassium permanganate), 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 diethyl ether (500 mL) to a 1000 mL three-necked flask. Cool the mixture to 0 °C and slowly add boron trifluoride diethyl etherate (36.04 g, 119.353 mmol, 0.48 equiv, the mass fraction of boron trifluoride in boron trifluoride diethyl etherate is 48%). React at 0 °C for 1 h and monitor the reaction by LCMS and TLC until completion. Slowly add saturated aqueous sodium bicarbonate solution (600 mL) to the reaction mixture, extract with diethyl ether, collect and combine the organic phases, wash with saturated sodium chloride solution, dry, concentrate, and perform column chromatography (ethyl acetate: petroleum ether = 15% - 40%, visualized by UV and potassium permanganate). Collect the target fraction and concentrate to obtain white solid I-1, 64.1 g, yield: 94.45%, purity: 99.75%. 1 1H NMR (400 MHz, Chloroform-d) δ 7.60–7.52 (m, 2H), 7.22 (dd, J = 7.7, 0.9 Hz, 2H), 3.93 (s, 2H), 3.87 (s, 2H), 3.52 (s, 2H), 2.16–1.99 (m, 4H); 19 19F NMR (377 MHz, Chloroform-d) δ -62.41.

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

[0090] Example 2

[0091]

[0092] Step 1:

[0093] Add dry N,N-dimethylformamide (400 mL) to a 1000 mL reaction flask, 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), and compound II (50 g, 204.980 mmol, 1 equiv). React at room temperature overnight and monitor the reaction by LCMS until completion. Pour the reaction mixture into 500 mL of ice water, extract with ethyl acetate, collect and combine the organic phases, wash with saturated sodium chloride solution, dry, and concentrate. Perform column chromatography (ethyl acetate: petroleum ether = 0 - 20%, visualized by potassium permanganate), 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 diethyl ether (400 mL) to a 500 mL reaction flask. Cool the mixture to 0 °C and slowly add lithium aluminum hydride (7.21 g, 190.049 mmol, 1.5 equiv). React at 0 °C for 30 min and monitor the completion of the reaction by LCMS. At 0 °C, add 7.2 mL of water, 7.2 mL of 15% aqueous sodium hydroxide solution, 21.6 mL of water, and 36 g of anhydrous sodium sulfate to the reaction mixture. Filter, concentrate, and perform column chromatography (ethyl acetate:petroleum ether = 20% - 40%, visualized with potassium permanganate). Collect the target fraction and concentrate to obtain Ⅴ-2, 23.5 g, yield: 91.41%.

[0096] Step 3:

[0097] Method 1: Add diethyl ether (125 mL) and Ⅴ-2 (25 g, 122.388 mmol, 1 equiv) to a 500 mL reaction flask. Cool the mixture to 0 °C and slowly dropwise add boron trifluoride diethyl etherate (17.74 g, 122.388 mmol, 1 equiv, 48%). React at 0 °C for 1 h and monitor the completion of the reaction by LCMS and TLC. Slowly add saturated aqueous sodium bicarbonate solution (125 mL) to the reaction mixture, extract with diethyl ether, collect and combine the organic phases, wash with saturated sodium chloride solution, dry, concentrate, and perform column chromatography (ethyl acetate:petroleum ether = 15% - 20%, visualized with potassium permanganate). Concentrate to obtain pale yellow oily Ⅰ-2, 23.3 g, yield: 91.27%. Purity: 97.93%. 1 H NMR (300 MHz, DMSO-d6) δ 7.36–7.28 (m, 2H), 7.25–7.18 (m, 1H), 7.16–7.09 (m, 2H), 4.58 (t, J = 5.4 Hz, 1H), 3.74 (d, J = 8.4 Hz, 4H), 3.27 (d, J = 5.5 Hz, 2H), 1.91 (d, J = 2.0 Hz, 4H).

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

[0099] Method 2: Add V-2 (500 mg, 2.448 mmol, 1 equiv), anhydrous diethyl ether (8 mL) to a 40 mL sample bottle. Cool the mixture to 0 °C, add boron trifluoride diethyl etherate (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. At 0 °C, slowly add 10 mL of saturated sodium bicarbonate solution to the reaction solution. Extract with diethyl ether, collect and combine the organic phases, wash with saturated sodium chloride, dry, concentrate by column chromatography (ethyl acetate: petroleum ether = 15%-25%, potassium permanganate coloring), and concentrate to obtain 423 mg of light yellow oily I-2. Yield: 83.50%. Purity: 98.70%. 1 H NMR (300 MHz, DMSO-d6) δ 7.36–7.28 (m, 2H), 7.25–7.18 (m, 1H), 7.16–7.09 (m, 2H), 4.58 (t, J = 5.4 Hz, 1H), 3.74 (d, J = 8.4 Hz, 4H), 3.27 (d, J = 5.5 Hz, 2H), 1.91 (d, J = 2.0 Hz, 4H).

[0100] The total yield of 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane prepared according to Method 2 is 51.7%. The 1 H NMR spectrum of compound I-2 is as 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 flask. Cool the mixture to 0 °C, and dropwise add a tetrahydrofuran solution of sodium hexamethyldisilazide (555 mL, 2 mol / L, 3 equiv). React at room temperature overnight. Monitor the complete reaction 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, and perform column chromatography (ethyl acetate: petroleum ether = 8%-20%, potassium permanganate coloring). Collect the target fraction and concentrate to obtain 54.6 g of yellow liquid IV-3. Yield: 90.69%.

[0105] Step 2:

[0106] Add dichloromethane (200 mL) and Ⅳ-3 (10 g, 61.267 mmol, 1 equiv) to a 500 mL reaction flask. Cool the mixture to -78 °C and slowly add diisobutylaluminum hydride (a 1 mol / L solution in n-hexane, 73.6 mL, 1.2 equiv). Slowly warm the reaction mixture to 0 °C and stir for 2 h. Monitor the reaction by LCMS until completion. Cool the reaction mixture to 0 °C, add 2.9 mL of water, 2.9 mL of 15% aqueous NaOH solution, and 7.3 mL of water. Stir at room temperature for 15 min, then add anhydrous sodium sulfate, filter, collect the filtrate, and perform column chromatography (ethyl acetate:petroleum ether = 7.5%-21%, visualized with potassium permanganate). Collect the target fraction and concentrate to obtain a pale 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 diethyl ether (140 mL) to a 500 mL reaction flask. Cool the mixture 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 monitor the reaction by LCMS until completion. Cool the reaction mixture to 0 °C, add 1.6 mL of water, 1.6 mL of 15% aqueous NaOH solution, and 4.8 mL of water. Then add anhydrous sodium sulfate, filter, collect the filtrate, and concentrate to obtain an off-white oily substance Ⅴ-3, 6.9 g, yield: 88.27%.

[0109] Step 4:

[0110] Add Ⅴ-3 (6.9 g, 41.014 mmol, 1 equiv) and diethyl ether (70 mL) to a 250 mL reaction flask. Cool the mixture to 0 °C and slowly add boron trifluoride diethyl etherate (5.82 g, 19.687 mmol, 0.48 equiv, 48%). React at 0 °C for 1 h and monitor the reaction by LCMS until completion. Slowly add saturated aqueous sodium bicarbonate solution (100 mL) to the reaction mixture, extract with diethyl ether, collect and combine the organic phases, wash with saturated sodium chloride solution, dry, concentrate, and perform column chromatography (ethyl acetate:petroleum ether = 8%-15%, visualized with potassium permanganate). Collect the target fraction and concentrate to obtain a colorless oily substance Ⅰ-3, 5.4 g, yield: 77.66%. Purity: 99.23%. 1 H NMR (400 MHz, Chloroform-d) δ 3.64 (d, J = 1.4 Hz, 4H), 3.24 (s, 2H), 1.26 (d, J = 1.3 Hz, 4H), 0.48 (tt, J = 8.3, 5.2 Hz, 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 is 45.2%. The 1 1H NMR spectrum of Compound I-3 is as 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 flask. Cool the temperature to 0 °C, and 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 by LCMS until it is complete. 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, and perform 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) and IV-4 (21.8 g, 78.318 mmol, 1 equiv) to a 500 mL reaction flask. Cool the temperature to -78 °C, and slowly add diisobutylaluminum hydride (1 mol / L n-hexane solution, 156 mL, 2.0 equiv). Slowly warm up to 0 °C and stir for 2 h. Monitor the reaction by LCMS until it is complete. Cool the temperature to 0 °C, add 5.8 mL of water, 5.8 mL of 15% aqueous sodium hydroxide solution, and 10 mL of water. Stir at room temperature for 15 min, then add anhydrous sodium sulfate, filter, collect the filtrate, and perform column chromatography (ethyl acetate: petroleum ether = 7.5% - 21%, potassium permanganate color development). Collect the target fraction and concentrate to obtain a pale 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 diethyl ether (250 mL) to a 500 mL reaction flask. Cool the mixture 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 monitor the completion of the reaction by LCMS. Cool the reaction mixture to 0 °C, add 1.2 mL of water, 1.2 mL of 15% sodium hydroxide solution, then add 3.6 mL of water, and then add anhydrous sodium sulfate. Filter the mixture, collect the filtrate, and concentrate it to obtain a white oily substance Ⅴ-4, 8.778 g, with a yield of 91.74%.

[0120] Step 4:

[0121] Add Ⅴ-4 (8.7 g, 30.702 mmol, 1 equiv) and diethyl ether (80 mL) to a 250 mL reaction flask. Cool the mixture to 0 °C and slowly add boron trifluoride diethyl etherate (1.82 g, 6.140 mmol, 0.2 equiv, 48%). React at 0 °C for 1 h and monitor the completion of the reaction by LCMS. Slowly add saturated aqueous sodium bicarbonate solution (100 mL) to the reaction mixture, extract with diethyl ether, collect and combine the organic phases, wash with saturated sodium chloride solution, dry, concentrate, and perform column chromatography (ethyl acetate: petroleum ether = 30% - 35%, developed with potassium permanganate). Collect the target fraction and concentrate to obtain a colorless oily substance Ⅰ-4, 6.79 g, with a yield of 78.05% and a purity of 95.24%. 1 H NMR (400 MHz, Chloroform-d) δ 3.90–3.82 (m, 4H), 3.70 (dd, J = 8.7, 5.7 Hz, 2H), 3.65 (s, 2H), 3.47 (s, 2H), 2.38 (tt, J = 8.5, 5.7 Hz, 1H), 1.76 (d, J = 2.6 Hz, 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 is 21.9%. The 1 H NMR spectrum of compound I-4 is as Figure 4 shown.

[0123] Example 5

[0124]

[0125] Step 1:

[0126] Add tetrahydrofuran (500 mL), II (58.51 g, 239.868 mmol, 1 equiv), and III-5 (53.8 g, 239.853 mmol, 1 equiv) to a 1000 mL reaction flask. Cool the mixture to 0 °C and slowly add a solution of sodium hexamethyldisilazide (361 mL, 2 mol / L, 12.300 mmol, 3 equiv) in tetrahydrofuran. React at room temperature overnight and monitor the reaction completion 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 solution, dry, concentrate, and perform column chromatography (ethyl acetate: petroleum ether = 28%-50%, visualized with potassium permanganate). Collect the target fractions 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 mmol, 1 equiv) to a 1000 mL reaction flask. Cool the mixture to -78 °C and slowly add diisobutylaluminum hydride (1 mol / L solution in n-hexane, 470 mL, 0.046 mmol, 1.2 equiv). Slowly warm the mixture to 0 °C and stir for 2 h. Monitor the reaction completion by LCMS. Cool the mixture to 0 °C and slowly add 18 mL of water, 18 mL of 15% aqueous sodium hydroxide solution, and 40 mL of water. Stir at room temperature for 15 min, then add anhydrous sodium sulfate, filter, collect the filtrate, and perform column chromatography (ethyl acetate: petroleum ether = 30%-50%, visualized with potassium permanganate). Collect the target fractions and concentrate to obtain a pale 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 diethyl ether (400 mL) to a 1000 mL reaction flask. Cool the mixture 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 monitor the reaction completion by LCMS. Cool the mixture to 0 °C, add 3 mL of water, 3 mL of 15% aqueous sodium hydroxide solution, 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), diethyl ether (150 mL) to a 250 mL reaction flask, cool the temperature to 0 °C, and slowly add boron trifluoride diethyl etherate (3.08 g, 10.404 mmol, 0.2 equiv, 48%). React at 0 °C for 1 h and monitor by LCMS until the reaction is complete. Slowly add saturated aqueous sodium bicarbonate solution (200 mL) to the reaction solution, extract with diethyl ether, collect and combine the organic phases, wash with saturated sodium chloride, dry, concentrate, and perform column chromatography (ethyl acetate: petroleum ether = 26.9% - 40%, potassium permanganate color development). Collect the target fraction and concentrate to obtain colorless oily substance I-5, 13.2 g, yield: 77.99%. Purity: 95.71%. 1 H NMR (400 MHz, Chloroform-d) δ 4.15 (d, J = 13.0 Hz, 2H), 3.77 (d, J = 11.6 Hz, 4H), 3.43 (s, 2H), 2.58 (t, J = 12.8 Hz, 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, 4.3 Hz, 2H).

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

[0134] Example 6

[0135]

[0136] Step 1:

[0137] Add a solution of compound II (10 g, 40.996 mmol, 1 equiv) in N,N-dimethylformamide (200 mL) to a 500 mL reaction flask, add III-6 (4.64 g, 40.996 mmol, 1 equiv), slowly add potassium carbonate (11.33 g, 81.992 mmol, 2 equiv), and react at room temperature overnight. Monitor the reaction by GCMS until it is complete. 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, concentrate; perform column chromatography (ethyl acetate: petroleum ether = 15% - 16%, potassium permanganate color development), collect the target fraction, and obtain light yellow solid IV-6, 2 g, yield: 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 flask. Cool the mixture to 0 °C, and add sodium borohydride (77.51 mg, 2.048 mmol, 2 equiv) portionwise. After the addition, stir the reaction mixture at room temperature overnight, and monitor the completion of the reaction by GCMS. Cool the reaction system to 0 °C, slowly add saturated sodium bicarbonate solution (4 mL) to quench the reaction, stir at room temperature for 4 h, filter by suction, concentrate the filtrate under reduced pressure to remove methanol, extract with ethyl acetate, collect and combine the organic phases, wash with saturated sodium chloride solution, dry, and concentrate to obtain 130 mg of white solid Ⅴ-6, with a yield of 72.15%.

[0140] Step 3:

[0141] Add tetrahydrofuran (3 mL) to an 8 mL reaction flask, cool to 0 °C, add Ⅴ-6 (130 mg, 0.849 mmol, 1 equiv), and slowly add boron trifluoride diethyl etherate (123.01 mg, 0.408 mmol, 0.48 equiv, 48%). React at 0 °C for 1 h, and monitor the completion of the reaction by LCMS. Slowly add saturated aqueous sodium bicarbonate solution (2 mL) to the reaction solution, extract with ethyl acetate, collect and combine the organic phases, wash with saturated sodium chloride solution, dry, and concentrate to obtain 100 mg of white solid Ⅰ-6, with a yield of 76.92%. 1 H NMR (400 MHz, Chloroform-d) δ 4.04 (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 is 13.9%. The 1 H NMR spectrum of compound I-6 is as Figure 6 shown.

[0143] Example 7

[0144]

[0145] Step 1:

[0146] Add N,N-dimethylformamide (270 mL) to a 1-L three-necked flask, cool down to 0 °C, slowly add sodium hydride (14.76 g, 2 equiv) while maintaining the temperature at 0 °C, dropwise add Compound III-7 (62.05 g, 2.1 equiv). After addition, restore the temperature to room temperature for reaction, then raise the temperature to 60 °C, slowly dropwise add Compound II (45 g, 1 equiv). After addition, slowly raise the temperature to 120 °C and react overnight at 120 °C. Monitor by LCMS. Cool the reaction solution to room temperature, pour it into ice water, add a small amount of ammonium chloride, extract with 400 mL of ethyl acetate, then backwash with 200 mL of water. Retain and dry the organic phase, rotary evaporate to obtain 60 g of crude product, purify by column chromatography (petroleum ether:ethyl acetate = 5%-6% to obtain the product), (TLC: petroleum ether / ethyl acetate = 5 / 1, developed with potassium permanganate), rotary evaporate to obtain a light yellow transparent liquid Compound VI-7 (22.93 g, yield 85.6%).

[0147] Step 2:

[0148] Dissolve Compound IV-7 (5.49 g, 22.661 mmol, 1 equiv) in dimethyl sulfoxide (21.6 mL), add sodium chloride (1.32 g, 22.587 mmol, 1 equiv) at room temperature, then add water (1 mL, 55.509 mmol, 2.45 equiv). Slowly raise the temperature to 160 °C and react for 24 hours. Monitor by GCMS. Cool to room temperature, drop the reaction solution into 30 mL of ice water, extract three times with a solution of 100 mL of ethyl acetate:petroleum ether = 1:2, dry over anhydrous sodium sulfate, concentrate, and perform column chromatography (petroleum ether:ethyl acetate = 10%-15%) 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 down 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 dropwise add the ether solution of Compound IV'-7 (2.8 g dissolved in 30 mL of anhydrous ether). After dropping, slowly restore the temperature to room temperature for reaction. After reacting at room temperature for 2 hours, monitor the reaction by TLC until it is complete. Cool to about 0 °C, slowly dropwise add water (1.54 g, 5 eq), stir for half an hour, add anhydrous sodium sulfate for drying, filter, and concentrate to obtain Compound V-7 (1.6 g, yield 72.1%).

[0151] Step 4:

[0152] To a 100 mL three-necked flask, add compound Ⅴ-7 (2.1 g, 16.384 mmol, 1 equiv), anhydrous diethyl ether (30 mL), cool down to 0 °C, add boron trifluoride diethyl etherate (2.33 g, 16.384 mmol, 1 equiv), maintain the reaction at 0 °C for two hours, monitor the reaction completion by TLC, slowly add 20 mL of saturated NaHCO 3 aqueous solution to quench the reaction, separate the layers, extract the aqueous phase with diethyl ether three times (50 mL each time), combine the organic phases, dry over anhydrous sodium sulfate and concentrate, perform column chromatography (n-pentane:ethyl acetate = 50%-54%), visualize with potassium permanganate, and obtain compound Ⅰ-7 (1.05 g, yield 48.0%). 1 1H NMR (300 MHz, Chloroform-d) δ 3.95 (d, J = 2.2 Hz, 2H), 3.88 (s, 2H), 3.41 (s, 2H), 2.38 - 2.32 (m, 1H), 1.93 (td, J = 6.2, 2.5 Hz, 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 is 19.8%. The 1 1H NMR spectrum of compound I-7 is as Figure 7 shown.

[0154] Taking Example 8 as an example, it shows 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, using the following route, with the compound 279 described on page 222 of WO2024 / 015497A1 and the compound Ⅰ-7 obtained in Example 7 of the present invention as raw materials, prepare the TYK2 inhibitor (i.e., the compound 324 on page 448 of WO2024 / 015497A1).

[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] Add V-2 (500 mg, 2.448 mmol, 1 equiv), hydrochloric acid (20%, 40 mL) to a 250 mL single-necked flask, reflux at 100 °C for 4 h, and monitor the complete reaction by LCMS. At 0 °C, slowly add 15% aqueous sodium hydroxide solution (60 mL) to the reaction solution, extract with diethyl ether, collect and combine the organic phases, wash with saturated sodium chloride, dry, concentrate by column, column chromatography (ethyl acetate: petroleum ether = 15% - 23%, potassium permanganate color development), concentrate to obtain pale yellow oily product I-2, 381 mg, yield: 75.25%. Purity: 95.05%. 1 HNMR (300 MHz, DMSO-d6) δ 7.36–7.28 (m, 2H), 7.25–7.18 (m, 1H), 7.16–7.09 (m, 2H), 4.58 (t, J = 5.4 Hz, 1H), 3.74 (d, J = 8.4 Hz, 4H), 3.27 (d, J = 5.5 Hz, 2H), 1.91 (d, J = 2.0 Hz, 4H).

[0162] Comparative Example 2

[0163]

[0164] Add V-2 (500 mg, 2.448 mmol, 1 equiv), sulfuric acid (6N, 40 mL) to a 250 mL single-necked flask, reflux at 100 °C for 4 h, and monitor the complete reaction by LCMS. At 0 °C, slowly add 15% aqueous sodium hydroxide solution (64 mL) to the reaction solution, extract with diethyl ether, collect and combine the organic phases, wash with saturated sodium chloride, dry, concentrate by column, column chromatography (ethyl acetate: petroleum ether = 15% - 22%, potassium permanganate color development), concentrate to obtain pale yellow oily product I-2, 386 mg, yield: 75.65%. Purity: 94.27%. 1 HNMR (300 MHz, DMSO-d6) δ 7.36–7.28 (m, 2H), 7.25–7.18 (m, 1H), 7.16–7.09 (m, 2H), 4.58 (t, J = 5.4 Hz, 1H), 3.74 (d, J = 8.4 Hz, 4H), 3.27 (d, J = 5.5 Hz, 2H), 1.91 (d, J = 2.0 Hz, 4H).

[0165] Comparing with Comparative Example 1, Comparative Example 2 and Method 2 of Step 3 in Example 2 of the present invention, it can be seen that under the same reaction scale of 500 mg, the yield of product I-2 obtained by Method 2 of Step 3 in Example 2 of the present invention is 83.50%, which is significantly higher than 75.25% and 75.65% of Comparative Examples 1 and 2; the purity of product I-2 obtained by Method 2 of Step 3 in Example 2 of the present invention is 98.70%, which is significantly higher than 95.05% and 94.27% of 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 for catalytic synthesis of 3-oxabicyclo[3.1.1]heptane compounds with boron trifluoride etherate as the catalyst in the present invention are significantly improved.

[0166] In summary, the present invention provides a 1,5-disubstituted-3-oxabicyclo[3.1.1]heptane and its synthesis method. Compared with the methods 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 generality, strong functional group compatibility, mild reaction conditions, higher yield, is suitable for industrial scale-up production, and the obtained product can be used as a high-value intermediate for further 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 is selected from hydrogen, cyano, unsubstituted 3-6 membered saturated cycloalkyl, b1 Substituted 3-6 membered saturated nitrogen heterocyclic group, unsubstituted phenyl; R b1 is selected from amino protecting groups.

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

3. 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.

4. The method according to claim 3, characterized in that: The molar ratio of the compound V to the catalyst is 1:0.2-1; the solvent of the reaction is tetrahydrofuran, 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, 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.

10. The method according to claim 9, characterized in that 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.

Images