Gem-difluoro-2-oxabicyclo [2.1. 1] hexane compound and preparation method thereof

Abstract

The invention discloses a gem-difluoro-2-oxabicyclo [2.1. 1] hexane compound and a preparation method thereof, 1, 1-difluoro-3-(vinyloxy) prop-1-ene and 3, 3-difluoro-3-(vinyloxy) prop-1-ene are used as initial raw materials, under the catalysis of a photocatalyst and the irradiation of visible light, intramolecular cycloaddition is carried out to obtain 6, 6-difluoro-2-oxabicyclo [2.1. 1] hexane and 3, 3-difluoro-3-(vinyloxy) prop-1-ene, and the gem-difluoro-2-oxabicyclo [2.1. 1] hexane compound is synthesized through the intramolecular cycloaddition of 6, 6-difluoro-2-oxabicyclo [2.1. 1] hexane. The invention relates to a 1, 3-difluoro-2-oxabicyclo [2.1. 1] hexane product. According to the gem-difluoro-2-oxabicyclo [2.1. 1] hexane compound provided by the invention, two different types of electron isosteres (2-oxabicyclo [2.1. 1] hexane and difluoromethylene) are combined together, so that a brand new mixed biological electron isostere is obtained, and a new structural unit is provided for the design and synthesis of drug molecules.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic chemical synthesis, and particularly relates to a kind of gem-difluoro 2-oxabicyclo[2.1.1]hexane compound and a preparation method thereof. BACKGROUND

[0002] As bioisosteric of benzene ring, bridged ring compounds (such as 1,3-bicyclo[1.1.1]pentane (BCP), bicyclo[2.1.1]hexane (BCH), bicyclo[3.1.1]heptane (BCHep)) show important value in drug molecule design and structure optimization. Among them, bicyclo[2.1.1]hexane (BCH) is of great concern because it can simulate different substitution types of aromatic hydrocarbons. In recent years, the introduction of heteroatoms (such as oxygen, nitrogen atoms) into the BCH skeleton not only enhances the water solubility of the compound, but also has the potential to improve drug efficacy, which has become an important class of BCH derivatives. Studies have shown that 2-oxabicyclo[2.1.1]hexane (2-oxa-BCH) is superior to traditional ether substituents in terms of biological activity, and can also improve microsomal stability and reduce efflux effect (A. Denisenko et al., Nat. Chem. 2023, 15, 1155-1163).

[0003] The introduction of fluorine atoms into drug molecules is a common modification strategy to improve metabolic stability, lipid solubility, and other properties. Therefore, the development of mixed bioisosteric compounds that combine the characteristics of bridged ring skeletons and fluorine atoms, i.e., the introduction of fluorine atoms or fluorine-containing groups into bridged ring compounds (such as oxabicyclo[2.1.1]hexane), has significant prospects. However, the synthesis of such structures still faces challenges, and existing methods mainly focus on introducing fluorine-containing alkyl substituents on 2-oxabicyclo[2.1.1]hexane, with representative examples such as:

[0004] Firstly, as disclosed in the method of document 1 (V. V. Levterov et al., Angew. Chem. Int. Ed. 2020, 59, 7161-7167), using nucleophilic substitution of fluoride ions, 1-hydroxymethyl-2-oxabicyclo[2.1.1]hexane can be converted to 1-fluoromethyl-2-oxabicyclo[2.1.1]hexane, and the specific reaction process is shown as follows:

[0005]

[0006] Secondly, as disclosed in the method of document 2 (A. A. Homon et al., Eur. J. Org. Chem. 2021, 6580-6590), using fluorine-substituted methylene cyclobutane as the starting material, the corresponding fluorine-containing oxabicyclo[2.1.1]hexane compound is obtained by cyclization reaction, and the specific reaction process is as follows:

[0007]

[0008] Although these methods successfully constructed fluorine-containing 2-oxabicyclo[2.1.1]hexane compounds, they are not suitable for directly introducing fluorine atoms into the bridged ring skeleton. In view of the unique physicochemical properties of bridged ring compounds and fluorine-containing compounds and the wide application prospect in new drug research and development, it is of great value to develop new fluorine-containing 2-oxabicyclo[2.1.1]hexane synthesis blocks which are easy to be derivatized.

[0009] To this end, the present application provides a novel gem-difluoro 2-oxabicyclo[2.1.1]hexane compound, aiming to provide a simple and convenient method for synthesizing target molecules containing the key fragment. SUMMARY

[0010] This section is intended to summarize some aspects of the embodiments of the present application and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the abstract and title of the specification to avoid obscuring the purpose of this section, the abstract and the title, and such simplifications or omissions cannot be used to limit the scope of the present application.

[0011] In view of the limitation of the existing structure type of fluorine-containing 2-oxabicyclo[2.1.1]hexane compounds, the present application provides a gem-difluoro 2-oxabicyclo[2.1.1]hexane compound and a synthesis method thereof. This kind of compound ingeniously combines gem-difluoromethylene and oxabridged ring compounds, two different isoelectronic bodies, to meet the needs of specific biological activity.

[0012] The present application provides a compound represented by general formula (I, II):

[0013]

[0014] wherein, R 1 is independently selected from 4-phenylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 4-vinylphenyl, naphthalen-2-yl, 4-acetylphenyl, 4-chlorophenyl; R 2 is independently selected from hydrogen, benzyl; R 3 is independently selected from ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, N-methyl-N-phenylcarbamoyl; R 4 is independently selected from 4-phenylphenyl, 4-ethoxycarbonylphenyl, 4-(N,N-dimethylcarbamoyl)phenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-methylsulfonylphenyl, 3-methoxy-4-fluorophenyl, 4-bromophenyl, naphthalen-2-yl, quinolin-3-yl; R 5 is independently selected from hydrogen, phenyl, naphthalen-2-yl; R6 independently selected from ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, N-methyl-N-phenylcarbamoyl, phenyl.

[0015] The gem-difluoro 2-oxabicyclo[2.1.1]hexane compounds of the present application are prepared using the following route:

[0016]

[0017] Using 1,1-difluoro-3-(vinyloxy)prop-1-ene (1) and 3,3-difluoro-3-(vinyloxy)prop-1-ene (2) as starting materials, under the catalysis of a photocatalyst and visible light irradiation, intramolecular cycloaddition can obtain 6,6-difluoro-2-oxabicyclo[2.1.1]hexane (3) and 3,3-difluoro-2-oxabicyclo[2.1.1]hexane (4) products.

[0018] The compounds synthesized in the present application can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination of the specific embodiments with other chemical synthetic methods, and the equivalent replacement methods well known to those skilled in the art, and preferred embodiments include but are not limited to the embodiments of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0019] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings needed in the embodiment description will be briefly introduced below. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can also be obtained by those skilled in the art without creative labor. Among them:

[0020] Figure 1 NMR hydrogen spectrum of 3a (main diastereoisomer) in the embodiment of the present application.

[0021] Figure 2 NMR fluorine spectrum of 3a (main diastereoisomer) in the embodiment of the present application.

[0022] Figure 3 NMR carbon spectrum of 3a (main diastereoisomer) in the embodiment of the present application.

[0023] Figure 4 NMR hydrogen spectrum of 4a (main diastereoisomer) in the embodiment of the present application.

[0024] Figure 5 NMR fluorine spectrum of 4a (main diastereoisomer) in the embodiment of the present application.

[0025] Figure 6This is the carbon NMR spectrum of 4a (the main diastereomer) in the present invention. Detailed Implementation

[0026] The present application will be described in further detail below with reference to the embodiments, but the implementation of the present application is not limited thereto.

[0027] Example 1: Synthesis of ethyl 4-(4-phenylphenyl)-6,6-difluoro-2-oxabicyclo[2.1.1]hexane-5-carboxylate (3a)

[0028]

[0029] In an inert gas atmosphere, ethyl (E)-3-[2-(4-phenylphenyl)-3,3-difluoroallyloxy]acrylate 1a (69 mg, 0.2 mmol) and photocatalyst (Ir(dF3(CF3)Ppy2(dtbbpy)PF6) (2 mg, 0.002 mmol)) were sequentially added to DCM (1 mL) to obtain a mixture, wherein the molar ratio of 1a to photocatalyst was 1:0.01;

[0030] The mixture was reacted for 6 hours at room temperature under an inert gas atmosphere and irradiated with a 20-watt blue light (wavelength 456 nm) LED lamp. After the reaction, the reaction solution was diluted with water (10 mL), then extracted with ethyl acetate (10 mL × 2), the organic phases were combined, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated to dryness to obtain a crude product. Column chromatography was used to separate ethyl 4-(4-phenylphenyl)-6,6-difluoro-2-oxabicyclo[2.1.1]hexane-5-carboxylate 3a (68 mg, 0.196 mmol), a white solid with a yield of 97%.

[0031] (Diastereomer ratio) 4:1. The main enantiomer analysis data are as follows: 1 H NMR (400MHz, CDCl3): δ7.64-7.57 (m, 4H), 7.51-7.40 (m, 4H), 7.39-7.34 (m, 1H), 4.87 (dd, J=1.9, 0.8Hz, 1H), 4.25 (dt, J=6.7, 1.2Hz, 1H), 4.18-4.06 (m, 3H), 3.33 (dd, J=17.7, 2.2Hz, 1H), 1.12 (t, J=7.1Hz, 3H). 19 F NMR (376MHz, CDCl3): δ-107.04 (dd, J=173.6, 17.5Hz), -144.33 (d, J=173.3Hz). 13 C NMR (100MH) z, CDCl3): δ 167.2, 141.3, 140.7, 128.9, 127.8, 127.6, 127.3, 127.2, 120.5 (dd, J = 304.9, 280.3 Hz), 80.8 (dd, J = 22.1, 20.7 Hz), 74.1 (dd, J = 3.8, 3.8 Hz), 63.2 (dd, J = 18.2. 18.2 Hz), 61.2, 51.5 (dd, J = 13.5, 2.5 Hz), 13.9. HRMS (ESI, m / z): calcd for C 12 H 19 F2O3, [M+H] + : 345.1297, found: 345.1294.

[0032] Example 2: Synthesis of tert-butyl 4-(4-phenylphenyl)-6,6-difluoro-2-oxabicyclo[2.1.1]hexane-5-carboxylate (3b)

[0033]

[0034] tert-butyl (E)-3-[2-(4-phenylphenyl)-3,3-difluoroallyloxy]acrylate 1b (74 mg, 0.2 mmol) and a photo-catalyst (Ir(dF3(CF3)PPy2(dtbbpy)PF6) (2 mg, 0.002 mmol) were added into DCM (1 mL) successively to give a mixture, wherein the molar ratio of 1b to photo-catalyst was 1:0.01;

[0035] The mixture was irradiated under inert gas atmosphere at 20 watt blue light (wavelength 456 nm) LED lamp and reacted at room temperature for 6 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL) and then extracted with ethyl acetate (10 mL x 2), the organic phase was combined, washed with saturated brine, dried over sodium sulfate, filtered and concentrated to dryness to give a crude product, which was separated by column chromatography to give tert-butyl 4-(4-phenylphenyl)-6,6-difluoro-2-oxabicyclo[2.1.1]hexane-5-carboxylate 3b (65 mg, 0.176 mmol), white solid, yield 88%, dr 2:1. The main diastereomer was analyzed as follows: 1 H NMR (400 MHz, CDCl3): δ 7.63-7.56 (m, 4H), 7.55-7.50 (m, 2H), 7.50-7.40 (m, 2H), 7.40-7.34 (m, 1H), 4.80-4.73 (m, 1H), 4.37-4.34 (m, 1H), 4.32-4.24 (m, 1H), 3.32 (ddd, J = 5.6, 4.1, 1.5 Hz, 1H), 1.50 (s, 9H).19 F NMR (376 MHz, CDC13): δ -118.73 (dd, J = 170.1, 4.3 Hz), -149.25 (d, J = 170.3, 5.8 Hz). 13 C NMR (100 MHz, CDC13): δ 166.7 (d, J = 10.2 Hz), 141.5, 140.6, 129.4, 128.9, 127.9, 127.6, 127.6, 127.2, 118.6 (dd, J = 306.9, 277.4 Hz), 82.5, 80.7 (dd, J = 22.6, 20.7 Hz), 68.7 (dd, J = 3.7, 3.7 Hz), 62.3 (dd, J = 18.1, 18.1 Hz), 47.8 (d, J = 13.3 Hz), 28.2. HRMS (ESI, m / z): calcd for C 22 H 23 F2O3, [M+H] + : 373.1610, found: 331.1619.

[0036] Examples 3 to 13 are substantially the same as Example 1, 2, except that:

[0037] Table 1 Examples 3 to 13

[0038]

[0039]

[0040]

[0041] Example 14: Synthesis of ethyl 4-([l,l'-biphenyl]-4-yl)-6,6-difluoro-2-oxabicyclo[2.1.1]hexane-5-carboxylate (4a)

[0042]

[0043] (E)-3-[2-(4-phenylphenyl)-l,l-difluoroallyloxy]acrylic acid ethyl ester 2a (69 mg, 0.2 mmol) and a photo-catalyst (Ir(dF3(CF3)ppy2(dtbbpy)PF6) (2 mg, 0.002 mmol) were added to DCM (1 mL) to give a mixture, wherein the molar ratio of 2a to photo-catalyst was 1:0.01;

[0044] The mixture was irradiated with a 20-watt blue light (wavelength 456 nm) LED lamp under an inert gas atmosphere and reacted at room temperature for 6 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL) and then extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated to dryness to obtain a crude product, which was separated by column chromatography to obtain 4-(4-phenylphenyl)-6,6-difluoro-2-oxabicyclo[2.1.1]hexane-5-carboxylic acid ethyl ester 4a (68 mg, 0.198 mmol), white solid, yield 99%, dr 6:1. The main diastereomer was analyzed as follows: 1 H NMR (400 MHz, CDCl3): δ 7.72-7.59 (m, 6H), 7.50-7.42 (m, 2H), 7.41-7.35 (m, 1H), 5.00-4.93 (m, 1H), 4.32-4.23 (m, 2H), 3.33 (d, J = 1.5 Hz, 1H), 2.70-2.61 (m, 1H), 2.30 (dd, J = 8.4, 1.1 Hz, 1H), 1.33 (t, J = 7.1 Hz, 3H). 19 F NMR (376 MHz, CDCl3): δ -81.91 (d, J = 136.7 Hz), -82.91 (d, J = 136.7 Hz). 13 C NMR (100 MHz, CDCl3): δ 167.4, 141.6, 140.6, 131.0, 129.2 (dd, J = 264.1, 264.1 Hz), 129.0, 128.4, 127.7, 127.3, 127.3, 62.2 (dd, J = 27.8, 25.0 Hz), 61.4, 59.7 (d, J = 2.6 Hz), 44.2 (d, J = 2.3 Hz), 14.2. HRMS (ESI, m / z): calcd for C 20 H 19 F2O3[M+H] + : 345.1297, found: 345.1288.

[0045] Examples 15 to 28 are substantially the same as Example 14, except that:

[0046] Table 2 Examples 15 to 28

[0047]

[0048]

[0049] In order to make the above objectives, features and advantages of the present application more apparent, the specific embodiments of the present application will be described in detail below with reference to the embodiments in the specification.

[0050] In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present application. However, it will be apparent to one skilled in the art that the present application can be practiced without the specific details and other implementations can be employed. Thus, the present application is not intended to be limited to the particular implementations described herein, which can be implemented independently of each other. The present description should be understood as but one possible implementation thereof and the general principles set forth below can be applied to other implementations and applications without departing from the scope of the present application.

[0051] Second, the "one embodiment" or "an embodiment" as referred to herein means a specific feature, structure, characteristic, or combination of features and / or characteristics described in this specification and which can be included in at least one implementation of the present application. The appearances of "in one embodiment" or "in an embodiment" in various places in the specification are not necessarily referring to the same embodiment nor are separate or alternative implementations mutually exclusive of other implementations.

[0052] The present application first provides a gem-difluoro 2-oxabicyclo[2.1.1]hexane, which is a brand new fluorine-containing bridged ring compound, and has short synthesis steps, simple reaction operation and post-treatment.

[0053] It should be noted that the above examples are only used to illustrate the technical solutions of the present application and are not limiting. Although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified or replaced by equivalents without departing from the spirit and scope of the present application, and they should be covered in the scope of the claims of the present application.

Claims

1. A 6,6-difluoro-2-oxabicyclo[2.1.1]hexane compound (I), characterized in that: The chemical structure of the compound is as follows: Among them, R 1 Independently selected from 4-phenylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 4-vinylphenyl, naphth-2-yl, 4-acetylphenyl, 4-chlorophenyl; R 2 Independently selected from hydrogen and benzyl; R 3 It is independently selected from ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, and N-methyl-N-phenylcarbamoyl.

2. A 3,3-difluoro-2-oxabicyclo[2.1.1]hexane compound, characterized in that: The chemical structure of the compound is as follows: Among them, R 4 Independently selected from 4-phenylphenyl, 4-ethoxycarbonylphenyl, 4-(N,N-dimethylcarbamoyl)phenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-methanesulfonylphenyl, 3-methoxy-4-fluorophenyl, 4-bromophenyl, naphth-2-yl, quinoline-3-yl; R 5 Independently selected from hydrogen, phenyl, and naphth-2-yl; R 6 It is independently selected from ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, N-methyl-N-phenylcarbamoyl, and phenyl.

3. The 6,6-difluoro-2-oxabicyclo[2.1.1]hexane compound of claim 1, comprising the following key steps: 2.1.1] Process for the preparation of hexane-based compounds, characterized in that: The 1,1-difluoro-3-(vinyloxy)prop-1-ene compound and the photocatalyst are sequentially added to the solvent under an inert gas atmosphere to obtain a mixture, wherein the molar ratio of the 1,1-difluoro-3-(vinyloxy)prop-1-ene compound to the photocatalyst is 1:0.

01. The above mixture is reacted at room temperature under LED lamp irradiation, and the 6,6-difluoro-2-oxabicyclo[2.1.1]hexane compound is collected from the reaction solution.

4. The 3,3-difluoro-2-oxabicyclo[2.1.1]hexane compound of claim 2, comprising the following key steps: The 3,3-difluoro-3-(vinyloxy)prop-1-ene and the photocatalyst are sequentially added to the solvent under an inert gas atmosphere to obtain a mixture, wherein the molar ratio of the 3,3-difluoro-3-(vinyloxy)prop-1-ene to the photocatalyst is 1:0.

01. The above mixture is reacted at room temperature under LED lamp irradiation, and the 3,3-difluoro-2-oxabicyclo[2.1.1]hexane compound is collected from the reaction solution. 2.1.1] Process for the preparation of hexane-based compounds, characterized in that:

5. The 6,6-difluoro-2-oxabicyclo[2.1.1]hexane and 3,3-difluoro-2-oxabicyclo[2.1.1]hexane compounds of claims 3 and 4, wherein the inert gas is one of nitrogen and argon.

6. The 6,6-difluoro-2-oxabicyclo[2.1.1]hexane and 3,3-difluoro-2-oxabicyclo[2.1.1]hexane compounds of claims 3 and 4, wherein the wavelength of the LED lamp is 450-460 nm.

7. The 6,6-difluoro-2-oxabicyclo[2.1.1]hexane and 3,3-difluoro-2-oxabicyclo[2.1.1]hexane compounds of claims 3 and 4, wherein the solvent is one of dichloromethane, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, and methanol.

8. The 6,6-difluoro-2-oxabicyclo[2.1.1]hexane and 3,3-difluoro-2-oxabicyclo[2.1.1]hexane compounds of claims 3 and 4, wherein the photocatalyst is one of benzophenone, 9-thioxanthone, 4-CzIPN, Ir(dF(CF3)ppy)2(bpy)(PF6), and Ir(dF(CF3)ppy)2(dtbbpy)(PF6). ​ 2.1.1] Process for the preparation of hexane-based compounds, characterized in that: ​ ​ 2.1.1] Process for the preparation of hexane-based compounds, characterized in that: ​ ​ 2.1.1] Process for the preparation of hexane-based compounds, characterized in that: ​ ​ 2.1.1] Process for the preparation of hexane-based compounds, characterized in that: ​

Images