A method for synthesizing monosubstituted bicyclo[1.1.1]pentane (BCP)

Abstract

The present application belongs to the technical field of preparation of pharmaceutical intermediates, and specifically relates to a method for synthesizing a monosubstituted bicyclo[1.1.1]pentane (BCP), which contains the steps of synthesizing a monosubstituted BCP compound by deiodination-hydrogenation of a bicyclo[1.1.1]pentane (BCP) iodide. The process route for preparing monosubstituted bicyclo[1.1.1]pentane (BCP) in the present application is not only inexpensive and safe for raw materials and reagents, but also easy to operate, and solves the technical problems of low atomic economy, expensive reagents, and high toxicity of reagents in the prior art. The yield of monosubstituted bicyclo[1.1.1]pentane prepared by the preparation method disclosed in the present application is as high as 73.6% and the purity is 98%.

Description

Technical Field

[0001] The present application belongs to the field of pharmaceutical intermediate preparation, and specifically relates to a method for synthesizing monosubstituted bicyclo[1.1.1]pentane (BCP). Background Art

[0002] The key to successful drug development is to find compounds that can act on the target efficiently and have ideal absorption, distribution, metabolism, excretion characteristics and safety toxicology indicators. Clinical candidate drugs that do not meet these stringent standards are often difficult to advance. In view of this, medicinal chemistry researchers are committed to optimizing the physicochemical properties of candidate drugs and widely apply the "bioisostere" and "escape plane" design concepts, aiming to improve sp by introducing more three-dimensional structures. 3 The ratio of hybridized carbon atoms is used to replace the planar benzene ring structure commonly seen in traditional drug design, thereby obtaining new drug molecules.

[0003] As a stable three-dimensional molecular skeleton, bicyclo[1.1.1]pentane (BCP) is gradually becoming a popular choice for modifying drug molecules and improving their drugability. The importance of this strategy is increasing day by day, and a large number of research cases have verified its effectiveness. Correspondingly, the number of drug patent applications involving BCP structures has increased significantly. At the same time, the synthesis methods for efficiently integrating BCP units into the target molecular skeleton using commercial raw materials are also becoming increasingly abundant, further accelerating the development of this field.

[0004] For example, in the design of the drug BMY-40062, researchers developed a structural analog of ciprofloxacin in which the key three-membered ring structure was replaced by a tert-butyl group, a change that significantly enhanced the compound's bactericidal potency. Unfortunately, it failed to effectively address the inherent drug resistance of ciprofloxacin. In response to this challenge, Barbachyn made innovative adjustments to the molecular structure of BMY-40062, attempting for the first time to replace the tert-butyl group with a bicyclo[1.1.1]pentane (BCP) skeleton. This strategy not only successfully surpassed ciprofloxacin in terms of antibacterial activity, but more importantly, it demonstrated excellent inhibitory ability against ciprofloxacin-resistant strains of Staphylococcus aureus, marking an important advance in addressing the problem of antibiotic resistance.

[0005]

[0006] In 2015, Westphal conducted a study to explore the possibility of replacing the original tert-butyl group with a bicyclo[1.1.1]pentane (BCP) skeleton in Bosentan, a drug for the treatment of pulmonary arterial hypertension, and Vercirnon, a drug for inflammatory bowel disease. This replacement strategy was evaluated at multiple levels, including the effects on the physicochemical properties, pharmacokinetic behavior, and biological activity of the drug. The results showed that the BCP skeleton is more compact in space than the tert-butyl group, which means that it occupies a smaller volume in the molecular structure. This change leads to a decrease in the overall lipophilicity of the drug molecule, which is particularly important for regulating the pharmacokinetic properties of the drug, such as absorption and distribution. In addition, the introduction of BCP is accompanied by changes in other physicochemical properties, such as enhanced stability and reduced metabolic clearance, which are very critical factors in drug development. Overall, such a molecular design strategy can not only maintain or improve the therapeutic effect of the drug, but also strive to solve problems in drug metabolism and safety, reflecting the continuous innovation of medicinal chemistry in the pursuit of more efficient and safer drug molecules.

[0007] As an important pharmaceutical intermediate, the study of the synthesis method of monosubstituted BCP is of great value. A common strategy for synthesizing monosubstituted BCP is to deiodinate iodinated BCP. The deiodinate methods of iodinated BCP reported in the literature are as follows:

[0008] Method 1: Synthesis method reported in Chem.Sci., 2018, 9, 5295 This route uses triethylborane (BEt3) as an efficient free radical initiator and an equivalent amount of tri(trimethylsilyl)silane (TTMSS) as a hydrogen donor for the reaction, which can effectively promote the deiodination and hydrogenation of BCP iodide.

[0009] Method 2: Synthesis method reported in Angew.Chem.Int.Ed.2021,60,2–9:

[0010] This route uses triethylborane as a free radical initiator by adjusting the amount from a catalytic amount to an equivalent amount, and adds 2-mercaptoethanol and tributyltin hydride (n-Bu3SnH) as auxiliary reagents to reduce the BCP free radical and successfully achieve deiodination and hydrogenation of the BCP iodide.

[0011] Method 1, the BCP iodide deiodination technology, uses triethylborane (BEt3) as a free radical initiator, but this method requires the use of expensive raw material tri(trimethylsilyl)silane (TTMSS), and the atom economy of this reagent is not high. Method 2 uses 2-mercaptoethanol, which is highly irritating and volatile, and tributyltin hydride (n-Bu3SnH). Organic tin compounds are not only highly toxic, but also pose a potential threat to the ecological environment and biological health. In addition, the strict operational requirements limit its practicality and sustainability. Therefore, it is necessary to develop a new method with high atom economy, low price, safe reagents and environmental friendliness to replace existing technologies, reduce production costs, improve operational safety, and reduce environmental impact. Summary of the invention

[0012] The present application provides a method for synthesizing a monosubstituted BCP compound from a bicyclo[1.1.1]pentane (BCP) iodide through deiodination-hydrogenation, which not only has low-cost raw materials and reagents and is safe, but also is easy to operate, thereby solving the technical problems in the prior art of low atom economy of the reagents used, high reagent prices, and high reagent toxicity.

[0013] The method for synthesizing a monosubstituted BCP compound from iodinated BCP via deiodination-hydrogenation described in the present application comprises the following reaction steps Wherein, R is a saturated heterocyclic ring containing 3 to 6 carbon atoms, -(CH2) 2-6 NHBoc, -CR a R b C(=O)OC2H5, where R a and R b Can be independently selected from H, F, CH3.

[0014] In some specific embodiments of the present application, N-Boc piperidinyl and N-Boc-azetidinyl are used to represent the possibility of N-Boc-nitrogen heterocyclic reaction, wherein the heterocyclic ring is a saturated heterocyclic ring containing 3-6 carbon atoms.

[0015] In some specific embodiments of the present application, N-Boc aminoethyl is used to represent azaalkyl-(CH2) 2-6 Reactivity of NHBoc.

[0016] In some specific examples of the present application, -CH(CH3)C(=O)OC2H5 and -CF2C(=O)OC2H5 are used to represent -CR a R b C(=O)OC2H5, where R a and R b Can be independently selected from H, F, CH3.

[0017] The catalyst is one or more of tetrakis(triphenylphosphine)palladium, bis(diphenylphosphine phenyl ether)palladium dichloride (II) and tetrakis(triphenylphosphine)nickel, and the molar ratio of the compound II to the catalyst is 1.0:(0.01-0.2).

[0018] Among the above-mentioned catalysts of similar types, tetrakis(triphenylphosphine)palladium has the best catalytic effect on the reaction; and the yield does not necessarily increase with the amount of catalyst used. The inventors infer that there may be other reactions that can be catalyzed by the catalyst in this reaction. Therefore, when the amount of catalyst used reaches 0.2 equivalents, the yield reverses and decreases.

[0019] The reaction temperature is not more than 40° C., preferably not more than 25° C. The inventors speculate that the photocatalytic reaction and the thermal energy reaction may compete with each other to generate other substances, so the reaction temperature should not be too high.

[0020] The solvent is one or more of isopropanol, 1,4-dioxane and ethanol;

[0021] The yield of isopropanol as solvent is greater than that of 1,4-dioxane, and that of ethanol is greater than that of methanol. This may be because, compared with methanol, ethanol and 1,4-dioxane, the free radicals generated after isopropanol provides hydrogen atoms are more stable and more conducive to promoting the hydrogen atom transfer process.

[0022] The base can be one or more of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, cesium carbonate and potassium phosphate, and the molar ratio of compound II to the base is 1.0:(1.0-5.0);

[0023] When the above-mentioned bases are used in the same amount, the yields are quite different. The yield of cesium carbonate is greater than that of potassium phosphate and greater than that of potassium acetate. The inventors did not find the rule of the influence of inorganic bases on the yield in the experiments of this application. This may be because the solubility of inorganic bases in organic solvents is not very good, and the effect of solvents also has a lot of influence on inorganic bases, so the alkalinity of inorganic bases in solvents is also quite difficult to measure.

[0024] The light source is an LED light source, which uses low-voltage direct current, with a supply voltage between 6 and 24V, stable light emission without flickering, and a spectrum mainly concentrated in the visible light region, with basically no interference from ultraviolet or infrared radiation. The light emitted by the LED light source is directional, and most of the light can be directly directed to the illuminated surface. The luminous brightness or output luminous flux of the LED light source basically changes with the positive current, and has good adjustability. The above technical solution of the present application utilizes the reduction and dehalogenation of light-induced free radicals and palladium complexes under mild conditions. This method has good functional group compatibility, and flow chemical reactions can be tried for gram-level or even hundred-gram-level reactions.

[0025] The beneficial effects of the above technical scheme are as follows: the reaction conditions of the synthesis route are mild, and the reduction and dehalogenation of light-induced free radicals and palladium complexes are utilized, which has high atom economy, low price, safe reagents and is environmentally friendly, thereby reducing production costs, improving operation safety, and reducing environmental impact; and the yield of the monosubstituted bicyclo[1.1.1]pentane prepared by the above technical scheme is as high as 73.6% and the purity is 98%.

[0026] Description of the drawings

[0027] Figure 1 :Compound II-1 1 H NMR (300 MHz, Chloroform-d) chart.

[0028] Figure 2 :Compound Ⅰ'-2 1 H NMR (300 MHz, Chloroform-d) chart.

[0029] Figure 3 :Compound Ⅰ'-3 1 H NMR (300 MHz, Chloroform-d) chart.

[0030] Figure 4 :Compound I-4 1 H NMR (300 MHz, Chloroform-d) chart.

[0031] Figure 5 :Compound I-5 1 H NMR (300 MHz, Chloroform-d) chart. DETAILED DESCRIPTION

[0032] The abbreviations involved in this application are as follows:

[0033] Pd(PPh3) 4: Tetrakis(triphenylphosphine)palladium, Cas No.: 14221-01-3;

[0034] iPrOH: isopropanol;

[0035] t-BuOK: potassium tert-butoxide;

[0036] LCMS: liquid chromatography mass spectrometry;

[0037] Boc: tert-butyloxycarbonyl;

[0038] LCMS: liquid chromatography mass spectrometry;

[0039] GCMS: gas mass spectrometry;

[0040] In the present application, bicyclo[1.1.1]pentane iodide is also called iodobicyclo[1.1.1]pentane.

[0041] In order to clearly and briefly illustrate the implementation scheme of the present application, the present application only uses one or two examples of a certain type of reaction or substituents with similar properties as representatives, for example: (1) potassium tert-butoxide and sodium tert-butoxide are used to represent the activation rules of potassium tert-butoxide, sodium, and lithium on tetrakis(triphenylphosphine)palladium and the influence of alkalinity on the reaction; (2) N-Boc piperidinyl and N-Boc-azetidinyl are used to represent the possibility of N-Boc-nitrogen heterocyclic reaction, wherein the heterocyclic ring is a saturated heterocyclic ring containing 3-6 carbon atoms of nitrogen; (3) N-Boc aminoethyl is used to represent the reaction of nitrogen alkyl -(CH2) 2-6 NHBoc; (4) -CH(CH3)C(=O)OC2H5, -CF2C(=O)OC2H5 represent the formula -CR a R b The reaction of C(=O)OC2H5, where R a and R b Can be independently selected from H, F, CH3.

[0042] That is, the specific embodiments of the present application are illustrated by cases in the experimental process, rather than the experimental process of the creative work of the present application, and it does not mean that this is the entire work of the present application.

[0043] Test example

[0044] Test Example Taking the starting material II-1 as an example, the reaction conditions were investigated. Based on compound I-1, we investigated the reaction conditions. The specific reaction equation is:

[0045]

[0046] Test Example 1

[0047] Preparation of compound Ⅰ-1: Add compound Ⅱ-1 (100 mg, 0.286 mmol, 1.0 eq), dry degassed isopropanol (2.3 mL), potassium tert-butoxide (64.27 mg, 0.572 mmol, 2.0 eq) and tetrakis(triphenylphosphine)palladium (9.9 mg, 0.009 mmol, 0.03 eq) to an 8 mL sample bottle at room temperature, and illuminate with Kessil A160WE tuna blue LED overnight at 25°C. LCMS monitoring showed no raw material, and 5 mL of water was added to the system, extracted with petroleum ether (5 mL*2), the organic phases were combined, washed with salt, and concentrated to obtain a light yellow liquid Ⅰ-1 (46.5 mg), with a yield of 73.0%.

[0048] Experimental Example 2 is different from Experimental Example 1 in that the base in the preparation of Compound I-1 from Compound II-1 is replaced with sodium tert-butoxide (55.04 mg, 0.572 mmol, 2 equiv), and LCMS monitoring shows that there is no starting material, and a light yellow liquid I-1 (38.2 mg) is obtained with a yield of 60.0%.

[0049] The inventors also investigated lithium tert-butoxide on the basis of Test Examples 1 and 2. The test results showed that the yield of potassium tert-butoxide was greater than that of sodium tert-butoxide and lithium. The inventors speculated that this may be caused by the fact that the alkalinity of potassium tert-butoxide, sodium and lithium weakened in sequence, and the activation and regeneration ability of tetrakis(triphenylphosphine)palladium weakened in sequence.

[0050] Experimental Example 3 is different from Experimental Example 1 in that the base in the preparation of Compound I-1 from Compound II-1 is replaced with cesium carbonate (186.60 mg, 0.572 mmol, 2 equiv), and LCMS monitoring shows that there is no raw material, and a light yellow liquid I-1 (36.3 mg) is obtained with a yield of 57%.

[0051] Experimental Example 4 is different from Experimental Example 1 in that the base in the preparation of compound I-1 from compound II-1 is replaced with potassium phosphate (121.57 mg, 0.572 mmol, 2 equiv), the reaction time is greater than 48 hours, and LCMS monitoring shows that there is still residual raw material to obtain a light yellow liquid I-1 (17.2 mg) with a yield of 27%.

[0052] Experimental Example 5 is different from Experimental Example 1 in that the base in the preparation of compound I-1 from compound II-1 is replaced with potassium acetate (56.21 mg, 0.572 mmol, 2 equiv), the reaction time is greater than 48 hours, and LCMS monitoring shows that there is still residual raw material to obtain a light yellow liquid I-1 (7.0 mg) with a yield of 11%.

[0053] Compared with Experimental Examples 3-5, the amount of base used is the same, but the yields are quite different. The yield of cesium carbonate is greater than that of potassium phosphate and greater than that of potassium acetate. The inventors did not find the law of the influence of inorganic base on the yield in the experiment of this application. This may be because the solubility of inorganic base in organic solvent is not very good, and the effect of solvent also has a lot of influence on inorganic base, so the alkalinity of inorganic base in solvent is also quite difficult to measure.

[0054] According to the results of Experimental Examples 1-5, the preferred bases in this reaction are potassium tert-butoxide, sodium tert-butoxide and cesium carbonate.

[0055] The difference between Experimental Example 6 and Experimental Example 1 is that compound II-1 is used to prepare compound I-1 with the base potassium tert-butoxide (32.13 mg, 0.286 mmol, 1 eq). LCMS monitoring shows that there is no starting material, and a light yellow liquid I-1 (37.6 mg) is obtained with a yield of 59%.

[0056] Experimental Example 7 is different from Experimental Example 1 in that compound II-1 is used to prepare compound I-1 using potassium tert-butoxide (160.67 mg, 1.430 mmol, 5 equiv), and LCMS monitoring shows that there is no starting material, to obtain a light yellow liquid I-1 (40.8 mg) with a yield of 64%.

[0057] The dosage of potassium tert-butoxide in Experimental Examples 6, 1, and 7 is 1 equivalent, 2 equivalents, and 5 equivalents, respectively. The results show that as the dosage of potassium tert-butoxide increases, the yield first increases and then decreases. The preferred dosage of potassium tert-butoxide is 2 equivalents.

[0058] Experimental Example 8 is different from Experimental Example 1 in that the catalyst in the preparation of Compound I-1 from Compound II-1 is replaced with (2,2-bipyridine)dichloropalladium (II) (2.87 mg, 0.009 mmol, 0.03 equiv), and no reaction is detected by LCMS monitoring.

[0059] The difference between Experimental Example 9 and Experimental Example 1 is that the catalyst in the preparation of Compound I-1 from Compound II-1 is replaced with dichloro(1,10-phenanthroline)palladium(II) (3.07 mg, 0.009 mmol, 0.03 equiv), and no reaction is detected by LCMS monitoring.

[0060] The difference between Experimental Example 10 and Experimental Example 1 is that the catalyst in the preparation of Compound I-1 from Compound II-1 is replaced with bis(diphenylphosphinophenyl ether)palladium(II) dichloride (6.15 mg, 0.009 mmol, 0.03 equiv), and LCMS monitoring shows no raw material, to obtain a light yellow liquid I-1 (23.6 mg) with a yield of 37%.

[0061] Experimental Example 11 is different from Experimental Example 1 in that the catalyst in the preparation of Compound I-1 from Compound II-1 is replaced with tetrakis(triphenylphosphine)nickel (9.52 mg, 0.009 mmol, 0.03 equiv), and LCMS monitoring shows no raw material, to obtain a light yellow liquid I-1 (12.1 mg) with a yield of 19%.

[0062] Compared with Experimental Example 1, Experimental Examples 8-11 have different types of catalysts and the same dosage. No corresponding products are generated for (2,2-bipyridine)dichloropalladium (II) and dichloro(1,10-phenanthroline)palladium (II). The yields of bis(diphenylphosphinophenyl ether)dichloropalladium (II) and tetrakis(triphenylphosphine)nickel are 37% and 19%, respectively, while the yield of Experimental Example 1 is 73.0%. It can be seen that among the catalysts of the same or similar types selected in the present application, tetrakis(triphenylphosphine)palladium has the best catalytic effect on the reaction.

[0063] Experimental Example 12 is different from Experimental Example 1 in that tetrakis(triphenylphosphine)palladium (3.31 mg, 0.003 mmol, 0.01 eq) in Compound Ⅰ-1 is prepared from Compound Ⅱ-1. LCMS monitoring shows that there is no starting material, and light yellow liquid Ⅰ-1 (37 mg) is obtained with a yield of 59%.

[0064] Experimental Example 13 is different from Experimental Example 1 in that tetrakis(triphenylphosphine)palladium (33.1 mg, 0.029 mmol, 0.1 eq) in Compound I-1 is prepared from Compound II-1. LCMS monitoring shows that there is no starting material, and a light yellow liquid I-III (48.4 mg) is obtained with a yield of 76%.

[0065] Experimental Example 14 is different from Experimental Example 1 in that tetrakis(triphenylphosphine)palladium (66.18 mg, 0.057 mmol, 0.2 eq) in compound Ⅰ-1 is prepared from compound Ⅱ-1. LCMS monitoring shows that there is no starting material, and light yellow liquid Ⅰ-1 (37.6 mg) is obtained with a yield of 59%.

[0066] Compared with Test Example 1, Test Examples 12-14 use the same tetrakis(triphenylphosphine)palladium as the catalyst. The results show that the yield does not increase with increasing catalyst dosage. The inventors infer that there may be other reactions that can be catalyzed by the catalyst in this reaction. Therefore, when the catalyst dosage reaches 0.2 equivalents, the yield reverses and decreases.

[0067] Experimental Example 15 is different from Experimental Example 1 in that the solvent in the preparation of Compound I-1 from Compound II-1 is replaced with 1,4-dioxane (2.3 mL), and LCMS monitoring shows no starting material, to obtain a light yellow liquid I-1 (26.8 mg) with a yield of 42%.

[0068] Experimental Example 16 is different from Experimental Example 1 in that the solvent in the preparation of Compound I-1 from Compound II-1 was replaced with methanol (2.3 mL), and LCMS monitoring showed no starting material, yielding a light yellow liquid I-1 (6.4 mg) with a yield of 10%.

[0069] Experimental Example 17 is different from Experimental Example 1 in that the solvent in the preparation of Compound I-1 from Compound II-1 was replaced with ethanol (2.3 mL), and LCMS monitoring showed that there was no starting material, and light yellow liquid I-1 (21.7 mg) was obtained with a yield of 34%.

[0070] Compared with Experimental Example 1, Experimental Examples 15-17 show that the yield of isopropanol as a solvent is greater than that of 1,4-dioxane, greater than that of ethanol and greater than that of methanol. This may be because, compared with methanol, ethanol and 1,4-dioxane, the free radicals generated after isopropanol provides hydrogen atoms are more stable and more conducive to promoting the hydrogen atom transfer process.

[0071] The difference between Experiment 18 and Experiment 1 is that the reaction temperature was increased from 25°C to 40°C, and LCMS monitoring showed that there was no starting material, and a light yellow liquid Ⅰ-1 (42.1 mg) was obtained with a yield of 66%.

[0072] The yield of Comparative Test Example 18 decreased by nearly 8% compared with Test Example 1, which is not within the reasonable fluctuation range. The inventor believes that the yield is significantly lower than that of Test Example 1. The inventor speculates that the photocatalytic reaction and the thermal energy reaction may compete with each other to generate other substances. Therefore, the reaction temperature should not be too high. The preferred temperature is not more than 40°C, and more preferably not more than 25°C.

[0073] Example

[0074] Example 1 Preparation of Compound Ⅰ-1:

[0075]

[0076] The specific experimental operations are as follows:

[0077] In a 1L single-mouth bottle, add Ⅱ-1 (20.4g, 58.417mmol, 1equiv), isopropanol (480mL), potassium tert-butoxide (13.11g, 116.834mmol, 2equiv) and tetrakis(triphenylphosphine)palladium (2.03g, 1.753mmol, 0.03equiv), bubble with nitrogen for 10min, seal, and illuminate overnight at 25°C using Kessil A160WE tuna blue LED. LCMS monitors the completion of the reaction of Ⅱ-1. Add 500mL of water to the system, extract with petroleum ether (800mL*2), combine the organic phases, wash with salt, filter, and concentrate to obtain a light yellow liquid Ⅰ-1 (9.6g), with a yield of 73.6% and a purity of 98% by LCMS. 1 H NMR (300MHz, Chloroform-d) δ3.88 (t, J = 8.4 Hz, 2H), 3.62 (dd, J = 8.5, 5.4 Hz, 2H), 2.62–2.39 (m, 2H), 1.70 (s, 6H), 1.43 (s, 9H).

[0078] Example 2 Preparation of Compounds Ⅰ-2 and Ⅰ'-2:

[0079]

[0080] The specific experimental operations are as follows:

[0081] In a 2L single-mouth bottle, add II-2 (34.14 g, 116.070 mmol, 1 equiv), isopropanol (925 mL), potassium tert-butoxide ((26.05 g, 232.140 mmol, 2 equiv) and tetrakis(triphenylphosphine)palladium (4.02 g, 3.482 mmol, 0.03 equiv), bubble with nitrogen for 10 min, seal, and use Kessil A160WE tuna blue at 25 °C. LED illumination overnight. GCMS monitoring Ⅱ-2 reaction is complete. The system was cooled to 0°C, and a solution of sodium hydroxide (23.21 g, 580.350 mmol, 5 equiv) in water (925 mL) was added, and the reaction was allowed to proceed at 50°C overnight. The system was concentrated to remove isopropanol, extracted with ether (2*500 mL), the aqueous phase was collected, the pH was adjusted to 1-2 with 3M hydrochloric acid, extracted with ether (2*500 mL), the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and eluted with column chromatography (petroleum ether: ethyl acetate = 95:5) to obtain a white solid Ⅰ'-2 (6 g), with a continuous two-step yield of 36.88%, and a nuclear magnetic purity of >95%. 1 H NMR (300MHz, Chloroform-d) δ2.60 (q, J = 7.0 Hz, 1H), 2.52 (s, 1H), 1.76 (s, 6H), 1.12 (d, J = 7.0 Hz, 3H).

[0082] Example 3 Preparation of Compounds Ⅰ-3 and Ⅰ'-3:

[0083]

[0084] The specific experimental operations are as follows:

[0085] In a 2L single-mouth bottle, add Ⅱ-3 (27.67 g, 87.539 mmol, 1 equiv), isopropanol (700 mL), potassium tert-butoxide (19.65 g, 175.078 mmol, 2 equiv) and tetrakis(triphenylphosphine)palladium (3.03 g, 2.626 mmol, 0.03 equiv), bubble with nitrogen for 10 min, seal, and illuminate overnight at 25°C using Kessil A160WE tuna blue LED. GCMS monitors the completion of the reaction of Ⅱ-3. The system is cooled to 0°C, and a solution of sodium hydroxide (17.51 ​​g, 437.695 mmol, 5 equiv) in water (175 mL) is added, and the reaction is allowed to proceed at 50°C overnight. The system was concentrated to remove isopropanol, extracted with diethyl ether (2*500 mL), the aqueous phase was collected, the pH was adjusted to 1-2 with 3M hydrochloric acid, extracted with diethyl ether (2*500 mL), the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and eluted with column chromatography (petroleum ether: ethyl acetate = 95:5) to obtain a white solid Ⅰ'-3 (2.84 g), with a two-step yield of 19.06% and a nuclear magnetic purity of >95%. 1 H NMR (300MHz, Chloroform-d) δ6.31(s,1H),2.60(s,1H),2.02(s,6H).

[0086] Example 4 Preparation of Compound I-4:

[0087]

[0088] The specific experimental operations are as follows:

[0089] In a 1L single-mouth bottle, add Ⅱ-4 (9.9g, 29.359mmol, 1equiv), isopropanol (235mL), potassium tert-butoxide (6.59g, 58.718mmol, 2equiv) and tetrakis(triphenylphosphine)palladium (1.02g, 0.881mmol, 0.03equiv), bubble with nitrogen for 10min, seal, and illuminate overnight at 25°C using Kessil A160WE tuna blue LED. LCMS monitors the completion of the reaction of Ⅱ-4. Add 500mL of water to the system, extract with petroleum ether (800mL*2), combine the organic phases, wash with salt, filter, and concentrate to obtain a light yellow liquid Ⅰ-4 (3.2g), with a yield of 51.58% and a nuclear magnetic purity of>95%. Compound Ⅰ-4 1 H NMR (300MHz, Chloroform-d) δ3.11 (q, J = 6.8 Hz, 2H), 2.46 (s, 1H), 1.69 (s, 6H), 1.59 (t, J = 7.3 Hz, 2H), 1.44 (s, 9H).

[0090] Example 5 Preparation of Compound Ⅰ-5:

[0091]

[0092] The specific experimental operations are as follows:

[0093] In a 1L single-mouth bottle, add Ⅱ-5 (9.19 g, 24.359 mmol, 1 equiv), isopropanol (194.87 mL, 73.077 mmol), potassium tert-butoxide (5.47 g, 48.718 mmol, 2 equiv) and tetrakis(triphenylphosphine)palladium (0.84 g, 0.731 mmol, 0.03 equiv), bubble with nitrogen for 10 min, and remove air. Use Kessil A160WE tunablue LED to illuminate overnight at 25°C. LCMS monitors the completion of the reaction of Ⅱ-5 (9.19 g, 24.359 mmol, 1 equiv). Add 500 mL of water to the system, extract with petroleum ether (800 mL*2), combine the organic phases, wash with salt, filter, and concentrate to obtain a light yellow liquid Ⅰ-5 (4 g), with a yield of 65.32% and a nuclear magnetic purity of >95%. 1H NMR(300MHz,Chloroform-d)δ4.11(d,J=13.5Hz,2H),2.62(t,J=12.9Hz,2H),2.47(s,1H),1.60(s,6 H), 1.53 (d, J = 13.1Hz, 2H), 1.45 (s, 9H), 1.38 (dt, J = 11.7, 3.7Hz, 1H), 1.05 (qd, J = 12.6, 4.4Hz, 2H).

[0094] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make modifications to the present embodiment without any creative contribution as needed, but such modifications are protected by the patent law as long as they are within the scope of the claims of the present application.

Claims

1. A method for synthesizing a monosubstituted bicyclo[1.1.1]pentane, characterized in that: The synthesis method comprises the step of deiodination and hydroiodination of bicyclo[1.1.1]pentane iodide, and the specific reaction equation is: R is a saturated heterocyclic ring containing 3 to 6 carbon atoms, -(CH2) 2-6 NHBoc or -CR a R b C(=O)OC2H5; wherein R a and R b May be independently selected from H, F, CH3; The catalyst is one or more of tetrakis(triphenylphosphine)palladium, bis(diphenylphosphine phenyl ether)palladium(II) dichloride and tetrakis(triphenylphosphine)nickel; The reaction temperature is no more than 40°C; The solvent is one or more of 1,4-dioxane, isopropanol and ethanol; The base is one or more of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, cesium carbonate and potassium phosphate, and the molar ratio of the compound II to the base is 1.0:(1.0-5.0).

2. The method for synthesizing a monosubstituted bicyclo[1.1.1]pentane according to claim 1, characterized in that: The R is N-Boc piperidinyl, N-Boc-azetidinyl, N-Boc aminoethyl, -CH(CH3)C(=O)OC2H5 or -CF2C(=O)OC2H5.

3. The method for synthesizing monosubstituted bicyclo[1.1.1]pentane according to claim 1, characterized in that: The molar ratio of the compound II to the catalyst is 1.0:(0.01-0.2).

4. The method for synthesizing monosubstituted bicyclo[1.1.1]pentane according to claim 1, characterized in that: The reaction temperature is not more than 25°C.

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