Preparation method of crisaborole and intermediate thereof

Abstract

The invention provides a method for preparing crisaborole through metal-free catalysis. The method comprises the following steps: taking 4-[4-bromo-3-(hydroxymethyl) phenoxy] benzonitrile as a raw material, and cyclizing by adopting a metal-free catalytic borane reaction to obtain crisaborole. The process method has the advantages of short steps, adoption of metal-free free radical reaction for boronization, avoiding of the use of an expensive metal catalyst and harsh reaction conditions, no generation of the problem of metal residue in the product, simple and safe post-treatment operation, low cost, high total yield, good economic benefits, suitableness for industrial production, and good application prospects.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis, specifically relating to the preparation of criborone and its intermediates. Background Technology

[0002] Criborone (AN2728) is a nonsteroidal phosphodiesterase 4 (PDE-4) inhibitor with the structure shown below. A 2% criborone ointment can be used for topical treatment of mild to moderate atopic dermatitis in patients aged 3 months and older.

[0003]

[0004] 4-[4-bromo-3-(hydroxymethyl)phenoxy]benzonitrile is an important intermediate in the synthesis of criborone, and its structure is shown in compound IIa.

[0005]

[0006] Patent CN101914109 reports the following three synthetic routes of criborone via compound IIa:

[0007]

[0008] The route first involves aldehyde protection, followed by the Williamson reaction, which reduces the compound to IIa. The hydroxyl group on IIa is protected with tetrahydropyran, and then halogen and boron ester exchange is performed at ultra-low temperature under the action of n-butyllithium. Finally, hydrolysis and cyclization are performed to obtain the product.

[0009]

[0010] This route does not employ protecting groups and directly proceeds with the Williamson named reaction, resulting in numerous side reactions. Reduction yields compound IIa, which then has its hydroxyl group protected with an acetyl group and undergoes Suzuki coupling to obtain a borate ester compound. Finally, hydrolysis and cyclization give the product.

[0011]

[0012] This route uses a hydroxyl-halogen substitution reaction to prepare compound IIa, then protects the hydroxyl group with an acetyl group and uses Suzuki coupling to obtain a borate ester structure, followed by catalytic deprotection and hydrolytic cyclization to obtain the product.

[0013] The main methods for introducing boric acid groups are: (1) reacting with boric acid reagent in the presence of n-butyllithium, which requires an anhydrous, oxygen-free, and extremely low temperature environment. The reaction conditions are harsh and accidents are prone to occur, making it unsuitable for industrial production. (2) reacting with boric acid reagent under the catalysis of transition metal catalysts such as palladium. Although the reaction conditions are mild, the catalyst is expensive and results in high levels of heavy metal residues in the product, which are difficult to remove.

[0014] Therefore, developing green, environmentally friendly routes for the synthesis of borate esters with mild reaction conditions has broad application prospects. Summary of the Invention

[0015] To overcome the above technical difficulties, the present invention provides a method for preparing creborone, specifically including the following steps:

[0016] (1) Compound II undergoes a free radical reaction in the presence of a basic reagent and a boriding reagent to generate compound I, as follows:

[0017]

[0018] in,

[0019] The free radical reaction is initiated by light or a free radical initiator;

[0020] The boryling agent is selected from tetrahydroxydiborane or borate esters, and the borate ester has the following structure:

[0021]

[0022] (2) After the reaction in step (1) is complete, it is hydrolyzed and cyclized to generate creborol;

[0023] in,

[0024] X is selected from Cl, Br, and I;

[0025] R1 is selected from H or a hydroxyl protecting group;

[0026] R, R2 and R3 are each independently selected from the following members: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted aryl, and R2 and R3 together with the atoms to which they are attached may optionally be combined to form 4 to 7 membered rings;

[0027] When R1 of compound II in step (1) is H and the borizing agent is tetrahydroxydiborane, creborone can be directly generated via step (1) without the hydrolysis and cyclization process in step (2).

[0028] In some embodiments, X of compound II in step (1) is Br.

[0029] In some embodiments, R1 of compound II is H.

[0030] In some embodiments, R1 of compound II is a hydroxyl protecting group selected from methoxymethyl, ethoxyethyl, tetrahydropyran-2-yl, trimethylsilyl, tert-butyldimethylsilyl, and acetyl. In some preferred embodiments, R1 of compound II is selected from acetyl, tetrahydropyran-2-yl, and trimethylsilyl.

[0031] In some embodiments, the basic reagent in step (1) is selected from one or more of pyridine, 4-cyanopyridine, potassium carbonate, cesium carbonate, potassium methoxide, potassium tert-butoxide, sodium methoxide, and sodium tert-butoxide. In some embodiments, the basic reagent in step (1) is selected from one or more of 4-cyanopyridine, potassium methoxide, and potassium tert-butoxide. In some embodiments, the molar ratio of the basic reagent in step (1) to compound II is 1 to 5:1. In some embodiments, the molar ratio of the basic reagent in step (1) to compound II is 2 to 3:1.

[0032] In some preferred embodiments, the alkaline reagent is selected from potassium tert-butoxide.

[0033] In some preferred embodiments, the alkaline reagent is selected from a mixture of potassium methoxide and 4-cyanopyridine, wherein the potassium methoxide and 4-cyanopyridine can be added to the reaction system separately or mixed together. In some preferred embodiments, the molar ratio of potassium methoxide to 4-cyanopyridine is 1:12.

[0034] In some embodiments, the illumination wavelength in step (1) is 180nm to 600nm; in some embodiments, the illumination wavelength in step (1) is 400nm to 450nm; in some preferred embodiments, the illumination wavelength in step (1) is 450nm blue light.

[0035] In some embodiments, the free radical initiator in step (1) is selected from one or more of benzoyl peroxide, tert-butyl peroxide, tert-butyl hydroperoxide, and azobisisobutyronitrile. In some embodiments, the molar ratio of the free radical initiator to compound II is 1:0.01 to 0.1, preferably 1:0.02 to 0.06.

[0036] In some embodiments, the molar ratio of compound II to borate in step (1) is 1:1 to 10; in some embodiments, the molar ratio of compound II to borate in step (1) is 1:3 to 6.

[0037] The tetrahydroxydiborane structure described in this invention is as follows:

[0038]

[0039] In some embodiments, the R, R2, and R3 of the borate ester in step (1) are each independently selected from the following members: H, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted phenyl, and substituted or unsubstituted benzyl; in some embodiments, the R2 and R3 of the borate ester in step (1), together with the atoms to which they are bonded, may optionally form members selected from the following members: substituted or unsubstituted dioxoboronyl pentane, substituted or unsubstituted dioxoboronyl hexane, and substituted or unsubstituted dioxoboronyl heptane.

[0040] In some embodiments, preferred substituents for various groups are selected from: -halogen, -CN, -NO2, =O, -OR', -NR'R”, -SR', -OC(O)R', -C(O)R', -CO2R', -CONR'R”, -S(O)R', -S(O)2R', substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted aryl, wherein the substituted substituents are selected from methyl, ethyl, propyl, and isopropyl; R' and R” each preferably independently refer to hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted aryl, wherein the substituted substituents are selected from methyl, ethyl, propyl, and isopropyl. In some embodiments, preferred substituents for various groups are selected from methyl, ethyl, propyl, and isopropyl.

[0041] In some embodiments, in step (1), the R2 and R3 of the borate ester, together with the atoms to which they are bonded, form members selected from:

[0042]

[0043] In some embodiments, the R of the borate ester in step (1) is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, phenyl, or benzyl substituted with any C1-C3 alkyl group.

[0044] In some embodiments, the borate ester in step (1) is selected from pinacol methylborate, pinacol ethylborate, pinacol isopropylborate, and dipinacol boronic acid ester, with the following structures:

[0045]

[0046] In some embodiments, the borate ester in step (1) is selected from dimethyl methylborate, diethyl ethylborate, diisopropyl borate, and dibutyl butyl borate.

[0047] In some embodiments, the borate ester in step (1) is selected from dipinacol borate ester, with the following structure:

[0048]

[0049] In some embodiments, step (1) is carried out in an organic solvent selected from one or more of DMF, DMSO, MTBE, THF, methanol, and acetonitrile. In some embodiments, the mass-to-volume ratio of compound II to the organic solvent is 1:2 to 20 (g / mL); in some embodiments, the mass-to-volume ratio of compound II to the organic solvent is 1:2 to 10.

[0050] In some embodiments, the reaction temperature of step (1) is 20–100°C, and the reaction time is 8–50 h. In some embodiments, the reaction temperature of step (1) is 20–60°C, and the reaction time is 24–48 h.

[0051] In some preferred embodiments, the reaction temperature of step (1) is 20-30°C and the reaction time is 48h.

[0052] In some preferred embodiments, the reaction temperature of step (1) is 60°C and the reaction time is 24h.

[0053] In some implementations, the hydrolytic cyclization in step (2) is carried out in an acidic aqueous solution.

[0054] In some implementations, the hydrolytic cyclization in step (2) is carried out in an alkaline aqueous solution.

[0055] In some embodiments, the hydrolysis-cyclization reaction temperature of step (2) is 10–50°C and the reaction time is 1–5 h.

[0056] In some implementations, the hydrolysis-cyclization reaction temperature of step (2) is 20–30°C and the reaction time is 1–3 h.

[0057] In some preferred embodiments, compound II can be reacted with a boriding agent in a one-pot reaction in steps (1) and (2) to prepare criborone.

[0058] In some preferred embodiments, after the reaction in step (1) is complete, the mixture is cooled to room temperature and, without post-treatment, is directly hydrolyzed and cyclized with water to generate criborone.

[0059] In some preferred embodiments, after the reaction in step (1) is complete, the mixture is cooled to room temperature, and without post-treatment, water and hydrochloric acid are added directly and the pH is adjusted to 1-3. Then, the mixture is hydrolyzed and cyclized to generate criborone.

[0060] In some preferred embodiments, the criborone obtained by the method of the present invention can be further purified by extraction, crystallization, or other methods. As a preferred embodiment, the extraction solvent is ethyl acetate, and the crystallization solvent is selected from one or both of ethyl acetate and n-heptane.

[0061] On the other hand, the present invention further provides a method for preparing compound II, comprising the following steps:

[0062] (a) Compound IV reacts with NH2R4 to form compound V, as follows:

[0063]

[0064] (b) Compound V reacts with p-fluorobenzonitrile to form compound VI, as follows:

[0065]

[0066] (c) Compound VI undergoes hydrolysis, reduction, and optional protection of the p-hydroxyl group to generate compound II, as follows:

[0067]

[0068] Where X and R1 are as described above; R4 is substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C6-C 12 Cycloalkyl, substituted or unsubstituted C6-C 12 Aryl.

[0069] In some embodiments, the substituents are -halogen, -CN, -NO2, =O, -OR', -NR'R”, -SR', -OC(O)R', -C(O)R', -CO2R', -CONR'R”, -S(O)R', -S(O)2R', substituted or unsubstituted C1-C3 alkyl groups.

[0070] In some embodiments, R4 is n-butyl, cyclohexyl, or phenyl.

[0071] In some preferred embodiments, R4 is cyclohexyl.

[0072] In some embodiments, step (a) is carried out in the presence of a dehydrating agent selected from one or more of anhydrous magnesium sulfate, anhydrous sodium sulfate, and molecular sieves. In some embodiments, the molar ratio of the dehydrating agent to compound IV is 0.05 to 0.5:1. In some embodiments, the molar ratio of the dehydrating agent to compound IV is 0.2 to 0.4:1.

[0073] In some preferred embodiments, step (a) is carried out in the presence of a dehydrating agent selected from anhydrous magnesium sulfate.

[0074] In some embodiments, the molar ratio of NH2R4 to compound IV in step (a) is 1 to 10:1; in some embodiments, the molar ratio of NH2R4 to compound IV in step (a) is 1 to 3:1.

[0075] In some embodiments, step (a) is carried out in an organic solvent selected from one or more of dichloromethane, tetrahydrofuran, methanol, toluene, acetonitrile, and ethanol; in some embodiments, the mass-to-volume ratio of compound IV to the organic solvent is 1:1 to 10 (g / mL); in some embodiments, the mass-to-volume ratio of compound IV to the organic solvent is 1:1 to 3 (g / mL). In some preferred embodiments, the organic solvent is selected from dichloromethane.

[0076] In some embodiments, the reaction temperature of step (a) is 10–50°C; in some embodiments, the reaction temperature of step (a) is 30–50°C.

[0077] In some embodiments, step (b) is carried out in an alkaline reagent selected from one or more of potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium tert-butoxide, and sodium methoxide; in some embodiments, the molar ratio of the alkaline reagent to compound V is 1 to 6:1, and in some embodiments, the molar ratio of the alkaline reagent to compound V is 1 to 2:1. In some preferred embodiments, the alkaline reagent is selected from potassium carbonate.

[0078] In some embodiments, the molar ratio of compound V to p-fluorobenzonitrile in step (b) is 1:1 to 6, and in some embodiments, the molar ratio of compound V to p-fluorobenzonitrile in step (b) is 1:1 to 3.

[0079] In some embodiments, step (b) is carried out in an organic solvent selected from one or more of tetrahydrofuran, toluene, acetonitrile, DMF, DMSO, and NMP; in some embodiments, the mass-to-volume ratio of compound V in step (b) to the reaction solvent is 1:3 to 10 (g / mL), and in some embodiments, the mass-to-volume ratio of compound V in step (b) to the reaction solvent is 1:4 to 6 (g / mL). In some preferred embodiments, the reaction solvent is DMF.

[0080] In some embodiments, the reaction temperature of step (b) is 50–150°C; in some embodiments, the reaction temperature of step (b) is preferably 100–115°C.

[0081] In some embodiments, the hydrolysis reaction in step (c) is carried out under acidic conditions, wherein the acid is selected from one or more of hydrochloric acid, sulfuric acid, acetic acid, methanesulfonic acid, and phosphoric acid; in some embodiments, the molar ratio of the acid to compound VI is 1 to 5:1. In some preferred embodiments, the acid is selected from hydrochloric acid.

[0082] In some embodiments, the hydrolysis reaction solvent in step (c) is selected from one or more of water, dichloromethane, tetrahydrofuran, toluene, and acetonitrile; in some embodiments, the mass-to-volume ratio of compound VI to the reaction solvent is 1:1 to 10 (g / mL); in some embodiments, the mass-to-volume ratio of compound VI to the reaction solvent is 1:1 to 3 (g / mL). In some preferred embodiments, the hydrolysis reaction solvent in step (c) is selected from water.

[0083] In some embodiments, the hydrolysis reaction temperature in step (c) is 10–50°C; in some preferred embodiments, the hydrolysis reaction temperature in step (c) is 20–25°C.

[0084] In some embodiments, the reducing agent used in step (c) is selected from one or more of lithium aluminum hydride, sodium borohydride, potassium borohydride, and sodium cyanoborohydride; in some embodiments, the molar ratio of the reducing agent to compound VI is 0.5 to 2:1; in some embodiments, the molar ratio of the reducing agent to compound VI is 0.5 to 1:1. In some preferred embodiments, the reducing agent is selected from sodium borohydride.

[0085] In some embodiments, the reduction reaction solvent in step (c) is selected from one or more of dichloromethane, tetrahydrofuran, methanol, acetonitrile, and ethanol; in some embodiments, the mass-to-volume ratio of compound VI to the solvent is 1:3 to 10 (g / mL); in some embodiments, the mass-to-volume ratio of compound VI to the solvent is 1:4 to 6 (g / mL). In some preferred embodiments, the reduction reaction solvent in step (c) is preferably a mixture of methanol and dichloromethane. In some preferred embodiments, the volume ratio of methanol to dichloromethane is 1:6.

[0086] In some embodiments, the reduction reaction temperature in step (c) is -5 to 10°C; in some embodiments, the reduction reaction temperature in step (c) is 0 to 5°C.

[0087] In some embodiments, the hydroxyl protecting agent used in step (c) to protect the hydroxyl group is selected from acetic anhydride, benzoyl chloride, ethylene glycol, 3,4-dihydropyran, and trimethylchlorosilane. In some preferred embodiments, the hydroxyl protecting agent used in step (c) to protect the hydroxyl group is selected from acetic anhydride and 3,4-dihydropyran.

[0088] In some embodiments, an acid-binding agent is added when protecting the hydroxyl group in step (c), and the acid-binding agent is selected from one or two of triethylamine, pyridine, diisopropylamine, potassium carbonate, and sodium carbonate; in some preferred embodiments, the acid-binding agent is selected from triethylamine.

[0089] In some embodiments, an acid, selected from camphor sulfonic acid, is added to protect the hydroxyl group in step (c).

[0090] In some embodiments, the reaction temperature for protecting the hydroxyl group in step (c) is 0–100°C, preferably 20–25°C.

[0091] Preferably, the present invention further provides a method for preparing creborone, specifically including the following steps:

[0092] (a) Compound IV reacts with NH2R4 to form compound V, as follows:

[0093]

[0094] (b) Compound V reacts with p-fluorobenzonitrile to form compound VI, as follows:

[0095]

[0096] (c) Compound VI undergoes hydrolysis, reduction, and optional protection of the p-hydroxyl group to generate compound II, as follows:

[0097]

[0098] (d) Compound II undergoes a free radical reaction in the presence of a basic reagent and a boriding reagent to generate compound I, as follows:

[0099]

[0100] in,

[0101] The boryling agent is selected from tetrahydroxydiborane or borate esters, wherein the borate ester has the following structure:

[0102]

[0103] The free radical reaction is initiated by light or a free radical initiator;

[0104] (e) After the reaction in step (d) is complete, craborone is generated via hydrolysis and cyclization.

[0105] in,

[0106] X is selected from Cl, Br, and I;

[0107] R1 is selected from H or a hydroxyl protecting group;

[0108] R, R2 and R3 are each independently selected from the following members: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted aryl. R2 and R3, together with the atoms to which they are attached, may optionally be combined to form 4 to 7-membered rings.

[0109] R4 is selected from substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C6-C 12 Cycloalkyl, substituted or unsubstituted C6-C 12 Aryl;

[0110] When R1 of compound II in step (d) is H and the borizing agent is tetrahydroxydiborane, creborone can be directly generated via step (d) without the hydrolysis and cyclization process in step (e).

[0111] Furthermore, the reaction reagents, substituents, basic reagents, boriding reagents, light irradiation, free radical initiators, and reaction conditions in steps (a) to (e) of the method for preparing criborone are further specified as described above.

[0112] Compared with the prior art, the present invention has the following significant features:

[0113] (1) The reaction conditions are mild, the post-processing is simple, the steps are short, the operation is simple, and the raw materials are cheap and readily available;

[0114] (2) It does not require meeting the stringent reaction requirements such as anhydrous, oxygen-free, and ultra-low temperature, and has low requirements for production conditions and equipment, making it suitable for industrial-scale production.

[0115] (3) No expensive palladium catalyst is required, there is no palladium residue problem in the product, it does not pollute the environment, and it is suitable for industrial production. Attached Figure Description

[0116] Figure 1 : is the 4-bromo-3-(cyclohexylimino)methyl-phenol obtained in step (a) of Example 1. 1 H NMR spectrum.

[0117] Figure 2: is the 4-{4-bromo-3-[1-(cyclohexylimino)methyl]phenoxy}benzylnitrile obtained in step (b) of Example 1. 1 HNMR spectrum.

[0118] Figure 3 : is the 4-{4-bromo-3-[1-(phenylimino)methyl]phenoxy}benzylnitrile obtained in step (b) of Example 2. 1 HNMR spectrum.

[0119] Figure 4 : This refers to the criborone obtained in Example 6. 1 H NMR spectrum. Detailed Implementation

[0120] The technical solution of the present invention will be further described and illustrated below with reference to specific embodiments. However, the scope and content of protection claimed by the present invention are not limited to the following embodiments.

[0121] This embodiment is only a part of the embodiments of the present invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the protection scope of the present invention.

[0122] Terminology:

[0123] The terms “include” and “include” should be interpreted as open-ended, indicating the presence of the listed elements but excluding the presence, occurrence, or addition of any other unlisted elements.

[0124] All ranges described in this article include those endpoints that list the range between two values. Whether indicated or not, all values ​​listed in this article include the expected degree of experimental, technical, and instrumental error of the given technique used to measure that value.

[0125] The specific values ​​given for numbers or ranges as used in this article can be understood as that specific value or approximately that specific value (e.g., that specific value plus or minus 10%).

[0126] Unless otherwise stated, the term "alkyl" means a straight-chain or branched saturated or unsaturated alkyl group.

[0127] The raw materials and reagents used in this invention can all be purchased through conventional commercial channels, and the raw materials can also be prepared using existing methods.

[0128] The abbreviations used in this invention are explained as follows:

[0129] 1 H NMR: Hydrogen nuclear magnetic resonance

[0130] LC-MS: Liquid chromatography-mass spectrometry

[0131] MTBE: Methyl tert-butyl ether

[0132] DMF: N,N-dimethylformamide

[0133] DMSO: Dimethyl sulfoxide

[0134] THF: Tetrahydrofuran

[0135] EA: Ethyl acetate

[0136] NMP: N-methylpyrrolidone

[0137] The detection instruments and methods used in this invention are as follows:

[0138] Agilent 6460 LC-MS / MS

[0139] Column: Agilent Proshell 120EC-C18 (4.6×100mm, 2.7μm) or a column with equivalent performance.

[0140] Column temperature: 30℃.

[0141] Sample chamber temperature: room temperature.

[0142] Mobile phase A: 0.1% H3PO4 aqueous solution (e.g., accurately transfer 1.0 mL of phosphoric acid, add it to 1000 mL of purified water, mix well, and degas by sonication).

[0143] Mobile phase B: Acetonitrile

[0144] gradient:

[0145]

[0146]

[0147] Flow rate: 1.0 mL / min.

[0148] Injector: Automatic injector.

[0149] Injection volume: 5 μL.

[0150] Detector wavelength: UV 254nm.

[0151] Running time: 53 minutes.

[0152] Example 1: Synthesis of 4-[4-bromo-3-(hydroxymethyl)phenoxy]benzyl nitrile

[0153]

[0154] Step (a): Synthesis of 4-bromo-3-(cyclohexylimino)methylphenol

[0155]

[0156] 100.5 g of 5-bromosalicylic acid and 20 g of anhydrous magnesium sulfate were added to 100 mL of dichloromethane. Stirring was started, and 45 g of cyclohexylamine was added dropwise. The mixture was heated to 40 °C and reacted for 18 h. Samples were taken for analysis. After the reaction was complete, the mixture was cooled, filtered, and the filtrate was concentrated to obtain 142 g of crude product. ¹H NMR (500 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.39 (s, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 1.9 Hz, 1H), 6.74 (dd, J = 7.7, 1.9 Hz, 1H), 3.41 (q, J = 6.6 Hz, 1H), 1.83 (m, 2H), 1.72–1.35 (m, 8H). Step (b): Synthesis of 4-{4-bromo-3-[1-(cyclohexylimino)methyl]phenoxy}benzyl nitrile

[0157]

[0158] 142 g of 4-bromo-3-[(cyclohexylimino)methyl]phenol, 121 g of p-fluorobenzonitrile, and 103.5 g of potassium carbonate were added to 700 mL of DMF. The mixture was heated to 100-115 °C and reacted for 14 h. After the reaction was complete, the mixture was cooled to room temperature, and 3 L of water was added. The aqueous phase was extracted twice with 300 mL of ethyl acetate (2 times). The organic phases were combined, washed with 100 mL of saturated brine (2 times), dried, concentrated, and crystallized from ethyl acetate and n-heptane to obtain 172 g of the product, with a yield of 90%. 1H NMR(500MHz,DMSO-d6)δ8.46(s,1H),7.79–7.73(m,2H),7.65(d,J=8.9Hz,1H),7.31(d,J=2.9Hz,1H), 7.14–7.01(m,2H),7.00(dd,J=8.8,2.9Hz,1H),3.38(q,J=6.6Hz,1H),1.82(m,2H),1.72–1.34(m,8H).

[0159] Step (c): Synthesis of 4-[4-bromo-3-(hydroxymethyl)phenoxy]benzyl nitrile

[0160]

[0161] 60 mL of 36% concentrated hydrochloric acid and 170 g of 4-{4-bromo-3-[1-(cyclohexylimino)methyl]phenoxy}benzyl nitrile were added to 300 mL of water and stirred at room temperature for 2 h. After the reaction was complete, 3 L of water was added, and the mixture was extracted twice with 300 mL of dichloromethane (300 mL x 2). 100 mL of methanol was added to the organic phase, and the mixture was cooled to 0–5 °C. 10.5 g of sodium borohydride was added in portions, and the mixture was stirred for 0.5 h after each addition. After the reaction was complete, the sample was taken for analysis. The reaction was quenched with hydrochloric acid, and 300 mL of water was added. The mixture separated into layers, and the aqueous phase was extracted once with 200 mL of dichloromethane. The organic phases were combined, washed once with water, dried, filtered, and concentrated. Crystallization with methanol yielded 123.3 g of the product, with a yield of 90%. LC-MS [MH] - =302.

[0162] Example 2: Synthesis of 4-[4-bromo-3-(hydroxymethyl)phenoxy]benzyl nitrile

[0163] Step (a): Synthesis of 4-bromo-3-[(phenylimino)methyl]phenol

[0164]

[0165] 100 g of 2-bromo-5-hydroxybenzaldehyde and 20 g of anhydrous magnesium sulfate were added to 300 mL of dichloromethane. Stirring was started, and 46.5 g of aniline was added dropwise. The mixture was heated to 40 °C and reacted for 18 h. Samples were taken for analysis. After the reaction was complete, the mixture was cooled, filtered, and the filtrate was concentrated to obtain 140 g of crude product. Step (b): Synthesis of 4-{4-bromo-3-[1-(phenylimino)methyl]phenoxy}benzyl nitrile

[0166]

[0167] 140 g of 4-bromo-3-[(phenylimino)methyl]phenol, 121 g of p-fluorobenzonitrile, and 103.5 g of potassium carbonate were added to 700 mL of DMF. The mixture was heated to 100-115 °C and reacted for 14 h. After the reaction was complete, the mixture was cooled to room temperature, and 3 L of water was added. The aqueous phase was extracted twice with 300 mL of ethyl acetate (2). The organic phases were combined, washed with 100 mL of saturated brine (2). The mixture was dried, concentrated, and crystallized from ethyl acetate and n-heptane to obtain 147.9 g of the product, with a yield of 78.5%. 1H NMR (600MHz, DMSO-d6) δ8.73(s,1H),7.87(d,J=8.8Hz,2H),7.82(d,J=8.7Hz,1H),7.77(d, J=3.0Hz,1H),7.42(t,J=7.8Hz,2H),7.33–7.23(m,4H),7.20(d,J=8.8Hz,2H).LC-MS[M+H] + =377.9.

[0168] Step (c): Synthesis of 4-[4-bromo-3-(hydroxymethyl)phenoxy]benzyl nitrile

[0169]

[0170] 43 mL of 36% concentrated hydrochloric acid and 120 g of 4-{4-bromo-3-[1-(phenylimino)methyl]phenoxy}benzyl nitrile were added to 250 mL of water and stirred at room temperature for 2 h. After the reaction was complete, 3 L of water was added, and the mixture was extracted twice with 300 mL of dichloromethane. 100 mL of methanol was added to the organic phase, and the temperature was lowered to 0-5 °C. 10.5 g of sodium borohydride was added in portions, and the mixture was stirred for 0.5 h after the addition was complete. After the reaction was complete, the raw materials were tested, and the reaction was quenched with hydrochloric acid. 300 mL of water was added, and the mixture was allowed to separate into layers. The aqueous phase was extracted once with 200 mL of dichloromethane. The organic phases were combined, washed once with water, dried, filtered, and concentrated. The product was crystallized from methanol to obtain 86.8 g, with a yield of 89.5%.

[0171] Example 3: Mass spectrum of 4-[[4-bromo-3-(acetoxy)methyl]phenoxy]benzyl nitrile.

[0172] Synthesis

[0173]

[0174] 30 g of 4-[4-bromo-3-(hydroxymethyl)phenoxy]benzyl nitrile and 24.2 g of triethylamine were added to 300 mL of dichloromethane. The mixture was cooled to 0–5 °C, and 12.2 g of acetic anhydride was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 hours. A sample was taken to indicate the completion of the reaction. The mixture was quenched with 30 mL of water, and the layers were extracted. The organic phase was washed with 150 mL of water (2 x 150 mL). The organic phase was dried, filtered, and concentrated to obtain 36.3 g of crude product. LC-MS [MH] - =344.

[0175] Example 4: Synthesis of 4-(4-bromo-3-{[(trimethylsilyl)oxy]methyl}phenoxy)benzylnitrile

[0176]

[0177] 30 g of 4-[4-bromo-3-(hydroxymethyl)phenoxy]benzyl nitrile and 24.2 g of triethylamine were added to 300 mL of dichloromethane. The mixture was cooled to 0–5 °C, and 13.0 g of trimethylchlorosilane was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 hours. A sample was taken to indicate the completion of the reaction. The mixture was quenched with 30 mL of water, and the layers were extracted. The organic phase was washed with 150 mL of water (2 x 150 mL), dried, filtered, and concentrated to obtain 38.6 g of crude product. LC-MS [MH] - =374.

[0178] Example 5: Synthesis of 4-[4-bromo-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]phenoxy]benzonitrile

[0179]

[0180] 30 g of 4-[4-bromo-3-(hydroxymethyl)phenoxy]benzyl nitrile and 1.5 g of camphorsulfonic acid were added to 300 mL of dichloromethane. The mixture was cooled to 10–15 °C, and 10.1 g of 3,4-dihydropyran was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 hours. A sample was taken to indicate the completion of the reaction. The mixture was quenched with 30 mL of water, and the layers were extracted. The organic phase was washed with 150 mL of water (2 x 150 mL), dried, filtered, and concentrated to obtain 40.2 g of an oily substance. LC-MS [MH] - =386.

[0181] Example 6: Synthesis of creborone

[0182]

[0183] 25.8 g of 4-[4-bromo-3-(hydroxymethyl)phenoxy]benzyl nitrile and 19.1 g of potassium tert-butoxide were added to 260 mL of methanol and stirred at room temperature for 10 min. The mixture was then cooled to 0 °C, and 38.1 g of tetrahydroxydiborane was added. After the addition was complete, the mixture was purged with nitrogen three times and irradiated with 450 nm blue light. The reaction was carried out at room temperature for 48 h. Samples were taken for analysis, indicating that the reaction of the starting material was complete. The reaction was quenched with 50 mL of 0.1 M HCl, and extracted with 100 mL of EA. The aqueous phase was separated, and the aqueous phase was extracted again with 100 mL of EA. The organic phases were combined, washed once with water, dried, concentrated, and crystallized with n-heptane to obtain 13.2 g of the product, with a yield of 62.1%. 1 H NMR (600MHz, DMSO-d6) δ9.25 (s, 1H), 7.87–7.82 (m, 2H), 7.80 (d, J = 8.0 Hz, 1H), 7.16–7.11 (m, 3H), 7.09 (dd, J = 8.0, 2.1 Hz, 1H), 4.97 (s, 2H). LC-MS[MH] - =250.

[0184] Example 7: Synthesis of Criborone

[0185]

[0186] 1.8 g of 4-cyanopyridine, 14.6 g of potassium methoxide, 31 g of tetrahydroxydiborane, and 30 g of methyl [2-bromo-5-(4-cyanophenoxy)phenyl]acetate were added to 60 mL of acetonitrile. After the addition was complete, the mixture was purged with nitrogen three times and irradiated with 450 nm blue light at room temperature for 48 h. Samples were taken for analysis. After the reaction was complete, the mixture was cooled to room temperature, and 240 mL of water was added. The mixture was reacted at room temperature for 2 h. 100 mL of EA was added, and the mixture was extracted and separated into layers. The aqueous phase was extracted again with 100 mL of EA. The organic phases were combined, washed with 50 mL of water twice, dried, filtered, and concentrated to dryness to obtain the crude product. Crystallization with EA yielded 12.8 g of the product, with a yield of 58.6%.

[0187] Example 8: Synthesis of Criborone

[0188]

[0189] 20 g of 4-[4-bromo-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]phenoxybenzonitrile, 52.4 g of dipinacol boronic acid ester, and 11.6 g of potassium tert-butoxide were added to 100 mL of MTBE. The mixture was purged with nitrogen three times, and 0.25 g of peroxybenzoyl was added. The mixture was heated to 60 °C and reacted for 24 h. After sampling and analysis, the reaction was considered complete. The mixture was cooled to room temperature, and 400 mL of water was added. The pH was adjusted to 1 with hydrochloric acid, and the reaction was continued for 3 h. 500 mL of EA was added, and the mixture was extracted. The aqueous phase was extracted again with 500 mL of EA. The organic phases were combined, washed with 200 mL of brine three times, dried, filtered, and concentrated to dryness to obtain the crude product. The crude product was obtained by crystallization with EA and n-heptane, yielding 6.1 g of the product, with a yield of 47.2%.

[0190] Example 9: Synthesis of Criborone

[0191]

[0192] 20 g of 4-[4-bromo-3-(hydroxymethyl)phenoxy]benzyl nitrile, 67.3 g of dipinacol boronic acid ester, and 14.8 g of potassium tert-butoxide were added to 120 mL of MTBE. The mixture was purged with nitrogen three times, irradiated with 450 nm blue light, and heated to 60 °C for 24 h. After sampling and analysis, the reactants were cooled to room temperature, 400 mL of water was added, and the mixture was stirred for 3 h. Then, 500 mL of EA was added, and the mixture was extracted. The aqueous phase was extracted again with 500 mL of EA. The organic phases were combined, washed with 200 mL of brine three times, dried, filtered, and concentrated to dryness to obtain the crude product. The product was then crystallized from EA and n-heptane to obtain 11.1 g of the crude product, with a yield of 66.7%.

[0193] Example 10: Synthesis of Criborone

[0194]

[0195] 1.8 g of 4-cyanopyridine, 14.6 g of potassium methoxide, 88.4 g of dipinacol boronic acid ester, and 30 g of methyl [2-bromo-5-(4-cyanophenoxy)phenyl]acetate were added to 300 mL of acetonitrile. After the addition was complete, the mixture was irradiated with 450 nm blue light and reacted at room temperature for 48 h. Samples were taken for analysis. After the reaction was complete, the mixture was cooled to room temperature, and 240 mL of water was added and stirred for 2 h. 100 mL of EA was added, and the mixture was extracted and separated into layers. The aqueous phase was extracted again with 100 mL of EA. The organic phases were combined, washed with 50 mL of water twice, dried, filtered, and concentrated to dryness to obtain the crude product. Crystallization with EA yielded 15.3 g of the product, with a yield of 70.1%.

Claims

1. A method for preparing creborol, characterized in that, It includes the following steps: (1) Compound II undergoes a free radical reaction in the presence of a basic reagent and a boriding reagent to generate compound I, as follows: in, The free radical reaction is initiated by light or a free radical initiator; The boryling agent is selected from tetrahydroxydiborane or borate esters, wherein the borate ester has the following structure: (2) After the reaction in step (1) is complete, it is hydrolyzed and cyclized to generate creborol; in, X is selected from Cl, Br, and I; R1 is selected from H or a hydroxyl protecting group; R, R2 and R3 are each independently selected from the following members: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted aryl. R2 and R3, together with the atoms to which they are attached, may optionally be combined to form 4 to 7-membered rings. When R1 of compound II in step (1) is H and the borizing agent is tetrahydroxydiborane, creborone can be directly generated via step (1) without the hydrolysis and cyclization process in step (2).

2. The preparation method according to claim 1, characterized in that, X is selected from Br.

3. The preparation method according to claim 1, characterized in that, In step (1), the hydroxyl protecting group is selected from methoxymethyl, ethoxyethyl, tetrahydropyran-2-yl, trimethylsilyl, tert-butyldimethylsilyl and acetyl; preferably acetyl, tetrahydropyran-2-yl and trimethylsilyl.

4. The preparation method according to claim 1, characterized in that, The alkaline reagent in step (1) is selected from one or more of pyridine, 4-cyanopyridine, potassium carbonate, cesium carbonate, potassium methoxide, potassium tert-butoxide, sodium methoxide, and sodium tert-butoxide; preferably, the alkaline reagent in step (1) is selected from one or more of 4-cyanopyridine, potassium methoxide, and potassium tert-butoxide.

5. The preparation method according to claim 1, characterized in that, The illumination wavelength in step (1) is 180nm to 600nm; preferably, the illumination wavelength in step (1) is 400 to 450nm; more preferably, the illumination wavelength in step (1) is 450nm blue light.

6. The preparation method according to claim 1, characterized in that, The free radical initiator in step (1) is selected from one or more of benzoyl peroxide, tert-butyl peroxide, tert-butyl hydroperoxide and azobisisobutyronitrile.

7. The preparation method according to claim 1, characterized in that, In step (1), the R, R2, and R3 of the borate ester are each independently selected from the following members: H, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted phenyl, and substituted or unsubstituted benzyl; preferably, the R2 and R3 of the borate ester in step (1), together with the atoms they are bonded to, may optionally form members selected from the following members: substituted or unsubstituted dioxoboronyl pentane, substituted or unsubstituted dioxoboronyl hexane, and substituted or unsubstituted dioxoboronyl heptane; more preferably, the borate ester in step (1) is selected from pinacol methylborate, pinacol ethylborate, pinacol isopropylborate, dipinacol bis(2-pinacol) boronic acid ester, dimethyl methylborate, diethyl ethylborate, diisopropyl isopropylborate, and dibutyl borate.

8. The preparation method according to any one of claims 1 to 7, characterized in that, Compound II was reacted with a boriding agent in steps (1) and (2) in a one-pot reaction to prepare compound I.

9. The preparation method according to any one of claims 1 to 7, characterized in that, The preparation of compound II further includes the following steps: (a) Compound IV reacts with NH2R4 to form compound V, as follows: (b) Compound V reacts with p-fluorobenzonitrile to form compound VI, as follows: (c) Compound VI undergoes hydrolysis, reduction, and optional protection of the p-hydroxyl group to generate compound II, as follows: Wherein, X and R1 are as described in claim 1; R4 is substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C6-C 12 Cycloalkyl, substituted or unsubstituted C6-C 12 Aryl.

10. The preparation method according to claim 9, characterized in that, R4 is n-butyl, cyclohexyl, or phenyl; preferably, R4 is cyclohexyl.

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