Method for preparing crisaborole through in-situ cyanation

Abstract

A method for preparing crisaborole through in-situ cyanation relates to the field of chemical synthesis, and adopts a cyano-free compound A and a cyano-free compound B as initial raw materials, and crisaborole is prepared through the reaction steps of nucleophilic coupling reaction, carbonyl protection, hydroxyl protection, borylation, deprotection, cyanation and the like. According to the preparation method, the traditional synthesis mode is changed, and the construction of cyano groups is finally carried out, so that the problem of side reaction caused by cyano groups in the borylation process is avoided. The preparation method is simple and convenient to operate, mild in reaction condition and relatively high in overall yield, avoids the use of a transition metal catalyst, is very suitable for being applied to medicine production, and has a relatively good application prospect.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis, and more specifically, to a method for preparing criborone by in-situ cyanohydrin. Background Technology

[0002] Crizoborole, chemically known as 4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborphane-5-yl)oxy)benzonitrile, has the molecular formula C 14 H 10 BNO3, with a molecular weight of 251.05, is a topical ointment called Eucrisa, containing 2% crisaborole. Originally indicated for patients aged 2 years and older with mild to moderate atopic dermatitis, it has been approved by the US FDA to extend the minimum age of application to patients aged 3 months and older with mild to moderate atopic dermatitis. It is also the only steroid-free drug for treating atopic dermatitis to date. In China, it is marketed as Shutanming.

[0003] Criborone, as a topical PDE4 inhibitor, greatly reduces the side effects of traditional drugs such as skin atrophy and liver and kidney toxicity. Clinically, it can be used for mild to moderate patients as young as three months old, with good safety and tolerability, and few adverse reactions and side effects.

[0004] There are two important functional groups in the molecular structure of criborone: one is a cyano group directly attached to the benzene ring, and the other is a benzo5-membered ring structure containing boron atoms. How to construct these two functional groups is the key to the synthesis of criborone.

[0005] In existing technologies, raw materials containing cyano groups are typically chosen as initial feedstocks. For example, in patent CN107759625B, p-fluorobenzonitrile is used as one of the initial feedstocks. The core framework is constructed through a coupling reaction, and then reacted with a borate ester to form a five-membered ring structure. Due to the presence of the cyano group, the butyllithium reagent used in the final reaction with the borate ester attacks the cyano group to generate a carbonyl group. This side reaction significantly affects the reaction yield, increases the loss of butyllithium, and makes the purification of the product from this step more difficult.

[0006] To address this issue, some patents have offered improvements. For example, patent CN108047261B uses B2Pin2 as the boron source and introduces a boron ester under palladium catalysis, ultimately completing the ring-closure construction of the crucial benzo[a] five-membered ring structure containing boron atoms. While this method improves the side reaction problem initiated by the cyano group, the palladium reagent is expensive and difficult to remove and recover, remaining a challenging issue in drug production.

[0007] Therefore, it is essential to develop a new synthetic method that can effectively avoid side reactions and the use of transition metal catalysts. Summary of the Invention

[0008] The purpose of this invention is to provide a method for preparing criborone that is simple to operate, has mild reaction conditions, effectively avoids side reactions, and uses transition metal catalysts, making it suitable for application in pharmaceutical production.

[0009] The embodiments of the present invention are implemented as follows:

[0010] A method for preparing criborone by in-situ cyanidation, comprising:

[0011] Using compounds A and B as raw materials, a nucleophilic coupling reaction was carried out to obtain compound C;

[0012] Protecting the carbonyl group of compound C yields compound D;

[0013] The hydroxyl group of compound D was protected to obtain compound E;

[0014] Compound E was subjected to a borylation reaction with a borate ester, followed by the removal of the carbonyl protecting group and the hydroxyl protecting group to obtain compound F;

[0015] The carbonyl group of compound F was converted to a cyano group to obtain criborone.

[0016] The structural formula of compound A is as follows: The structural formula of compound B is The structural formula of compound C is The structural formula of compound D is The structural formula of compound E is The structural formula of compound F is The structural formula of criborone is

[0017]

[0018] In the formula, R1 is a carbonyl protecting group, and the two R1s are independently selected from C1 to C4 alkyl groups, or the two R1s together form a C1 to C6 short-chain alkyl group; R2 is a hydroxyl protecting group, selected from TMS, TES, TBDMS, TBDPS, or TIPS.

[0019] The beneficial effects of the embodiments of the present invention are:

[0020] This invention provides a method for the in-situ cyanolation preparation of criborone. Using cyano-free compounds A and B as starting materials, the method involves nucleophilic coupling, carbonyl protection, hydroxyl protection, borylation, deprotection, and cyanation to obtain criborone. This method departs from traditional synthetic approaches by placing the cyano group construction at the end, thus avoiding side reactions initiated by the cyano group during borylation. The method is simple and convenient to operate, with mild reaction conditions, high overall yield, and avoids the use of transition metal catalysts, making it highly suitable for pharmaceutical production and demonstrating promising application prospects. Attached Figure Description

[0021] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0022] Figure 1 The criborone provided in Embodiment 6 of the present invention 1 H NMR spectrum;

[0023] Figure 2 The criborone provided in Embodiment 6 of the present invention 13 C10 NMR spectrum. Detailed Implementation

[0024] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0025] The following is a detailed description of a method for preparing criborone by in-situ cyanohydrin according to an embodiment of the present invention.

[0026] A method for preparing criborone by in-situ cyanidation, comprising:

[0027] Using compounds A and B as raw materials, a nucleophilic coupling reaction was carried out to obtain compound C;

[0028] Protecting the carbonyl group of compound C yields compound D;

[0029] The hydroxyl group of compound D was protected to obtain compound E;

[0030] Compound E was subjected to a borylation reaction with a borate ester, followed by the removal of the carbonyl protecting group and the hydroxyl protecting group to obtain compound F;

[0031] The carbonyl group of compound F was converted to a cyano group to obtain criborone.

[0032] The structural formula of compound A is as follows: The structural formula of compound B is The structural formula of compound C is The structural formula of compound D is The structural formula of compound E is The structural formula of compound F is The structural formula of criborone is

[0033]

[0034] In the formula, R1 is a carbonyl protecting group, and the two R1s are independently selected from C1 to C4 alkyl groups, or the two R1s together form a C1 to C6 short-chain alkyl group; R2 is a hydroxyl protecting group, selected from TBDPS, TBS, TMS, TES, TBDMS or TIPS.

[0035] The coupling reaction between compound A and compound B is carried out at 60–120°C under the catalysis of an alkaline reagent. Optionally, the alkaline reagent includes at least one selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydride. The reaction is carried out in an organic solvent, such as DMF, THF, or CH3CN. Preferably, DMF is used as the solvent, as it provides better dissolution of the raw materials and facilitates the reaction.

[0036] Furthermore, the molar ratio of compound A to compound B is 1:1 to 1.5. Under these reaction ratios, the reaction can be better promoted, and the product yield can be increased.

[0037] Further, the carbonyl group in compound C is protected by reacting compound C with an alcohol reagent to generate an acetal, wherein the alcohol reagent includes at least one of methanol, ethanol, propanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, or 2,3-butanediol. When using a monohydric alcohol, such as methanol, ethanol, or propanol, the two corresponding R1s are independently selected from C1 to C4 alkyl groups. When using a dihydric alcohol, such as ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, or 2,3-butanediol, the two corresponding R1s together constitute a C1 to C6 short-chain alkyl group.

[0038] Optionally, the hydroxyl protecting group is selected from TMS, TES, TBDMS, TBDPS, or TIPS. Depending on the different hydroxyl protecting groups, the corresponding deprotection and deprotection reaction reagents and conditions are selected. Taking the TBDMS protecting group as an example, TBSCl can be selected to react with compound D, and imidazole can be added as an acid-binding agent. Correspondingly, hydrochloric acid can be used for deprotection.

[0039] The boronization reaction of compound E involves reacting compound E with a borate ester. Optionally, the borate ester includes at least one selected from trimethyl borate, triethyl borate, tri-n-propyl borate, triisopropyl borate, and tri-n-butyl borate. During the reaction, n-butyllithium is added to promote the reaction. The n-butyllithium is added slowly dropwise to compound E at low temperature, and after the addition is complete, the mixture is brought to room temperature for further reaction. After the reaction is complete, the hydroxyl protecting group is removed to obtain compound F. Optionally, the molar ratio of compound E to the borate ester is 1:1.2–3. Within this ratio range, it is ensured that compound E reacts sufficiently, thereby achieving a high yield.

[0040] Furthermore, the carbonyl group of compound F is converted to a cyano group by reacting compound F with hydroxylamine-O-sulfonic acid, wherein the molar ratio of compound F to hydroxylamine-O-sulfonic acid is 1:1 to 1.5. This reaction is carried out in a mixed solvent of acetic acid and water at a temperature of 40 to 70 °C.

[0041] The features and performance of the present invention will be further described in detail below with reference to embodiments.

[0042] Example 1

[0043] This embodiment provides a method for preparing compound C, the reaction formula of which is as follows:

[0044]

[0045] Its specific preparation steps include:

[0046] Compound A (3.00 g, 14.78 mmol, 1.00 eq) was weighed and placed in a 100 mL round-bottom flask. DMF (30.0 mL) was added to dissolve it, followed by K₂CO₃ (3.50 g, 25.3 mmol, 1.71 eq) and compound B (2.20 g, 17.74 mmol, 1.20 eq). The mixture was heated to 80 °C under argon protection. After the reaction was completed by TLC monitoring, 50 mL of water was added, and the mixture was extracted with EtOAc (3 × 50.0 mL). The combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated. The crude product was then subjected to silica gel column chromatography (V) PE :V EAThe mixture was prepared by mixing 5 parts of the compound with 1 part of the extract to obtain a yellow oily substance, namely compound C, in a yield of 4.35 g, with a yield of 95.8%.

[0047] The characterization of compound C is as follows:

[0048] 1 H NMR (400MHz, CDCl3), δ (ppm): 9.77 (s, 1H), 7.72 (d, J = 8.3Hz, 2H), 7.43 (d, J = 8.6Hz, 1H), 7 .18(s,1H),6.94(d,J=8.4Hz,2H),6.78(dd,J=8.6,3.0Hz,1H),4.62(s,2H),2.95(s,1H).

[0049] 13 C NMR (100MHz, CDCl3), δ (ppm): 191.0, 162.7, 154.8, 142.3, 133.9, 132.1, 131.5, 120.5, 120.2, 117.8, 116.9, 64.4.

[0050] Example 2

[0051] This embodiment provides a method for preparing compound D, the reaction formula of which is as follows:

[0052]

[0053] Its specific preparation steps include:

[0054] Compound C (2.50 g, 8.14 mmol, 1.00 eq) was weighed and placed in a 100 mL round-bottom flask. Toluene (25.0 mL), ethylene glycol (5.56 mL, 99.7 mmol, 12.20 eq), and p-toluenesulfonic acid (28.0 mg, 0.163 mmol, 0.02 eq) were added sequentially. The reaction was carried out under argon protection at 135 °C under reflux. Water was separated using a water separator. After the reaction was completed, the reaction solution was allowed to cool naturally to room temperature and then added to a saturated NaHCO3 solution. Extraction was performed with EtOAc (3 × 50.0 mL). The combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the crude product obtained by concentration was subjected to silica gel column chromatography (V). PE :V EA The mixture was prepared by mixing (5:1) to obtain a colorless oily substance, namely compound D, 2.57 g, with a yield of 90.0%.

[0055] The characterization of compound D is as follows:

[0056] 1H NMR (400MHz, CDCl3), δ (ppm): 7.44 (dd, J=8.6, 1.7Hz, 3H), 7.15 (d, J=3.0Hz, 1H), 7.05–6.93 ( m,2H),6.79(dd,J=8.6,3.0Hz,1H),5.76(s,1H),4.63(s,2H),4.17–3.99(m,4H),2.38(s,1H).

[0057] 13 C NMR (100MHz, CDCl3), δ (ppm): 157.6, 156.8, 141.6, 133.5, 133.1, 128.3, 119.3, 119.1, 118.8, 115.4, 103.4, 65.3, 64.6.

[0058] Example 3

[0059] This embodiment provides a method for preparing compound E, the reaction formula of which is as follows:

[0060]

[0061] Its specific preparation steps include:

[0062] Compound D (4.40 g, 12.5 mmol, 1.00 eq) was weighed and placed in a 100 mL round-bottom flask. CH₂Cl₂ (20.0 mL) was added to dissolve it. Then, imidazole (1.19 g, 17.0 mmol, 2.20 eq) and tert-butyldimethylchlorosilane (TBSCl, 2.56 g, 17.0 mmol, 1.36 eq) were added sequentially. The mixture was stirred at room temperature. After the reaction was monitored by TLC, saturated NH₄Cl solution was added to quench the reaction. The mixture was extracted with CH₂Cl₂ (3 × 20.0 mL). The extracted organic phases were combined, dried, concentrated, and then subjected to rapid column chromatography on a short silica gel column (V). PE :V EA =20:1) yielded 35.71g of colorless oily substance B-, with a yield of 98.0%.

[0063] The characterization of compound E is as follows:

[0064] 1H NMR (400MHz, CDCl3), δ (ppm): 7.41–7.34 (m, 2H), 7.32 (d, J = 8.6Hz, 1H), 7.13 (dd, J = 3.0, 1.0Hz, 1H), 6.93 (d, J = 8.5Hz, 2H ),6.70–6.64(m,1H),5.71(s,1H),4.59(d,J=1.2Hz,2H),4.09–3.85(m,4H),0.80(d,J=0.8Hz,9H),0.00(d,J=0.7Hz,6H).

[0065] 13 C NMR (100MHz, CDCl3), δ (ppm): 157.5, 157.0, 142.2, 133.3, 133.0, 128.2, 119.1, 118.4, 118.0, 114.0, 103.4, 65.3, 64.4, 25.9, 18.3, -5.4.

[0066] Example 4

[0067] This embodiment provides a method for preparing compound F, the reaction formula of which is as follows:

[0068]

[0069] Its specific preparation steps include:

[0070] Compound E (301 mg, 0.646 mmol, 1.00 eq) was weighed and placed in a pre-dried double-necked round-bottom flask under argon protection. Then, ultra-dry anhydrous tetrahydrofuran (15.0 mL) and triisopropyl borate (B(i-PrO)3, 0.224 mL, 0.969 mmol, 1.50 eq) were added sequentially, and the mixture was stirred thoroughly in a -78°C magnetically stirred cryogenic bath. After half an hour, n-BuLi (0.445 mL, 0.711 mmol, 1.10 eq) was slowly added dropwise to the reaction system. After the addition was complete, the reaction was allowed to proceed for one hour. The mixture was then slowly brought to room temperature, and 6N HCl (0.99 mL) was added. The reaction was stirred overnight at room temperature. 20 mL of water was added to the reaction solution, and the mixture was extracted with EtOAc (3 × 20.0 mL). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was then subjected to silica gel column chromatography (V... PE :V EA The ratio of compounds was 3:1 to 1:1 to give a white solid, namely compound F, 133 mg, with a yield of 81.0%.

[0071] The characterization of compound F is as follows:

[0072] 1H NMR (400MHz, DMSO-d6), δ (ppm): 9.94 (s, 1H), 9.27 (s, 1H), 7.95 (d, J = 8.5Hz, 2H), 7. 80(d,J=7.9Hz,1H),7.18(d,J=8.6Hz,3H),7.11(dd,J=8.0,2.1Hz,1H),4.98(s,2H).

[0073] 13 C NMR (100MHz, DMSO), δ (ppm): 192.1, 162.4, 157.8, 157.1, 133.0, 132.5, 132.0, 119.4, 118.7, 113.2, 70.2.

[0074] Example 5

[0075] This embodiment provides a method for preparing creborone, the reaction formula of which is as follows:

[0076]

[0077] Its specific preparation steps include:

[0078] Compound F (200 mg, 0.788 mmol, 1.00 eq) was weighed and placed in a 25 mL round-bottom flask. Hydroxylamine-O-sulfonic acid (98.0 mg, 0.866 mmol, 1.10 eq), acetic acid (45.1 mL, 0.788 mmol, 1.00 eq), and water (5.00 mL) were added sequentially. The mixture was heated to 50 °C and stirred. After the reaction was completed by TLC monitoring, 1.00 mL of saturated NaHCO3 solution was added to the reaction solution, and the mixture was extracted with EtOAc (3 × 10.0 mL). The combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain a pale yellow solid. The solid was then subjected to silica gel column chromatography (V...). PE :V EA =1:1) to obtain a white solid, namely criborone (181 mg, yield 91.5%).

[0079] The proton and carbon spectra of criborone are as follows: Figure 1 and Figure 2 As shown, the specific characteristics are as follows:

[0080] 1H NMR (400MHz, DMSO-d6) δ (ppm): 9.31 (s, 1H), 7.92 (d, J = 8.8Hz, 2H), 7.86 (d, J = 8.0Hz ,1H),7.17(s,1H),7.16(d,J=8.8Hz,2H),7.10(dd,J=8.0,2.1Hz,1H),4.97(s,2H).

[0081] 13 C NMR (100MHz, DMSO) δ (ppm): 161.1, 157.6, 157.2, 135.2, 133.1, 119.5, 119.2, 119.1, 113.2, 106.0, 70.2.

[0082] In summary, this invention provides a method for the in-situ cyanolation preparation of criborone. Using cyano-free compounds A and B as starting materials, the method involves nucleophilic coupling, carbonyl protection, hydroxyl protection, borylation, deprotection, and cyanation to obtain criborone. This method departs from traditional synthetic approaches by placing the cyano group construction at the end, thus avoiding side reactions caused by the cyano group during borylation. This method is simple and convenient to operate, operates under mild conditions, achieves a high overall yield, and avoids the use of transition metal catalysts, making it highly suitable for pharmaceutical production and demonstrating promising application prospects.

[0083] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing criborone by in-situ cyanohydrin, characterized in that, include: Using compounds A and B as raw materials, a nucleophilic coupling reaction was carried out to obtain compound C; The carbonyl group of compound C is protected to obtain compound D; The hydroxyl groups of compound D are protected to obtain compound E; Compound E was subjected to a borylation reaction with a borate ester, followed by the removal of the carbonyl protecting group and the hydroxyl protecting group to obtain compound F; The carbonyl group of compound F is converted to a cyano group to obtain criborone. Wherein, the structural formula of compound A is The structural formula of compound B is as follows: The structural formula of compound C is as follows: The structural formula of compound D is as follows: The structural formula of compound E is as follows: The structural formula of compound F is as follows: The structural formula of the criborone is: In the formula, R1 is a carbonyl protecting group, and the two R1s are independently selected from C1 to C4 alkyl groups, or the two R1s together form a short-chain alkyl group of C2 to C6; R2 is a hydroxyl protecting group, selected from TBDPS, TBS, TMS, TES, TBDMS or TIPS.

2. The method according to claim 1, characterized in that, The coupling reaction between compound A and compound B is carried out at 60–120°C under the catalysis of an alkaline reagent; the alkaline reagent includes at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydride.

3. The method according to claim 2, characterized in that, The molar ratio of compound A to compound B is 1:1 to 1.

5.

4. The method according to claim 1, characterized in that, Protecting the carbonyl group of compound C involves reacting compound C with an alcohol reagent to generate an acetal, wherein the alcohol reagent includes at least one selected from methanol, ethanol, propanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, or 1,3-butanediol.

5. The method according to claim 1, characterized in that, The borate esters include at least one of trimethyl borate, triethyl borate, tri-n-propyl borate, triisopropyl borate, and tri-n-butyl borate.

6. The method according to claim 5, characterized in that, The molar ratio of compound E to the borate ester is 1:1.2 to 3.

7. The method according to claim 1, characterized in that, The carbonyl group of compound F is converted to a cyano group by reacting compound F with hydroxylamine-O-sulfonic acid.

8. The method according to claim 7, characterized in that, The molar ratio of compound F to hydroxylamine-O-sulfonic acid is 1:1 to 1.

5.

9. The method according to claim 8, characterized in that, The compound G reacts with the hydroxylamine-O-sulfonic acid in a mixed solvent of acetic acid and water at a temperature of 40–70 °C.

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