Process for the preparation of chiral octalide hemiacetal compounds and their reaction with ibuprofen drug molecules
By using raw materials such as sulfinyl dibenzaldehyde, the problem of synthesizing novel chiral eight-membered ring hemiacetal compounds in existing technologies has been solved. This method achieves efficient and stereoselective synthesis, filling a gap in the field and showing broad application prospects.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- GUANGXI UNIV FOR NATITIES
- Filing Date
- 2026-03-01
- Publication Date
- 2026-06-02
AI Technical Summary
No chiral eight-membered ring hemiacetal compounds with the same or similar structure as the present invention have been reported in the prior art, making it difficult to achieve the synthesis of chiral eight-membered ring hemiacetal compounds with novel structure, synthetic accessibility and stereoselectivity.
Using sulfinyl dibenzaldehyde, acetone, dimethyl sulfoxide and anhydrous acetonitrile as raw materials, a novel class of chiral eight-membered ring hemiacetal compounds were synthesized through a series of steps including stirring, extraction, washing, drying and chromatographic separation. The specific steps include S1 to S14.
A novel class of chiral eight-membered ring hemiacetals was synthesized efficiently and stereocontrollably with good yields, suitable for derivatization, and has broad application prospects.
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Abstract
Description
Technical Field
[0001] This invention relates to the fields of organic synthetic chemistry and medicinal chemistry, specifically to a series of novel chiral eight-membered ring hemiacetal compounds and their preparation methods, as well as their reactions with ibuprofen drug molecules. Background Technology
[0002] The hemiacetal structure is a key pharmacophore in many natural products (such as certain iridoids and sugars) and bioactive molecules, and its formation often involves dynamic stereochemical control. However, the organic combination of a chiral center with a specific-sized eight-membered ring skeleton and hemiacetal functional groups, especially achieving its controllable first synthesis, remains a significant challenge. No chiral eight-membered ring hemiacetal compounds with the same or similar structures as those of this invention have been reported in the prior art. Therefore, developing a class of novel chiral eight-membered ring hemiacetal compounds with synthetic accessibility and stereoselectivity is of great significance for expanding the library of medium-ring compounds and discovering new chiral catalysts or lead drug molecules. Summary of the Invention
[0003] The primary objective of this invention is to provide a class of novel, optically active chiral eight-membered ring hemiacetal compounds. The second objective of this invention is to provide a method for preparing the above-mentioned chiral eight-membered ring hemiacetal compound, which should have the characteristics of simple route, stereocontrollable structure, and good yield. A third objective of this invention is to provide a linking mechanism between the aforementioned chiral eight-membered ring hemiacetal compound and a pharmaceutical chemical intermediate. Furthermore, the eight-membered ring compound is any one of the following: (5S,7R,12R)-12-oxo-7-(2-oxopropyl)-5H,7H-dibenzo[c,f][1,5]oxothiazine-5-ylacetate, abbreviated as A1, has the following structural formula: (5S,7R,12R)-3,9-dichloro-12-oxo-7-(2-oxopropyl)-5H,7H-dibenzo[c,f][1,5]oxothiazine-5-ylacetate, abbreviated as A2, has the following structural formula: (5S,7R,12R)-12-oxo-7-(2-oxohexyl)-5H,7H-dibenzo[c,f][1,5]oxothiazine-5-ylacetate, abbreviated as A3, has the following structural formula: (5S,7S,12R)-12-oxo-7-(2-oxopropyl)-5H,7H-dibenzo[c,f][1,5]oxothiathiophene-5-yl 2-(4-isobutylphenyl)propionate, abbreviated as A4, has the following structural formula: The present invention also provides a method for preparing the above-mentioned eight-membered ring compound, comprising the following steps: S1: Sulfodibenzaldehyde, acetone, dimethyl sulfoxide and anhydrous acetonitrile are mixed into a solution, and then L-proline is added to it. The mixture is stirred at room temperature. After the reaction is completed, the crude product of the first product is obtained. S2: Extract the crude product of the first product with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and dry; separate by chromatography to obtain the first product; S3: Dissolve the first product in dichloromethane, add triethylamine and acetyl chloride, and stir; S4: After the reaction is complete, the solvent is evaporated and the target product A1 is obtained by column chromatography. S5: Mix 6,6'-sulfinylbis(3-chlorobenzaldehyde), acetone, dimethyl sulfoxide and anhydrous acetonitrile into a solution, then add L-proline to it, stir at room temperature, and after the reaction is complete, the crude product of the first product is obtained; S6: Extract the crude product of the first product with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and dry; separate by chromatography to obtain the first product; S7: Dissolve the first product in dichloromethane, add triethylamine and acetyl chloride, and stir; S8: After the reaction is complete, the solvent is evaporated and the target product A2 is obtained by column chromatography. S9: Sulfodibenzaldehyde, 2-hexanone, dimethyl sulfoxide and anhydrous acetonitrile are mixed into a solution, and then L-proline is added to it. The mixture is stirred at room temperature. After the reaction is completed, the crude product of the first product is obtained. S10: Extract the crude product of the first product with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and dry; separate by chromatography to obtain the first product; S11: Dissolve the first product in dichloromethane, add triethylamine and acetyl chloride, and stir; S12: After the reaction is complete, the solvent is evaporated and the target product A3 is obtained by column chromatography. S13: Dissolve the first product in anhydrous acetonitrile, add dicyclohexylcarbodiimide, finely powdered 4-dimethylaminopyridine and ibuprofen, stir at room temperature to obtain the target product; S14: After the reaction is complete, the solvent is evaporated and the target product A4 is obtained by column chromatography. Furthermore, in step S1, acetone accounts for 20% of the total volume. Furthermore, in step S1, the volume ratio of dimethyl sulfoxide to anhydrous acetonitrile is 1:1, and the time is 6 hours. Furthermore, in step S3, the temperature is 5°C and the time is 30 minutes. Furthermore, in step S9, 2-hexanone accounts for 20% of the total volume. Furthermore, in step S13, the mixture is stirred at room temperature for 1 hour. The present invention has the following beneficial effects: 1. Structural novelty: This invention is the first to synthesize and confirm a novel chiral eight-membered ring hemiacetal skeleton, filling a gap in this structural field. 2. Highly efficient synthesis method: The provided preparation method starts from sulfinyl dibenzaldehyde and constructs a challenging chiral eight-membered ring system efficiently and stereoselectively through a key intramolecular cyclization step. The method is simple to operate and suitable for derivatization. 3. Structural diversity: By changing the substituents (R1) and ketones of the benzene ring precursor, a series of structurally diverse analogs can be systematically synthesized, providing a material basis for structure-activity relationship studies. 4. Broad application prospects: The unique chiral eight-membered ring hemiacetal structure of this type of compound makes it potentially valuable in fields such as asymmetric catalysis, molecular recognition, and drug discovery. Attached Figure Description Figure 1 The 1H NMR spectrum of compound A1 obtained in Example 1 of this invention. Figure 2 The carbon NMR spectrum of compound A1 obtained in Example 1 of this invention. Figure 3 The high-performance liquid chromatogram of compound A1 obtained in Example 1 of this invention. Figure 4 The 1H NMR spectrum of compound A2 obtained in Example 1 of this invention. Figure 5 The carbon NMR spectrum of compound A2 obtained in Example 1 of this invention. Figure 6 The high-performance liquid chromatogram of compound A2 obtained in Example 1 of this invention. Figure 7 The 1H NMR spectrum of compound A3 obtained in Example 1 of this invention. Figure 8 The carbon NMR spectrum of compound A3 obtained in Example 1 of this invention. Figure 9 The high-performance liquid chromatogram of compound A3 obtained in Example 1 of this invention. Figure 10 The 1H NMR spectrum of compound A4 obtained in Example 1 of this invention. Figure 11 The carbon NMR spectrum of compound A4 obtained in Example 1 of this invention. Figure 12 The high-performance liquid chromatogram of compound A4 obtained in Example 1 of this invention. Detailed Implementation To facilitate a better understanding of the present invention, the following examples are provided. These examples fall within the scope of protection of the present invention, but do not limit the scope of protection of the present invention. All reagents and raw materials used are commercially available or synthesized using methods known in the art. Example 1 Its synthetic route is as follows: Compound A1: Compound A2: Compound A3: Product A1, white solid, 75% yield, melting point 154.7–155.1 °C. 1 H NMR (400 MHz, CDCl3) δ8.20 (d, J = 8.1 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.49– 7.43 (m, 1H), 7.43 – 7.33 (m, 3H), 7.18 (d, J = 7.6 Hz, 1H), 6.73 (s, 1H), 5.87 (dd, J = 8.7, 4.7 Hz, 1H), 3.38 (dd, J = 17.1, 8.7 Hz, 1H), 2.89 (dd, J =17.1, 4.7 Hz, 1H), 2.29 (s, 3H), 2.19 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ204.48, 170.94, 144.73, 141.70, 138.90, 134.60, 130.72, 130.33, 129.99,129.84, 127.01, 126.62, 124.07, 123.92, 95.14, 79.63, 50.17, 30.91,21.20. HRMS(ESI, m / z): Mass calcd. for C 19 H 19 O5S + [M+H] + , 359.0948; found359.0953. HPLC analysis (Chiralcel IC; 25 °C, IPA / Hexane = 20 / 80, 0.5 mL / min, 254 nm), Rt1(minor) = 41.1 min, Rt2(major) = 46.4 min; 3:97 er. Product A2, white solid, yield 76%, melting point 189.3–190.7 °C. 1 H NMR (400 MHz, CDCl3) δ8.10 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.37 (s, 1H), 7.16 (s, 1H), 6.65 (s, 1H), 5.82 (dd,J = 8.1, 4.8 Hz, 1H), 3.34 (dd, J = 17.4, 8.4 Hz, 1H), 2.90 (dd, J = 17.4,4.5 Hz, 1H), 2.31 (s, 3H), 2.20 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 203.79,170.72, 142.94, 140.53, 139.92, 137.19, 136.65, 136.22, 130.45, 130.21,127.16, 126.88, 125.75, 125.70, 94.51, 79.18, 49.85, 30.73, 21.13. HRMS (ESI,m / z): Mass calcd. for C 19 H 16 Cl2NaO5S + [M+Na] + , 448.9988; found 448.9987. HPLC analysis(Chiralcel IC; 25 °C, IPA / Hexane = 15 / 85, 0.5 mL / min, 254 nm), Rt1(minor) = 34.7 min, Rt2(major) = 39.8 min; 3:97 er. Product A3, an oily substance, with a yield of 64%. 1 H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.48 – 7.33 (m, 4H), 7.17 (d, J = 7.7 Hz, 1H), 6.72 (s, 1H), 5.88 (dd, J = 8.7, 4.7 Hz, 1H), 3.35 (dd, J = 16.8, 8.8 Hz, 1H), 2.84 (dd, J = 16.8, 4.7 Hz, 1H), 2.45 (ddd, J = 16.7, 15.9, 7.5 Hz,2H), 2.28 (s, 3H), 1.54 (dd, J = 15.3, 7.7 Hz, 2H), 1.28 (dt, J = 11.2, 5.7 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 206.88, 170.84, 144.84,141.77, 139.06, 134.70, 130.69, 130.31, 129.93, 129.82, 127.01, 126.62,124.05, 123.92, 95.17, 79.90, 49.31, 43.69, 25.69, 22.35, 21.18, 13.96. HRMS (ESI, m / z): Mass calcd. for C 22 H 25 O5S + [M+H] + , 401.1417; found 401.1419. HPLC analysis(Chiralcel ID; 25 °C, IPA / Hexane = 20 / 80, 0.5 mL / min, 254 nm), Rt1(minor) = 43.8 min, Rt2(major) = 71.3 min; 4:96 er. Application Example: Linkage with Ibuprofen Drug Molecules An eight-membered ring hemiacetal, dicyclohexylcarbodiimide, and finely powdered 4-dimethylaminopyridine were added to an anhydrous acetonitrile solution of ibuprofen. The reaction mixture was concentrated under vacuum. The crude product was purified by silica gel column chromatography to give the target compound A4. Product A3, an oily substance, with a yield of 85%. 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 4.5 Hz, 1H), 8.02 (d, J = 2.3 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.46 – 7.44 (m, 1H), 7.36–7.39 (m, 2H), 7.30 (d, J = 8.1 Hz, 2H), 7.16 (m, 3H), 6.97 (d, J = 7.6 Hz,1H), 6.67 (s, 1H), 5.96 (dd, J = 8.8, 4.6 Hz, 1H), 3.98 – 3.92 (m, 1H), 3.40(dd, J = 17.0, 8.8 Hz, 1H), 2.91 (dd, J = 17.0, 4.6 Hz, 1H), 2.49 (d, J = 3.2 Hz, 2H), 2.20 (s, 3H), 1.92–1.82 (m, 1H), 1.66 (d, J = 7.1 Hz, 3H), 0.91 (d, J = 6.6Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 204.53, 174.62, 174.49, 144.37, 144.17,141.18, 141.06, 141.04, 140.98, 139.01, 138.91, 137.22, 136.49, 134.67,130.73, 130.72, 130.18, 130.09, 129.98, 129.96, 129.72, 129.61, 129.51,127.44, 127.42, 127.03, 127.00, 126.51, 126.31, 124.05, 123.96, 123.72,95.03, 94.77, 79.77, 79.38, 50.67, 50.08, 49.96, 45.38, 45.12, 45.07, 45.03,30.78, 30.76, 30.29, 30.26, 22.42, 22.40, 22.36, 17.90.HRMS (ESI, m / z): Masscalcd. for C 30 H 33 O5S + [M+H] + , 505.2043; found 505.2048. HPLC analysis (ChiralcelID; 25 °C, IPA / Hexane = 20 / 80, 1 mL / min, 254 nm), Rt1(minor) = 14.7 min, Rt2(major) = 19.5 min; 6:94 er. 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 a chiral eight-membered ring hemiacetal compound and its reaction with ibuprofen drug molecules are provided.
2. According to the method described in claim 1, the following four eight-membered ring compounds were obtained: (5S,7R,12R)-12-oxo-7-(2-oxopropyl)-5H,7H-dibenzo[c,f][1,5]oxothiazine-5-ylacetate, abbreviated as A1, has the following structural formula: (5S,7R,12R)-3,9-dichloro-12-oxo-7-(2-oxopropyl)-5H,7H-dibenzo[c,f][1,5]oxothiazine-5-ylacetate, abbreviated as A2, has the following structural formula: (5S,7R,12R)-12-oxo-7-(2-oxohexyl)-5H,7H-dibenzo[c,f][1,5]oxothiazine-5-ylacetate, abbreviated as A3, has the following structural formula: (5S,7S,12R)-12-oxo-7-(2-oxopropyl)-5H,7H-dibenzo[c,f][1,5]oxothiathiophene-5-yl 2-(4-isobutylphenyl)propionate, abbreviated as A4, has the following structural formula:
3. A method for preparing an eight-membered ring compound as described in claim 1 or 2, characterized in that, Includes the following steps: S1: Sulfodibenzaldehyde, acetone, dimethyl sulfoxide and anhydrous acetonitrile are mixed into a solution, and then L-proline is added to it. The mixture is stirred at room temperature. After the reaction is completed, the crude product of the first product is obtained. S2: Extract the crude product of the first product with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and dry; separate by chromatography to obtain the first product; S3: Dissolve the first product in dichloromethane, add triethylamine and acetyl chloride, and stir; S4: After the reaction is complete, the solvent is evaporated and the target product A1 is obtained by column chromatography. S5: Mix 6,6'-sulfinylbis(3-chlorobenzaldehyde), acetone, dimethyl sulfoxide and anhydrous acetonitrile into a solution, then add L-proline to it, stir at room temperature, and after the reaction is complete, the crude product of the first product is obtained; S6: Extract the crude product of the first product with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and dry; separate by chromatography to obtain the first product; S7: Dissolve the first product in dichloromethane, add triethylamine and acetyl chloride, and stir; S8: After the reaction is complete, the solvent is evaporated and the target product A2 is obtained by column chromatography. S9: Sulfodibenzaldehyde, 2-hexanone, dimethyl sulfoxide and anhydrous acetonitrile are mixed into a solution, and then L-proline is added to it. The mixture is stirred at room temperature. After the reaction is completed, the crude product of the first product is obtained. S10: Extract the crude product of the first product with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and dry; separate by chromatography to obtain the first product; S11: Dissolve the first product in dichloromethane, add triethylamine and acetyl chloride, and stir; S12: After the reaction is complete, the solvent is evaporated and the target product A3 is obtained by column chromatography. S13: Dissolve the first product in anhydrous acetonitrile, add dicyclohexylcarbodiimide, finely powdered 4-dimethylaminopyridine and ibuprofen, stir at room temperature to obtain the target product; S14: After the reaction is complete, the solvent is evaporated and the product A4 is obtained by column chromatography.
4. The method for preparing the eight-membered ring compound according to claim 3, characterized in that: In step S1, acetone accounts for 20% of the total volume.
5. The method for preparing the eight-membered ring compound according to claim 3, characterized in that: In step S1, the volume ratio of dimethyl sulfoxide to anhydrous acetonitrile is 1:
1.
6. The method for preparing the eight-membered ring compound according to claim 3, characterized in that: In step S1, stir at room temperature for 6 hours.
7. The method for preparing the eight-membered ring compound according to claim 3, characterized in that: In step S3, the temperature is 5°C and the time is 30 minutes.
8. The method for preparing the eight-membered ring compound according to claim 3, characterized in that: In step S9, 2-hexanone accounts for 20% of the total volume.
9. The method for preparing the eight-membered ring compound according to claim 3, characterized in that: In step S13, stir at room temperature for 1 hour.