Bicyclic hemiketal structure compound and preparation method thereof

Abstract

The invention discloses a compound containing a bicyclic hemiketal structure and a preparation method thereof, alkynyl allyl carbonate is used as a raw material, in the presence of a nucleophilic catalyst, alkynyl allyl carbonate reacts with a benzoylacetonitrile derivative, ABB'multi-component reaction is carried out through a continuous [5 + 1] / addition / cyclization reaction sequence, and the compound containing the bicyclic hemiketal structure is obtained. Bicyclic hemiketal derivatives commonly seen in natural product structures are obtained with good to excellent diastereoselectivity. The method has the advantages of good diastereoselectivity products, excellent chemical selectivity, greenness, mild reaction conditions, convenience in operation, few byproducts and the like, the synthesis steps are good in economy, and four chemical bonds and three continuous chiral centers are simultaneously constructed through one-step operation. Meanwhile, the compound with the bicyclic hemiketal structure has important application value in multiple fields of medicinal chemistry, natural product chemistry, traditional Chinese medicine chemistry and the like, and an efficient preparation means and a series of candidate compounds are provided for development of functionality or biological activity of related compounds with the bicyclic hemiketal / hemiacetal structure.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a bicyclic hemiketal compound and its preparation method. Background Technology

[0002] Cyclic compounds containing bicyclic hemiacetal / hemiacetal structures have extremely important application value in many fields such as medicinal chemistry, natural product chemistry, and pesticide chemistry.Functionalized bicyclic hemiacetal / hemiacetal structures are core structural units of many pharmacological compounds; for example, dihydroartemisinin is an artemisinin derivative with antimalarial activity. It generates reactive oxygen species (ROS) through peroxy-bridge cleavage, which disrupts the membrane structure of Plasmodium and inhibits its hemoglobin metabolism (Wang CZ, Wan CP, Li CH, Liang GG, Luo Y., Zhang CF, et al. Ruthenium-dihydroartemisinin complex: a promising new compound for colon cancer prevention via G1 cell cycle arrest, apoptotic induction, and adaptive immuneregulation [J]. Cancer Chemotherapy and Pharmacology, 2024, 93(5): 411-425.); oridonin, as an antitumor active molecule, has activities such as inducing apoptosis, inhibiting cancer cell proliferation, and epigenetic regulation (Li CY, Wang EQ, Cheng Y., Bao JK Oridonin: An active diterpenoid targeting cell cycle arrest, apoptotic and Autophagic pathways for cancer therapeutics [J]. Int J Biochem Cell Biol, 2011, 43(5): 701-704.); Sauchinone has been reported to have anti-inflammatory, antioxidant, and anti-tumor activities (Lee AK, Sung SH, Kim YC, Kim SG Inhibition of lipopolysaccharide-inducible nitricoxide synthase, TNF-α and COX-2 expression by sauchinone effects on I-κBαphosphorylation, C / EBP and AP-1 activation [J]. Br J Pharmacol, 2003, 139(1):11-20.). These natural products or drug molecules all contain bicyclic hemiacetal / hemiacetal structures.Examples with more similar structures include: Chemical A is a taste modifier that can reduce or correct unpleasant tastes in food (WO9310677 A11993-06-10). Compound B is a phenylpropanoid compound extracted from the root of the dwarf tree Murraya paniculata, which is also a component of the traditional Chinese medicine Sanjiu Weitai (J. Nat. Prod. 2018, 81, 22−33). Compound C is a natural product derived from mulberry tree with DA addition and broad biological activity; it is both a multi-target agent for Alzheimer's disease and has inhibitory activity against ATP-citrate lyase, potentially useful for the treatment of chronic and metabolic diseases (BiochemicalSystematics Ecology 2025, 121, 104992, Phytochemistry 2019, 157, 82−91).

[0003]

[0004] . Summary of the Invention

[0005] The purpose of this invention is to provide an efficient and convenient method for synthesizing bicyclic hemiacetal compounds, enabling the one-pot preparation of structurally complex bicyclic hemiacetal compounds from readily available raw materials with high procedural economy.

[0006] The method for synthesizing compounds containing bicyclic hemiketal structures of the present invention uses alkynyl allyl carbonate and benzoyl acetonitrile as shown in Formula I as raw materials, and reacts them in the presence of a nucleophilic catalyst. After separation and purification, the bicyclic hemiketal structure is obtained. It has the advantages of simple process, convenient operation, high yield, good diastereoselectivity, broad substrate range, and few by-products.

[0007] The present invention discloses a compound containing a bicyclic hemiketal structure, the general structural formula of which is shown in Formula II:

[0008]

[0009] In Formula II, R is at least one of phenyl, 4-FC6H4, 4-ClC6H4, 4-IC6H4, 4-BrC6H4, 4-MeOC6H4, 4-MeC6H4, 3-ClC6H4, 3-MeC6H4, 3-MeOC6H4, and 3-thienyl.

[0010] The method for preparing the compound containing the bicyclic hemiketal structure involves using an alkynyl allyl ester (J Org Chem, 2003, 68(3): 692-700.) synthesized from readily available raw materials and a commercially available compound of the formula... The compound shown is used as a starting material. After reaction and separation in a solvent at room temperature under the action of a catalyst, the compound containing a bicyclic hemiketal structure shown in Formula II is obtained. The chemical reaction equation is as follows:

[0011]

[0012] The benzoyl acetonitrile derivatives of Formula I include at least one of the following: benzoyl acetonitrile (2a), 4-fluorobenzoyl acetonitrile (2b), 4-chlorobenzoyl acetonitrile (2c), 4-iodobenzoyl acetonitrile (2d), 4-bromobenzoyl acetonitrile (2e), 4-methoxybenzoyl acetonitrile (2f), 4-methylbenzoyl acetonitrile (2g), 3-chlorobenzoyl acetonitrile (2h.), 3-methylbenzoyl acetonitrile (2i), 3-methoxybenzoyl acetonitrile (2j), and 3-oxo-3-(thiophen-3-yl)propionitrile (2k).

[0013]

[0014] The reaction time can be 36-48 hours, and the reaction temperature can be room temperature. The catalyst is triethylenediamine, 4-dimethylaminopyridine, 4-(4-pyridylmorpholine) or 4-pyrrolidinylpyridine, preferably 4-pyrrolidinylpyridine.

[0015] This invention uses alkynyl allyl ester carbonate as a starting material and reacts it with benzoylacetonitrile derivatives in the presence of a nucleophilic catalyst. Through a continuous [5 + 1] / addition / cyclization reaction sequence, an ABB'-type multicomponent reaction occurs, yielding bicyclic hemiketal derivatives commonly found in natural product structures with high diastereoselectivity. This invention offers advantages such as excellent diastereoselectivity (dr values ​​all greater than 8 / 1), superior chemoselectivity, being green and efficient, with mild reaction conditions, convenient operation, relatively short reaction time (within 48 hours), and fewer byproducts. The method described in this invention has high synthetic efficiency, enabling the simultaneous construction of four chemical bonds and three consecutive chiral centers in a one-pot operation.

[0016] This invention uses alkynyl allyl ester carbonate and formula Using the compound shown as a starting material, the reaction is carried out under the action of a catalyst. After separation and purification, compounds containing a bicyclic hemiketal structure are obtained. This method offers advantages such as simple process, convenient operation (requiring only one step), moderate to excellent yield (38-80%), good diastereoselectivity (dr values ​​all greater than 8 / 1), broad substrate range, and relatively few byproducts. Bicyclic hemiketal compounds have extremely wide and important applications in many fields such as medicinal chemistry, natural products, and traditional Chinese medicine chemistry. For example, anticoagulation therapy is a major intervention for thrombotic diseases, and coagulation factor XIa is a highly promising antithrombotic target. The series of compounds synthesized using this application were used to evaluate the inhibitory activity of coagulation factor XIa. The results showed that the representative compound has good FXIa inhibitory activity, laying the foundation for further research on anticoagulant drugs. This invention provides an efficient and green preparation method for the synthesis of bicyclic hemiketal compounds, and provides candidate molecules for the development of related bioactive molecules. Detailed Implementation

[0017] The following embodiments are further illustrations of the present invention and serve as explanations of the technical content of the present invention. However, the essence of the present invention is not limited to the embodiments described below. Those skilled in the art can and should know that any simple changes or substitutions based on the spirit of the present invention should fall within the protection scope claimed by the present invention.

[0018] Example 1:

[0019] The preparation of methyl (1S*,4aS*,8aR*)-7-carboxylate-1-hydroxy-4,8a-dicyano-1,3-bis(phenyl)-4a,5,8,8a-tetrahydro-1H-isochromene (3a) is as follows:

[0020]

[0021] Add alkynyl allyl ester 1a (24.0 mg, 0.1 mmol), benzoyl acetonitrile 2a (14.6 mg, 0.1 mmol), THF (1 mL), and 4-pyrrolidinyl pyridine (14.8 mg, 0.1 mmol) to a 10 mL reaction flask equipped with a stir bar. Stir the mixture at room temperature and monitor the reaction until completion by TLC. Separate the reaction system by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1) to obtain the target product 3a (14.2 mg), yield: 69%, white solid, melting point: 174.0–176.1 °C. f = 0.26 (developing solvent is petroleum ether / ethyl acetate = 100 / 50, v / v); 1H NMR (acetone-d6, 600MHz)δ 7.72-7.71 (m, 3H), 7.64-7.63 (m, 2H), 7.44-7.38 (m, 6H), 7.01 (m, 1H), 3.56(s, 3H), 3.51 (dd, J = 12.0, 5.6 Hz, 1H), 2.94 (m, 1H), 2.68 (m, 1H), 2.43(m, 1H), 2.21 (d, J = 17.5 Hz, 1H); 13 C NMR (acetone-d6, 150 MHz) δ 165.8,162.6, 137.2, 137.1, 133.0, 131.1, 130.0, 128.6, 128.2, 128.1, 127.6, 127.1,117.5, 117.2, 99.2, 87.1, 51.4, 44.8, 32.9, 30.2, 28.6; HRMS (ESI) m / z: [M +H] + calcd for C 25 H 21 N2O4: 413.1501, found 413.1506.

[0022] Example 2:

[0023] The preparation of methyl (1S*,4aS*,8aR*)-7-carboxylate-1-hydroxy-4,8a-dicyano-1,3-bis(4-fluorophenyl)-4a,5,8,8a-tetrahydro-1H-isochromene is as follows:

[0024]

[0025] Add alkynyl allyl ester 1a (24.0 mg, 0.1 mmol), 4-fluorobenzoyl acetonitrile 2b (16.4 mg, 0.1 mmol), THF (1 mL), and 4-pyrrolidinyl pyridine (14.8 mg, 0.1 mmol) to a 10 mL reaction flask equipped with a stir bar. Stir the mixture at room temperature and monitor the reaction until completion by TLC. Purify the reaction system by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1) to obtain the target product 3b (16.0 mg), yield: 72%, a light brown oil. f =0.15 (developing solvent is petroleum ether / ethyl acetate = 100 / 50); 11H NMR (CDCl3, 600 MHz) δ 7.75 (dd, J = 8.9, 5.3 Hz, 2H), 7.63 (dd, J = 8.9, 5.3 Hz, 2H), 7.12 (t, J = 8.6 Hz, 2H), 7.09 (t, J = 8.7 Hz, 2H), 7.04 (m, 1H), 5.38 (s, 1H), 3.69 (s, 3H), 3.03 (dd, J = 11.9, 5.3 Hz, 1H), 2.92 - 2.87 (m, 1H), 2.68 - 2.64 (m, 1H), 2.56 - 2.50 (m, 1H), 2.35 (d, J = 17.2 Hz, 1H); 13 13C NMR (CDCl3, 150 MHz) δ 166.2, 164.3 (d, 1 J CF = 254 Hz), 163.8 (d, 1 J CF = 250 Hz), 161.9, 137.2, 132.3 (d, 4 J CF = 2.5 Hz), 130.4 (d, 3 J CF = 9.1 Hz), 129.4 (d, 3 J CF = 9.0 Hz), 128.3 (d, 4 J CF = 3.7 Hz), 126.9, 117.5, 117.1, 115.8 (d, 2 J CF = 21.9 Hz), 115.7 (d, 2 J CF = 22.5 Hz), 98.8, 86.5, 52.2, 44.6, 33.0, 29.9, 28.5; 19 19F NMR (CDCl3, 564 MHz) δ -107.2, -110.2; HRMS (ESI) m / z: [M + H] + calcd for C 25 H 19 F2N2O4: 449.1313, found 449.1318.

[0026] Example 3:

[0027] The preparation of (1S*,4aS*,8aR*)-7-carboxylic acid methyl ester-1-hydroxy-1,3-bis(4-chlorophenyl)-4,8a-dicyano-4a,5,8,8a-tetrahydro-1H-isochromene (3c) is as follows:

[0028]

[0029] Add alkynyl allyl ester 1a (24.0 mg, 0.1 mmol), 4-chlorobenzoyl acetonitrile 2c (18.0 mg, 0.1 mmol), THF (1 mL), and 4-pyrrolidinyl pyridine (14.8 mg, 0.1 mmol) to a 10 mL reaction flask equipped with a stir bar. Stir the mixture at room temperature and monitor the reaction until completion by TLC. Purify the reaction system by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1) to obtain the target product 3c (13.2 mg), yield: 55%, light green solid, melting point: 115.6–118.5 °C. f = 0.41 (developing solvent is petroleum ether / ethyl acetate = 100 / 50); 1 H NMR (acetone-d6,600MHz) δ 7.95 (br, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.7 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 9.0 Hz, 2H), 7.00 (m, 1H), 3.56 (s,3H), 3.15 (dd, J = 11.9, 5.4 Hz, 1H), 2.93 (m, 1H), 2.66 (m, 1H), 2.43 (m,1H), 2.22 (d, J = 17.5 Hz, 1H); 13 C NMR (acetone-d6, 150 MHz) δ 165.7, 161.2,137.0, 136.7, 136.0, 135.7, 131.5, 130.0, 129.5, 128.8, 127.0, 117.3, 116.8,99.1, 87.8, 51.4, 44.7, 32.9, 30.1, 28.5; HRMS (ESI) m / z: [M + H] + calcd forC 25 H 19 Cl2N2O4: 481.0722, found 481.0727.

[0030] Example 4:

[0031] The preparation of (1S*,4aS*,8aR*)-7-carboxylic acid methyl ester-1-hydroxy-4,8a-dicyano-1,3-bis(4-iodophenyl)-4a,5,8,8a-tetrahydro-1H-isochromene (3d) is as follows:

[0032]

[0033] Add alkynyl allyl ester 1a (24.0 mg, 0.1 mmol), 4-iodobenzoyl acetonitrile 2d (22.4 mg, 0.1 mmol), THF (1 mL), and 4-pyrrolidinyl pyridine (14.8 mg, 0.1 mmol) to a 10 mL reaction flask equipped with a stir bar. Stir the mixture at room temperature and monitor the reaction until completion by TLC. Purify the reaction system by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1) to obtain the target product 3d (21.8 mg), yield: 80%, pale yellow solid, melting point: 142.2–144.4 °C. f = 0.18 (developing solvent is petroleum ether / ethyl acetate = 100 / 50); 1 H NMR (DMSO-d6, 600MHz) δ 9.21 (s, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 7.09 (m, 1H), 3.68 (s,3H), 3.21 (dd, J = 11.9, 5.5 Hz, 1H), 3.01 (m, 1H), 2.67 (d, J = 17.5 Hz,1H), 2.43 (m, 1H), 2.19 (d, J = 17.0 Hz, 1H); 13 C NMR (DMSO-d6, 150 MHz) δ170.8, 166.7, 142.9, 142.8, 142.4, 141.9, 137.0, 134.9, 134.8, 131.5, 122.8,122.5, 104.3, 104.0, 102.3, 92.1, 57.2, 49.3, 37.5, 34.8, 33.5; HRMS (ESI) m / z: [M + H] + calcd for C 25 H 19I2N2O4: 664.9434, found 664.9438.

[0034] Example 5:

[0035] The preparation of (1S*,4aS*,8aR*)-7-carboxylic acid methyl ester-1-hydroxy-4,8a-dicyano-1,3-bis(4-bromophenyl)-4a,5,8,8a-tetrahydro-1H-isochromene (3e) is as follows:

[0036]

[0037] Add alkynyl allyl ester 1a (24.0 mg, 0.1 mmol), 4-bromobenzoylacetonitrile 2e (27.2 mg, 0.1 mmol), THF (1 mL), and 4-pyrrolidinylpyridine (14.8 mg, 0.1 mmol) to a 10 mL reaction flask equipped with a stir bar. Stir the mixture at room temperature and monitor the reaction until completion by TLC. Purify the reaction system by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1) to obtain the target product 3e (16.2 mg), yield: 57%, white solid, melting point: 188.1–189.4 °C. f = 0.42 (developing solvent is petroleum ether / ethyl acetate = 100 / 50); 1 H NMR (CDCl3,600MHz) δ 7.63 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H), 7.56 (d, J =7.8 Hz, 2H), 7.53 (d, J = 9.1 Hz, 2H), 7.06 (m, 1H), 4.81 (s, 1H), 3.71 (s,3H), 3.02 (dd, J = 11.9, 5.8 Hz, 1H), 2.92 (m, 1H), 2.67 (m, 1H), 2.56 (m,1H), 2.38 (d, J = 17.0 Hz, 1H); 13 C NMR (CDCl3, 150 MHz) δ 166.1, 161.5,137.1, 135.2, 131.9, 130.8, 129.5, 128.8, 126.8, 126.1, 125.2, 117.1, 116.8,98.8, 87.1, 52.2, 44.3, 32.9, 29.8, 28.4; HRMS (ESI) m / z: [M + H] + calcd forC25 H 19 Br2N2O4: 568.9712, found 568.9715.

[0038] Example 6:

[0039] The preparation of (1S*,4aS*,8aR*)-7-carboxylic acid methyl ester-1-hydroxy-4,8a-dicyano-1,3-bis(4-methoxyphenyl)-4a,5,8,8a-tetrahydro-1H-isochromene (3f) is as follows:

[0040]

[0041] Add alkynyl allyl ester 1a (24.0 mg, 0.1 mmol), 4-methoxybenzoylacetonitrile 2f (17.6 mg, 0.1 mmol), THF (1 mL), and 4-pyrrolidinylpyridine (14.8 mg, 0.1 mmol) to a 10 mL reaction flask equipped with a stir bar. Stir the mixture at room temperature and monitor the reaction until completion by TLC. Purify the reaction system by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain the target product 3f (9.0 mg), yield: 38%, light green solid, melting point: 98.4–102.3 °C. f = 0.13 (developing solvent is petroleum ether / ethyl acetate = 100 / 50); 1 H NMR (CDCl3, 600MHz) δ 7.74 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 8.9 Hz, 2H), 7.05 (m, 1H), 6.94 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 4.82 (s, 1H), 3.82 (s,6H), 3.69 (s, 3H), 3.01 (dd, J = 11.9, 5.4 Hz, 1H), 2.90 (dt, J = 19.1, 4.2Hz, 1H), 2.66 (d, J = 17.0 Hz, 1H), 2.54 (m, 1H), 2.42 (d, J = 17.2 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ 166.3, 162.6, 161.8, 160.9, 137.3, 129.7, 128.6,126.9, 124.6, 118.2, 117.3, 113.8, 113.7, 98.7, 84.7, 55.4, 55.3, 52.1, 44.7,33.0, 29.9, 28.7 (additional peaks are observed due to diastereoisomer); HRMS(ESI) m / z: [M + H] + calcd for C 27 H 25 N2O6: 473.1713, found 473.1716.

[0042] Example 7:

[0043] The preparation of (1S*,4aS*,8aR*)-7-carboxylic acid methyl ester-1-hydroxy-4,8a-dicyano-1,3-bis(4-methylphenyl)-4a,5,8,8a-tetrahydro-1H-isochromene (3g) is as follows:

[0044]

[0045] Add 24.0 mg (0.1 mmol) of alkynyl allyl ester 1a, 2 g (16.0 mg, 0.1 mmol) of 4-methylbenzoyl acetonitrile, 1 mL of THF, and 14.8 mg (0.05 mmol) of 4-pyrrolidinyl pyridine to a 10 mL reaction flask equipped with a stir bar. Stir the mixture at room temperature and monitor the reaction by TLC until completion. Purify the reaction system by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1) to obtain 3 g (9.0 mg) of the target product, yield: 41%, white solid, melting point: 125.3–126.8 °C. f = 0.51 (developing solvent is petroleum ether / ethyl acetate = 100 / 50); 1H NMR (CDCl3,600MHz) δ 7.66 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 7.23 (d, J =8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.01 (m, 1H), 4.98 (br, 1H), 3.68 (s,3H), 2.99 (dd, J = 11.9, 5.2 Hz, 1H), 2.86 (m, 1H), 2.66 (m, 1H), 2.51 (m,1H), 2.38 (d, J = 16.5 Hz, 1H), 2.37 (s, 6H); 13 C NMR (CDCl3, 150 MHz) δ166.4, 163.2, 141.8, 140.4, 137.4, 133.6, 129.6, 129.3, 129.2, 128.1, 127.1,127.0, 118.0, 117.3, 98.9, 85.6, 52.1, 44.6, 32.9, 30.0, 28.7, 21.5, 21.2;HRMS (ESI) m / z: [M + H] + calcd for C 27 H 25 N2O4: 441.1814, found 441.1817.

[0046] Example 8:

[0047] The preparation of (1S*,4aS*,8aR*)-7-carboxylic acid methyl ester-1-hydroxy-4,8a-dicyano-1,3-bis(3-chlorophenyl)-4a,5,8,8a-tetrahydro-1H-isochromene (3h) is as follows:

[0048]

[0049] Add alkynyl allyl ester 1a (24.0 mg, 0.1 mmol), 3-chlorobenzoyl acetonitrile 2h (18.0 mg, 0.1 mmol), THF (1 mL), and 4-pyrrolidinyl pyridine (14.8 mg, 0.1 mmol) to a 10 mL reaction flask equipped with a stir bar. Stir the mixture at room temperature and monitor the reaction until completion by TLC. Purify the reaction system by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain the target product 3h (10.4 mg), yield: 43%, pale yellow solid, melting point: 180.5–182.6 °C.f = 0.20 (developing solvent is petroleum ether / ethyl acetate = 100 / 50); 1 H NMR (acetone-d6, 600MHz) δ 8.00 (br, 1H), 7.72-7.70 (m, 2H), 7.63 (d, J = 0.9 Hz, 1H), 7.61-7.60 (m, 1H), 7.49-7.43 (m, 4H), 7.01 (m, 1H), 3.57 (s, 3H), 3.17 (dd, J= 12.0, 5.6 Hz, 1H), 2.95 (m, 1H), 2.67 (m, 1H), 2.46 (m, 1H), 2.23 (d, J =17.5 Hz, 1H); 13 C NMR (acetone-d6, 150 MHz) δ 165.7, 160.7, 139.3, 137.0,134.6, 134.1, 133.9, 131.2, 130.5, 130.2, 128.0, 127.5, 126.9, 126.8, 126.3,117.2, 116.6, 98.9, 88.6, 51.4, 44.7, 33.1, 30.1, 28.4; HRMS (ESI) m / z: [M +H] + calcd for C 25 H 19 Cl2N2O4: 481.0722, found 481.0728.

[0050] Example 9:

[0051] The preparation of methyl (1S*,4aS*,8aR*)-7-carboxylate-1-hydroxy-4,8a-dicyano-1,3-bis(3-methylphenyl)-4a,5,8,8a-tetrahydro-1H-isochromene (3i) is as follows:

[0052]

[0053] Add alkynyl allyl ester 1a (24.0 mg, 0.1 mmol), 3-methylbenzoylacetonitrile 2i (16.0 mg, 0.1 mmol), THF (1 mL), and 4-pyrrolidinylpyridine (14.8 mg, 0.1 mmol) to a 10 mL reaction flask equipped with a stir bar. Stir the mixture at room temperature and monitor the reaction until completion by TLC. Purify the reaction system by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain the target product 3i (15.2 mg), yield: 69%, white solid, melting point: 112.7–114.3 °C. f = 0.27 (developing solvent is petroleum ether / ethyl acetate = 100 / 50); 1 H NMR(CDCl3, 600MHz) δ 7.58 (s, 1H), 7.56 (d, J = 7.1 Hz, 1H), 7.49 (s, 1H), 7.46(d, J = 7.9 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.29(m, 2H), 7.05 (m, 1H), 4.57 (br, 1H), 3.69 (s, 3H), 3.03 (dd, J = 12.0, 5.5Hz, 1H), 2.91 (m, 1H), 2.68 (m, 1H), 2.57 (m, 1H), 2.42 (s, 3H), 2.41 (d, J =17.0 Hz, 1H), 2.37 (s, 3H); 13 C NMR (CDCl3, 150 MHz) δ 166.3, 163.2, 138.5,138.3, 137.3, 136.4, 132.3, 132.1, 131.2, 128.7, 128.6, 128.5, 127.7, 127.0,125.4, 124.3, 117.7, 117.1, 98.8, 86.5, 52.1, 44.5, 33.0, 30.0, 28.6, 21.6,21.4; HRMS (ESI) m / z: [M + H] + calcd for C 27 H 25 N2O4: 441.1814, found 441.1817.

[0054] Example 10:

[0055] The preparation of methyl (1S*,4aS*,8aR*)-7-carboxylate-1-hydroxy-4,8a-dicyano-1,3-bis(3-methoxyphenyl)-4a,5,8,8a-tetrahydro-1H-isochromene (3j) is as follows:

[0056]

[0057] Add alkynyl allyl ester 1a (24.0 mg, 0.1 mmol), 3-methoxybenzoylacetonitrile 2j (17.6 mg, 0.1 mmol), THF (1 mL), and 4-pyrrolidinylpyridine (14.8 mg, 0.1 mmol) to a 10 mL reaction flask equipped with a stir bar. Stir the mixture at room temperature and monitor the reaction until completion by TLC. Purify the reaction system by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain the target product 6j (12.6 mg), yield: 53%, light green solid, melting point: 90.6–94.1 °C. f = 0.16 (developing solvent is petroleum ether / ethyl acetate = 100 / 50); 1 H NMR(acetone-d6, 600MHz) δ 7.73 (br, 1H), 7.33-7.28 (m, 3H), 7.26 (m, 1H), 7.20(d, J = 8.5 Hz, 1H), 7.17 (m, 1H), 7.01-6.98 (m, 2H), 6.96 (dd, J = 8.2, 2.6Hz, 1H), 3.71 (s, 3H), 3.70 (s, 3H), 3.57 (s, 3H), 3.13 (dd, J = 12.2, 5.5Hz, 1H), 2.93 (m, 1H), 2.65 (m, 1H), 2.43 (m, 1H), 2.24 (dd, J = 17.4 Hz, 1H); 13 C NMR (acetone-d6, 150 MHz) δ 165.8, 162.3, 159.7, 159.6, 138.7, 137.0,129.7, 129.4, 127.1, 120.4, 119.7, 117.2, 116.7, 115.0, 113.7, 99.1, 87.2,55.0, 54.9, 51.4, 44.7, 33.0, 30.2, 28.6; HRMS (ESI) m / z: [M + H] + calcd forC 27 H 25N2O6: 473.1713, found 473.1719.

[0058] Example 11:

[0059] The preparation of methyl (1S*,4aS*,8aR*)-7-carboxylate-1-hydroxy-4,8a-dicyano-1,3-bis(thiophen-3-yl)-4a,5,8,8a-tetrahydro-1H-isochromene (3k) is as follows:

[0060]

[0061] Add alkynyl allyl ester 1a (24.0 mg, 0.1 mmol), 3-oxo-3-(thiophen-3-yl)propionitrile 2k (15.2 mg, 0.1 mmol), THF (1 mL), and 4-pyrrolidinylpyridine (14.8 mg, 0.1 mmol) to a 10 mL reaction flask equipped with a stir bar. Stir the mixture at room temperature and monitor the reaction until completion by TLC. Purify the reaction system by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain the target product 3k (15.1 mg), yield: 71%, light green solid, melting point: 85.4–87.1 °C. f = 0.42 (developing solvent is petroleum ether / ethyl acetate = 50 / 100); 1 H NMR(acetone-d6, 600MHz) δ 7.72-7.71 (m, 3H), 7.64-7.63 (m, 2H), 7.44-7.38 (m,6H), 7.01 (m, 1H), 3.56 (s, 3H), 3.51 (dd, J = 12.0, 5.6 Hz, 1H), 2.94 (m,1H), 2.68 (m, 1H), 2.43 (m, 1H), 2.21 (d, J = 17.5 Hz, 1H); 13 C NMR (acetone-d6, 150 MHz) δ 171.0, 162.2, 144.5, 142.2, 139.2, 133.9, 132.3, 132.2, 132.0,131.7, 131.6, 131.4, 131.3, 122.9, 122.7, 103.4, 90.3, 56.6, 50.0, 37.8,35.4, 33.8; HRMS (ESI) m / z: [M + H] + calcd for C 21 H 17N2O4S2: 425.0630, found425.0634.

[0062] Assay for the inhibitory activity of the compound against the FXIa enzyme (coagulation factor plasma serine protease)

[0063] a: Preparation of buffer solution: Prepare a solution with pH = 7.4 by mixing 50 mM Tris / HCl, 100 mM NaCl, 5 mM CaCl2 and 0.1% BSA.

[0064] b: Substrate preparation: Dissolve the substrate in ultrapure water to prepare a stock solution of 2.5 mg / mL, and then dilute it with ultrapure water to prepare a 0.5 mg / mL (1 mM) solution.

[0065] c: Preparation of Human FⅪa reaction solution: Human FⅪa (Haematologic Technologies inc) was diluted with the buffer solution prepared above to a final concentration of 1 nM and stored in a refrigerator at 2 ~ 8 ℃.

[0066] d: Sample solution preparation: Weigh 1-2 mg of the sample (target compound to be tested) and dissolve it in dimethyl sulfoxide (DMSO) to prepare a 1 mM solution. Then dilute it with buffer to prepare a solution with a concentration of 0.001-2,000 nM and a DMSO content of < 0.1%.

[0067] e: Assay method for FXIa enzyme activity: Add 40 μL each of Human FXIa reaction solution and sample solutions of different concentrations to a 96-well plate. The negative wells contain an equal volume of buffer solution instead of sample solution. Shake for 1 min, then incubate at 37 ℃ for 30 min. Immediately add 40 μL of substrate reaction solution and place the plate in a microplate reader. Scan at 24 ℃ and A405 nm wavelength once per minute for 60 min. After detection, export the absorbance data and process the data in Ggraphpad Prism software to obtain the half-maximal inhibitory concentration (IC50) of the compound against Human FXIa.

[0068] Activity assay results

[0069] Activity assays were performed on representative compounds 3a-3k. The experimental data in Table 1 show that the compounds in this application possess FXIa enzyme inhibitory activity, with compound 3b exhibiting the best FXIa enzyme inhibitory activity (IC50). 50 = 11.5 μM).

[0070] Table 1: Inhibitory activity of compounds 3a-3k against coagulation factor XIa

[0071]

[0072] It should be noted that the above-described technical content of this invention is merely an explanation and clarification to enable those skilled in the art to understand the technical essence of this invention, and therefore is not intended to limit the scope of protection of this invention. The scope of protection of this invention should be determined by the claims. Those skilled in the art should understand that any modifications, equivalent substitutions, and improvements made based on the essential spirit of this invention should be within the scope of protection of this invention.

Claims

1. A bicyclic hemiketal compound with the general structural formula shown in Formula II: ， in, R is at least one of phenyl, 4-FC6H4, 4-ClC6H4, 4-IC6H4, 4-BrC6H4, 4-MeOC6H4, 4-MeC6H4, 3-ClC6H4, 3-MeC6H4, 3-MeOC6H4, and 3-thienyl.

2. The method for preparing the bicyclic hemiketal compound of claim 1, wherein it comprises using an alkynyl allyl ester and the compound of formula... The compound shown is used as a raw material. After reaction and separation in a solvent under the action of a catalyst, the product of formula [formula missing] is obtained. The chemical reaction equation for the compound containing the bicyclic hemiketal structure shown is as follows: 。 3. The method for preparing the bicyclic hemiketal compound as described in claim 2, characterized in that, The catalyst is triethylenediamine, 4-dimethylaminopyridine, 4-(4-pyridylmorpholine) or 4-pyrrolidinylpyridine, preferably 4-pyrrolidinylpyridine.

4. The method for preparing the bicyclic hemiketal compound as described in claim 2, characterized in that, The solvent is any one of dichloromethane, tetrahydrofuran, chloroform, acetonitrile, or ethyl acetate, preferably tetrahydrofuran.

5. The method for preparing the compound containing a bicyclic hemiketal structure as described in claim 2, characterized in that, The molar ratio of the alkynyl allyl ester, the compound of formula I, and the catalyst synthesized from readily available raw materials is 1-2:1-2:1-2.

6. The method for preparing the bicyclic hemiketal compound as described in claim 2, characterized in that, The alkynyl allyl ester, formula The molar ratio of compound, catalyst, and base is 1:1:

1.

7. The method for preparing the bicyclic hemiketal compound as described in claim 2, characterized in that, The compound of Formula I includes at least one of the following: benzoyl acetonitrile, 4-fluorobenzoyl acetonitrile, 4-chlorobenzoyl acetonitrile, 4-iodobenzoyl acetonitrile, 4-bromobenzoyl acetonitrile, 4-methoxybenzoyl acetonitrile, 4-methylbenzoyl acetonitrile, 3-chlorobenzoyl acetonitrile, 3-methylbenzoyl acetonitrile, 3-methoxybenzoyl acetonitrile, 3-oxo-3-(thiophen-3-yl)propionitrile.

8. The method for preparing the bicyclic hemiketal compound as described in claim 2, characterized in that, The reaction time is 36-48 hours, and the reaction temperature is room temperature.

9. The method for preparing the bicyclic hemiketal compound as described in claim 2, characterized in that, The separation was performed using column chromatography, with the eluent being petroleum ether:ethyl acetate = 6:1 ~ 5:1, v / v.

10. The use of the bicyclic hemiketal compound of claim 1 or the preparation method of any one of claims 2-9 in the preparation of FXIa enzyme inhibitors or anticoagulant drugs.

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