CN114805286B - Preparation method of naphthoxythiazepine derivative - Google Patents
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Abstract
The invention relates to the field of chemical synthesis, in particular to a preparation method of naphthoxythiazepine derivatives. The method realizes the efficient synthesis of the naphthoxythiozepine derivative under the mild condition of 50 ℃ by taking the sulfur-containing internal onium salt and the alpha-alkynyl naphthalene-2-alcohol compound as the base and taking the 1, 2-dichloroethane as the solvent. The reaction operation is simple, noble metal catalyst is not used, the post-treatment is convenient, the yield is generally high, the inert gas is not needed to protect the product in the preparation process, the applicability of the substrate is wide, the operation is simple, and the method is suitable for large-scale synthesis.
Description
Technical Field
The invention relates to the field of chemical synthesis, in particular to a preparation method of naphthoxythiazepine derivatives.
Background
The development of a method for the rapid and efficient synthesis of heterocyclic compounds, which has a potential biological activity, is an important topic of organic chemistry and pharmaceutical chemistry. The molecular structure of a bisheteroatom cyclic compound can generally be modulated by changing the type, oxidation state and position of the heteroatom. Seven-or larger-membered heterocyclic compounds, which are distinguished from five-membered and six-membered cyclic compounds, are still insufficiently studied in their biological properties because of their great difficulty of synthesis, but are fully expected. The design of the synthesized macrocyclic compound is often to overcome the inherent entropy of the transition state, the intermolecular forces and other adverse factors. Benzooxathiazepines are an important one of the hetero seven-membered rings containing oxygen and sulfur atoms (particularly, the oxygen and sulfur atoms are in 1, 5-positions), are used as an important pharmacophore and are connected with groups such as purine, pyrimidine and the like, show very good living activity, are widely studied by pharmaceutical chemists, and have the effects of inhibiting cardiac sodium current, resisting ischemia and the like. The following two molecular structures (a and B):
compound C is an active molecule patented by the company aoso-macneille pharmaceutical in the united states of america with the patent number: ZL00818604.9, a calcium channel antagonist mainly used for cardiovascular, antiasthmatic and anti-bronchoconstrictor activities, defines its use as a medicament.
Disclosure of Invention
The invention aims to provide naphthoxythiozepine derivatives with a structural formula shown as III,
wherein: r is phenyl or substituted phenyl (substituents include 4-methoxy, 4-methyl, 4-fluoro, 4-chloro, 4-bromo, 3-methyl), heterocyclic substituents (2-thienyl), alkyl substituents (1-hexenyl, cyclopropenyl, butenyl); EWG (EWG) 1 Is methoxycarbonyl, ethoxycarbonyl, benzoyl, trifluoromethyl; EWG (EWG) 2 Is methoxycarbonyl groupEthoxycarbonyl, benzoyl, p-methylbenzoyl, p-bromobenzoyl.
The invention further provides a preparation method of the naphthoxythiozepine derivative, which is shown as the following formula:
wherein the preparation steps of the compound III are as follows:
s1, placing a compound I, a compound II and triethylamine into a reaction solvent for reaction;
s2, after the compound II disappears completely, removing the organic solvent from the reaction mixture under the condition of reducing pressure;
s3, eluting by using silica gel column chromatography to obtain a compound III.
The 1, 2-dichloroethane is used as a reaction solvent, triethylamine is used as a base, and the compound I and the compound II react at 50 ℃.
The molar ratio of the compound I to the compound II is I, II=1.05:1.0, and the concentration of the 1, 2-dichloroethane solution is 0.1M.
The reaction solvent can also be dichloromethane, tetrahydrofuran, acetonitrile, 1, 4-dioxane.
The triethylamine may also be replaced by potassium carbonate, sodium carbonate, cesium carbonate, 1, 8-diazabicyclo undec-7-ene, 4-dimethylaminopyridine, quinine.
The eluent used by the silica gel column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio V Petroleum ether :V Acetic acid ethyl ester ＝5:1～3:1。
The beneficial effects of the invention are as follows: the method realizes the efficient synthesis of naphthalene ring fused oxathiazepine derivatives by taking sulfur-containing internal onium salt and alpha-alkynyl naphthalene-2-alcohol compounds as alkali and 1, 2-dichloroethane as solvent under the mild condition of 50 ℃. The reaction operation is simple, noble metal catalyst is not used, the post-treatment is convenient, the yield is generally high, the inert gas is not needed to protect the product in the preparation process, the applicability of the substrate is wide, the operation is simple, and the method is suitable for large-scale synthesis. Through pharmacological experiments on mice, the compounds are found to have no cytotoxicity, can inhibit proliferation of mouse T lymphocytes activated by mitogen ConA (canavalin), have immunosuppressive activity, and are expected to be developed into novel small-molecule drugs with anti-inflammatory and immunoregulatory effects and applied to autoimmune diseases.
Drawings
FIG. 1 is a nuclear magnetic spectrum (hydrogen spectrum) of a product III-1 obtained in the example of the present invention;
FIG. 2 is a nuclear magnetic spectrum (carbon spectrum) of a product III-1 obtained in the example of the present invention;
FIG. 3 is a graph showing the effect of naphthoxythiazepine derivatives on the cytotoxicity of normal mouse lymphocytes;
FIG. 4 is a graph showing proliferation of in vitro inhibition of mitogen ConA activated mouse T lymphocytes by naphthooxathiazepine derivatives;
Detailed Description
The technical scheme of the invention is further described below by specific embodiments with reference to the accompanying drawings:
the following are preferred examples of the preparation of the compounds of the invention. In all of the examples below, nuclear magnetic resonance spectroscopy was performed on CDCl by Bruker 400, JEOL 400 apparatus 3 Obtained by the method. Delta is the relative value of the internal standard (CHCl) 3 Scaling delta 7.26 1 H NMR and 77.16 13 C NMR. High Resolution Mass Spectrometry (HRMS) was obtained by a 4G quadrupole time-of-flight (QTof) mass spectrometer.
Example 1
The reaction scheme of example 1, the specific compounds I-1, II-1 and III-1 used are as follows, and experiments show that the preferred organic solvent of the invention is 1, 2-dichloroethane, the highest yield of the reaction product is 98%, and the best molar ratio of starting materials is the molar ratio of compound I to compound II of I-1: II-1=1.05:1.0, the optimal concentration of the solution is 0.1M.
Specific experimental procedureThe method comprises the following steps: : 25mg (0.10 mmol,1.0 eq.) of Compound II-1 and 30mg (0.105 mmol,1.05 eq.) of Compound I-1 are dissolved in 1.2-dichloroethane (2 mL) and reacted at 50℃after which the solvent residue is removed by rotary evaporation under reduced pressure of a water pump to give a 200-300 mesh silica gel, eluent (volume ratio V Petroleum ether :V Acetic acid ethyl ester =5:1-3:1) column chromatography to obtain the compound shown in III-1, and identifying the product by nuclear magnetism (hydrogen spectrum, carbon spectrum) and high-resolution mass spectrum.
The product III-1 was oil-free and had a yield of 98%. 1 H NMR(400MHz,(CD 3 ) 2 CO)δ8.09(d,J＝9.2Hz,1H),7.96(d,J＝8.0Hz,1H),7.65–7.60(m,2H),7.58(s,1H),7.47–7.41(m,1H),7.36–7.31(m,1H),7.13–6.96(m,5H),3.88(s,3H),3.74(s,3H)； 13 C NMR(100MHz,(CD 3 ) 2 CO)δ164.6,162.8,155.1,141.6,139.9,135.7,133.0,132.3,130.8,129.6,129.5,129.4,129.1,129.0,128.9,128.4,127.0,125.4,123.2,121.5,53.6,53.3；ESI-HRMS m/z calcd for C 24 H 19 O 5 S[M+H] + 419.0948,found 419.0944.
Example 2
The procedure used for the preparation of the examples of the other compounds according to the invention (compounds III-2 to III-12) is the same as in example 1, the reaction conditions being as follows: compound II (0.10 mmol,1.0 eq.) and compound I (0.105 mmol,1.05 eq.) are dissolved in 1.2-dichloroethane (2 mL) and reacted at 50 ℃. After the reaction was completed, the solvent was removed by rotary evaporation of the reaction mixture under reduced pressure by a water pump. The residue was purified on 200-300 mesh silica gel, eluent (volume ratio V Petroleum ether :V Acetic acid ethyl ester =5:1 to 3:1) column chromatography to give iii.
The starting materials used for the preparation of compounds I-2 to I-10 have the following structures:
the preparation method of the compounds II-1 to II-12 is referred to as follows: "Yb (OTf) 3-Catalyzed Alkyne-Carbonyl Metathesis-Oxa-Michael Addition Relay for Diastereoselective Synthesis of Functionalized Naphtho [2,1-b ] furans," Ting Xu, ke Chen, hong-Yu Zhu, wen-Juan Hao, shu-JiangTu, and Bo Jiang, org. Lett.2020,22,2414-2418. Starting from 2-iodonaphthol, MOM protecting groups are firstly arranged on phenolic hydroxyl groups, then Sonogashira coupling reaction is carried out on the MOM protecting groups and corresponding terminal alkynes, and then the MOM protecting groups are removed to obtain alpha-alkynyl naphthalene-2-alcohol compounds.
The preparation method of the compounds I-1 to I-5 comprises the following steps: 4-methoxypyridine (100 mmol) and sulfur powder (100 mmol) are fully stirred and mixed in dichloromethane (300 mL), the temperature is reduced to 0 ℃, then the corresponding electron-withdrawing internal alkyne (100 mmol) is dropwise added for reaction for 12h, and after the reaction is finished, suction filtration and petroleum ether washing are carried out to obtain the sulfonium salt compound.
The structure and data of each product obtained are characterized as follows:
the product III-2 was obtained as a yellow oil in 98% yield. 1 H NMR(400MHz,CDCl 3 )δ7.91(d,J＝8.8Hz,1H),7.84(d,J＝8.4Hz,1H),7.56–7.50(m,2H),7.43–7.38(m,2H),7.33–7.28(m,1H),6.89–6.83(m,2H),6.71–6.64(s,2H),3.90(s,3H),3.80(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ164.4,162.5(d,J＝248.8Hz),162.4,154.1,139.9,138.0,132.0,131.4,130.9(d,J＝3.3Hz),130.7(d,J＝8.6Hz),128.7,128.2,128.0,127.6,126.2,124.7,122.3(2C),120.9,115.5(d,J＝21.5Hz),53.6,53.1； 19 F NMR(376MHz,CDCl 3 )δ-111.6(s,1F)；ESI-HRMS m/z calcd for C 24 H 18 FO 5 S[M+H] + 437.0853,found 437.0853.
The product III-3 was obtained as a yellow oil in 97% yield. 1 H NMR(400MHz,(CD 3 ) 2 CO)δ8.13(d,J＝9.2Hz,1H),8.00(d,J＝8.4Hz,1H),7.80–7.75(m,2H),7.70–7.63(m,4H),7.61(s,1H),7.49–7.43(m,1H),7.37–7.31(m,1H),7.14–6.99(m,5H),3.70(s,3H)； 13 C NMR(100MHz,(CD 3 ) 2 CO)δ187.8,162.6,155.2,140.2,138.9,137.8,135.7,135.3,133.0,132.5,131.4,129.6(2C),129.5,129.2,129.0,128.4,127.0,125.4,123.3,121.5,53.0,(3C peak is merged with other peaks)；ESI-HRMS m/z calcd for C 29 H 20 BrO 4 S[M+H] + 543.0260,found 543.0264.
Product III-4 was obtained as a yellow oil with a yield of 94%. 1 H NMR(400MHz,(CD 3 ) 2 CO)δ8.10(d,J＝8.8Hz,1H),8.02–7.98(m,1H),7.68–7.64(m,1H),7.60(d,J＝8.8Hz,1H),7.51–7.45(m,2H),7.41–7.36(m,1H),6.94–6.89(m,2H),6.63–6.58(m,2H),3.88(s,3H),3.73(s,3H),3.65(s,3H)； 13 C NMR(100MHz,(CD 3 ) 2 CO)δ164.7,162.9,160.8,154.9,141.3,139.8,133.0,132.1,131.3,131.1,129.6,129.3,129.2,128.4,128.2,127.0,125.5,121.6119.7,114.6,55.4,53.6,53.2；ESI-HRMS m/z calcd for C 25 H 21 O 6 S[M+H] + 449.1053,found 449.1052
The product III-5 was yellow oil in 98% yield. 1 H NMR(400MHz,CDCl 3 )δ8.01–7.97(m,2H),7.89–7.86(m,2H),7.83(d,J＝8.4Hz,1H),7.79(d,J＝9.2Hz,1H),7.64–7.56(m,2H),7.52–7.44(m,4H),7.43–7.33(m,3H),7.32–7.27(m,1H),7.12–7.07(m,1H),7.06–7.00(m,2H),6.97–6.93(m,2H),6.91(d,J＝8.8Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ189.2,187.8,154.0,144.9,139.9,138.8,136.5,135.6,134.6,133.6,132.9,131.9,131.4,130.1,129.0,128.8,128.7,128.6,128.4,128.3,127.5,126.1,125.0,123.5,120.4,(3C peak is merged with other peaks)；ESI-HRMS m/z calcd for C 34 H 23 O 3 S[M+H] + 511.1362,found 511.1364.
Product III-6 was a yellow solid with 97% yield. 1 H NMR(400MHz,(CD 3 ) 2 CO)δ8.10(d,J＝8.8Hz,1H),7.98(d,J＝8.0Hz,1H),7.61(d,J＝8.8Hz,2H),7.55(s,1H),7.49–7.43(m,1H),7.39–7.34(m,1H),7.25–7.20(m,2H),6.93–6.88(m,2H),3.89(s,3H),3.73(s,3H)； 13 C NMR(100MHz,(CD 3 ) 2 CO)δ164.5,162.8,155.3,141.8,138.4,134.9,133.0,132.5,132.3,131.3,130.6,129.6,128.8,128.5,128.4,127.1,125.2,124.6,123.0,121.5,53.7,53.3.ESI-HRMS m/z calcd for C 24 H 18 BrO 5 S[M+H] + 497.0053,found497.0060.
Product III-7 was a yellow oil with 97% yield. 1 H NMR(400MHz,(CD 3 ) 2 CO)δ8.10(d,J＝8.8Hz,1H),7.98(d,J＝8.4Hz,1H),7.65–7.59(m,2H),7.53(s,1H),7.48–7.43(m,1H),7.38–7.32(m,1H),6.93–6.83(m,3H),6.72–6.63(m,1H),3.88(s,3H),3.73(s,3H),2.02(s,3H)； 13 C NMR(100MHz,(CD 3 ) 2 CO)δ164.6,162.8,155.1,141.6,140.0,138.6,135.6,132.9,132.2,130.9,130.6,130.1,129.5,129.1,129.0(2C),128.3,126.9,126.5,125.4,122.9,121.4,53.6,53.2,21.1.ESI-HRMS m/z calcd for C 25 H 21 O 5 S[M+H] + 433.1104,found 433.1105.
Product III-8 was yellow oil in 95% yield. 1 H NMR(400MHz,(CD 3 ) 2 CO)δ8.10(d,J＝8.8Hz,1H),7.99(d,J＝8.0Hz,1H),7.66–7.63(m,1H),7.60(d,J＝8.8Hz,1H),7.53(s,1H),7.49–7.44(m,1H),7.40–7.34(m,1H),6.86(s,4H),3.88(s,3H),3.73(s,3H),2.13(s,3H)； 13 C NMR(100MHz,(CD 3 ) 2 CO)δ164.6,162.8,155.0,141.5,140.0,139.5,133.0,132.9,132.2,130.9,129.8,129.7,129.6,129.2,129.1,128.4,127.0,125.4,121.8,121.5,53.6,53.2,21.1；ESI-HRMS m/z calcd for C 25 H 21 O 5 S[M+H] + 433.1104,found 433.1107.
Product III-9 was a yellow solid with a yield of 95%. 1 H NMR(400MHz,(CD 3 ) 2 CO)δ8.11(d,J＝9.2Hz,1H),7.98(d,J＝8.4Hz,1H),7.61(d,J＝8.8Hz,2H),7.57(s,1H),7.49–7.43(m,1H),7.40–7.34(m,1H),7.10–7.05(m,2H),7.00–6.95(m,2H),3.89(s,3H),3.73(s,3H)； 13 C NMR(100MHz,(CD 3 ) 2 CO)δ164.5,162.8,155.3,141.8,138.3,134.6,134.5,133.0,132.5,131.1,130.6,129.6,129.3,128.8,128.5,128.4,127.1,125.2,124.4,121.5,53.7,53.3；ESI-HRMS m/z calcd for C 24 H 18 ClO 5 S[M+H] + 453.0558,found 453.0564.
Product III-10 was obtained as a colorless oil in 99% yield. 1 H NMR(400MHz,(CD 3 ) 2 CO)δ8.15(d,J＝8.8Hz,1H),8.01(d,J＝8.4Hz,1H),7.85–7.81(m,2H),7.70–7.59(m,4H),7.50–7.44(m,3H),7.38–7.32(m,1H),7.14–6.99(m,5H),3.66(s,3H)； 13 C NMR(100MHz,(CD 3 ) 2 CO)δ188.6,162.5,155.4,139.9,139.4,137.9,136.3,135.7,134.6,133.0,132.5,129.7,129.6(2C),129.4,129.2,129.1,129.0,128.4,127.0,125.4,123.6,121.5,52.8,(1C peak is merged with other peaks)；ESI-HRMS m/z calcd for C 29 H 21 O 4 S[M+H] + 465.1155,found 465.1152.
III-11 was obtained as a colourless oil with a yield of 98%. 1 H NMR(400MHz,(CD 3 ) 2 CO)δ8.10(d,J＝9.2Hz,1H),7.98(d,J＝8.4Hz,1H),7.66–7.60(m,2H),7.58(s,1H),7.48–7.43(m,1H),7.38–7.32(m,1H),7.12–7.01(m,3H),7.00–6.96(m,2H),4.40–4.26(m,2H),4.20(q,J＝7.2Hz,2H),1.38(t,J＝7.2Hz,3H),1.22(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,(CD 3 ) 2 CO)δ164.0,162.3,155.2,141.8,139.7,135.7,132.9,132.3,130.6,129.6,129.5,129.3,129.1,129.0(2C),128.3,126.9,125.4,123.4,121.5,63.1,62.7,14.4,14.0；ESI-HRMS m/z calcd for C 26 H 23 O 5 S[M+H] + 447.1261,found 447.1260.
III-12 was yellow oil in 70% yield. 1 H NMR(400MHz,CDCl 3 )δ7.90–7.84(m,2H),7.74–7.70(m,1H),7.57–7.47(m,2H),7.45(d,J＝8.8Hz,1H),6.56(dd,J＝8.8,6.0Hz,1H),3.88(s,3H),3.78(s,3H),2.00–1.90(m,1H),1.85–1.74(m,1H),1.40–1.31(m,2H),1.29–1.05(m,2H),0.73(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ164.7,162.5,154.3,143.2,139.6,131.7,131.3,130.7,129.8,128.7,127.7,127.4,125.9,124.9,120.9,120.8,53.5,53.0,30.7,30.5,22.1,13.9.ESI-HRMS m/z calcd for C 22 H 23 O 5 S[M+H] + 399.1261,found 399.1264.
The invention also carries out preliminary researches on potential pharmacological activity of the naphthoxythiozepine compound, and the experimental results are as follows:
1. the effect of naphthoxyzepine derivatives on the cytotoxicity test of normal mouse lymphocytes is shown in figure 3;
results: the inguinal and axillary lymph nodes of the mice were aseptically isolated and prepared as single cell suspensions. Preparation of 3X 10 with complete Medium RPMI-1640 6 cells/ml, seeded in 96-well plates, 3X 10 5 Each cell per well was incubated with compound for 24h. The CCK8 method is used for detecting the influence of naphthalene ring fused oxathiazepine derivatives on the cytotoxicity test of normal mouse lymphocytes. The results show that each naphthalene nucleus fused oxathiazepine derivative has no obvious cytotoxicity on normal mouse spleen cells in vitro at the concentration of 20 mu M.
2. The naphthooxazepine derivative inhibits proliferation of mitogen ConA (canavalin) -activated mouse T lymphocytes in vitro as shown in fig. 4:
results: to evaluate whether naphthalene nucleus fused oxathiazepine derivatives 1-12 have immunosuppressive activity, inguinal and axillary lymph nodes of mice were aseptically isolated and prepared as single cell suspensions. Preparation of 3X 10 with complete Medium RPMI-1640 6 cells/ml, seeded in 96-well plates, 3X 10 5 Each cell per well. T lymphocytes were stimulated to proliferate with 5. Mu.g/ml ConA. The compounds to be screened and activated T cells are applied for 48 hours, and the influence of each compound to be tested on T lymphocyte proliferation is examined by a CCK8 method. As shown, compounds 1-12 inhibited proliferation of ConA-activated T cells to varying degrees. The results suggest that the compounds have immunosuppressive activity, and are hopeful to be developed into novel small-molecule drugs with anti-inflammatory and immunoregulatory effects.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.
Claims (3)
1. A preparation method of naphthoxythiazepine derivatives, which has a structural formula shown in III,
wherein: r is phenyl or substituted phenyl or n-butyl; the substituent of the substituted phenyl is selected from: 4-methoxy, 4-methyl, 4-fluoro, 4-chloro, 4-bromo, 3-methyl;
EWG 1 is methoxycarbonyl, ethoxycarbonyl and benzoyl;
EWG 2 is methoxycarbonyl, ethoxycarbonyl, benzoyl and p-bromobenzoyl; the preparation method is characterized by comprising the following steps:
wherein the preparation steps of the compound III are as follows:
s1, placing a compound I, a compound II and triethylamine into a reaction solvent for reaction;
s2, after the compound II disappears completely, removing the organic solvent from the reaction mixture under the condition of reducing pressure;
s3, eluting by using silica gel column chromatography to obtain a compound III.
2. The method for preparing the naphthoxyzepine derivative according to claim 1, which is characterized in that: the molar ratio of the compound I to the compound II is I, II=1.05:1.0, and the concentration of the 1, 2-dichloroethane solution is 0.1M.
3. The method for preparing the naphthoxyzepine derivative according to claim 1, which is characterized in that: the eluent used by the silica gel column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio V Petroleum ether :V Acetic acid ethyl ester ＝5:1～3:1。
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