CN114805112A - PDE2 inhibitor amide derivative and preparation method thereof - Google Patents

PDE2 inhibitor amide derivative and preparation method thereof Download PDF

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CN114805112A
CN114805112A CN202210609310.8A CN202210609310A CN114805112A CN 114805112 A CN114805112 A CN 114805112A CN 202210609310 A CN202210609310 A CN 202210609310A CN 114805112 A CN114805112 A CN 114805112A
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宋国强
王贺成
唐龙
冯筱晴
黄险峰
狄万慧
范家如
朱子凡
张晨
谈颖
夏颜
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Changzhou University
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    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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Abstract

A PDE2 inhibitor amide derivative and a preparation method thereof, belonging to the field of pharmaceutical chemistry. The preparation method comprises the following steps: the raw materials of m-hydroxyaniline, anhydrous NaH and R 1 Adding X into anhydrous DMF, and carrying out a close-packed reaction for 4-8 h. After the reaction is finished, adding the reaction liquid into water, extracting by using ethyl acetate, evaporating the solvent in a rotary manner, and performing rapid preparation and liquid phase separation to obtain the m-hydroxyaniline derivatives. Adding meta-substituted benzoic acid into anhydrous thionyl chloride, and carrying out reflux reaction for 2-6 h. After the reaction is finished, the residual thionyl chloride is evaporated in a rotary mode to obtain meta-substituted benzoyl chloride. Adding m-hydroxyaniline derivatives, pyridine and meta-substituted benzoyl chloride into anhydrous THF, and reacting at room temperature for 8-24 h. After the reaction is finished, filtering to remove the precipitate, and evaporating the solvent in a rotary manner to obtain a crude product. And (3) dissolving the crude product in ethyl acetate at 75 ℃, cooling to room temperature, dropwise adding petroleum ether into the solution to obtain floccule, and filtering to obtain the PDE2 inhibitor amide derivative.

Description

PDE2 inhibitor amide derivative and preparation method thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to amide derivatives serving as inhibitors of phosphodiesterase 2(PDE 2).
Background
Phosphodiesterases (PDEs) are the only enzymes in the body that catalyze the hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), and thus PDEs terminate the biochemical events conducted by these second messengers. cAMP and cGMP play important regulatory roles in cell activity. And the regulation of its concentration is mainly determined by the balance between the synthesis of nucleotide cyclase and phosphodiesterase hydrolysis. PDE2 has high levels of expression in the limbic system of the brain, such as the isocortical, hippocampal, hypothalamus, and the like. Simultaneous expression of PDE2 in these regions makes it important in regulating mood and long-term memory. Thus, PDE2 is expected to be a viable target for the treatment of mood problems, cognitive disorders, and other neurodegenerative diseases. However, no PDE2 inhibitor drugs are available on the market, so the development of a novel PDE2 inhibitor is of great significance.
The urolithin compound is a metabolite of ellagitannin in vivo, has biological activities of resisting inflammation, resisting oxidative stress, resisting apoptosis and the like, can play a role in neuroprotective activity through a blood brain barrier, and is a potential active small molecule for intervening neurodegenerative diseases. Research aiming at the targeted small molecule PDE2 of the urolithin compounds has been started at home and abroad, but few researches are carried out aiming at the modification and the transformation of the urolithin amide compounds at present, so that the process of commercialization of the urolithin amide compounds is influenced.
Disclosure of Invention
Aiming at the insufficient research of the urinary calculi amide compounds targeting to PDE2 small molecules, the invention aims to develop the urinary calculi amide compounds and provide novel inhibitor small molecule compounds of PDE 2.
In order to realize the purpose of the invention, the technical scheme adopted by the invention is as follows:
a PDE2 inhibitor amide derivative, which has the following formula:
Figure BDA0003671468570000011
wherein R is one of a hydrogen atom, a methoxyl group or a hydroxyl group; r 1 Is C 2 -C 9 Alkyl, methylthio substituted C 2 -C 9 Alkyl, cycloalkyl substituted C 1 -C 9 Alkyl, ethyl ester group substituted C 1 -C 9 Alkyl, heterocyclyl substituted C 1 -C 9 Alkyl, hydroxy substituted C 1 -C 9 Alkyl, aryl substituted C 1 -C 9 Alkyl or C 2 -C 9 One of the heterocyclic radicals (e.g. "methylthio-substituted C) 2 -C 9 Alkyl "means R 1 Is C 2 -C 9 Alkyl radicals, but C 2 -C 9 Alkyl end substituted by methylthio).
The compound I is selected from compounds shown in formulas 1a-1j, 2a-2j or 3a-3 m:
Figure BDA0003671468570000021
Figure BDA0003671468570000031
a method for preparing PDE2 inhibitor amide derivatives comprises the following steps:
(1) etherification: the raw materials of m-hydroxyaniline, anhydrous NaH and R 1 Adding X into anhydrous DMF, and carrying out a close-packed reaction for 4-8h at the temperature of 80-120 ℃. The reaction was monitored by TLC. And after the reaction is finished, adding the reaction solution into water, extracting with ethyl acetate, evaporating the solvent in a rotary mode, and quickly preparing a liquid phase to obtain the m-hydroxyaniline derivative.
(2) Preparing acyl chloride: adding the meta-substituted benzoic acid serving as a raw material into anhydrous thionyl chloride, and reacting for 2-6h under reflux. The reaction was monitored by TLC. After the reaction is finished, the residual thionyl chloride is evaporated in a rotary mode to obtain meta-substituted benzoyl chloride.
(3) Amidation: and (2) adding the m-hydroxyaniline derivatives obtained by etherification in the step (1), pyridine and meta-substituted benzoyl chloride obtained in the step (2) into anhydrous THF, controlling the temperature at room temperature, and reacting for 8-24 h. The reaction was monitored by TLC. After the reaction is finished, filtering the reaction solution, removing the precipitate, and evaporating the solvent in a rotary manner to obtain a crude product. Completely dissolving the crude product in ethyl acetate at 75 ℃, cooling to room temperature (20-30 ℃), dropwise adding petroleum ether serving as a small polar solvent into the solution, and filtering to obtain the PDE2 inhibitor amide derivative with high purity.
The synthetic route is shown as the following formula:
Figure BDA0003671468570000041
wherein R is one of a hydrogen atom, a methoxyl group or a hydroxyl group; x is Cl or Br;
wherein R is 1 Is C 2 -C 9 Alkyl, methylthio substituted C 2 -C 9 Alkyl, cycloalkyl substituted C 1 -C 9 Alkyl, ethyl ester group substituted C 1 -C 9 Alkyl, heterocyclyl substituted C 1 -C 9 Alkyl, hydroxy substituted C 1 -C 9 Alkyl, aryl substituted C 1 -C 9 Alkyl or C 2 -C 9 One of heterocyclic groups;
wherein, the m-hydroxyaniline, anhydrous NaH and R 1 The molar ratio of X is 1:2-3.5:0.5-0.7, the molar ratio of the meta-substituted benzoic acid to the thionyl chloride is 1:2-2.5, and the molar ratio of the m-hydroxyaniline derivatives to the meta-substituted benzoyl chloride is 1: 1.1-1.5;
the invention has the beneficial effects that: the invention provides novel PDE2 inhibitor compounds, mainly comprising 33 compounds of N- (3-methoxyphenyl) benzamide, 3-methoxy-N- (3-hydroxyphenyl) benzamide and 3-hydroxy-N- (3-hydroxyphenyl) benzamide derivatives, which have good PDE2 inhibition activity, have the potential of treating central nervous system diseases, such as memory deficiency, cognitive disorder, anxiety, depression and the like, and can be used as active ingredients for preparing medicaments for inhibiting PDE2 activity. In addition, a corresponding synthesis method is provided for the provided compound structure, the synthesis method is simple, the yield is high, the etherification reaction is carried out in a closed tank, the feeding ratio is 1:0.7, the maximum mono-substitution reaction is ensured, the post-treatment uses a rapid preparation liquid phase, the efficiency and the environmental protection are realized, the thionyl chloride generated in the acyl chlorination reaction is a reaction reagent and a reaction solvent, the complete reaction, the energy conservation and the environmental protection are ensured, and the post-treatment method in the amidation reaction creatively uses an anti-solvent crystallization method for separation and purification, so that complicated column chromatography is omitted, and the method is suitable for the requirement of industrial large-scale production.
Detailed Description
The present invention will be further described with reference to the following embodiments. The following embodiments are only used to more clearly illustrate the technical solutions of the present invention, and the protection scope of the present invention is not limited thereby.
Example 1
Preparation of Compounds 1a-1 j:
anhydrous DMF (20mL) was added to a 100mL round bottom flask, and the starting materials m-hydroxyaniline (9.2mmol), anhydrous NaH (27.5mmol, 0.66g) and R were added 1 X (6.4mmol) at 80-120 deg.C (specific temperature is corresponding to R) 1 The boiling point of X), and carrying out a close-tank reaction for 6 h. The reaction was monitored by TLC (oil puzzle: ethyl acetate 4: 1). After the reaction is finished, adding 200mL of water into the reaction solution, extracting with ethyl acetate, evaporating the solvent, and performing rapid preparative liquid phase separation (petroleum ether: ethyl acetate is 3-5: 1 (the specific ratio is determined by the polarity of the product)) to obtain the m-hydroxyaniline derivative with higher purity.
The starting benzoic acid (13.8mmol) was added to anhydrous thionyl chloride (34.5mmol) and the reaction was carried out for 4h with temperature control at reflux. The reaction was monitored by TLC. After the reaction is finished, the residual thionyl chloride is evaporated in a rotary mode to obtain benzoyl chloride.
Anhydrous THF (20mL) was charged into a 100mL round-bottom flask, and the starting m-hydroxyanilines (12.7mmol), pyridine (0.2mL) and benzoyl chloride (16.5mmol) were added, and the temperature was controlled at room temperature, followed by reaction for 14 h. The reaction was monitored by TLC (petroleum ether: ethyl acetate 3: 1). After the reaction is finished, filtering the reaction solution, removing the precipitate, and evaporating the solvent in a rotary manner to obtain a crude product. Completely dissolving the crude product in ethyl acetate at 75 ℃, cooling to room temperature (20-30 ℃), dropwise adding petroleum ether serving as a small polar solvent into the solution, generating a large amount of floccules, and filtering to obtain the N- (3-methoxyphenyl) benzamide derivative with high purity.
1a: 1 H NMR(300MHz,DMSO-d 6 )δ10.20(s,1H),8.00–7.92(m,2H),7.61–7.47(m,4H),7.36(ddd,J＝8.2,2.1,1.0Hz,1H),7.23(t,J＝8.1Hz,1H),6.67(ddd,J＝8.2,2.6,1.0Hz,1H),3.95(t,J＝6.0Hz,2H),1.78-1.68(m,2H),1.48–1.27(m,4H),0.91(t,J＝6.0Hz,3H). 13 C NMR(75MHz,DMSO-d 6 )δ166.03,159.31,140.80,135.44,132.04,129.82,129.73,129.03,128.85,128.09,112.87,110.19,106.97,67.81,28.84,28.20,22.38,14.40.
1b: 1 H NMR(300MHz,DMSO-d 6 )δ10.24(s,1H),8.00–7.87(m,2H),7.64–7.46(m,4H),7.46–7.40(m,1H),7.26(t,J＝8.2Hz,1H),6.67(ddd,J＝8.2,2.6,0.9Hz,1H),4.76(s,2H),4.19(q,J＝6.0Hz,2H),1.23(t,J＝7.5Hz,3H). 13 C NMR(75MHz,DMSO-d 6 )δ169.18,166.12,158.25,140.85,135.40,132.08,129.90,128.87,128.11,113.65,109.86,107.18,65.10,61.13,14.52.
1c: 1 H NMR(300MHz,DMSO-d 6 )δ10.21(s,1H),8.05–7.90(m,2H),7.67–7.19(m,6H),6.67(ddd,J＝8.2,2.5,1.0Hz,1H),4.75(t,J＝6.0Hz,1H),4.01(t,J＝6.2Hz,4H),3.79–3.64(m,2H),2.01–1.80(m,3H),1.39-1.32(m,1H). 13 C NMR(75MHz,DMSO-d 6 )δ166.04,159.08,140.83,135.40,132.06,129.88,128.86,128.10,112.99,110.30,106.77,99.26,66.56,63.48,35.06,25.84.
1d: 1 H NMR(300MHz,DMSO-d 6 )δ10.19(s,1H),8.03–7.87(m,2H),7.68–7.43(m,4H),7.36(ddd,J＝8.1,2.0,1.0Hz,1H),7.23(t,J＝8.1Hz,1H),6.67(ddd,J＝8.2,2.5,1.0Hz,1H),3.83(d,J＝6.0Hz,2H),2.37-2.27(m,1H),1.85–1.70(m,2H),1.67–1.46(m,4H),1.40–1.22(m,2H). 13 C NMR(75MHz,DMSO-d 6 )δ166.01,159.45,140.79,135.43,132.04,129.81,128.85,128.09,112.87,110.25,107.00,72.02,39.02,29.50,25.43.
1e: 1 H NMR(400MHz,DMSO-d 6 )δ10.22(s,1H),8.02–7.88(m,2H),7.64–7.47(m,4H),7.38(dd,J＝8.0,1.9Hz,1H),7.25(t,J＝8.1Hz,1H),6.69(dd,J＝8.1,2.5Hz,1H),5.01(t,J＝6.0Hz,1H),4.07(t,J＝8.0Hz,2H),4.00–3.90(m,2H),3.87–3.77(m,2H),2.06(td,J＝8.0,4.0Hz,2H). 13 C NMR(75MHz,DMSO-d 6 )δ166.04,159.03,140.84,135.42,132.05,129.89,129.73,129.04,128.86,128.10,113.06,110.19,106.88,101.67,64.74,63.87.
1f: 1 H NMR(300MHz,DMSO-d 6 )δ10.19(s,1H),8.07–7.85(m,2H),7.66–7.40(m,4H),7.35(ddd,J＝8.2,2.1,1.0Hz,1H),7.22(t,J＝8.1Hz,1H),6.66(ddd,J＝8.2,2.5,1.0Hz,1H),3.76(d,J＝6.0Hz,2H),2.03–1.54(m,6H),1.35–0.98(m,5H). 13 C NMR(75MHz,DMSO-d 6 )δ166.01,159.46,140.81,135.43,132.04,129.81,129.73,129.04,128.85,128.09,112.82,110.30,106.89,73.16,37.55,29.76,26.52,25.75.
1g: 1 H NMR(300MHz,DMSO-d 6 )δ10.24(s,1H),8.00–7.91(m,2H),7.67–7.50(m,5H),7.48–7.39(m,2H),7.32–7.22(m,3H),6.80(ddd,J＝8.3,2.6,1.0Hz,1H),5.14(s,2H). 13 C NMR(75MHz,DMSO-d 6 )δ166.09,158.80,140.90,135.42,132.07,131.03,130.98,130.86,130.75,129.96,129.73,129.04,128.87,128.11,125.04,124.99,124.42,124.23,116.00,115.72,113.47,110.33,107.33,63.93,63.89.
1h: 1 H NMR(300MHz,DMSO-d 6 )δ10.22(s,1H),8.07–7.82(m,2H),7.66–7.47(m,4H),7.39(ddd,J＝8.1,2.0,1.0Hz,1H),7.25(t,J＝8.1Hz,1H),6.71(ddd,J＝8.2,2.6,1.0Hz,1H),5.22(t,J＝6.0Hz,1H),4.03–3.82(m,6H). 13 C NMR(75MHz,DMSO-d 6 )δ166.07,158.82,140.83,135.41,132.07,129.93,128.87,128.11,113.36,110.09,107.10,101.65,68.66,65.01.
1i: 1 H NMR(300MHz,DMSO-d 6 )δ10.23(s,1H),8.05–7.82(m,2H),7.63–7.49(m,4H),7.37(ddd,J＝8.1,2.0,1.0Hz,1H),7.25(t,J＝8.1Hz,1H),6.75(ddd,J＝8.2,2.5,1.0Hz,1H),6.62(d,J＝2.3Hz,2H),6.45(t,J＝2.3Hz,1H),5.04(s,2H),3.75(s,6H). 13 C NMR(75MHz,DMSO-d 6 )δ166.07,161.00,158.91,140.84,139.93,135.43,132.06,129.88,128.87,128.11,113.31,110.37,107.49,105.84,99.89,69.51,55.65.
1j: 1 H NMR(300MHz,DMSO-d 6 )δ10.24(s,1H),8.07–7.86(m,2H),7.63–7.49(m,4H),7.41–7.36(m,1H),7.27(t,J＝8.1Hz,1H),6.80(ddd,J＝8.1,2.6,1.0Hz,1H),6.16(s,1H),5.09(s,2H),3.75(s,3H),2.12(s,3H). 13 C NMR(75MHz,DMSO-d 6 )δ166.10,158.49,146.01,140.85,138.45,135.40,132.08,129.90,128.88,128.11,113.59,110.35,107.53,106.94,60.41,36.54,13.64.
Example 2
Preparation of Compounds 2a-2 j:
anhydrous DMF (20mL) was added to a 100mL round bottom flask, and the starting materials m-hydroxyaniline (9.2mmol), anhydrous NaH (27.5mmol, 0.66g) and R were added 1 X (6.4mmol) at 80-120 deg.C (specific temperature is corresponding to R) 1 Boiling point of X), and carrying out a close-packed reaction for 6 hours. The reaction was monitored by TLC (oil puzzle: ethyl acetate 4: 1). After the reaction is finished, adding 200mL of water into the reaction solution, extracting with ethyl acetate, evaporating the solvent, and performing rapid preparative liquid phase separation (petroleum ether: ethyl acetate is 3-5: 1 (the specific ratio is determined by the polarity of the product)) to obtain the m-hydroxyaniline derivative with higher purity.
The starting material, m-methoxybenzoic acid (13.8mmol), was added to anhydrous thionyl chloride (34.5mmol) and the reaction was carried out for 4h with temperature control at reflux. The reaction was monitored by TLC. After the reaction is finished, the residual thionyl chloride is evaporated in a rotary mode to obtain the m-methoxybenzoyl chloride.
Anhydrous THF (20mL) was charged into a 100mL round-bottom flask, and the starting m-hydroxyaniline derivative (12.7mmol), pyridine (0.2mL) and m-methoxybenzoyl chloride (16.5mmol) were added, and the temperature was controlled at room temperature, followed by reaction for 14 h. The reaction was monitored by TLC (petroleum ether: ethyl acetate 3: 1). After the reaction is finished, filtering the reaction solution, removing the precipitate, and evaporating the solvent in a rotary manner to obtain a crude product. Completely dissolving the crude product in ethyl acetate at 75 ℃, cooling to room temperature (20-30 ℃), dropwise adding petroleum ether serving as a small polar solvent into the solution, generating a large amount of floccules, and filtering to obtain the 3-methoxy-N- (3-hydroxyphenyl) benzamide derivative with high purity.
2a: 1 H NMR(300MHz,DMSO-d 6 )δ10.16(s,1H),7.54(dt,J＝7.7,1.3Hz,1H),7.50–7.42(m,3H),7.37–7.32(m,1H),7.22(t,J＝8.1Hz,1H),7.18–7.13(m,1H),6.69–6.64(m,1H),4.39–4.27(m,1H),3.85(s,3H),1.75–1.50(m,2H),1.25(d,J＝6.0Hz,3H),0.94(t,J＝7.4Hz,3H). 13 C NMR(75MHz,DMSO)δ165.73,159.65,158.44,140.80,136.88,130.01,129.83,120.29,117.73,113.38,112.87,111.47,108.18,74.65,55.79,29.07,19.54,10.05.
2b: 1 H NMR(300MHz,DMSO-d 6 )δ10.19(s,1H),7.53(dt,J＝7.7,1.4Hz,1H),7.50–7.42(m,3H),7.40–7.35(m,1H),7.25(t,J＝8.1Hz,1H),7.19–7.14(m,1H),6.68–6.73(m,1H),4.14(t,J＝6.6Hz,2H),3.84(s,3H),2.86(t,J＝6.6Hz,2H),2.17(s,3H). 13 C NMR(75MHz,DMSO)δ165.76,159.64,158.84,140.77,136.79,130.04,129.92,120.29,117.79,113.36,113.23,110.25,107.08,67.42,55.81,32.66,15.75.
2c: 1 H NMR(300MHz,DMSO-d 6 )δ10.21(s,1H),7.53(dt,J＝7.7,1.4Hz,1H),7.49–7.38(m,4H),7.26(t,J＝8.2Hz,1H),7.19–7.14(m,1H),6.70–6.65(m,1H),4.76(s,2H),4.18(q,J＝7.1Hz,2H),3.84(s,3H),1.23(t,J＝7.1Hz,3H). 13 C NMR(75MHz,DMSO)δ169.17,165.81,159.65,158.25,140.79,136.79,130.04,129.89,120.31,117.78,113.70,113.40,109.89,107.26,65.10,61.12,55.80,14.51.
2d: 1 H NMR(300MHz,DMSO-d 6 )δ10.16(s,1H),7.53(dt,J＝7.7,1.3Hz,1H),7.49–7.41(m,3H),7.38–7.32(m,1H),7.23(t,J＝8.1Hz,1H),7.19–7.13(m,1H),6.71–6.65(m,1.0Hz,1H),3.87–3.79(m,5H),2.40–2.23m,1H),1.87–1.26(m,8H). 13 C NMR(75MHz,DMSO)δ165.73,159.64,159.44,140.69,136.78,130.04,129.82,120.29,117.79,113.33,112.95,110.32,107.07,72.02,55.80,39.01,29.49,25.42.
2e: 1 H NMR(300MHz,DMSO-d 6 )δ10.19(s,1H),7.56–7.41(m,4H),7.40–7.35(m,1H),7.25(t,J＝8.1Hz,1H),7.19–7.14(m,1H),6.74–6.68(m,1H),5.22(t,J＝4.0Hz,1H),4.01–3.95(m,4H),3.93–3.86(m,2H),3.84(s,3H). 13 C NMR(75MHz,DMSO)δ165.78,159.65,158.82,140.76,136.79,130.04,129.92,120.30,117.80,113.43,113.37,110.15,107.17,101.65,68.67,65.01,55.81.
2f: 1 H NMR(300MHz,DMSO-d 6 )δ10.17(s,1H),7.53(dt,J＝7.7,1.3Hz,1H),7.49–7.41(m,3H),7.39–7.34(m,1H),7.24(t,J＝8.1Hz,1H),7.18–7.13(m,1H),6.70–6.66(m,1H),5.00(t,J＝4.9Hz,1H),4.06(t,J＝6.6Hz,2H),3.96–3.90(m,2H),3.84(s,3H),3.83–3.77(m,2H),2.09–2.01(m,2H). 13 C NMR(75MHz,DMSO)δ165.74,159.65,159.03,140.77,136.80,130.03,129.88,120.30,117.78,113.37,113.12,110.26,106.94,101.67,64.74,63.87,55.81,33.77.
2g: 1 H NMR(300MHz,DMSO-d 6 )δ10.15(s,1H),7.53(dt,J＝7.7,1.3Hz,1H),7.49–7.41(m,3H),7.37–7.32(m,1H),7.22(t,J＝8.1Hz,1H),7.18–7.13(m,1H),6.69–6.64(m,1H),3.84(s,3H),3.76(d,J＝6.2Hz,2H),1.86–1.62(m,6H),1.30–1.00(m,5H). 13 C NMR(75MHz,DMSO)δ165.71,159.65,159.46,140.73,136.81,130.02,129.80,120.29,117.77,113.35,112.88,110.36,106.95,73.16,55.81,37.55,29.75,26.52,25.75.
2h: 1 H NMR(300MHz,DMSO-d 6 )δ10.17(s,1H),7.54(dt,J＝7.6,1.3Hz,1H),7.51–7.41(m,3H),7.38–7.33(m,1H),7.24(t,J＝8.1Hz,1H),7.18–7.13(m,1H),6.71–6.66(m,1H),3.92–3.85(m,2H),3.84(s,3H),3.82(d,J＝6.5Hz,2H),3.35–3.28(m,2H),2.09–1.93(m,1H),1.73–1.63(m,2H),1.42–1.26(m,2H). 13 C NMR(75MHz,DMSO)δ165.72,159.65,159.33,140.75,136.80,130.02,129.83,120.29,117.77,113.36,113.02,110.31,107.03,72.49,67.12,55.80,34.94,29.73.
2i: 1 H NMR(300MHz,DMSO-d 6 )δ10.18(s,1H),7.57–7.33(m,5H),7.24(t,J＝8.1Hz,1H),7.19–7.13(m,1H),6.67(dd,J＝8.2,2.4Hz,1H),4.75(t,J＝5.2Hz,1H),4.06–3.96(m,4H),3.84(s,3H),3.73(td,J＝12.1,2.5Hz,2H),2.03–1.79(m,3H),1.39–1.31(m,1H). 13 C NMR(75MHz,DMSO)δ165.75,159.64,159.06,140.75,136.78,130.04,129.88,120.29,117.79,113.35,113.06,110.36,106.83,99.25,66.57,63.47,55.80,35.06,25.84.
2j: 1 H NMR(300MHz,DMSO-d 6 )δ10.22(s,1H),7.57–7.51(m,2H),7.49–7.36(m,3H),7.27(t,J＝8.1Hz,1H),7.19–7.14(m,1H),6.83–6.78(m,1H),6.16(s,1H),5.09(s,2H),3.84(s,3H),3.75(s,3H),2.12(s,3H). 13 C NMR(75MHz,DMSO)δ165.80,159.64,158.48,146.01,140.77,138.45,136.78,130.06,129.91,120.31,117.81,113.66,113.37,110.40,107.60,106.95,60.41,55.81,36.54,13.64.
Example 3
Preparation of Compounds 3a-3 m:
anhydrous DMF (20mL) was added to a 100mL round bottom flask, and the starting materials m-hydroxyaniline (9.2mmol), anhydrous NaH (27.5mmol, 0.66g) and R were added 1 X (6.4mmol) at 80-120 deg.C (specific temperature is corresponding to R) 1 Boiling point of X), and carrying out a close-packed reaction for 6 hours. The reaction was monitored by TLC (oil puzzle: ethyl acetate 4: 1). After the reaction is finished, adding 200mL of water into the reaction solution, extracting with ethyl acetate, evaporating the solvent, and performing rapid preparative liquid phase separation (petroleum ether: ethyl acetate is 3-5: 1 (the specific ratio is determined by the polarity of the product)) to obtain the m-hydroxyaniline derivative with higher purity.
The starting material, m-hydroxybenzoic acid (13.8mmol), was added to anhydrous thionyl chloride (34.5mmol) and the reaction was carried out for 4h with temperature controlled at reflux. The reaction was monitored by TLC. After the reaction is finished, the residual thionyl chloride is evaporated in a rotary mode to obtain m-hydroxy benzoyl chloride.
Anhydrous THF (20mL) was charged into a 100mL round-bottom flask, and the starting m-hydroxyanilide derivatives (12.7mmol), pyridine (0.2mL) and m-hydroxybenzoyl chloride (16.5mmol) were added, and the temperature was controlled at room temperature, followed by reaction for 14 h. The reaction was monitored by TLC (petroleum ether: ethyl acetate 3: 1). After the reaction is finished, filtering the reaction solution, removing the precipitate, and evaporating the solvent in a rotary manner to obtain a crude product. Completely dissolving the crude product in ethyl acetate at 75 ℃, cooling to room temperature (20-30 ℃), dropwise adding a small polar solvent petroleum ether into the solution, generating a large amount of floccules, and filtering to obtain the high-purity 3-hydroxy-N- (3-hydroxyphenyl) benzamide derivative.
3a: 1 H NMR(300MHz,DMSO-d 6 )δ10.12(s,1H),9.78(s,1H),7.47(t,J＝2.1Hz,1H),7.39–7.28(m,4H),7.22(t,J＝8.1Hz,1H),6.97(ddd,J＝7.6,2.5,1.5Hz,1H),6.66(ddd,J＝8.1,2.4,0.7Hz,1H),3.95(t,J＝6.5Hz,2H),1.77–1.64(m,2H),1.44(dq,J＝14.4,7.3Hz,2H),0.94(t,J＝7.4Hz,3H). 13 C NMR(75MHz,DMSO-d 6 )δ166.06,159.29,157.81,140.85,136.90,129.89,129.79,118.94,118.61,114.95,112.81,110.09,106.88,67.49,31.22,19.23,14.19.
3b: 1 H NMR(300MHz,DMSO-d 6 )δ10.11(s,1H),9.77(s,1H),7.47(t,J＝2.1Hz,1H),7.37–7.28(m,4H),7.21(t,J＝8.1Hz,1H),6.97(ddd,J＝7.5,2.5,1.5Hz,1H),6.65(ddd,J＝8.1,2.4,0.8Hz,1H),3.94(t,J＝6.5Hz,2H),1.72(p,J＝6.7Hz,2H),1.38(tt,J＝9.1,4.7Hz,4H),0.90(t,J＝7.0Hz,3H). 13 C NMR(75MHz,DMSO-d 6 )δ166.05,159.29,157.81,140.85,136.90,129.89,129.79,118.94,118.61,114.95,112.80,110.07,106.88,67.78,28.84,28.20,22.38,14.41.
3c: 1 H NMR(300MHz,DMSO-d 6 )δ10.11(s,1H),9.79(s,1H),7.44(t,J＝2.2Hz,1H),7.40–7.26(m,4H),7.21(t,J＝8.1Hz,1H),6.97(ddd,J＝7.4,2.6,1.7Hz,1H),6.64(ddd,J＝8.2,2.5,1.0Hz,1H),4.56(hept,J＝6.0Hz,1H),1.28(d,J＝6.0Hz,6H). 13 C NMR(75MHz,DMSO-d 6 )δ166.08,158.06,157.82,140.90,136.94,129.92,129.84,118.94,118.63,114.95,112.71,111.26,107.95,69.57,22.33.
3d: 1 H NMR(300MHz,DMSO-d 6 ))δ10.12(s,1H),9.79(s,1H),7.47(t,J＝2.2Hz,1H),7.42–7.27(m,4H),7.21(t,J＝8.1Hz,1H),6.97(ddd,J＝7.5,2.5,1.5Hz,1H),6.66(ddd,J＝8.2,2.5,1.0Hz,1H),3.98(t,J＝6.6Hz,2H),1.79(dp,J＝13.1,6.6Hz,1H),1.62(q,J＝6.7Hz,2H),0.94(d,J＝6.6Hz,6H). 13 C NMR(75MHz,DMSO-d 6 )δ166.06,159.29,157.81,140.85,136.90,129.89,129.79,118.94,118.61,114.95,112.81,110.09,106.88,66.25,37.89,25.10,22.92.
3e: 1 H NMR(300MHz,DMSO-d 6 )δ10.10(s,1H),9.77(s,1H),7.44(t,J＝2.2Hz,1H),7.40–7.26(m,4H),7.21(t,J＝8.1Hz,1H),6.97(ddd,J＝7.5,2.5,1.5Hz,1H),6.65(ddd,J＝8.2,2.5,1.0Hz,1H),3.80(d,J＝6.9Hz,2H),1.24(s,1H),0.78–0.06(m,4H). 13 C NMR(75MHz,DMSO-d 6 )δ166.08,158.42,157.82,140.92,136.95,129.91,129.84,118.94,118.63,114.96,112.74,111.33,108.02,72.37,10.63,3.57,3.56.
3f: 1 H NMR(300MHz,DMSO-d 6 )δ10.12(s,1H),9.79(s,1H),7.47(t,J＝2.2Hz,1H),7.42–7.27(m,4H),7.21(t,J＝8.1Hz,1H),6.97(ddd,J＝7.5,2.5,1.5Hz,1H),6.66(ddd,J＝8.2,2.5,1.0Hz,1H),3.82(d,J＝7.0Hz,2H),1.78(q,J＝12.3,9.8Hz,2H),1.68–1.46(m,4H),1.45–1.12(m,3H). 13 C NMR(75MHz,DMSO-d 6 )δ166.05,159.42,157.82,140.84,136.88,129.92,129.81,118.96,118.62,114.95,112.80,110.14,106.89,71.99,39.01,29.51,25.44.
3g: 1 H NMR(300MHz,DMSO-d 6 )δ10.10(s,1H),9.76(s,1H),7.46(t,J＝2.2Hz,1H),7.39–7.28(m,4H),7.21(t,J＝8.1Hz,1H),6.97(ddd,J＝7.5,2.5,1.5Hz,1H),6.65(ddd,J＝8.2,2.5,1.0Hz,1H),3.75(d,J＝6.2Hz,2H),1.84(s,1H),1.80–1.65(m,4H),1.34–1.13(m,4H),1.04(q,J＝11.3Hz,2H). 13 C NMR(75MHz,DMSO-d 6 )δ166.04,159.43,157.81,140.84,136.88,129.89,129.78,118.94,118.61,114.95,112.77,110.20,106.82,73.13,37.54,29.75,26.52,25.75.
3h: 1 H NMR(300MHz,DMSO-d 6 )δ10.16(s,1H),9.78(s,1H),7.46(t,J＝2.2Hz,1H),7.42–7.28(m,4H),7.24(t,J＝8.1Hz,1H),6.97(ddd,J＝7.5,2.5,1.5Hz,1H),6.65(ddd,J＝8.2,2.6,0.9Hz,1H),4.75(s,2H),4.19(t,J＝7.1Hz,2H),1.22(t,J＝7.1Hz,3H). 13 C NMR(75MHz,DMSO-d 6 )δ169.18,166.12,158.21,157.81,140.90,136.85,129.92,118.98,118.63,114.95,113.56,109.75,107.08,65.06,61.12,14.53.
3i: 1 H NMR(300MHz,DMSO-d 6 )δ10.16(s,1H),9.79(s,1H),7.57(t,J＝2.2Hz,1H),7.40–7.29(m,4H),7.24(t,J＝8.1Hz,1H),6.98(ddd,J＝7.4,2.5,1.5Hz,1H),6.74(ddd,J＝8.2,2.5,1.0Hz,1H),6.62(d,J＝2.3Hz,2H),6.45(t,J＝2.3Hz,1H),5.03(s,2H),3.75(s,6H). 13 C NMR(75MHz,DMSO-d 6 )δ166.11,161.00,158.88,157.83,140.89,139.93,136.88,129.94,129.87,118.98,118.64,114.96,113.23,110.26,107.39,105.84,99.87,69.46,55.65.
3j: 1 H NMR(300MHz,DMSO-d 6 )δ10.17(s,1H),9.78(s,1H),7.58(t,J＝2.2Hz,1H),7.42–7.33(m,2H),7.33–7.27(m,2H),7.27–7.15(m,4H),6.98(ddd,J＝7.4,2.5,1.6Hz,1H),6.76(ddd,J＝8.2,2.6,1.0Hz,1H),5.15(d,J＝2.6Hz,2H). 13 C NMR(75MHz,DMSO-d 6 )δ166.14,158.52,157.83,140.97,136.86,129.94,119.00,118.64,114.97,113.54,111.03,110.70,110.28,107.40,68.24.
3k: 1 H NMR(300MHz,DMSO-d 6 )δ10.30(s,1H),9.80(s,1H),8.67(d,J＝4.8Hz,2H),7.71(t,J＝2.2Hz,1H),7.64(ddd,J＝8.1,2.1,1.0Hz,1H),7.41–7.34(m,2H),7.34–7.25(m,3H),6.98(ddd,J＝7.5,2.5,1.5Hz,1H),6.93(ddd,J＝8.1,2.4,1.0Hz,1H). 13 C NMR(75MHz,DMSO-d 6 )δ166.23,165.24,160.61,157.85,153.38,141.01,136.68,130.09,129.97,119.10,118.67,117.48,117.33,117.16,114.98,113.74.
3l: 1 H NMR(300MHz,DMSO-d 6 )δ10.15(s,1H),9.78(s,1H),7.57(t,J＝2.2Hz,1H),7.46(td,J＝8.0,7.5,1.6Hz,2H),7.40(dq,J＝7.9,1.4Hz,2H),7.37–7.29(m,5H),7.24(t,J＝8.1Hz,1H),6.97(ddd,J＝7.5,2.5,1.5Hz,1H),6.76(ddd,J＝8.2,2.6,1.0Hz,1H),5.10(s,2H). 13 C NMR(75MHz,DMSO-d 6 )δ166.12,158.97,157.83,140.92,137.56,136.90,129.86,128.93,128.31,128.16,118.97,118.64,114.97,113.22,110.29,107.38,69.59.
3m: 1 H NMR(300MHz,DMSO-d 6 )δ10.14(s,1H),9.77(s,1H),7.48(t,J＝2.2Hz,1H),7.40–7.28(m,4H),7.23(t,J＝8.1Hz,1H),6.97(ddd,J＝7.5,2.5,1.6Hz,1H),6.69(ddd,J＝8.2,2.5,0.9Hz,1H),5.21(t,J＝4.0Hz,1H),4.01–3.90(m,4H),3.90–3.82(m,2H). 13 C NMR(75MHz,DMSO-d 6 )δ166.11,158.80,157.83,140.88,136.86,129.92,118.99,118.64,114.97,113.30,109.99,107.03,101.65,68.63,65.01.
TABLE 1N- (3-methoxyphenyl) benzamide derivatives
Figure BDA0003671468570000131
TABLE 23 methoxy-N- (3-hydroxyphenyl) benzamide derivatives
Figure BDA0003671468570000141
TABLE 33-hydroxy-N- (3-hydroxyphenyl) benzamide derivatives
Figure BDA0003671468570000151

Claims (5)

1. A PDE2 inhibitor amide derivative, which is characterized by the following general formula:
Figure FDA0003671468560000011
wherein R is one of a hydrogen atom, a methoxyl group or a hydroxyl group; r 1 Is C 2 -C 9 Alkyl, methylthio substituted C 2 -C 9 Alkyl, cycloalkyl substituted C 1 -C 9 Alkyl, ethyl ester group substituted C 1 -C 9 Alkyl, heterocyclyl substituted C 1 -C 9 Alkyl, hydroxy substituted C 1 -C 9 Alkyl, aryl substituted C 1 -C 9 Alkyl or C 2 -C 9 One of the heterocyclic groups.
2. The PDE2 inhibitor amide derivative of claim 1, wherein compound i is selected from compounds represented by formulae 1a-1j, 2a-2j or 3a-3 m:
Figure FDA0003671468560000012
Figure FDA0003671468560000021
3. the process for preparing amide derivatives of PDE2 inhibitors according to claim 1 or 2, wherein the synthetic route is represented by the following formula:
Figure FDA0003671468560000031
wherein R is one of a hydrogen atom, a methoxyl group or a hydroxyl group; x is Cl or Br;
wherein R is 1 Is C 2 -C 9 Alkyl, methylthio substituted C 2 -C 9 Alkyl, cycloalkyl substituted C 1 -C 9 Alkyl, ethyl ester group substituted C 1 -C 9 Alkyl, heterocyclyl substituted C 1 -C 9 Alkyl, hydroxy substituted C 1 -C 9 Alkyl, aryl substituted C 1 -C 9 Alkyl or C 2 -C 9 One of the heterocyclic groups.
4. The preparation method of the amide derivative of PDE2 inhibitor according to claim 3, which comprises the following steps:
(1) etherification: the raw materials of m-hydroxyaniline, anhydrous NaH and R 1 Adding X into anhydrous DMF, and carrying out a close-packed reaction for 4-8h at the temperature of 80-120 ℃; the reaction was monitored by TLC; after the reaction is finished, adding the reaction solution into water, extracting with ethyl acetate, evaporating the solvent in a rotary manner, and quickly preparing a liquid phase to obtain the m-hydroxyaniline derivative;
(2) preparing acyl chloride: adding the meta-substituted benzoic acid serving as a raw material into anhydrous thionyl chloride, and controlling the temperature under reflux to react for 2-6 h; the reaction was monitored by TLC; after the reaction is finished, the residual thionyl chloride is evaporated in a rotary mode to obtain meta-substituted benzoyl chloride;
(3) amidation: adding m-hydroxyaniline derivatives obtained by etherification in the step (1), pyridine and meta-substituted benzoyl chloride obtained in the step (2) into anhydrous THF, controlling the temperature at room temperature, and reacting for 8-24 h; the reaction was monitored by TLC; after the reaction is finished, filtering the reaction solution, removing the precipitate, and evaporating the solvent in a rotary manner to obtain a crude product; completely dissolving the crude product in ethyl acetate at 75 ℃, cooling to room temperature, dropwise adding petroleum ether serving as a small polar solvent into the solution, and filtering to obtain the PDE2 inhibitor amide derivative, wherein a large amount of floccules appear.
5. The method for preparing the amide derivatives as PDE2 inhibitors according to claim 4, wherein the m-hydroxyaniline, anhydrous NaH and R are 1 The molar ratio of X is 1:2-3.5:0.5-0.7, the molar ratio of the meta-substituted benzoic acid to the thionyl chloride is 1:2-2.5, and the molar ratio of the m-hydroxyaniline derivative to the meta-substituted benzoyl chloride is 1: 1.1-1.5.
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