CN115260136B - Phthalide compound and preparation method thereof - Google Patents

Abstract

The present invention provides a kind of phthalide compound and preparation method thereof, have the structure shown in formula I: Wherein, R1 is -H, a halogen group, a methoxy group or a methyl group; R2 is an aryl group, an alkyl group or hydrogen. Mix N-methoxybenzamide, a catalyst and an organic solvent to carry out a synthesis reaction. The temperature of the synthesis reaction is 70-80° C., and the time of the synthesis reaction is 10-12 hours to obtain phthalide compounds. The preparation provided by the invention The method does not use precious metals, the required reaction time is shorter, and the reaction conditions are mild; N-methoxybenzamide is used as a raw material to synthesize phthalides in one step. The method is simple, fast, and has wide substrate applicability.

Description

A kind of phthalide compound and preparation method thereof

technical field

The invention relates to the technical field of organic synthesis, in particular to a phthalide compound and a preparation method thereof.

Background technique

Phthalide is an important class of heterocyclic compounds existing in nature, and many drugs or drug intermediates contain phthalide units. More and more studies have shown that phthalide derivatives have pharmacological activities such as antipyretic, analgesic, antitumor and antibacterial fungi. Such as: pomalidomide (Pomalyst) has very good antitumor activity.

In 2020, Yu Jinquan's group reported the synthesis of phthalides (Ligand-EnabledPd(II)-Catalyzed C(sp3)–H Lactonization Using Molecular Oxygen as Oxidant.Org. Lett. 2020, 22, 3960-3963). Although the reaction is efficient, the cost of the raw material synthesis catalyst is high, the reaction conditions are high, and the reaction time is long. Based on the above factors, a phthalide compound and its preparation method have been specially developed, which has a cost advantage compared with the traditional precious metal method. Moreover, the reaction time is short, simple and efficient, and the reaction conditions are mild.

Contents of the invention

The object of the present invention is to provide a kind of phthalide compound and its preparation method, and its preparation method has cost advantage compared with traditional noble metal method, and this method synthesizes phthalide compound in one step, and method is simple, fast, and substrate applicability is wide.

The object of the present invention is to be realized by the following technical scheme: a kind of phthalide compound has the structure shown in formula I:

Wherein, R1 is -H, halogen group, methoxy group or methyl group; R2 is aryl group, alkyl group or hydrogen.

Further, the halogen group includes -F, -Cl or -Br.

Further, the preparation method of phthalide compound comprises the following steps:

Mix N-benzamide, catalyst, methanol and organic solvent to carry out a synthesis reaction, the temperature of the synthesis reaction is 70-80°C, and the time of the synthesis reaction is 10-12h, to obtain phthalide compounds;

The N-methoxybenzamide has a structure shown in formula II;

The N-benzamide preferably includes one of N-methoxybenzamide, N-(4-methoxyphenyl)benzamide, and N-pivaloyloxybenzamide.

Further, specifically: N-methoxy-2 ethyl-benzamide, ferrous chloride and methanol are added to 1,4-dioxane and mixed, and the resulting reaction solution is heated under nitrogen and light conditions to 70°C, carry out the synthesis reaction for 12 hours, filter the resulting reaction solution, and separate the resulting filtrate by column chromatography to obtain: 3-methylisobenzofuran-1(3H)-one, the separation yield is 80%, the synthesis reaction The equation is as follows:

Further, specifically: N-methoxy-2methyl-benzamide, ferrous chloride and methanol are added to 1,4-dioxane and mixed, and the resulting reaction solution is heated under nitrogen and light conditions to 70°C, carry out the synthesis reaction for 10 h, filter the obtained reaction liquid, and separate the obtained filtrate by column chromatography to obtain isobenzofuran-1(3H)-one, the separation yield is 75%, and the synthesis reaction equation is as follows:

Further, the molar ratio of the N-methoxybenzamide to the catalyst is 1:0.2-0.4.

Further, the catalyst is ferrous chloride or ferric chloride; the molar percentage of the catalyst is 20-40%.

Further, the organic solvent includes 1,2-dichloroethane, 1.4-dioxane or tetrahydrofuran.

Compared with prior art, the beneficial effect of the present invention is:

The invention provides a preparation method of phthalide compounds. The method does not use noble metals, has simple and mild reaction conditions and shorter reaction time.

The method of the invention uses the simple and easy-to-obtain N-methoxybenzamide as a raw material to synthesize phthalide compounds in one step, and the method is simple and fast, and the substrate has wide applicability.

Description of drawings

Fig. 1 is a schematic diagram of the structure of 4-phthalide compounds;

Figure 2 is the synthesis reaction equation.

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only some of the embodiments of the present invention, not all of them. Based on The embodiments of the present invention and all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

The present invention is further elaborated in conjunction with Fig. 1-2, the present invention provides a kind of phthalide compound, has the structure shown in formula I:

Wherein, R1 is -H, halogen group, methoxy group or methyl group; R2 is aryl group, alkyl group or hydrogen. In the present invention, the halogen group preferably includes -F, -Cl or -Br; in the present invention,

The aryl group is preferably a phenyl group, and the alkyl group is preferably a methyl group or an ethyl group.

The present invention provides the synthetic method of the phthalide compound described in above-mentioned technical scheme, comprises the following steps:

Mixing N-methoxybenzamide, a catalyst, additionally added methanol and an organic solvent, and performing a synthesis reaction under light to obtain phthalide compounds;

The N-methoxybenzamide has a structure shown in formula II;

In the present invention, the N-benzamide preferably includes N-methoxybenzamide, N-(4-methoxyphenyl)benzamide, and N-pivaloyloxybenzamide.

In the present invention, the catalyst is preferably ferrous chloride, ferric chloride;

The molar percentage of the N-methoxybenzamide and the catalyst is preferably 20-40%, more preferably 30-40%.

In the present invention, the organic solvent preferably includes 1,2-dichloroethane, 1,4-dioxane or tetrahydrofuran.

The present invention has no special limitation on the mixing process, and the mixing process well known to those skilled in the art can be selected.

In the present invention, the temperature of the synthesis reaction is 70-80° C., and the time of the synthesis reaction is 10-12 hours. After the synthesis reaction is completed, the present invention preferably filters the obtained reaction liquid, and then separates the obtained filtrate by column chromatography to obtain phthalide compounds.

The present invention has no special limitations on the specific methods and conditions of the filtration and column chromatography separation, and the methods and conditions well-known to those skilled in the art can be selected.

The phthalide compounds provided by the present invention and their preparation methods are described in detail below in conjunction with the examples, but they cannot be interpreted as limiting the protection scope of the present invention.

Example 1

N-methoxy-2methyl-benzamide (1a, 0.10M), ferrous chloride (40mol%) and methanol (1eq, 0.10M) were added to 1,4 dioxane and mixed. The obtained reaction solution was heated to 70° C. under nitrogen and light conditions, and the synthesis reaction was carried out for 10 h. The obtained reaction solution was filtered, and the obtained filtrate was separated by column chromatography to obtain isobenzofuran-1(3H)-one (4a). Isolation yield is 75%; The synthetic reaction equation of embodiment 1 is as follows:

1H NMR (400MHz, CDCl3) δ7.91–7.89(m,1H),7.69–7.65(m,1H),7.54–7.48(m,2H),5.31(s,2H).13C{1H}NMR(100MHz , CDCl3) δ170.7, 146.5, 134.0, 125.7, 125.7, 122.0, 69.7; HRMS (ESI-TOF): ([M+H]+) calcd for C8H7O2+: 135.0446; found: 135.0445.

Example 2

N-methoxy-2 ethyl-benzamide (1b, 0.10M), ferrous chloride (40mol%) and methanol (1eq, 0.10M) were added to 1,4 dioxane and mixed. The obtained reaction solution was heated to 70° C. under nitrogen and light conditions, and the synthesis reaction was carried out for 10 hours. The obtained reaction solution was filtered, and the obtained filtrate was separated by column chromatography to obtain: 3-methylisobenzofuran-1(3H)-one (4b). The separation yield is 80%; the synthetic reaction equation of embodiment 2 is as follows:

1H NMR (400MHz, CDCl3) δ7.77–7.75(m,1H),7.62–7.58(m,1H),7.45–7.38(m,2H),5.49(q,J=6.3Hz,1H),1.54( d, J=6.7Hz, 3H).13C{1H}NMR (100MHz, CDCl3) δ170.5, 151.2, 134.1, 129.0, 125.5, 125.4, 121.7, 77.8, 20.3; IR (NaCl); HRMS (ESI-TOF): ([M+H]+) calcd for C10H11O2+: 149.0603; found: 149.0609.

Example 3

2-benzyl-N-methoxybenzamide (1c, 0.10M), ferrous chloride (40mol%) and methanol (1eq, 0.10M) were added to 1,4 dioxane and mixed. The obtained reaction solution was heated to 70° C. under nitrogen and light conditions, and the synthesis reaction was carried out for 10 h. The obtained reaction solution was filtered, and the obtained filtrate was separated by column chromatography to obtain 3-phenylisobenzofuran-1(3H)-one ( 4a). Isolation yield is 68%; The synthetic reaction equation of embodiment 3 is as follows:

1H NMR (400MHz, CDCl3) δ7.99–7.94(m,1H),7.66–7.62(m,1H),7.58–7.53(m,1H),7.42–7.23(m,7H),6.40(s,1H ); 13C{1H}NMR (100MHz, CDCl3) δ170.6, 149.7, 136.4, 134.3, 129.4, 129.3, 129.0, 127.0, 125.7, 125.56, 122.9, 82.7; HRMS (ESI-TOF): ([M+H]+ ) calcd for C14H11O2+: 211.0759; found: 211.0756.

Example 4

Add 2-ethyl-N,5-dimethoxybenzamide (1d, 0.10M), ferrous chloride (40mol%) and methanol (1eq, 0.10M) to 1,4-dioxane Mix, heat the obtained reaction solution to 70°C under nitrogen and light conditions, carry out the synthesis reaction for 10 hours, filter the obtained reaction solution, and separate the obtained filtrate by column chromatography to obtain 6-methoxy-3-methylisobenzofuran -1(3H)-one (4d). Isolation yield is 61%; The synthetic reaction equation of embodiment 4 is as follows:

1H NMR (400MHz, CDCl3) δ7.30–7.25(m,2H),7.21–7.19(m,1H),5.49(q,J=6.6Hz,1H),3.83(s,3H),1.57(d, J=6.6Hz,3H).13C{1H}NMR(100MHz,CDCl3)δ170.7,170.5,160.6,143.7,123.0,122.4,107.4,77.7,55.8,20.5; HRMS(ESI-TOF):([M+H ]+) calcd for C10H11O3+: 179.0708; found: 179.0713.

Example 5

Add 5-chloro-2-ethyl-N-methoxybenzamide (1e, 0.10M), ferrous chloride (40mol%) and methanol (1eq, 0.10M) to 1,4-dioxane mixed in , the resulting reaction solution was heated to 70°C under nitrogen and light conditions, and the synthesis reaction was carried out for 10 hours, the resulting reaction solution was filtered, and the resulting filtrate was separated by column chromatography to obtain 6-chloro-3-methylisobenzofuran -1(3H)-one (4e). Isolation yield is 61%; The synthetic reaction equation of embodiment 5 is as follows:

1H NMR (400MHz, CDCl3) δ7.82(s,1H),7.62–7.60(m,1H),7.37–7.35(m,1H),5.53(q,J＝6.6Hz,6.1Hz,1H),1.60 (d, J=5.8Hz, 3H).13C{1H}NMR (100MHz, CDCl3) δ168.9, 149.3, 135.4, 134.3, 127.6, 125.6, 122.9, 77.6, 20.3; HRMS (ESI-TOF): ([M+ H]+) calcd for C9H8ClO2+: 183.0213; found: 183.0218.

Example 6

2-Methyl-N,4,5-trimethoxybenzamide (1f, 0.10M), ferrous chloride (40mol%) and methanol (1eq, 0.10M) were added to 1,4 dioxane Mixed in , the resulting reaction solution was heated to 70 ° C under nitrogen and light conditions, the synthesis reaction was carried out for 10 hours, the resulting reaction solution was filtered, and the resulting filtrate was separated by column chromatography to obtain 5,6-dimethoxyisobenzofuran -1(3H)-one (4f). Isolation yield is 61%; The synthetic reaction equation of embodiment 6 is as follows:

1H NMR (400MHz, CDCl3) δ7.29(s,1H),6.89(s,1H),5.20(s,2H),3.96(s,3H),3.92(s,3H).13C{1H}NMR( 100MHz, CDCl3) δ171.5, 154.9, 150.4, 141.0, 117.6, 106.1, 103.4, 69.1, 56.4, 56.3; HRMS (ESI-TOF): ([M+H]+) calcdforC10H11O4+: 195.0657; found: 195.0665.

Example 7

5-Bromo-N-methoxy-2-methylbenzamide (1g, 0.10M), ferrous chloride (40mol%) and methanol (1eq, 0.10M) were added to 1,4-dioxane mixed in , the resulting reaction solution was heated to 70°C under nitrogen and light conditions, and the synthesis reaction was carried out for 10 hours. The resulting reaction solution was filtered, and the resulting filtrate was separated by column chromatography to obtain 6-bromoisobenzofuran-1(3H) - Ketones (4 g). Isolation yield is 61%; The synthetic reaction equation of embodiment 7 is as follows:

1H NMR (400MHz, CDCl3) δ8.03(s,1H),7.79(d,J=8.0Hz,1H),7.38(d,J=8.0Hz,1H),5.27(s,2H).13C{1H }NMR (100MHz, CDCl3) δ169.5, 145.1, 137.1, 128.8, 127.8, 123.7, 123.0, 69.5; HRMS (ESI-TOF): ([M+H]+) calcd for C8H6BrO2+: 212.9551; found: 212.9557.

Example 8

N-methoxy-2-pentylbenzamide (1h, 0.10M), ferrous chloride (40mol%) and methanol (1eq, 0.10M) were added to 1,4 dioxane and mixed. The obtained reaction solution was heated to 70° C. under nitrogen and light conditions, and the synthesis reaction was carried out for 10 hours. The obtained reaction solution was filtered, and the obtained filtrate was separated by column chromatography to obtain 3-butylbenzofuran-1(3H)-one (4h) . Isolation yield is 61%; The synthetic reaction equation of embodiment 8 is as follows:

1H NMR (400MHz, CDCl3) δ7.92–7.83(m,1H),7.70–7.62(m,1H),7.54–7.47(m,1H),7.45–7.40(m,1H),5.46(dd,J ＝7.0,3.5Hz,1H),2.06–1.99(m,1H),1.79–1.70(m,1H),1.48–132(m,4H),0.89(t,J＝6.1Hz,3H).13C{ 1H}NMR(100MHz,CDCl3)δ170.7,150.1,133.9,129.0,126.1,125.6,121.7,81.4,34.4,26.9,22.4,13.9; HRMS(ESI-TOF):([M+H]+)calcd for C10H11O2+ :191.1072; found: 191.1066.

As can be seen from the above examples, the present invention provides a phthalide compound and a preparation method thereof, the method of the present invention does not use noble metals, the reaction time is shorter, and the reaction conditions are mild; the method of the present invention is simple and easy to obtain N-methoxybenzamide is used as a raw material to synthesize phthalide compounds in one step, and the method is simple, fast and has wide substrate applicability.

It will be apparent to those skilled in the art that the invention is not limited to the details of the above-described exemplary embodiments, but that the invention can be embodied in other specific forms without departing from the spirit or essential characteristics of the invention. Accordingly, the embodiments should be regarded in all points of view as exemplary and not restrictive, the scope of the invention being defined by the appended claims rather than the foregoing description, and it is therefore intended that the scope of the invention be defined by the appended claims rather than by the foregoing description. All changes within the meaning and range of equivalents of the elements are embraced in the present invention. Any reference sign in a claim should not be construed as limiting the claim concerned.

In addition, it should be understood that although this specification is described according to implementation modes, not each implementation mode only includes an independent technical solution, and this description in the specification is only for clarity, and those skilled in the art should take the specification as a whole , the technical solutions in the various embodiments can also be properly combined to form other implementations that can be understood by those skilled in the art.

Claims (4)

1. a preparation method of phthalide compound, is characterized in that, comprises the following steps: Mix N-methoxybenzamide, catalyst, methanol and an organic solvent to carry out a synthesis reaction, the temperature of the synthesis reaction is 70-80° C., and the time of the synthesis reaction is 10-12 hours to obtain phthalide compounds; the catalyst Be ferrous chloride or ferric chloride, the molar ratio of described N-methoxybenzamide, catalyst is 1:0.2-0.4; Described N-methoxybenzamide has structure shown in formula II; Wherein, R1 is -H, halogen group, methoxy group or methyl group; R2 is aryl group, alkyl group or hydrogen. 2. the preparation method of a kind of phthalide compound according to claim 1 is characterized in that, specifically: N-methoxy-2 ethyl-benzamide, ferrous chloride and methyl alcohol are added to 1 , mixed with 4 dioxane, the resulting reaction solution was heated to 70°C under nitrogen and light conditions, the synthesis reaction was carried out for 12 hours, the resulting reaction solution was filtered, and the resulting filtrate was separated by column chromatography to obtain: 3-methyliso Benzofuran-1(3H)-one, the isolated yield is 80%, and the synthesis reaction equation is as follows: 3. the preparation method of a kind of phthalide compound according to claim 1 is characterized in that, specifically: N-methoxy-2 methyl-benzamide, ferrous chloride and methyl alcohol are added to 1 , mixed with 4 dioxane, the resulting reaction solution was heated to 70°C under nitrogen and light conditions, the synthesis reaction was carried out for 10 hours, the resulting reaction solution was filtered, and the obtained filtrate was separated by column chromatography to obtain isobenzofuran-1 (3H)-ketone, the isolated yield is 75%, and the synthesis reaction equation is as follows: 4. the preparation method of a kind of phthalide compound according to claim 1 is characterized in that, described organic solvent comprises 1,2-dichloroethane, 1.4-dioxane or tetrahydrofuran.