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1. (WO2019062561) SYNTHESIS METHODS OF FIROCOXIB AND INTERMEDIATE THEREOF
Document

Description

Title of Invention  (R37.2) 0001   0002   0003   0004   0005   0006   0007   0008   0009   0010   0011   0012   0013   0014   0015   0016   0017   0018   0019   0020   0021   0022   0023   0024   0025   0026   0027   0028   0029   0030   0031   0032   0033   0034   0035   0036   0037   0038   0039   0040   0041   0042   0043   0044   0045   0046   0047   0048   0049   0050   0051   0052   0053   0054   0055   0056   0057   0058   0059   0060   0061   0062   0063   0064   0065   0066   0067   0068   0069   0070   0071   0072   0073   0074   0075   0076   0077   0078   0079   0080   0081   0082   0083   0084   0085   0086   0087   0088   0089   0090   0091   0092   0093   0094   0095   0096   0097   0098   0099   0100   0101   0102   0103   0104   0105   0106   0107   0108   0109   0110   0111   0112   0113   0114   0115   0116   0117   0118   0119   0120   0121   0122   0123   0124   0125   0126   0127   0128   0129   0130   0131   0132   0133   0134   0135   0136   0137   0138   0139   0140   0141   0142   0143   0144   0145   0146   0147  

Claims

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Description

Title of Invention : [Title established by the ISA under Rule 37.2] SYNTHESIS METHODS OF FIROCOXIB AND INTERMEDIATE THEREOF

FIELD OF THE INVENTION

[0001]
The present invention relates to the field of drug synthesis, and particularly it relates to synthesis methods of firocoxib and an intermediate thereof.

BACKGROUND OF THE INVENTION

[0002]
Firocoxib, i.e. 3- (cyclopropylmethoxy) -5, 5-dimethyl-4- [4- (methylsulfonyl) phenyl] -2 (5H) -furanone, and its molecular formula is C 17H 20O 5S.
[0003]
Firocoxib is an important non-steroidal anti-inflammatory drug. Currently, the reported synthesis methods of firocoxib are not much and they mainly focus on the following two synthetic routes:
[0004]
The first synthetic route is described in patents US5981576, US6020343A and WO9716435A1. The starting material, thioanisole, is reacted with isobutyl chloride to give Compound A, which is hydroxylated to yield Compound B. The oxidation of Compound B with an oxidative agent (MMPP, magnesium monoperoxyphthalate) affords the corresponding Compound C, which is reacted with acetoxyacetyl chloride to form Compound D, which is cyclized to form Compound E under the treatment of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) . Compound E reacts with cyclopropyl methyl bromide to form the target compound firocoxib. The first synthetic route is shown in Scheme 1.
[0005]
[0006]
Scheme 1
[0007]
The second synthetic route is described in Patent No. CN104803956A. The starting material is thioanisole, which reacts with isobutyryl chloride to form Compound A. Compound A is treated with liquid bromine to give a brominated product, and the brominated product is hydroxylated to produce Compound B. Compound B is oxidized with an oxidative agent to form Compound C. Compound C reacts with acetoxyacetyl chloride to form Compound D, Compound D undergoes DBU treatment to form Compound E, and Compound E reacts with cyclopropyl methyl bromide to form firocoxib. The second synthetic route is shown as follows.
[0008]
[0009]
Scheme 2
[0010]
The above two synthetic routes of firocoxib have the following disadvantages:
[0011]
Disadvantage 1: The starting material is thioanisole, and sulfides generally have unpleasant odors. In case of fire open flames or high heat, they can easily burn and explode. This material easily causes pollution to the environment and has a heavy environmental burden when production.
[0012]
Disadvantage 2: The above two routes are provided for preparing Compound B. In the first route, it is prepared by using two-phase system of sodium hydroxide solution and carbon tetrachloride under phase transfer catalyst Aliquat 336 (trioctylmethylammonium chloride) . This route requires the use of carbon tetrachloride, which belongs to Class 1 solvents. Class 1 solvents are known to be carcinogenic and harmful to humans and environment. Where possible, use of such solvents should be avoided. At the same time, in the post treatment process, in order to obtain relatively pure Compound B, a silica gel chromatography purification is needed, which is not suitable for large-scale industrial production. In the second route, Compound B is first brominated with liquid bromine, and then sodium hydroxide solution is used to hydroxylate under an action of a phase transfer catalyst. This route uses liquid bromine, which is extremely toxic and corrosive and extremely unfavorable to environment and occupational health. Therefore, it should be avoided as far as possible.
[0013]
SUMMARY OF THE INVENTION
[0014]
The object of the present invention is to provide a method for synthesizing a firocoxib intermediate through selecting different starting materials and carrying out under milder reaction conditions, avoiding environmentally unfriendly thioethers as starting materials, which is suitable for large-scale production.
[0015]
More specifically, the present invention relates to the following:
[0016]
A method for synthesizing a firocoxib intermediate, which comprises the following steps:
[0017]
a) p-Bromopropiophenone, as a starting material, is methylated by a methylating agent through a methylation reaction, or bromobenzene, as a starting material, is acylated by an acylating agent through a Friedel-Crafts acylation reaction to form a first intermediate;
[0018]
b) The first intermediate is sulfonated with sodium methanesulfinate through a sulfonation reaction under catalysis of cuprous iodide to obtain a second intermediate;
[0019]
c) The second intermediate is hydroxylated through a hydroxylation reaction under catalysis of N-bromosuccinimide (NBS) to obtain the firocoxib intermediate;
[0020]
The structural formula of the first intermediate is the structural formula of the second intermediate is and the structural formula of the firocoxib intermediate is
[0021]
Further, according to a preferred embodiment of the present invention, the methylating agent is one selected from the group consisting of methyl halide, dimethyl sulfate or methyl p-toluenesulfonate; preferably, the methylating agent is methyl halide, and more preferably, the methyl halide is methyl iodide.
[0022]
Further, according to a preferred embodiment of the present invention, the methylation reaction comprises: p-bromopropiophenone is dissolved in a first solvent, and then a strong base and the methylating agent are added; after the reaction is completed, an organic solvent and water are added into the reaction mixture to extract, and the organic phase is separated, dried and evaporated the solvents to obtain the first intermediate.
[0023]
Preferably, the first solvent is one selected from the group consisting of dimethylformamide, dimethyl sulfoxide and tert-butanol, and the strong base is one or more selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide and potassium tert-butoxide.
[0024]
Further, according to a preferred embodiment of the present invention, the Friedel-Crafts acylation reaction comprises: bromobenzene is added into a fourth solvent, followed by adding a Lewis acid and an acylating agent. After the reaction is completed, ethyl acetate and water are added into the reaction mixture to extract, and the organic phase is separated, dried and evaporated the solvents to obtain the first intermediate, wherein the acylating agent is isobutyric anhydride or isobutyryl chloride.
[0025]
Further, the fourth solvent is one selected from the group consisting of heptane, cyclohexane and dichloromethane; the Lewis acid is one selected from the group consisting of aluminum trichloride, aluminum tribromide and titanium tetrachloride.
[0026]
Further, the molar ratio of bromobenzene, the Lewis acid, and the acylating agent is 1: (2-3) : (1-1.5) , and the mass-to-volume ratio of bromobenzene to the fourth solvent is 1g/0.5mL-1g/5mL.
[0027]
Further, according to a preferred embodiment of the present invention, the sulfonation reaction comprises: the first intermediate, sodium methylsulfinate, and L-proline are added into a second solvent to obtain a mixture. Cuprous iodide is added into the mixture after the temperature is raised to 80-120℃. The mixture reacts for 40-50 hours and is cooled to room temperature to obtain a reaction mixture. An organic solvent and water are added into the reaction mixture to extract, and the organic phase is separated, dried, and evaporated the solvents under reduced pressure. Then n-heptane is added to crystallize the residue to obtain the second intermediate, wherein the second solvent is dimethyl sulfoxide.
[0028]
Further, according to a preferred embodiment of the present invention, the sulfonation reaction comprises: the first intermediate, sodium methylsulfinate, and L-proline are added into dimethyl sulfoxide to obtain a mixture. Cuprous iodide is added into the mixture after the temperature is raised to 100℃. The mixture reacts for 48 hours and is cooled to room temperature to obtain a reaction mixture. An organic solvent and water are added into the reaction mixture to extract, and the organic phase is separated, dried and evaporated the solvents under reduced pressure. Then n-heptane is added to crystallize the residue to obtain the second intermediate.
[0029]
Further, according to a preferred embodiment of the present invention, the method comprises re-crystallization with ethyl acetate and n-heptane between the crystallization and obtaining the second intermediate.
[0030]
Further, according to a preferred embodiment of the present invention, the hydroxylation reaction comprises: the second intermediate is dissolved in a third solvent, and then N-bromosuccinimide is added to obtain a mixture. The mixture reacts for 10-14 hours after the temperature is raised to 80-120℃, and the reaction mixture is cooled to room temperature. An organic solvent and water are added into the reaction mixture to extract, and the organic phase is separated, dried, and evaporated the solvents under reduced pressure. Then methyl tert-butyl ether and n-heptane are added to crystallize the residue to obtain the firocoxib intermediate, wherein the third solvent is dimethyl sulfoxide.
[0031]
Further, according to a preferred embodiment of the present invention, the hydroxylation reaction comprises: the second intermediate is dissolved in dimethyl sulfoxide, and then N-bromosuccinimide is added to obtain a mixture. The mixture reacts for 12 hours after the temperature is raised to 100℃, and the reaction mixture is cooled to room temperature. An organic solvent and water are added into the reaction mixture to extract, and the organic phase is separated, dried, and evaporated the solvents under reduced pressure. Then methyl tert-butyl ether and n-heptane are added to crystallize the residue to obtain the firocoxib intermediate.
[0032]
Another object of the present invention is to provide a method for synthesizing firocoxib, wherein the method comprises the above-mentioned method for synthesizing the firocoxib intermediate. The method can synthesize firocoxib in a milder and more environmentally friendly manner.
[0033]
Thus, the present invention also relates to a method for synthesizing firocoxib, wherein the method comprises the above-mentioned method for synthesizing the firocoxib intermediate. Further, according to a preferred embodiment of the present invention, the method for synthesizing firocoxib comprises the following steps:
[0034]
The firocoxib intermediate obtained by the above-mentioned method reacts with acetoxyacetyl chloride to form 2-methyl-1- [4- (methylsulfonyl) phenyl] -2- (2-acetoxyacetoxy) -1-propanone. The reaction scheme is as follows:
[0035]
[0036]
2-Methyl-1- [4- (methylsulfonyl) phenyl] -2- (2-acetoxyacetoxy) -1-propanone is cyclized with DBU to afford 3-hydroxy-5, 5-dimethyl-4- [4- (methylsulfonyl) phenyl] -2 (5H) -furanone. The reaction scheme is as follows:
[0037]
[0038]
3-Hydroxy-5, 5-dimethyl-4- [4- (methylsulfonyl) phenyl] -2 (5H) -furanone reacts with cyclopropylbromomethane to afford firocoxib. The reaction scheme is as follows:
[0039]
[0040]
The preparation of the firocoxib intermediate and the preparation of firocoxib with the intermediate thereof in the present invention have the following advantages:
[0041]
(1) The method for synthesizing the firocoxib intermediate in the present invention starts with p-bromopropiophenone or bromobenzene, avoiding environmentally unfriendly thioethers as starting materials. In addition, the second intermediate is directly obtained by the sulfonation reaction of the first intermediate, thus the sulfidation reaction and the oxidization reaction are shortened to a one-step reaction. The sulfonation reaction greatly simplifies the reaction steps, shortens the reaction time, and improves the reaction efficiency.
[0042]
(2) In the present invention, an NBS catalyst system is also used to directly obtain the firocoxib intermediate by the hydroxylation reaction of the second intermediate. Compared with the mentioned-above first route in the prior art, the use of harmful agent (carbon tetrachloride) is avoided and the column chromatography purification is not required in the method of the present invention, and thus the method of the present invention is feasible for large-scale production. Compared with the mentioned-above second route in the prior art, the use of liquid bromine is avoided and further the two-step reaction is shortened to a one-step reaction. Therefore, the reaction rate is greatly increased. In addition, the reagents are commonly used reagents and commercially available, thus the method of the present invention can be performed in a more environmentally friendly manner.
[0043]
(3) Firocoxib can be synthesized in a milder and more environmentally friendly manner by using the method of the present invention. The method is advantageous for improving preparation efficiency and yield of the firocoxib, and more suitable for large-scale industrial production.

DETAILED DESCRIPTION OF THE INVENTION

[0044]
The embodiments of the present invention will be described in detail below. The skilled in the art can understand that the following embodiments are only the preferred ones of the present invention, and are not intended to limit the scope of the present invention. If no specific conditions are specified in the examples, they are carried out according to the general conditions or the conditions recommended by the manufacturer. The used reagents or instruments, if not indicated by the manufacturers specifically, are conventional products which are obtained by commercially available purchase.
[0045]
The method for synthesizing firocoxib and the intermediate thereof in the examples of the present invention will be specifically described below.
[0046]
Herein, the room temperature means an ambient temperature of 10-25℃.
[0047]
A method for synthesizing a firocoxib intermediate having the structure represented by Compound C is shown in Scheme 3:
[0048]
[0049]
Scheme 3
[0050]
Specifically, the method for synthesizing the firocoxib intermediate comprises the following steps:
[0051]
S1: The first intermediate A1 has two synthetic ways as described in the following 1) and 2) :
[0052]
1) p-Bromopropiophenone, as a starting material, is methylated with a methylating agent to obtain the first intermediate A1.
[0053]
Specifically, p-bromopropiophenone is dissolved in the first solvent, followed by addition of a strong base and a methylating agent. After the reaction is completed, ethyl acetate and water are added to extract. The organic phase is separated, dried over anhydrous sodium sulfate, and evaporated the solvents under reduced pressure to obtain the first intermediate A1.
[0054]
According to the above embodiment of the present invention, the first intermediate A1 is formed by methylating p-bromopropiophenone. The methylation reaction is carried out at room temperature and the reaction condition is mild. In addition, the use of environmentally unfriendly thioethers as the starting materials is avoided.
[0055]
More specifically, p-bromopropiophenone is added into the first solvent, followed by addition of a strong base. The mixture is stirred until the solid is dissolved. Finally, the methylating agent is added dropwise and the reaction mixture is stirred at room temperature overnight. In the reaction, the methylating agent is slowly added in a dropwise manner, and the dropping rate should not be too fast, so as to prevent violent reaction which causes the sudden release of materials.
[0056]
Wherein, the first solvent is one selected from the group consisting of dimethylformamide, dimethyl sulfoxide and tert-butanol; the strong base is one or more selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide and potassium t-butoxide; and the methylating agent is one selected from the group consisting of methyl halide, dimethyl sulfate and methyl p-toluenesulfonate. The methylating agent causes the hydrogen of p-bromopropiophenone to be substituted by a methyl group. Preferably, the methylating agent is a methyl halide, particularly preferably methyl iodide. These reagents are commonly used reagents in chemical reactions and commercially available. The combination use of these reagents can obtain methylation products in high yields.
[0057]
The molar ratio of p-bromopropiophenone, the strong base and the methylating agent is 1: (1-4) : (1-2) , and the mass-to-volume ratio of p-bromopropiophenone to the first solvent is 1g/2mL-1g/10mL. The molar ratio and the mass-to-volume ratio are the preferred values obtained by the inventors through creative labor and their own experience. If the methylation reaction is carried out within the above preferred ratio range, the reaction rate is faster, the yield is higher, and side reactions are less. More preferably, the molar ratio of p-bromopropiophenone, the strong base and the methylating agent is 1: (1.5-4) : (1.5-2) ; the ratio of p-bromopropiophenone to the first solvent is 1g/4mL-1g/8mL, and more preferably, the ratio is 1g/4mL.
[0058]
2) Bromobenzene, as a starting material, is acylated through Friedel-Crafts acylation with an acylating agent to obtain the first intermediate A1.
[0059]
Specifically, bromobenzene is dissolved in the fourth solvent, followed by addition of a Lewis acid and an acylating agent. After the reaction is completed, dichloromethane and water are added to extract. The organic phase is separated, dried over anhydrous sodium sulfate, and evaporated the solvents under reduced pressure to obtain the first intermediate A1.
[0060]
According to the above embodiment of the present invention, the first intermediate A1 is formed by Friedel-Crafts acylation of bromobenzene. Compared to the method reported by Rennison et al (Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, #24 p. 6629-6636) , the yield of acylation reaction is relatively high and the reaction is easier to be monitored, which facilitates the scale-up of the production. More specifically, bromobenzene is added into the fourth solvent, followed by addition of the Lewis acid. The acylating agent such as acyl chloride and acid anhydride is added dropwise after the reaction mixture is raised to high temperature. The mixture is stirred at high temperature overnight. The acylating agent such as acyl chloride and acid anhydride is slowly added in a dropwise manner, and the dropping rate should not be too fast, so as to prevent the violent reaction which causes the sudden release of materials.
[0061]
Wherein, the fourth solvent is one selected from the group consisting of heptane, cyclohexane and dichloromethane; and the Lewis acid is one or more selected from the group consisting of aluminum trichloride, aluminum tribromide and titanium tetrachloride. The Friedel-Crafts acylating agent is one selected from the group consisting of isobutyryl chloride and isobutyric anhydride. These reagents are commonly used reagents in chemical reactions and commercially available. The combination use of these reagents can obtain the Friedel-Crafts acylated products in high yields.
[0062]
The molar ratio of bromobenzene, the Lewis acid and the acylating agent is 1: (2-3) : (1-1.5) , and the mass-to-volume ratio of bromobenzene to the fourth solvent is 1g/0.5mL-1g/5mL. The molar ratio and the mass-to-volume ratio are the preferred values obtained by the inventors through creative labor and their own experience. If the Friedel-Crafts reaction is carried out within the preferred ratio range, the reaction rate is faster, the yield is higher, and side reactions are less.
[0063]
S2: the first intermediate A1 is sulfonated with sodium methanesulfinate under catalysis of cuprous iodide to obtain the second intermediate B1.
[0064]
Particularly, the first intermediate A1, sodium methylsulfinate and L-proline are added into the second solvent to obtain a mixture. The cuprous iodide is added into the mixture after the temperature is raised to 80-120℃. The obtained mixture reacts for 40-50 hours at 80-120℃and is cooled to room temperature after the reaction is completed to obtain a reaction mixture. Ethyl acetate and water are added into the reaction mixture to extract. The organic phase is separated, dried, and evaporated the solvents under reduced pressure, and then n-heptane is added to crystallize the residue to obtain the second intermediate B1, wherein the second solvent is dimethyl sulfoxide.
[0065]
Further, the method comprises re-crystallization with ethyl acetate and n-heptane between the crystallization and obtaining the second intermediate B1. Namely, the product after crystallization is dissolved in the solvent system of ethyl acetate and n-heptane and re-crystallized from the solvent system. Re-crystallization can purify the crude product and thereby can obtain a purer second intermediate B1.
[0066]
The molar ratio of the first intermediate A1, sodium methylsulfinate, L-proline and cuprous iodide is 1: (1-2) : (0.2-0.5) : (0.2-0.5) , preferably, the molar ratio is 1: 1.5: 0.2: 0.2; the mass-to-volume ratio of the first intermediate A1 to the second solvent is 1g/1mL-1g/5mL, preferably, the ratio is 1g/1mL-1g/3mL; most preferably, the ratio is 1g/2mL. The molar ratio and the mass-to-volume ratio are the preferred values obtained by the inventors through creative labor and their own experience. If the sulfonation reaction is carried out within the preferred ratio range, the reaction rate is faster, the yield is higher, and side reactions are less. S3: The second intermediate B1 is hydroxylated by dimethyl sulfoxide under catalysis of N-bromosuccinimide to obtain the firocoxib intermediate C.
[0067]
Particularly, the second intermediate B1 is dissolved in the third solvent, followed by addition of N-bromosuccinimide (NBS) . The mixture is raised to 80-120℃ and reacts for 10-14 hours. After reaction is completed, the mixture is cooled to room temperature. Ethyl acetate and water are added into the reaction mixture. The separated organic phase is extracted, dried, and evaporated the solvents under reduced pressure. Then methyl tert-butyl ether and n-heptane are added to crystallize the residue to obtain the firocoxib intermediate C, wherein the third solvent is dimethyl sulfoxide (DMSO) .
[0068]
The NBS/DMSO system used in the embodiment of the present invention directly obtains the firocoxib intermediate C by hydroxylation reaction of the second intermediate B1. Compared with the above-mentioned first route in the prior art, the use of carbon tetrachloride, which is harmful to the environment and human, is avoided, and the column chromatography purification is not required in the method of the present invention, and thus the method of the present invention is feasible for large-scale production. Compared with the mentioned-above second route in the prior art, the use of liquid bromine is avoided and a two-step reaction is replaced by a one-step reaction in the present invention. The method increases the reaction rate and simplifies the reaction step to a great degree.
[0069]
The molar ratio of the second intermediate B1 and N-bromosuccinimide is 1: (0.2-0.5) , preferably, the molar ratio is 1: 0.2; the mass-to-volume ratio of the second intermediate B1 to the third solvent is 1g/2mL-1g/10mL, preferably, the ratio is 1g/3mL-1g/7mL; most preferably, the ratio is 1g/5mL. The molar ratio and the mass-to-volume ratio are the preferred values obtained by the inventors through creative labor and their own experience. If the hydroxylation reaction is carried out within the preferred ratio range, the reaction rate is faster, the yield is higher, and side reactions are less.
[0070]
A method for synthesizing firocoxib comprises a method for synthesizing the above-mentioned firocoxib intermediate.
[0071]
Further, according to a preferred embodiment of the present invention, the synthesis of firocoxib comprises the following steps:
[0072]
The firocoxib intermediate obtained by the above method reacts with acetoxyacetyl chloride to form 2-methyl-1- [4- (methylsulfonyl) phenyl] -2- (2-acetoxyacetoxy) -1-propanone. The reaction scheme is as follows:
[0073]
[0074]
2-Methyl-1- [4- (methylsulfonyl) phenyl] -2- (2-acetoxyacetoxy) -1-propanone is cyclized with DBU to afford 3-hydroxy-5, 5-dimethyl-4- [4- (methylsulfonyl) phenyl] -2 (5H) -furanone. The reaction scheme is as follows:
[0075]
[0076]
3-Hydroxy-5, 5-dimethyl-4- [4- (methylsulfonyl) phenyl] -2 (5H) -furanone reacts with cyclopropylbromomethane to afford firocoxib. The reaction scheme is as follows:
[0077]
[0078]
EXAMPLES
[0079]
The present invention is further described by the following examples.
[0080]
Examples 1-5 provide a synthesis method of the first intermediate A1.
[0081]
[0082]
Example 1 Preparation of 1- (4-bromophenyl) -2-methylacetone
[0083]
The example provides a synthesis method of the first intermediate A1, wherein p-bromopropiophenone, as a starting material, is methylated with a methylating agent to obtain the first intermediate A1. The detailed preparation steps are as follows:
[0084]
p-Bromopropiophenone (100g, 1eq) is dissolved in 400mL of dimethylformamide at room temperature, followed by addition of sodium hydroxide (56.3g, 3eq) and methyl iodide (133.3g, 2eq) to obtain a mixture. The mixture is stirred at room temperature overnight. After the reaction is completed, 500mL of ethyl acetate and 500mL of water are added to extract. The organic phase is separated, dried over anhydrous sodium sulfate, and evaporated the solvents under reduced pressure to give the first intermediate A1, i.e. 1- (4-bromophenyl) -2-methylacetone (110g, pale yellow liquid) .
[0085]
Example 2 Preparation of 1- (4-bromophenyl) -2-methylacetone
[0086]
The example provides a synthesis method of the first intermediate A1, wherein p-bromopropiophenone, as a starting material, is methylated with a methylating agent to obtain the first intermediate A1. The preparation steps are as follows:
[0087]
p-Bromopropiophenone (5.0g, 1eq) is dissolved in 20mL of DMSO at room temperature, followed by addition of lithium hydroxide (2.0g, 3.7eq) . After the solid is dissolved under stirring, methyl iodide (5.0g, 1.5eq) is added dropwise and the mixture is stirred at room temperature overnight. After the reaction is completed, 30mL of ethyl acetate and 30mL of water are added to extract, and the organic phase is separated, dried over anhydrous sodium sulfate and evaporated the solvents under reduced pressure to give the first intermediate A1 i.e. 1- (4-bromophenyl) -2-methylacetone (5.8g, pale yellow liquid) .
[0088]
Example 3 Preparation of 1- (4-bromophenyl) -2-methylacetone
[0089]
The example provides a synthesis method of the first intermediate A1, wherein p-bromopropiophenone, as a starting material, is methylated with a methylating agent to obtain the first intermediate A1. The preparation steps are as follows:
[0090]
p-Bromopropiophenone (5.0g, 1eq) is dissolved in 20mL of tert-butanol at room temperature, and then potassium t-butoxide (3.9g, 1.5eq) is added, followed by addition of methyl iodide (5.0g, 1.5eq) in a dropwise manner. The mixture is stirred at room temperature overnight. After completion of the reaction, 30mL of ethyl acetate and 30mL of water are added. The organic phase is separated, dried over anhydrous sodium sulfate and evaporated the solvents under reduced pressure to give the first intermediate A1, i.e. 1- (4-bromophenyl) -2-methylacetone (5.4g, pale yellow liquid) .
[0091]
Example 4 Preparation of 1- (4-bromophenyl) -2-methylacetone
[0092]
p-Bromopropiophenone (21.3g, 0.1mol) is dissolved in 100mL of dimethylformamide at room temperature, and potassium hydroxide (11.2g, 0.2mol) is added with stirring, followed by the addition of dimethyl sulfate (25.2g, 0.2mol) . The reaction is carried out at room temperature overnight. After completion of the reaction, 100mL of ethyl acetate is added, and the insoluble substance is filtered off and then water is added to extract. The separated organic phase is dried over anhydrous sodium sulfate, and evaporated the solvents under reduced pressure to give the first intermediate A1, i.e. 1- (4-bromophenyl) -2-methylacetone (22g, pale yellow liquid) .
[0093]
Example 5 Preparation of 1- (4-bromophenyl) -2-methylacetone
[0094]
p-Bromopropiophenone (21.3g, 0.1mol) is dissolved in 100mL of dimethylformamide at room temperature, and potassium hydroxide (11.2g, 0.2mol) is added with stirring, followed by the addition of methyl p-toluenesulfonate (37.2g, 0.2mol) . The reaction is carried out at room temperature overnight. After completion of the reaction, 100mL of ethyl acetate is added, and the insoluble substance is filtered off and then water is added to extract. The separated organic phase is dried over anhydrous sodium sulfate, and evaporated the solvents under reduced pressure to give the first intermediate A1, i.e. 1- (4-bromophenyl) -2-methylacetone (22.5g, pale yellow liquid) .
[0095]
Examples 6-9 provide an additional synthesis method of the first intermediate A1, wherein bromobenzene, as a starting material, is reacted with an acylating agent to obtain the first intermediate A1 through Friedel-Crafts acylation.
[0096]
Example 6 Preparation of 1- (4-bromophenyl) -2-methylacetone
[0097]
Under a nitrogen atmosphere, 4.5mL of heptane, 4.5g of bromobenzene (28.7mmol) and 8.4g (63.2mmol) of aluminum trichloride are added into a 100mL three-necked flask with uniform magnetic stirring. The mixture is cooled to an internal temperature of 10℃ with an ice water bath, and 5.0g (31.6mmol) of isobutyric anhydride is added dropwise. After the dropwise addition, the temperature is raised to 50 ± 5℃ to react for 12 h.
[0098]
The reaction is cooled by an ice bath, and then is quenched by slowly adding 25mL of water in a dropwise manner. The phases are separated and the upper aqueous phase is extracted once more with 25mL of dichloromethane. The separated organic phases are combined and washed with 25mL of saturated brine. The separated organic phase is dried over anhydrous sodium sulfate and filtered. The filtrate is distilled under reduced pressure at 80℃ until no significant fraction is obtained. A crude product of 6.1g is obtained, yield 93.8%.
[0099]
Example 7 Preparation of 1- (4-bromophenyl) -2-methylacetone
[0100]
Under a nitrogen atmosphere, 9.0mL of dichloromethane, 4.5g of bromobenzene (28.7mmol) and 19.1g (71.6mmol) of aluminum tribromide are added into a 100mL three-necked flask with uniform magnetic stirring. The mixture is cooled to an internal temperature of 10℃ with an ice water bath, and 4.6g (43mmol) of isobutyryl chloride is added dropwise. After the dropwise addition, the temperature is raised to 25 ± 5℃ to react for 12h.
[0101]
The reaction is cooled by an ice bath, and then is quenched by slowly adding 25mL of water in a dropwise manner. The phases are separated and the upper aqueous phase is extracted once more with 25mL of dichloromethane. The separated organic phases are combined and washed with 25mL of saturated brine. The separated organic phase is dried over anhydrous sodium sulfate and filtered. The filtrate is distilled under reduced pressure at 80℃ until no significant fraction is obtained. A crude product of 5.9g is obtained, yield 90.7%.
[0102]
Example 8 Preparation of 1- (4-bromophenyl) -2-methylacetone
[0103]
Under a nitrogen atmosphere, 22.5mL of cyclohexane, 4.5g of bromobenzene (28.7mmol) and 16.3g (86.1mmol) of titanium tetrachloride are added into a 100mL three-necked flask with uniform magnetic stirring. The mixture is cooled to an internal temperature of 10℃ with an ice water bath, and 3.3g (30.1mmol) of isobutyryl chloride is added dropwise. After the dropwise addition, the temperature is raised to 50 ± 5℃ to react for 12h.
[0104]
The reaction is cooled by an ice bath, and then is quenched by slowly adding 25mL of water in a dropwise manner. The phases are separated and the upper aqueous phase is extracted once more with 25mL of dichloromethane. The separated organic phases are combined and washed with 25mL of saturated brine. The separated organic phase is dried over anhydrous sodium sulfate and filtered. The filtrate is distilled under reduced pressure at 80℃ until no significant fraction is obtained. A crude product of 6.0g is obtained, yield 92.3%.
[0105]
Example 9 Preparation of 1- (4-bromophenyl) -2-methylacetone
[0106]
Under a nitrogen atmosphere, 12mL of heptane, 4.5g of bromobenzene (28.7mmol) and 7.7g (57.7mmol) of aluminum trichloride are added into a 100mL three-necked flask with uniform magnetic stirring. The mixture is cooled to an internal temperature of 10℃ with an ice water bath, and 5.4g (34.4mmol) of isobutyric anhydride is added dropwise. After the dropwise addition, the temperature is raised to 50 ± 5℃ to react for 12h.
[0107]
The reaction is cooled by an ice bath, and then is quenched by slowly adding 25mL of water in a dropwise manner. The phases are separated and the upper aqueous phase is extracted once more with 25mL of dichloromethane. The separated organic phases are combined and washed with 25mL of saturated brine. The separated organic phase is dried over anhydrous sodium sulfate and filtered. The filtrate is distilled under reduced pressure at 80℃ until no significant fraction is obtained. A crude product of 5.9g is obtained, yield 90.7%.
[0108]
Examples 10-13 provide a synthesis method of the second intermediate B1
[0109]
[0110]
Example 10 Preparation of 2-methyl- [4- (methylsulfonyl) phenyl] acetone
[0111]
The example provides a synthesis method of the second intermediate B1, wherein the first intermediate A1 is used as a reaction substrate to obtain the second intermediate B1. The specific preparation steps are as follows:
[0112]
The first intermediate A1 (110g, 1eq) , sodium methylsulfinate (74.1g, 1.5eq) and L-proline (11.1g, 0.2eq) are added into 220mL of dimethyl sulfoxide to obtain a mixture. After the temperature of the mixture is raised to 100℃, cuprous iodide (18.5g, 0.2eq) is added. The mixture reacts at 100℃ for 48h. After the reaction is completed, the mixture is cooled to room temperature. Ethyl acetate and water are added to extract. The separated organic phase is dried and evaporated the solvents under reduced pressure, and then n-heptane is added to crystallize the residue to obtain the crude of the second intermediate B1. Finally, ethyl acetate and n-heptane are added into the crude product to re-crystallize to obtain the pure second intermediate B1, i.e. 2-methyl- [4- (methylsulfonyl) phenyl] acetone (80g, yield 72.7%, pale yellow solid) .
[0113]
Example 11 Preparation of 2-methyl- [4- (methylsulfonyl) phenyl] acetone
[0114]
The example provides a synthesis method of the second intermediate B1, wherein the first intermediate A1 is used as a reaction substrate to obtain the second intermediate B1. The specific preparation steps are as follows:
[0115]
The first intermediate A1 (165g, 1eq) , sodium methylsulfinate (112.2g, 1.5eq) and L-proline (16.5g, 0.2eq) are added into 330mL of dimethyl sulfoxide. After the temperature of the mixture is raised to 100℃, cuprous iodide (27.8g, 0.2eq) is added. The mixture reacts at 100℃ for 48h. After the reaction is completed, the mixture is cooled to room temperature. Ethyl acetate and water are added to extract. The separated organic phase is dried and evaporated the solvents under reduced pressure. Ethyl acetate and n-heptane are added to obtain the second intermediate B1, i.e. 2-methyl- [4- (methylsulfonyl) phenyl] acetone (124.8g, yield 75.6%, pale yellow solid) .
[0116]
Example 12 Preparation of 2-methyl- [4- (methylsulfonyl) phenyl] acetone
[0117]
The example provides a synthesis method of the second intermediate B1, wherein the first intermediate A1 is used as a reaction substrate to obtain the second intermediate B1. The specific preparation steps are as follows:
[0118]
The first intermediate A1 (227g, 1eq) , sodium methylsulfinate (102.1g, 1eq) and L-proline (34.53g, 0.3eq) are added into 681mL of dimethyl sulfoxide. After the temperature of the mixture is raised to 80℃, cuprous iodide (57.1g, 0.3eq) is added. The mixture reacts at 80℃for 50h. After the reaction is completed, the mixture is cooled to room temperature. Ethyl acetate and water are added to extract. The separated organic phase is dried and evaporated the solvents under reduced pressure, and then n-heptane is added to crystallize the residue to obtain the crude of the second intermediate B1. Finally, ethyl acetate and n-heptane are added to re-crystallize the residue to obtain the pure second intermediate B1, i.e. 2-methyl- [4- (methylsulfonyl) phenyl] acetone (166g, yield 73.1%, pale yellow solid) .
[0119]
Example 13 Preparation of 2-methyl- [4- (methylsulfonyl) phenyl] acetone
[0120]
The example provides a synthesis method of the second intermediate B1, wherein the first intermediate A1 is used as a reaction substrate to obtain the second intermediate B1. The specific preparation steps are as follows:
[0121]
The first intermediate A1 (110g, 1eq) , sodium methylsulfinate (99g, 2eq) and L-proline (27.9g, 0.5eq) are added into 110mL of dimethyl sulfoxide. After the temperature of the mixture is raised to 120℃, cuprous iodide (46.1g, 0.5eq) is added. The mixture reacts at 120℃ for 40h. After the reaction is completed, the mixture is cooled to room temperature. Ethyl acetate and water are added to extract. The separated organic phase is dried and evaporated the solvents under reduced pressure, and then n-heptane is added to crystallize the residue to obtain the crude of the second intermediate B1. Finally, ethyl acetate and n-heptane are added to re-crystallize the residue to obtain the pure second intermediate B1, i.e. 2-methyl- [4- (methylsulfonyl) phenyl] acetone (78.4g, yield 72.2%, pale yellow solid) .
[0122]
Examples 14-16 provide a synthesis method of the firocoxib intermediate C.
[0123]
[0124]
Example 14 Preparation of 2-hydroxy-2-methyl- [4- (methylsulfonyl) phenyl] -1-propanone The example provides a synthesis method of the firocoxib intermediate C, wherein the second intermediate B1 is used as a reaction substrate to obtain the firocoxib intermediate C. The specific preparation steps are as follows:
[0125]
The second intermediate B1 (80g, 1eq) is dissolved in 400mL DMSO, followed by addition of NBS (12.6g, 0.2eq) . The mixture reacts at 100℃ for 12h. After the reaction is completed, the mixture is cooled to room temperature. Ethyl acetate and water are added to extract. The separated organic phase is dried and evaporated the solvents. Methyl tert-butyl ether and n-heptane are added to crystallize the residue to obtain the pure compound C, i.e. 2-hydroxy-2-methyl- (4-methylsulfonyl) phenyl-1-propanone (72.8g, yield 85%, pale yellow solid) .
[0126]
The characterization results of the firocoxib intermediate C provided in this example are as follows:
[0127]
1HNMR (DMSO-d6) δ1.62 (6H, s) , 2.63 (1H, s) , 3.09 (3H, s) , 8.01-8.21 (4H, m)
[0128]
Example 15 Preparation of 2-hydroxy-2-methyl- [4- (methylsulfonyl) phenyl] -1-propanone The example provides a synthesis method of the firocoxib intermediate C, wherein the second intermediate B1 is used as a reaction substrate to obtain firocoxib intermediate C. The specific preparation steps are as follows:
[0129]
The second intermediate B1 (80g, 1eq) is dissolved in 560mL DMSO, followed by addition of NBS (31.1g, 0.5eq) . The mixture reacts for 14h after the temperature is raised to 80℃. After the reaction is completed, the mixture is cooled to room temperature. Ethyl acetate and water are added to extract. The separated organic phase is dried and evaporated the solvents under reduced pressure. Methyl tert-butyl ether and n-heptane are added to crystallize the residue to obtain the pure compound C, i.e. 2-hydroxy-2-methyl- (4-methylsulfonyl) phenyl-1-propanone (75g, yield 86%, pale yellow solid) .
[0130]
Example 16 Preparation of 2-hydroxy-2-methyl- [4- (methylsulfonyl) phenyl] -1-propanone The example provides a synthesis method of the firocoxib intermediate C, wherein the second intermediate B1 is used as a reaction substrate to obtain firocoxib intermediate C. The specific preparation steps are as follows:
[0131]
The second intermediate B1 (80g, 1eq) is dissolved in 240mL DMSO, followed by addition of NBS (18.9g, 0.3eq) . The mixture reacts for 10h after the temperature is raised to 120℃. After the reaction is completed, the mixture is cooled to room temperature. Ethyl acetate and water are added to extract. The separated organic phase is dried and evaporated the solvents under reduced pressure. Methyl tert-butyl ether and n-heptane are added to crystallize the residue to obtain the pure compound C, i.e. 2-hydroxy-2-methyl- (4-methylsulfonyl) phenyl-1-propanone (71.2g, yield 82.8%, pale yellow solid) .
[0132]
Example 17 Preparation of 2-methyl-1- [4- (methylsulfonyl) phenyl] -2- (2-acetoxyacetoxy) -1-propanone
[0133]
The example provides a synthesis method of the intermediate D:
[0134]
[0135]
The intermediate C 5.0g, triethylamine 4.2g and DMAP 0.5g are added into 50mL of dichloromethane and stirred. When temperature of the mixture is lowered to 0℃, 4.2g of acetoxyacetyl chloride is added dropwise. After the reaction is completed, water is added to extract. The separated organic phase is dried and evaporated the solvents under reduced pressure to give the intermediate D, i.e. 2-methyl-1- [4- (methylsulfonyl) phenyl] -2- (2-acetoxy acetoxy) -1-propanone (7.0g, yield 99.5%, yellow solid) .
[0136]
Example 18 Preparation of 3-hydroxy-5, 5-dimethyl-4- [4- (methylsulfonyl) phenyl] -2 (5H) -furanone
[0137]
The example provides a synthesis method of the intermediate E:
[0138]
[0139]
The intermediate D 7.0g is dissolved in 50mL acetonitrile, followed by addition of DBU 6.2g. The reaction mixture is refluxed for 12h. After completion of the reaction, the mixture is cooled to room temperature and evaporated to dry via rotary evaporation. Dichloromethane and water are added to extract, and the separated organic phase is dried and evaporated the solvents under reduced pressure. Ethyl acetate is added into the residue with stirring and a solid is precipitated. After filtration, re-crystallization with ethyl acetate is performed to yield the intermediate E, i.e. 3-hydroxy-5, 5-dimethyl-4- [4- (methylsulfonyl) phenyl] -2 (5H) -furanone (4.0g, yield 70%, pale yellow solid) .
[0140]
Example 19
[0141]
The example provides a synthesis method of firocoxib:
[0142]
[0143]
Intermediate E 7.0g is dissolved in 400mL toluene with stirring. 2.4g of a 50%aqueous solution of sodium hydroxide, 2.6mL of cyclopropylbromomethane and 0.92g of tetrabutylammonium bromide are added, and the mixture is heated to 70℃ to react 10-18 hours. The mixture is filtrated, and allows the obtained filtrate stand still to separate. The separated organic phase is dried over anhydrous sodium sulfate and concentrated to dry to obtain firocoxib, yield 54%.
[0144]
The characterization results of the firocoxib provided in this example are as follows: 1HNMR (CD 3COCD 3) δ0.30 (2H, m) , 5 (2H, m) , 1.15 (1H, m) , 1.60 (6H, s) , 3.32 (3H, s) , 4.20 (2H, d) , 8.00 (4H, s)
[0145]
In conclusion, the method for synthesizing the firocoxib intermediate provided by the examples of the present invention uses p-bromopropiophenone or bromobenzene as a starting material, avoiding the use of environmentally unfriendly thioethers. Further, the first intermediate is directly subjected to a sulfonation reaction to obtain a second intermediate, wherein the sulfidation reaction and the oxidization reaction are shortened to an one-step reaction and thus the sulfonation step greatly simplifies the reaction steps, shortens the reaction time, and improves the reaction efficiency. At the same time, the NBS/DMSO system is used to directly obtain the firocoxib intermediate by hydroxylation reaction of the second intermediate. Compared with the mentioned-above first route in the prior art, the use of harmful carbon tetrachloride is avoided and no requirement of column chromatography purification is feasible for large-scale production; compared with the mentioned-above second route in the prior art, the use of liquid bromine is avoided and a two-step reaction is replaced by an one-step reaction in the present invention. In addition, the reaction reagents are commonly used, easily available reagents, and have no obvious harm to human beings and environment. These reagents can be directly purchased from the market and used in combination to obtain a high yield of firocoxib intermediate.
[0146]
In addition, the method for synthesizing firocoxib provided by the present invention comprises the above-mentioned synthetic method of the firocoxib intermediate, which can synthesize firocoxib under a milder and more environmentally friendly condition. The method is beneficial to improve the preparation efficiency and yield of firocoxib, and more suitable for industrial large-scale production.
[0147]
The above description is only the preferred embodiment of the present invention, and is not intended to limit the scope of the present invention in any way. For those skilled in the art, the present invention may have various changes and modifications. All modifications, equivalent substitutes and improvements made without departing from the spirit and principle of the present invention shall be within the protection scope of the present invention.

Claims

[Claim 1]
A method for synthesizing a firocoxib intermediate, which comprises the following steps: a) p-Bromopropiophenone, as a starting material, is methylated by a methylating agent through a methylation reaction, or bromobenzene, as a starting material, is acylated by an acylating agent through a Friedel-Crafts acylation reaction to form a first intermediate; b) The first intermediate is sulfonated with sodium methanesulfinate through a sulfonation reaction under catalysis of cuprous iodide to obtain a second intermediate; c) The second intermediate is hydroxylated through a hydroxylation reaction under a catalysis of N-bromosuccinimide to obtain the firocoxib intermediate; The structural formula of the first intermediate is the structural formula of the second intermediate is and the structural formula of the firocoxib intermediate is
[Claim 2]
The method for synthesizing the firocoxib intermediate according to claim 1, wherein the methylating agent is one selected from the group consisting of methyl halide, dimethyl sulfate or methyl p-toluenesulfonate; preferably, the methylating agent is methyl halide, and more preferably, the methyl halide is methyl iodide.
[Claim 3]
The method for synthesizing the firocoxib intermediate according to claim 1, wherein the methylation reaction comprises: p-bromopropiophenone is dissolved in a first solvent, and then a strong base and the methylating agent are added; after the reaction is completed, an organic solvent and water are added into the reaction mixture to extract, and the organic phase is separated, dried and evaporated the solvents to obtain the first intermediate; preferably, the first solvent is one selected from the group consisting of dimethylformamide, dimethyl sulfoxide and tert-butanol, and the strong base is one or more selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide and potassium tert-butoxide.
[Claim 4]
The method for synthesizing the firocoxib intermediate according to claim 1, wherein the sulfonation reaction comprises: the first intermediate, the sodium methylsulfinate and L-proline are added into a second solvent to obtain a mixture; the cuprous iodide is added into the mixture after the temperature is raised to 80-120 ℃; the obtained mixture reacts for 40-50 hours and is cooled to room temperature to obtain a reaction mixture; an organic solvent and water are added into the reaction mixture to extract, and the organic phase is separated, dried and evaporated the solvents under reduced pressure; and then n-heptane is added to crystallize the residue to obtain the second intermediate, wherein the second solvent is dimethyl sulfoxide.
[Claim 5]
The method for synthesizing the firocoxib intermediate according to claim 1, wherein the sulfonation reaction comprises: the first intermediate, sodium methylsulfinate and L-proline are added into dimethyl sulfoxide to obtain a mixture; the cuprous iodide is added into the mixture after the temperature is raised to 100 ℃; the obtained mixture reacts for 48 hours and is cooled to room temperature to obtain a reaction mixture; an organic solvent and water are added into the reaction mixture to extract, and the organic phase is separated, dried and evaporated the solvents under reduced pressure; and then n-heptane is added to crystallize the residue to obtain the second intermediate.
[Claim 6]
The method for synthesizing the firocoxib intermediate according to claim 4 or 5, wherein the method further comprises re-crystallization with ethyl acetate and n-heptane between the crystallization and obtaining the second intermediate.
[Claim 7]
The method for synthesizing the firocoxib intermediate according to claim 1, wherein the hydroxylation reaction comprises: the second intermediate is dissolved in a third solvent, and then N-bromosuccinimide is added to obtain a mixture; the mixture reacts for 10-14 hours after the temperature is raised to 80-120 ℃, and the reaction mixture is cooled to room temperature; an organic solvent and water are added into the reaction mixture to extract, and the organic phase is separated, dried and evaporated the solvents under reduced pressure; and then methyl tert-butyl ether and n-heptane are added to crystallize the residue to obtain the firocoxib intermediate, wherein the third solvent is dimethyl sulfoxide.
[Claim 8]
The method for synthesizing the firocoxib intermediate according to claim 1, wherein the hydroxylation reaction comprises: the second intermediate is dissolved in dimethyl sulfoxide; and then N-bromosuccinimide is added to obtain a mixture; the mixture reacts for 12 hours after the temperature is raised to 100 ℃, and the reaction mixture is cooled to room temperature; an organic solvent and water are added into the reaction mixture to extract, and the organic phase is separated, dried and evaporated the solvents under reduced pressure; and then methyl tert-butyl ether and n-heptane are added to crystallize the residue to obtain the firocoxib intermediate.
[Claim 9]
The method for synthesizing the firocoxib intermediate according to claim 1, wherein the Friedel-Crafts acylation reaction comprises: bromobenzene, the acylating agent and a Lewis acid are added into a fourth solvent to obtain the first intermediate; the acylating agent is isobutyric anhydride or isobutyryl chloride, and the fourth solvent is one selected from the group consisting of heptane, cyclohexane and dichloromethane; the Lewis acid is one selected from the group consisting of aluminum trichloride, aluminum tribromide and titanium tetrachloride; preferably, the molar ratio of bromobenzene, the Lewis acid and the acylating agent is 1: (2-3) : (1-1.5) , and the mass-to-volume ratio of bromobenzene to the fourth solvent is 1g/0.5mL-1g/5mL.
[Claim 10]
A method for synthesizing firocoxib, wherein the method includes any one of the method for synthesizing the firocoxib intermediate according to claim 1 to claim 9.
[Claim 11]
The method for synthesizing firocoxib according to claim 10, wherein the method comprises the following steps: the firocoxib intermediate obtained by the method for synthesizing the firocoxib intermediate reacts with acetoxyacetyl chloride to form 2-methyl-1- [4- (methylsulfonyl) phenyl] -2- (2-acetoxyacetoxy) -1-propanone, and the reaction scheme is as follows: 2-Methyl-1- [4- (methylsulfonyl) phenyl] -2- (2-acetoxyacetoxy) -1-propanone is cyclized with DBU to afford 3-hydroxy-5, 5-dimethyl-4- [4- (methylsulfonyl) phenyl] -2 (5H) -furanone, and the reaction scheme is as follows: 3-Hydroxy-5, 5-dimethyl-4- [4- (methylsulfonyl) phenyl] -2 (5H) -furanone reacts with cyclopropylbromomethane to afford firocoxib, and the reaction scheme is as follows: