Synthesis method of disopyramide
By using raw materials such as 1-phenyl-1-formamide ethylene and 3-chloropropylene, combined with olefin metathesis, addition and affinity substitution reactions, the production cost of dispyramide is successfully reduced and an efficient and economical synthesis process is achieved.
Patent Information
- Application Number
- CN202411770450.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-04
- Publication Date
- 2025-03-11
AI Technical Summary
In the existing dispyramide synthesis method, the raw materials benzyl acetate and N,N-diisopropyl-2-chloroethaneamine are difficult to obtain, and the price is high, resulting in excessive production costs.
1-phenyl-1-formamide ethylene and 3-chloropropylene were used as raw materials to obtain compound 2 by metathesis of olefins, followed by addition reaction with 2-bromopyridine, followed by affinity substitution reaction with N,N-diisopropylamine, and finally obtained dispyramide by recrystallization by methanol.
This method makes the raw materials cheap, the reaction conditions are mild, easy to control, the reaction route is short, the total conversion rate is high, the target product has qualified purity, and is suitable for industrial production.
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Figure CN119591541A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of drug intermediate synthesis, and particularly relates to a method for synthesizing disopyramide. Background Art
[0002] Disopyramide is a cardiac medication that is primarily used as an antiarrhythmic. It works by blocking sodium ion channels in the myocardial cell membrane, slowing the heart's electrical conduction, thereby helping to control abnormal heart rhythms. Disopyramide is commonly used to treat supraventricular and ventricular arrhythmias, including supraventricular tachycardia, atrial fibrillation, and atrial flutter.
[0003] Disopyramide was developed in 1970 by Hoechst AG (now part of Sanofi-Aventis) in Germany and was first approved by the FDA in the United States in 1981. Its chemical name is 1-[2,6-dimethyl-4-(2-dimethylaminoethoxy)phenyl]-1-propanone, and its molecular formula is C 19 H 27 NO 2 .
[0004] The currently reported synthesis method of disopyramide is to start from benzyl cyanide, first undergo a coupling reaction with 2-chloropyridine to obtain an intermediate, then continue to undergo a coupling reaction with N,N-diisopropyl-2-chloroethaneamine, and finally hydrolyze to obtain disopyramide. The main problem with this reaction route is that the raw materials benzyl cyanide and N,N-diisopropyl-2-chloroethaneamine are both precursor chemicals, which are difficult to obtain and are expensive, making the overall production cost very high. Summary of the invention
[0005] The technical problem to be solved by the present invention is to provide a method for synthesizing disopyramide in view of the deficiencies of the above-mentioned prior art. The method uses 1-phenyl-1-formamidoethylene and 3-chloropropylene as raw materials, obtains compound 2 through olefin metathesis reaction, then generates compound 3 through addition reaction with 2-bromopyridine, and then undergoes affinity substitution reaction with N,N-diisopropylamine, and finally obtains the target compound through methanol recrystallization. The raw and auxiliary materials are low in price, the reaction conditions are mild, easy to control, the reaction route is short, the total conversion rate is high, the purity of the target product is qualified, and it is suitable for industrial scale-up production.
[0006] To achieve the above object, the technical solution adopted by the present invention is as follows: a method for synthesizing disopyramide, characterized in that the synthetic route of the method is as follows:
[0007]
[0008] The above-mentioned method for synthesizing disopyramide is characterized in that it comprises the following steps:
[0009] Step 1, compound 1, 3-chloropropylene and a catalyst are mixed in a solvent, reacted at 40°C to 60°C under nitrogen protection, evaporated the solvent after the reaction, added ethyl acetate to dissolve again, filtered, evaporated to dryness, and obtained compound 2; the compound 1 is 1-phenyl-1-formamidoethylene;
[0010] Step 2: Compound 2, 2-bromopyridine, an inorganic base and a catalyst are mixed in a solvent, and reacted at 60°C to 90°C under nitrogen protection. After the reaction, the solvent is evaporated, ethyl acetate is added to dissolve again, filtered, and evaporated to dryness to obtain compound 3;
[0011] Step 3: Mix compound 3, potassium hydroxide and N,N-diisopropylamine in a solvent, react at 40°C to 80°C, evaporate the solvent after the reaction, add ethyl acetate and water, stir and let stand to separate the layers, separate the layers, wash the organic phase with water and evaporate to dryness, and recrystallize with methanol to obtain the target compound disopyramide.
[0012] The above-mentioned method for synthesizing disopyramide is characterized in that the molar ratio of compound 1 to 3-chloropropylene in step 1 is 1:(1-2), and the molar amount of the catalyst is 0.01-0.1 times the molar amount of compound 1.
[0013] The above-mentioned method for synthesizing disopyramide is characterized in that the catalyst used in step 1 is bis(tricyclohexylphosphine)benzylideneruthenium dichloride, 3-dimethylimidazolidine-2-yl)(2-isopropoxybenzylidene)ruthenium chloride, tricyclohexylphosphine [1,3-bis(2,4,6-trimethylphenyl)imidazol-2-yl][3-phenyl-1H-indene-1-yl] dichloride ruthenium, tricyclohexylphosphine [4,5-dimethyl-1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][2-thienylmethylene]ruthenium dichloride, (3-phenyl-1H-inden-1-ylidene)bis(tricyclohexylphosphine)ruthenium dichloride, dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](3-methyl-2-butenyl)(tricyclohexylphosphine)ruthenium, [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](3-methyl-2-butenyl)(tricyclohexylphosphine)ruthenium (2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro-(3-phenyl-1H-inden-1-yl)(tricyclohexylphosphine)ruthenium, dichloro(3-methyl-2-butenylidene)bis(tricyclohexylphosphine)ruthenium, dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][3-(2-pyridyl)propylidene]ruthenium, [1,3-bis(2,6-diisopropylphenyl) The solvent used in step 1 is one or more of tetrahydrofuran, dichloromethane, dimethyl sulfoxide, methanol, ethanol, acetonitrile and toluene.
[0014] The above-mentioned method for synthesizing disopyramide is characterized in that the inorganic base used in step 2 is KOH, NaOH, LiOH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 、NaHCO 3 , KHCO 3 , KOAc and K 3 PO 4 One or more of the .
[0015] The above-mentioned method for synthesizing disopyramide is characterized in that the catalyst used in step 2 is one or more of tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride, 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride, dichloromethane complex of bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium, bis(acetylacetone)palladium, (1,5-cyclooctadiene)palladium dichloride, bis(tri-o-tolylphosphine)palladium chloride, bis(tricyclohexylphosphine)palladium dichloride, di-tert-butyl-(4-dimethylaminophenylphosphine)palladium dichloride, bis(di-tert-butylphenylphosphine)palladium dichloride and di(tri-tert-butylphosphine)palladium.
[0016] The above-mentioned method for synthesizing disopyramide is characterized in that the molar amount of 2-bromopyridine in step 2 is 1 to 2 times the molar amount of compound 1 in step 1, the molar amount of the inorganic base is 2 to 5 times the molar amount of compound 1 in step 1, and the molar amount of the catalyst is 0.01 to 0.1 times the molar amount of compound 1 in step 1.
[0017] The above-mentioned method for synthesizing disopyramide is characterized in that the solvent used in step 2 is one or more of tetrahydrofuran, dichloromethane, dimethyl sulfoxide, methanol, ethanol, acetonitrile and toluene.
[0018] The above-mentioned method for synthesizing disopyramide is characterized in that the molar amount of potassium hydroxide in step 3 is 3 to 5 times the molar amount of compound 1 in step 1, and the molar amount of N,N-diisopropylamine is 1 to 1.1 times the molar amount of compound 1 in step 1; the solvent used in step 3 is one or more of tetrahydrofuran, dichloromethane, dimethyl sulfoxide, methanol, ethanol, acetonitrile and toluene.
[0019] Compared with the prior art, the present invention has the following advantages:
[0020] 1. The present invention uses 1-phenyl-1-formamidoethylene and 3-chloropropylene as raw materials, obtains compound 2 through olefin metathesis reaction, then generates compound 3 through addition reaction with 2-bromopyridine, then undergoes affinity substitution reaction with N,N-diisopropylamine, and finally obtains the target compound disopyramide through methanol recrystallization. The raw and auxiliary materials used are all commercially available and inexpensive.
[0021] 2. The present invention greatly improves the yield of disopyramide, and can purify the product through simple post-treatment steps including extraction, evaporation, filtration, crystallization, etc., avoiding the use of column chromatography separation. The total yield of the route can reach up to 71.1%, and the purity of the target product can reach 99.0%. It has the characteristics of high conversion rate, mild reaction process, easy control of reaction process, few by-products, and low energy consumption.
[0022] 3. The method of the present invention is used to synthesize disopyramide, which is low-cost, economical and environmentally friendly, has no harsh reaction conditions, and is suitable for industrial scale-up production.
[0023] The technical solution of the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. BRIEF DESCRIPTION OF THE DRAWINGS
[0024] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the target compound synthesized in Example 3 of the present invention.
[0025] Figure 2 This is the HPLC chromatogram of the target compound synthesized in Example 3 of the present invention.
[0026] Figure 3 This is the HPLC chromatogram of the target compound synthesized in Example 6 of the present invention.
[0027] Figure 4 This is the HPLC chromatogram of the target compound synthesized in Example 9 of the present invention. DETAILED DESCRIPTION
[0028] The specific embodiments of the present invention are described in detail below. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.
[0029] The endpoints and any values of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, the endpoint values of each range, the endpoint values of each range and the individual point values, and the individual point values can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.
[0030] The present invention will be described in detail below by way of examples. In the following examples, unless otherwise specified, the raw materials used are all commercially available industrial grade products.
[0031] Compound 1 (1-phenyl-1-formamidoethylene) can be prepared with a yield of 90% according to the literature (ChemCatChem, 2018, 10(19), 4264-4268).
[0032] The synthetic method of disopyramide of the present invention, the synthetic route is as follows:
[0033]
[0034] The synthesis method comprises the following steps:
[0035] Step 1, compound 1, 3-chloropropylene and a catalyst are mixed in a solvent, reacted at 40°C to 60°C under nitrogen protection, evaporated the solvent after the reaction, added ethyl acetate to dissolve again, filtered, evaporated to dryness, and obtained compound 2; the compound 1 is 1-phenyl-1-formamidoethylene; the molar ratio of compound 1 to 3-chloropropylene is 1:(1-2), and the molar amount of the catalyst is 0.01 to 0.1 times the molar amount of compound 1; the catalyst used is bis(tricyclohexylphosphine)benzylideneruthenium dichloride, 3-dimethylimidazolidin-2-ylidene)(2-isopropoxybenzylidene)ruthenium chloride, tricyclohexylphosphine [1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][3-phenyl-1H-inden-1-ylidene] dichloride, tricyclohexylphosphine [4,5-dimethyl-1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][2-thienylmethylene] dichloride, (3-phenyl-1H-inden-1-ylidene) bis(tricyclohexylphosphine) )Ruthenium dichloride, dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](3-methyl-2-butenylidene)(tricyclohexylphosphine)ruthenium, [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro-(3-phenyl-1H-inden-1-yl)(tricyclohexylphosphine)ruthenium, dichloro(3-methyl-2-butenylidene)bis(tricyclohexylphosphine)ruthenium, dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro-(3-phenyl-1H-inden-1-yl)(tricyclohexylphosphine)ruthenium One or more of [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]-[2-isopropoxy-5-(trifluoroacetylamino)phenyl]methylenedichlororuthenium and dichloro[1,3-bis(2-methylphenyl)-2-imidazolidineylidene](2-isopropoxybenzylidene)ruthenium; the solvent used is one or more of tetrahydrofuran, dichloromethane, dimethyl sulfoxide, methanol, ethanol, acetonitrile and toluene;
[0036] Step 2, compound 2, 2-bromopyridine, an inorganic base and a catalyst are mixed in a solvent, reacted at 60°C to 90°C under nitrogen protection, evaporated the solvent after the reaction, added ethyl acetate to dissolve again, filtered, and evaporated to obtain compound 3; the molar amount of 2-bromopyridine is 1 to 2 times the molar amount of compound 1 in step 1, the molar amount of the inorganic base is 2 to 5 times the molar amount of compound 1 in step 1, and the molar amount of the catalyst is 0.01 to 0.1 times the molar amount of compound 1 in step 1; the inorganic base used is KOH, NaOH, LiOH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 、NaHCO 3 , KHCO3 , KOAc and K 3 PO 4 The catalyst used is one or more of tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride, 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride dichloromethane complex, bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium, bis(acetylacetone)palladium, (1,5-cyclooctadiene)palladium dichloride, bis(tri-o-tolylphosphine)palladium chloride, bis(tricyclohexylphosphine)palladium dichloride, di-tert-butyl-(4-dimethylaminophenylphosphine)palladium dichloride, bis(di-tert-butylphenylphosphine)palladium dichloride and di(tri-tert-butylphosphine)palladium; the solvent used is one or more of tetrahydrofuran, dichloromethane, dimethyl sulfoxide, methanol, ethanol, acetonitrile and toluene;
[0037] Step 3: Compound 3, potassium hydroxide and N,N-diisopropylamine are mixed in a solvent, reacted at 40°C to 80°C, evaporated the solvent after the reaction, added ethyl acetate and water, stirred and allowed to stand for stratification, separated, the organic phase was washed with water and evaporated to dryness, and recrystallized with methanol to obtain the target compound disopyramide; the molar amount of potassium hydroxide is 3 to 5 times the molar amount of compound 1 in step 1, and the molar amount of N,N-diisopropylamine is 1 to 1.1 times the molar amount of compound 1 in step 1; the solvent used is one or more of tetrahydrofuran, dichloromethane, dimethyl sulfoxide, methanol, ethanol, acetonitrile and toluene.
[0038] Example 1: Preparation of Compound 2
[0039]
[0040] 147.2 g of compound 1 (1-phenyl-1-formamidoethylene, 1.0 mol), 114.8 g of 3-chloropropylene (1.5 mol) and 8.2 g of bis(tricyclohexylphosphine)benzylideneruthenium dichloride (0.01 mol) were mixed in 200 mL of dichloromethane, and reacted at 60 ° C for 12 hours under nitrogen protection. After the reaction, the solvent was evaporated, 100 mL of ethyl acetate was added to dissolve it again, filtered, and evaporated to obtain 211.1 g of viscous liquid of compound 2, which was directly used for the next reaction.
[0041] The catalyst of this embodiment can be bis(tricyclohexylphosphine)benzylidene ruthenium dichloride, 3-dimethylimidazolidin-2-ylidene)(2-isopropoxybenzylidene)ruthenium chloride, tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][3-phenyl-1H-inden-1-ylidene]dichloride, tricyclohexylphosphine[4,5-dimethyl-1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][2-thienylmethylene]dichloride, (3-phenyl-1H-inden-1-ylidene)bis(tricyclohexylphosphine)dichloride, dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidin-2-ylidene](3-methyl-2-butenyl)(tricyclohexylphosphine) The ruthenium dichloride can be replaced by one or more of [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro-(3-phenyl-1H-inden-1-yl)(tricyclohexylphosphine)ruthenium, [3-methyl-2-butenylidene)bis(tricyclohexylphosphine)ruthenium dichloride, [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][3-(2-pyridyl)propylidene]ruthenium dichloride, [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]-[2-isopropoxy-5-(trifluoroacetylamino)phenyl]methylenedichlororuthenium and [1,3-bis(2-methylphenyl)-2-imidazolidinylidene](2-isopropoxybenzylidene)ruthenium dichloride.
[0042] The solvent of this embodiment can be replaced by one or more of tetrahydrofuran, dichloromethane, dimethyl sulfoxide, methanol, ethanol, acetonitrile and toluene.
[0043] Example 2: Preparation of Compound 3
[0044]
[0045] 211.1 g of the viscous liquid of compound 2 obtained in Example 1, 237.0 g of 2-bromopyridine (1.5 mol), 168.3 g of KOH (3.0 mol) and 57.8 g of tetrakis(triphenylphosphine)palladium (0.05 mol) were mixed in 400 mL of tetrahydrofuran, and reacted at 60° C. for 3 hours under nitrogen protection. After the reaction, the solvent was evaporated and 300 mL of ethyl acetate was added to dissolve it again, filtered, and evaporated to dryness to obtain 282.3 g of viscous liquid of compound 3, which was directly used for the next step reaction.
[0046] The inorganic base in this embodiment can be KOH, NaOH, LiOH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 、NaHCO 3 , KHCO3 , KOAc and K 3 PO 4 One or more of them can be used as replacements.
[0047] The catalyst of this embodiment can be replaced by one or more of tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride, 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride dichloromethane complex, bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium, bis(acetylacetone)palladium, (1,5-cyclooctadiene)palladium dichloride, bis(tri-o-tolylphosphine)palladium chloride, bis(tricyclohexylphosphine)palladium dichloride, di-tert-butyl-(4-dimethylaminophenylphosphine)palladium dichloride, bis(di-tert-butylphenylphosphine)palladium dichloride and di(tri-tert-butylphosphine)palladium.
[0048] The solvent of this embodiment can be replaced by one or more of tetrahydrofuran, dichloromethane, dimethyl sulfoxide, methanol, ethanol, acetonitrile and toluene.
[0049] Example 3: Preparation of target compound
[0050]
[0051] 282.3 g of the viscous liquid of compound 3 obtained in Example 2, 224.4 g of KOH (4.0 mol) and 101.2 g of N,N-diisopropylamine (1.0 mol) were mixed in 500 mL of tetrahydrofuran and reacted at 70°C for 4 hours. After the reaction, the solvent was evaporated and 400 mL of ethyl acetate and 150 mL of water were added. The mixture was stirred and allowed to stand for stratification. The organic phase was washed with water and evaporated to dryness, dissolved in 200 mL of methanol, cooled to -5°C and allowed to stand for crystallization. After complete crystallization, the filter cake was obtained by filtration, and 241.9 g of the target compound was obtained after vacuum drying at room temperature for 3 hours.
[0052] The total yield of Example 1-3 is 71.1%. Figure 2 As shown, HPLC: 99.2%, maximum single impurity 0.5%.
[0053] The solvent of this embodiment can be one or more of tetrahydrofuran, dichloromethane, dimethyl sulfoxide, methanol, ethanol, acetonitrile and toluene.
[0054] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the target compound synthesized in this example, and the data are as follows:
[0055] 1HNMR(DMSO-d6,400M): δ(ppm)8.54-8.53(m,1H),7.86(s,1H),7.73-7.70(m,1H),7.31-7.19(m, 8H), 2.92-2.88(m,2H),2.50-2.44(m,2H),2.21-2.16(m,1H),2.12-2.07(m,1H),0.83(d,12H).
[0056] The mass spectrum of the target compound is MS: m / z = 340.24 [M+H] +
[0057] Example 4: Preparation of Compound 2
[0058] 147.2 g of compound 1 (1.0 mol), 153.1 g of 3-chloropropylene (2.0 mol) and 82.7 g of dichloro(3-methyl-2-butenylidene)bis(tricyclohexylphosphine)ruthenium (0.1 mol) were mixed in 300 mL of tetrahydrofuran, and reacted at 40 °C for 12 hours under nitrogen protection. After the reaction, the solvent was evaporated, 100 mL of ethyl acetate was added to dissolve it again, filtered, and evaporated to obtain 243.5 g of viscous liquid of compound 2, which was directly used for the next reaction.
[0059] The catalyst of this embodiment can be bis(tricyclohexylphosphine)benzylidene ruthenium dichloride, 3-dimethylimidazolidin-2-ylidene)(2-isopropoxybenzylidene)ruthenium chloride, tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][3-phenyl-1H-inden-1-ylidene]dichloride, tricyclohexylphosphine[4,5-dimethyl-1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][2-thienylmethylene]dichloride, (3-phenyl-1H-inden-1-ylidene)bis(tricyclohexylphosphine)dichloride, dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidin-2-ylidene](3-methyl-2-butenyl)(tricyclohexylphosphine) The ruthenium dichloride can be replaced by one or more of [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro-(3-phenyl-1H-inden-1-yl)(tricyclohexylphosphine)ruthenium, [3-methyl-2-butenylidene)bis(tricyclohexylphosphine)ruthenium dichloride, [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][3-(2-pyridyl)propylidene]ruthenium dichloride, [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]-[2-isopropoxy-5-(trifluoroacetylamino)phenyl]methylenedichlororuthenium and [1,3-bis(2-methylphenyl)-2-imidazolidinylidene](2-isopropoxybenzylidene)ruthenium dichloride.
[0060] The solvent of this embodiment can be replaced by one or more of tetrahydrofuran, dichloromethane, dimethyl sulfoxide, methanol, ethanol, acetonitrile and toluene.
[0061] Example 5: Preparation of Compound 3
[0062] 243.5 g of the viscous liquid of compound 2 obtained in Example 1, 316.0 g of 2-bromopyridine (2.0 mol), 200.0 g of NaOH (5.0 mol) and 70.2 g of bis(triphenylphosphine)palladium dichloride (0.1 mol) were mixed in 450 mL of tetrahydrofuran, and reacted at 90° C. for 3 hours under nitrogen protection. After the reaction, the solvent was evaporated, 300 mL of ethyl acetate was added to dissolve again, filtered, and evaporated to obtain 325.1 g of viscous liquid of compound 3, which was directly used in the next step reaction.
[0063] The inorganic base in this embodiment can be KOH, NaOH, LiOH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 、NaHCO 3 , KHCO 3 , KOAc and K 3 PO 4 One or more of them can be used as replacements.
[0064] The catalyst of this embodiment can be replaced by one or more of tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride, 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride dichloromethane complex, bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium, bis(acetylacetone)palladium, (1,5-cyclooctadiene)palladium dichloride, bis(tri-o-tolylphosphine)palladium chloride, bis(tricyclohexylphosphine)palladium dichloride, di-tert-butyl-(4-dimethylaminophenylphosphine)palladium dichloride, bis(di-tert-butylphenylphosphine)palladium dichloride and di(tri-tert-butylphosphine)palladium.
[0065] The solvent of this embodiment can be replaced by one or more of tetrahydrofuran, dichloromethane, dimethyl sulfoxide, methanol, ethanol, acetonitrile and toluene.
[0066] Example 6: Preparation of target compound
[0067] 325.1 g of the viscous liquid of compound 3 obtained in Example 2, 280.5 g of KOH (5.0 mol) and 111.3 g of N,N-diisopropylamine (1.1 mol) were mixed in 600 mL of methanol and reacted at 80°C for 4 hours. After the reaction, the solvent was evaporated and 400 mL of ethyl acetate and 200 mL of water were added. The mixture was stirred and allowed to stand for stratification. The organic phase was washed with water and evaporated to dryness, dissolved in 200 mL of methanol, cooled to -5°C and allowed to stand for crystallization. After complete crystallization, the filter cake was obtained by filtration, and 235 g of the target compound was obtained after vacuum drying at room temperature for 3 hours.
[0068] The total yield of Example 4-6 is 69.1%. Figure 3 As shown, HPLC: 99.5%, maximum single impurity 0.2%.
[0069] The H NMR spectrum and mass spectrum of the target compound are the same as those in Example 3.
[0070] The solvent of this embodiment can be replaced by one or more of tetrahydrofuran, dichloromethane, dimethyl sulfoxide, methanol, ethanol, acetonitrile and toluene.
[0071] Example 7: Preparation of Compound 2
[0072] 147.2 g of compound 1 (1.0 mol), 76.6 g of 3-chloropropylene (1.0 mol) and 46.2 g of (3-phenyl-1H-inden-1-ylidene)bis(tricyclohexylphosphine)dichlororuthenium (0.05 mol) were mixed in 300 mL of dichloromethane, and reacted at 50 °C for 12 hours under nitrogen protection. After the reaction, the solvent was evaporated, 100 mL of ethyl acetate was added to dissolve it again, filtered, and evaporated to obtain 201.1 g of viscous liquid of compound 2, which was directly used for the next reaction.
[0073] The catalyst of this embodiment can be bis(tricyclohexylphosphine)benzylidene ruthenium dichloride, 3-dimethylimidazolidin-2-ylidene)(2-isopropoxybenzylidene)ruthenium chloride, tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][3-phenyl-1H-inden-1-ylidene]dichloride, tricyclohexylphosphine[4,5-dimethyl-1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][2-thienylmethylene]dichloride, (3-phenyl-1H-inden-1-ylidene)bis(tricyclohexylphosphine)dichloride, dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidin-2-ylidene](3-methyl-2-butenyl)(tricyclohexylphosphine) The ruthenium dichloride can be replaced by one or more of [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro-(3-phenyl-1H-inden-1-yl)(tricyclohexylphosphine)ruthenium, [3-methyl-2-butenylidene)bis(tricyclohexylphosphine)ruthenium dichloride, [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][3-(2-pyridyl)propylidene]ruthenium dichloride, [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]-[2-isopropoxy-5-(trifluoroacetylamino)phenyl]methylenedichlororuthenium and [1,3-bis(2-methylphenyl)-2-imidazolidinylidene](2-isopropoxybenzylidene)ruthenium dichloride.
[0074] The solvent of this embodiment can be replaced by one or more of tetrahydrofuran, dichloromethane, dimethyl sulfoxide, methanol, ethanol, acetonitrile and toluene.
[0075] Example 8: Preparation of Compound 3
[0076] The viscous liquid of compound 2 obtained in Example 1 (201.1 g), 158.0 g 2-bromopyridine (1.0 mol), 276.4 g K 2 CO 3 (2.0 mol) and 5.1 g of di(tri-tert-butylphosphine)palladium (0.01 mol) were mixed in 350 mL of tetrahydrofuran, and reacted at 80 °C for 3 hours under nitrogen protection. After the reaction, the solvent was evaporated and 300 mL of ethyl acetate was added to dissolve it again, filtered, and evaporated to obtain 267.7 g of viscous liquid of compound 3, which was directly used for the next step reaction.
[0077] The inorganic base in this embodiment can be KOH, NaOH, LiOH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 、NaHCO 3 , KHCO 3, KOAc and K 3 PO 4 One or more of them can be used as replacements.
[0078] The catalyst of this embodiment can be replaced by one or more of tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride, 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride dichloromethane complex, bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium, bis(acetylacetone)palladium, (1,5-cyclooctadiene)palladium dichloride, bis(tri-o-tolylphosphine)palladium chloride, bis(tricyclohexylphosphine)palladium dichloride, di-tert-butyl-(4-dimethylaminophenylphosphine)palladium dichloride, bis(di-tert-butylphenylphosphine)palladium dichloride and di(tri-tert-butylphosphine)palladium.
[0079] The solvent of this embodiment can be replaced by one or more of tetrahydrofuran, dichloromethane, dimethyl sulfoxide, methanol, ethanol, acetonitrile and toluene.
[0080] Example 9: Preparation of target compound
[0081] 267.7 g of the viscous liquid of compound 3 obtained in Example 2, 168.3 g of KOH (3.0 mol) and 101.2 g of N,N-diisopropylamine (1.0 mol) were mixed in 500 mL of tetrahydrofuran and reacted at 40°C for 4 hours. After the reaction, the solvent was evaporated and 300 mL of ethyl acetate and 100 mL of water were added, stirred, allowed to stand for stratification, and separated. The organic phase was washed with water and evaporated to dryness, dissolved in 200 mL of methanol, cooled to -5°C and allowed to stand for crystallization. After complete crystallization, it was filtered to obtain a filter cake, which was dried in vacuo at room temperature for 3 hours to obtain 228.6 g of the target compound.
[0082] The total yield of Examples 7-9 is 67.2%. Figure 4 As shown, HPLC: 98.2%, maximum single impurity 1.8%.
[0083] The H NMR spectrum and mass spectrum of the target compound are the same as those in Example 3.
[0084] The solvent of this embodiment can be replaced by one or more of tetrahydrofuran, dichloromethane, dimethyl sulfoxide, methanol, ethanol, acetonitrile and toluene.
[0085] Comparative Example 1: Preparation of Compound 4
[0086] This comparative example provides a method for synthesizing disopyramide, which is basically the same as Example 1, except that 3-bromopropylene is used instead of 3-chloropropylene for the reaction.
[0087]
[0088] 147.2 g of compound 1 (1.0 mol), 181.5 g of 3-bromopropylene (1.5 mol) and 8.2 g of bis(tricyclohexylphosphine)benzylideneruthenium dichloride (0.01 mol) were mixed and dissolved in 200 mL of dichloromethane. The mixture was reacted at 60 °C for 12 hours under nitrogen protection. After the reaction, the solvent was evaporated and 100 mL of ethyl acetate was added to dissolve it again, filtered and evaporated to obtain 225.5 g of viscous liquid of compound 4, which was directly used in the next step reaction.
[0089] Comparative Example 2: Preparation of Compound 5
[0090]
[0091] 225.5 g of the viscous liquid of compound 4 obtained in comparative example 1, 237.0 g of 2-bromopyridine (1.5 mol), 168.3 g of KOH (3.0 mol), and 57.8 g of tetrakis(triphenylphosphine)palladium (0.05 mol) were dissolved in tetrahydrofuran, and reacted at 60° C. for 3 hours under nitrogen protection. After the reaction, the solvent was evaporated and ethyl acetate was added to dissolve again, filtered, and evaporated to obtain 299.6 g of the viscous liquid of compound 5, which was directly used for the next step reaction;
[0092] Comparative Example 3: Preparation of target compound
[0093]
[0094] 299.6 g of the viscous liquid of compound 5 obtained in Comparative Example 2, 224.4 g of KOH (4.0 mol) and 101.2 g of N,N-diisopropylamine (1.0 mol) were dissolved in tetrahydrofuran solvent and reacted at 70°C for 4 hours. After the reaction, the solvent was evaporated and ethyl acetate and water were added. The mixture was stirred and allowed to stand for stratification. The liquids were separated and the organic phase was washed with water. The TLC monitoring system was too complicated to obtain the product by simple separation.
[0095] After analysis, the possible reason is that the boiling point of 3-bromopropene is 70℃~72℃, while the boiling point of 3-chloropropene is 44℃~46℃. 3-bromopropene has a higher boiling point and is difficult to remove by evaporation, resulting in residual 3-bromopropene in compound 4. This part of 3-bromopropene will interfere with the reaction process of compound 5 and compound 6, generating a variety of by-products, making it difficult to separate the target compound.
[0096] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any way. Any simple modification, change and equivalent changes made to the above embodiments based on the technical essence of the present invention still fall within the protection scope of the technical solution of the present invention.
Claims
1. A method for synthesizing disopyramide, characterized in that: The synthetic route of the method is as follows:
2. A method for synthesizing disopyramide according to claim 1, characterized in that, The following steps are involved: Step 1, compound 1, 3-chloropropylene and a catalyst are mixed in a solvent, reacted at 40°C to 60°C under nitrogen protection, evaporated the solvent after the reaction, added ethyl acetate to dissolve again, filtered, evaporated to dryness, and obtained compound 2; the compound 1 is 1-phenyl-1-formamidoethylene; Step 2: Compound 2, 2-bromopyridine, an inorganic base and a catalyst are mixed in a solvent, and reacted at 60°C to 90°C under nitrogen protection. After the reaction, the solvent is evaporated, ethyl acetate is added to dissolve again, filtered, and evaporated to dryness to obtain compound 3; Step 3: Mix compound 3, potassium hydroxide and N,N-diisopropylamine in a solvent, react at 40°C to 80°C, evaporate the solvent after the reaction, add ethyl acetate and water, stir and let stand to separate the layers, separate the layers, wash the organic phase with water and evaporate to dryness, and recrystallize with methanol to obtain the target compound disopyramide.
3. A method for synthesizing disopyramide according to claim 2, characterized in that, In step 1, the molar ratio of compound 1 to 3-chloropropylene is 1:(1-2), and the molar amount of the catalyst is 0.01-0.1 times the molar amount of compound 1.
4. A method for synthesizing disopyramide according to claim 2, characterized in that, The catalyst used in step 1 is bis(tricyclohexylphosphine)benzylidene ruthenium dichloride, 3-dimethylimidazolidin-2-yl)(2-isopropoxybenzylidene)ruthenium chloride, tricyclohexylphosphine [1,3-bis(2,4,6-trimethylphenyl)imidazol-2-yl][3-phenyl-1H-indene-1-yl] dichloride ruthenium, tricyclohexylphosphine [4,5-dimethyl-1,3-bis( 2,4,6-trimethylphenyl)imidazol-2-ylidene][2-thienylmethylene] dichlororuthenium, (3-phenyl-1H-inden-1-ylidene)bis(tricyclohexylphosphine) dichlororuthenium, dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidineylidene](3-methyl-2-butenyl)(tricyclohexylphosphine)ruthenium, [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidineylidene](3-methyl-2-butenyl)(tricyclohexylphosphine)ruthenium, one or more of dichloro-(3-phenyl-1H-inden-1-yl)(tricyclohexylphosphine)ruthenium, dichloro-(3-methyl-2-butenylidene)bis(tricyclohexylphosphine)ruthenium, dichloro-[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][3-(2-pyridyl)propylidene]ruthenium, [1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene]-[2-isopropoxy-5-(trifluoroacetylamino)phenyl]methylenedichlororuthenium and dichloro-[1,3-bis(2-methylphenyl)-2-imidazolidinylidene](2-isopropoxybenzylidene)ruthenium; the solvent used in step 1 is one or more of tetrahydrofuran, dichloromethane, dimethyl sulfoxide, methanol, ethanol, acetonitrile and toluene.
5. A method for synthesizing disopyramide according to claim 2, characterized in that, The inorganic base used in step 2 is one or more of KOH, NaOH, LiOH, Na2CO3, K2CO3, Cs2CO3, NaHCO3, KHCO3, KOAc and K3PO4.
6. The method for synthesizing disopyramide according to claim 2, wherein: The catalyst used in step 2 is one or more of tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride, 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride dichloromethane complex, bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium, bis(acetylacetone)palladium, (1,5-cyclooctadiene)palladium dichloride, bis(tri-o-tolylphosphine)palladium chloride, bis(tricyclohexylphosphine)palladium dichloride, di-tert-butyl-(4-dimethylaminophenylphosphine)palladium dichloride, bis(di-tert-butylphenylphosphine)palladium dichloride and di(tri-tert-butylphosphine)palladium.
7. The method for synthesizing disopyramide according to claim 2, wherein: The molar amount of 2-bromopyridine in step 2 is 1 to 2 times the molar amount of compound 1 in step 1, the molar amount of the inorganic base is 2 to 5 times the molar amount of compound 1 in step 1, and the molar amount of the catalyst is 0.01 to 0.1 times the molar amount of compound 1 in step 1.
8. The method for synthesizing disopyramide according to claim 2, wherein: The solvent used in step 2 is one or more of tetrahydrofuran, dichloromethane, dimethyl sulfoxide, methanol, ethanol, acetonitrile and toluene.
9. The method for synthesizing disopyramide according to claim 2, wherein: The molar amount of potassium hydroxide in step 3 is 3 to 5 times the molar amount of compound 1 in step 1, and the molar amount of N,N-diisopropylamine is 1 to 1.1 times the molar amount of compound 1 in step 1; the solvent used in step 3 is one or more of tetrahydrofuran, dichloromethane, dimethyl sulfoxide, methanol, ethanol, acetonitrile and toluene.