CN107973784B - Synthesis method of fimasartan - Google Patents
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- CN107973784B CN107973784B CN201711139742.2A CN201711139742A CN107973784B CN 107973784 B CN107973784 B CN 107973784B CN 201711139742 A CN201711139742 A CN 201711139742A CN 107973784 B CN107973784 B CN 107973784B
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
Abstract
The invention discloses a method for synthesizing fimasartan, which comprises the steps of reacting a compound VI with a compound VII in toluene to obtain a compound V; reacting the compound V with pentamidine hydrochloride in the presence of alkali metal hydroxide to obtain a compound IV; extracting hydrogen from the compound IV in a mixed solvent consisting of toluene and DMF by using lithium hydride, and carrying out N-alkylation reaction on the compound IV and 2-cyano-4' -bromomethyl biphenyl to obtain a compound III; reacting the compound III with sodium azide in DMF under the catalysis of zinc chloride to obtain a compound II; and carrying out thioamidation reaction on the compound II and a Lawson reagent to obtain a target product I. The method has the advantages of simple process, simple and convenient operation, easily obtained raw materials, economy and high efficiency, greatly reduces the production cost of the fimasartan, and is easy to realize industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a novel synthesis method of fimasartan, namely 2-butyl-5-dimethylaminothioformyl methyl-6-methyl-3- [ [2' - (1H-tetrazol-5-yl) biphenyl-4-yl ] methyl ] pyrimidin-4 (3H) -one.
Background
Fimasartan is an angiotensin ii receptor Antagonist (ARB) type antihypertensive agent with excellent antihypertensive effect, and has the structural formula shown in formula 1.
The synthesis route in patent WO9608476A1 is to condense pentamidine as a starting material with diethyl acetylsuccinate to synthesize 2-N-butyl-5-ethoxycarbonylmethyl-4-hydroxy-6-methylpyrimidine (compound 1), perform N-alkylation reaction on the compound 1 and 4- [2' -triphenyl-5-tetrazole ] phenyl-benzyl bromide under the action of NaH to obtain 2-N-butyl-5-ethoxycarbonylmethyl-6-methyl-3- [ [2' - (N-triphenylmethyl-5-tetrazolyl) -4-biphenyl ] methyl ] -4-pyrimidinone (compound 2), and hydrolyze the compound 2 to obtain 2-N-butyl-5-acetic acid-6-methyl-3- [ [2' - (N-triphenylmethyl- 5-tetrazolyl) -4-biphenyl ] methyl ] -4-pyrimidone (compound 3), carrying out amidation reaction on the compound 3 and dimethylamine in the presence of EDCI, HOBt and N-methylmorpholine to generate 2-N-butyl-5-dimethylaminocarbonylmethyl-6-methyl-3- [ [2'- (N-triphenylmethyl-5-tetrazolyl) -4-biphenyl ] methyl ] -4-pyrimidone (compound 4), and carrying out thiocarbonylation reaction on the compound 4 and a Lawson reagent to obtain 2-N-butyl-5-dimethylaminothioformyl methyl-6-methyl-3- [ [2' - (N-triphenylmethyl-5-tetrazolyl) -4-biphenyl ] methyl ] -4-pyrimidone (compound 4) 5) And deprotecting the compound 5 with an acid to obtain fimasartan. The synthetic route is shown below. The synthetic route comprises six reaction steps, the treatment of intermediates and final products is complicated, O-alkylation byproducts are inevitably introduced in the process of carrying out N-alkylation reaction on the compound 1 under the action of NaH, and the byproducts are isomers of the compound 2, so that the total yield is low and is only 1.28%.
Patent CN1558906A improves the synthesis procedure in patent WO9608476a 1. The hydrogen extraction reagent in the N-alkylation step is changed into LiH, so that the selectivity of the N-alkylation reaction is greatly improved, and the total yield is improved to 28.2%. However, DCC is selected as a condensing agent in the amidation reaction of carboxylic acid, and the dicyclohexylurea which is another product generated by the reaction has very low solubility in common organic phase but has some slight solubility, so that the dicyclohexylurea is difficult to completely remove by some common purification methods such as recrystallization, column chromatography and the like.
The synthesis method of Korean patent No. 10-2002-0061850 is shown in the following, pentamidine hydrochloride and diethyl acetylsuccinate undergo a ring-closing reaction under the action of alkali and are simultaneously hydrolyzed to generate 2- (2-N-butyl-4-hydroxy-6-methylpyrimidin-5-yl) acetic acid (compound 1), the compound 1 undergoes an amidation reaction with dimethylamine under the catalysis of DCC to synthesize 2- (2-N-butyl-4-hydroxy-6-methylpyrimidin-5-yl) -N, N-dimethylacetamide (compound 2), and the compound 2 undergoes an alkali reaction with 4- [2' -triphenyl-5-tetrazole ] phenyl-benzyl bromide to obtain 2-N-butyl-5-dimethylaminocarbonylmethyl-6-methyl-3- [ [2' - (N-methyl-5-carbonylamino-6-methyl-3- [ [2' - (N-methyl-5-tetrazol ] phenyl-benzyl bromide -triphenylmethyl-5-tetrazolyl) -4-biphenyl ] methyl ] -4-pyrimidone (compound 4), and the compound 4 is subjected to thiocarbonylation and deprotection to obtain the fimasartan. Although this route reduces the reaction in one step compared to the above route, it still requires the use of a DCC condensing agent, which makes purification of Compound 2 difficult.
In view of the drawback of the production of urea as a by-product, patent CN104478811A proposes a new method for amidating a carboxyl group, as shown below. 2- (2-N-butyl-4-hydroxy-6-methylpyrimidin-5-yl) acetic acid and carbonyldiimidazole react in the presence of organic base to generate a compound 1, and then the compound 1 reacts with dimethylamine to obtain an amidation product 2- (2-N-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl) -N, N-dimethylacetamide. Although the synthesis route avoids the generation of urea as a byproduct, the carbonyl diimidazole is expensive, so that the production cost of the intermediate 2- (2-N-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl) -N, N-dimethylacetamide is high, the reaction consumes carbonyl diimidazole with a high molecular weight, a large amount of reaction waste containing N heterocycles is generated, and the atom economy is not high.
Two new synthetic routes are described in patent CN102666496A and patent CN 104610164A. The first preparation process includes the first reaction of methyl acetoacetate and sodium methoxide in methanol to eliminate active hydrogen and form salt, and the subsequent dropping 2-chloro-N, N-dimethyl acetamide into the reaction liquid for S reactionN2 to obtain 2- (N, N-dimethylaminocarbonylmethyl) methyl acetoacetate (compound 1), and then condensing the methyl acetoacetate with pentamidine hydrochloride in methanol in the presence of KOH to obtain an intermediate 2- (2-N-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl) -N, N-dimethylacetamide. In the synthesis process of the compound 1 in the route, sodium alkoxide which is not completely reacted reacts with 2-chloro-N, N-dimethylacetamide to generate impurities, so that the reaction product needs to be purified by chromatography, the industrial production is not facilitated, and the yield is low and is only 57.1%.
The second preparation methods described in patent CN102666496A and patent CN104610164A are shown below. Pentamidine hydrochloride is firstly neutralized with KOH to obtain pentamidine, then the pentamidine and dimethyl acetylsuccinate are condensed and hydrolyzed in the presence of excessive alkali to obtain carboxylic acid shown as a compound 1, then the compound 1 and ethyl chloroformate react in the presence of triethylamine to obtain an active ester compound 2, and the compound 2 and dimethylamine undergo amidation reaction to obtain an intermediate 2- (2-N-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl) -N, N-dimethylacetamide. The route uses ethyl chloroformate with high toxicity, the raw materials are not easy to obtain, and the compound has strong irritation to eyes, skin and mucosa, and is not beneficial to operation of workshop workers. Further, the secondary amine does not have high reactivity with compound 2, and it is difficult to obtain a satisfactory yield.
In summary, the best synthetic route of fimasartan reported in the prior patent is shown below. However, the synthesis yield of the compound 1 in the route is low, only 57.1%, and the reaction generates many impurities, which require chromatographic purification and are not favorable for industrial production. Secondly, a larger side chain, namely N- (trityl) -5- (4' -bromomethyl biphenyl-2-yl) tetrazole, is introduced into the synthetic route, the side chain has low reaction activity due to the influence of the steric hindrance of the trityl, raw materials are difficult to react completely, and the reaction requires longer time and is not beneficial to industrial production. Thirdly, a larger trityl protecting group needs to be removed in the last step, and the atom economy is not high.
Disclosure of Invention
Based on this, in order to overcome the defects of the prior art, the invention provides a novel synthesis method of fimasartan. The method can obviously improve the atom economy of the fimasartan synthesis, reduce the production cost and is more beneficial to industrial production.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
a method of synthesizing fimasartan, said method comprising the steps of:
(1) under the action of alkali, the structural formula is
Compound VI withStructural formula is
The compound VII is reacted in toluene to obtain the compound with the structural formula
The compound of (1); wherein R is methyl or ethyl and X is Cl, Br or I; wherein the molar ratio of the compound VI to the alkali is 1: 1-1: 1.5, and the molar ratio of the compound VI to the compound VII is 1: 1-1: 1.5;
(2) neutralizing pentamidine hydrochloride with alkali metal hydroxide in alcohol to release pentamidine, and reacting with compound V to obtain pentamidine
Compound IV of (1); wherein the molar ratio of the pentamidine hydrochloride to the alkali metal hydroxide is 1: 1-1: 1.5; the molar ratio of the pentamidine hydrochloride to the compound V is 1: 1-1: 1.5;
(3) the compound IV reacts with alkali in a mixed solvent composed of toluene and DMF, and then reacts with 2-cyano-4' -bromomethyl biphenyl to obtain the compound with the structural formula
Compound III of (1); the volume ratio of toluene to DMF in the mixed solvent is 1: 1-50: 1; the molar ratio of the compound IV to alkali and 2-cyano-4' -bromomethyl biphenyl is 1:1: 1-1: 2: 1.5;
(4) reacting the compound III with sodium azide in a solvent in the presence of a catalyst to obtain a compound with a structural formula
Compound II of (1); the molar ratio of the compound III to the catalyst to the sodium azide is 1:1: 1-1: 4: 4;
(5) the compound II and Lawson reagent are subjected to thioamidation reaction in a solvent to obtain a target product I, namely fimasartan, and the structural formula of the fimasartan is
The solvent is one or two of toluene, acetonitrile and tetrahydrofuran, and the molar ratio of the compound II to the Lawson reagent is 1: 0.5-1: 1.
In some of these embodiments, compound VI in step (1) is methyl acetoacetate or ethyl acetoacetate, preferably methyl acetoacetate; the compound VII is 2-chloro-N, N-dimethylacetamide, 2-bromo-N, N-dimethylacetamide or 2-iodo-N, N-dimethylacetamide, preferably 2-chloro-N, N-dimethylacetamide.
In some of these embodiments, the base in step (1) is sodium amide, lithium amide, sodium hydride, lithium hydride, or calcium hydride, preferably sodium amide.
In some of these embodiments, the molar ratio of compound VI to base in step (1) is 1:1.05 and the molar ratio of compound VI to compound VII is 1:1.
In some embodiments, the step (1) is: firstly, adding toluene and alkali, carrying out nitrogen protection, dropwise adding a compound VI at normal temperature, then carrying out heat preservation and stirring at 80-85 ℃ for 1 hour, stopping heating, dropwise adding a compound VII, and controlling the temperature to be 80-90 ℃; after finishing, carrying out heat preservation reaction for 3 hours at the temperature of 80-85 ℃; then, the mixture is concentrated to remove toluene, water is added into the residue and the residue is extracted by dichloromethane, the organic layer is washed by water and then by saturated saline, dried by anhydrous sodium sulfate, decolored by active carbon, concentrated to remove dichloromethane, and finally purified by chromatography to obtain the compound V.
In some of these embodiments, the alcohol in step (2) is methanol or ethanol.
In some of these embodiments, the alkali metal hydroxide in step (2) is sodium hydroxide or potassium hydroxide.
In some of these embodiments, the molar ratio of pentamidine hydrochloride to alkali metal hydroxide in step (2) is 1:1 and the molar ratio of pentamidine hydrochloride to compound V is 1:1.
In some embodiments, the step (2) is: dissolving pentamidine hydrochloride in alcohol, cooling to 0-5 ℃ by using an ice water bath, adding an alkali metal hydroxide, stirring for 30 minutes in the ice water bath, adding the compound V, stirring for 1 hour in the ice water bath, then carrying out heat preservation reaction for 9 hours at the temperature of 25-30 ℃, concentrating to remove the solvent, adding water, adjusting the pH value of the solution to about 4 by using concentrated hydrochloric acid in the ice water bath, and filtering to obtain a compound IV.
In some of these embodiments, the base in step (3) is lithium hydride, lithium amide, or lithium carbonate, preferably lithium hydride.
In some of the embodiments, the volume ratio of toluene to DMF in the mixed solvent in step (3) is 30: 1.
In some of these embodiments, the molar ratio of compound IV to base, 2-cyano-4' -bromomethylbiphenyl in step (3) is 1: 1.1: 1.
in some embodiments, in the step (3), the compound IV is dispersed in a mixed solvent composed of toluene and DMF, alkali is added at normal temperature under the protection of nitrogen, then the temperature is gradually raised to 80-85 ℃ for reaction for 1 hour, when the reaction solution is clear, 2-cyano-4' -bromomethyl biphenyl is added, and then the reaction is carried out at 80-85 ℃ for 24 hours under the condition of heat preservation. Concentrating to remove toluene, adding ice water into the concentrate while the concentrate is hot, rapidly stirring, precipitating solid, filtering, washing with water, drying, and recrystallizing with ethanol to obtain compound III.
In some of these embodiments, the solvent in step (4) is DMF or toluene.
In some of these embodiments, the catalyst in step (4) is zinc chloride or triethylamine hydrochloride, preferably zinc chloride.
In some of the embodiments, the molar ratio of the compound III to the zinc chloride and the sodium azide in the step (4) is 1:2: 3.
According to the preparation method of fimasartan, the molar ratio of the compound III to triethylamine hydrochloride and sodium azide in the step (4) is 1:3: 3.
In some embodiments, the step (4) is: adding a compound III, zinc chloride and DMF into a reaction bottle, heating to 80-85 ℃ under stirring, adding sodium azide in batches after a substrate is molten, then continuously heating to 125-130 ℃, and stirring for reacting for 28 hours; then cooling the reaction liquid to 80 ℃, adding water into the reaction liquid, and stirring and cooling to room temperature; adding dichloromethane to dissolve reaction liquid clearly, then adding sodium nitrite, cooling the solution to 0-5 ℃ in an ice water bath, and then dropwise adding concentrated hydrochloric acid until yellow smoke is generated in a reaction bottle; separating the organic layer, adding water to wash for three times, concentrating, and recrystallizing the residue with ethanol to obtain compound II;
or adding the compound III, triethylamine hydrochloride, sodium azide and toluene into a reaction bottle, and heating, stirring and refluxing for reaction for 30 hours under the protection of nitrogen; concentrating to remove toluene (which cannot be concentrated to dryness), adding water and dichloromethane, stirring to dissolve residues, then adding sodium nitrite, cooling the solution to 0-5 ℃ in an ice water bath, and dropwise adding concentrated hydrochloric acid until yellow smoke is generated in a reaction bottle; the organic layer was separated, washed three times with water, concentrated and the residue recrystallized from ethanol to give compound II.
In some of these embodiments, the molar ratio of compound II to lawson's reagent in step (5) is 1: 0.6.
In some embodiments, the step (5) is: and (3) reacting the compound II with a Lawson reagent in a solvent at the temperature of 80-110 ℃ for 3-6 hours in a heat preservation manner, concentrating to remove the solvent after the reaction is finished, adding dichloromethane into the concentrate, stirring the mixture at normal temperature for crystallization, filtering, washing, and recrystallizing tetrahydrofuran to obtain the target compound I.
Compared with the prior art, the invention has the following beneficial effects:
1. the preparation method of the fimasartan improves the synthesis method of the compound V, so that the yield of the compound V is greatly improved;
2. the preparation method of fimasartan provided by the invention uses 2-cyano-4 '-bromomethyl biphenyl to replace N- (trityl) -5- (4' -bromomethyl biphenyl-2-yl) tetrazole adopted in the prior art as a side chain, so that the removal of large-group trityl is avoided, the yield of N-alkylation reaction is improved, and the process cost is reduced to a great extent;
3. according to the preparation method of fimasartan, a recrystallization mode is adopted for aftertreatment, a column chromatography purification method adopted in the prior art is avoided, a large amount of silica gel and a large amount of solvent are avoided, the requirement of cleanness and environmental protection advocated by the state is met, and industrial production is facilitated;
4. the preparation method of fimasartan provided by the invention has the advantages of simple process, easily obtained raw materials and high total yield.
Detailed Description
The invention will be further described with reference to specific examples, which are not described herein as being applicable to the prior art. Specific examples of the present invention are given below, but the examples are only for the purpose of further describing the present invention in detail and do not limit the claims of the present invention.
The starting materials used in the following examples were all commercially available.
The synthetic route of the fimasartan is as follows:
preparation example 1 preparation of methyl 2- (N, N-dimethylaminocarbonylmethyl) acetoacetate (V) using sodium amide as base
81.92 g (2.10mol) of sodium amide is added into 2000ml of toluene under the protection of nitrogen, stirring is started, 232.22 g (2.00mol) of methyl acetoacetate is added dropwise into the mixture within 1 hour, and after the completion, the mixture is stirred and reacted for 1 hour at 80 ℃ to obtain white suspension. The heating was stopped, 243.14 g (2.00mol) of 2-chloro-N, N-dimethylacetamide was added dropwise over 1 hour, followed by reflux reaction for 3 hours. The reaction solution was concentrated to remove toluene, and then 1300 ml of dichloromethane and 1300 ml of purified water were added thereto, stirred and the organic layer was separated. The organic layer was concentrated, and purified by chromatography using a mixed solvent of ethyl acetate and n-hexane (v/v ═ 1:5) to give 370 g (yield 92%, purity 99.5%) of a pale yellow transparent oil.
1H-NMR(600MHz，CDCl3):δ2.40(s，1H)，2.91(s，3H)，3.04(s，3H)，3.10-2.75(m，2H)，3.75(s，1H)，4.15(m，1H)
Preparation example 2 preparation of methyl 2- (N, N-dimethylaminocarbonylmethyl) acetoacetate (V) Using lithium hydride as base
Under the protection of nitrogen, 16.70 g (2.10mol) of lithium hydride was added to 2000ml of toluene, stirring was started, 232.22 g (2.00mol) of methyl acetoacetate were added dropwise thereto over 1 hour, and after completion, the reaction was stirred at 80 ℃ for 1 hour to obtain a white suspension. The heating was stopped, 243.14 g (2.00mol) of 2-chloro-N, N-dimethylacetamide was added dropwise over 1 hour, followed by reflux reaction for 3 hours. The reaction solution was concentrated to remove toluene, and then 1300 ml of chloroform and 1300 ml of purified water were added thereto, stirred and the organic layer was separated. The organic layer was concentrated, and purified by chromatography using a mixed solvent of ethyl acetate and n-hexane (v/v ═ 1:5) to give 366.22 g (yield 91%, purity 99.3%) of a pale yellow transparent oil.
1H-NMR(600MHz，CDCl3):δ2.40(s，1H)，2.91(s，3H)，3.04(s，3H)，3.10-2.75(m，2H)，3.75(s，1H)，4.15(m，1H)
Preparation example 3 preparation of ethyl 2- (N, N-dimethylaminocarbonylmethyl) acetoacetate (V)
81.92 g (2.10mol) of sodium amide is added into 2000ml of toluene under the protection of nitrogen, then 260.28 g (2.00mol) of methyl acetoacetate is added into the mixture dropwise in 1 hour under the condition of stirring, and after the completion, the mixture is stirred and reacted for 1 hour at 80 ℃ to obtain white suspension. The heating was stopped, 243.14 g (2.00mol) of 2-chloro-N, N-dimethylacetamide was added dropwise over 1 hour, followed by reflux reaction for 3 hours. The reaction solution was concentrated to remove toluene, and then 1300 ml of chloroform and 1300 ml of purified water were added thereto, stirred and the organic layer was separated. The organic layer was concentrated, and purified by chromatography using a mixed solvent of ethyl acetate and n-hexane (v/v ═ 1:5) to give 344.38 g (yield 80%, purity 99.0%) of colorless transparent oil.
1H-NMR(600MHz，CDCl3):δ1.08(t，3H)，1.20(t，3H)，1.30(t，3H)，2.40(s，2H)，2.80(dd，1H)，3.04(dd，1H)，3.34(m，4H)，4.17(t，2H)，4.20(m，1H)
EXAMPLE 1 preparation of 2- (2-N-butyl-4-hydroxy-6-methylpyrimidin-5-yl) -N, N-dimethylacetamide (IV) using methyl 2- (N, N-dimethylaminocarbonylmethyl) acetoacetate
319.69 g (2.34mol) of pentamidine hydrochloride was dissolved in 2000mL of methanol, and then 93.58 g (2.34mol) of sodium hydroxide was added thereto, and the reaction was incubated in an ice-water bath for 30 minutes. 470.8 g (2.34mol) of methyl 2- (N, N-dimethylaminocarbonylmethyl) acetoacetate from preparation example 1 were added in one portion, and the mixture was reacted in an ice-water bath for 1 hour and then at 25 to 30 ℃ for 9 hours. After the reaction, the reaction mixture was concentrated to remove methanol, 900mL of purified water was added thereto, and the pH of the solution was adjusted to about 4 with concentrated hydrochloric acid, whereby a large amount of white solid was precipitated. Filtration and rinsing of the filter cake with 300mL of purified water yielded 421 g of a white solid (yield 71.7%, purity 99.6%).
1H-NMR(600MHz，CDCl3):δ0.85(t，3H)，1.30(m，2H)，1.65(m，2H)，2.25(s，3H)，2.53(t，2H)，2.89(s，3H)，3.09(s,3H)，3.49(s,2H)
Example 2: preparation of 2- (2-N-butyl-4-hydroxy-6-methylpyrimidin-5-yl) -N, N-dimethylacetamide (IV) using ethyl 2- (N, N-dimethylaminocarbonylmethyl) acetoacetate
319.69 g (2.34mol) of pentamidine hydrochloride was dissolved in 2000mL of ethanol, and then 93.58 g (2.34mol) of sodium hydroxide was added thereto, and the reaction was incubated in an ice-water bath for 30 minutes. 470.8 g (2.34mol) of ethyl 2- (N, N-dimethylaminocarbonylmethyl) acetoacetate from preparation example 3 were added in one portion, and the mixture was reacted in an ice-water bath for 1 hour and then at 25 to 30 ℃ for 9 hours. After the reaction, the reaction solution was concentrated to remove ethanol, 900mL of purified water was added thereto, and the pH of the solution was adjusted to about 4 with concentrated hydrochloric acid, whereby a large amount of white solid was precipitated. Filtration and rinsing of the filter cake with 300mL of purified water yielded 295.81 g of a white solid (yield 50.3%, purity 99.6%).
1H-NMR(600MHz，CDCl3):δ0.85(t，3H)，1.30(m，2H)，1.65(m，2H)，2.25(s，3H)，2.53(t，2H)，2.89(s，3H)，3.09(s，3H)，3.49(s，2H)
EXAMPLE 3 preparation of 2- (1- ((2 '-cyano- [1, 1' -biphenyl ] -4-yl) methyl) -2-butyl-4-methyl-6-carbonyl-1, 6-dihydropyrimidin-5-yl) -N, N-dimethylacetamide (III) with lithium hydride as base
362.57 g (1.443mol) of 2- (2-N-butyl-4-hydroxy-6-methylpyrimidin-5-yl) -N, N-dimethylacetamide obtained in example 1 is dispersed in a mixed solvent consisting of 2100mL of toluene and 70mL of DMF (v/v is 30:1), 12.62 g (1.587mol) of LiH is added into the reaction solution at normal temperature under the protection of nitrogen, the reaction solution is stirred for 1 hour, then the temperature is raised to 80-85 ℃ for continuous reaction for 1 hour, 392.70 g (1.443mol) of 2-cyano-4' -bromomethylbiphenyl is added after the reaction solution is clear, and then the reaction is carried out at 80-85 ℃ for 24 hours under the condition of heat preservation. The reaction solution was concentrated, and then 2000mL of ice water was added to the residue and stirred rapidly to precipitate a white solid. Filtration, washing of the filter cake with 1000mL of purified water and drying, and recrystallization of the resulting white solid from ethanol gave 532 g of a white solid (yield 83%, purity 99.5%).
1H-NMR(600MHz，CDCl3):δ0.89(t，3H),1.31～1.43(m，2H)，1.62～1.72(m，2H)，2.34(s，3H)，2.65(t，2H)，2.97(s，3H)，3.17(s，3H)，3.63(s，2H)，7.28(s，2H)，7.41～7.53(m，4H)，7.61～7.66(m，1H)，7.75(d，1H)。
EXAMPLE 4 preparation of 2- (1- ((2 '-cyano- [1, 1' -biphenyl ] -4-yl) methyl) -2-butyl-4-methyl-6-carbonyl-1, 6-dihydropyrimidin-5-yl) -N, N-dimethylacetamide (III) with lithium amide as base
362.57 g (1.443mol) of 2- (2-N-butyl-4-hydroxy-6-methylpyrimidin-5-yl) -N, N-dimethylacetamide obtained in example 1 was dispersed in a mixed solvent of 2100mL of toluene and 70mL of DMF (v/v. 30:1), and 36.45 g (1.587mol) of LiNH was added to the reaction mixture at room temperature under nitrogen protection2Stirring and reacting for 1 hour, heating to 80-85 ℃, continuing to react for 1 hour, adding 392.70 g (1.443mol) of 2-cyano-4' -bromomethyl biphenyl after the reaction solution is clear, and then keeping the temperature and reacting for 24 hours at 80-85 ℃. The reaction solution was concentrated, and then 2000mL of ice water was added to the residue and stirred rapidly to precipitate a white solid. Filtration, washing of the filter cake with 1000mL of purified water and subsequent drying, and recrystallization of the resulting white solid from ethanol gave 450.21 g of a white solid (yield 70.5%, purity 99.5%).
1H-NMR(600MHz，CDCl3):δ0.89(t，3H)，1.31～1.43(m，2H)，1.62～1.72(m，2H)，2.34(s，3H)，2.65(t，2H)，2.97(s，3H)，3.17(s，3H)，3.63(s，2H)，7.28(s，2H)，7.41～7.53(m，4H)，7.61～7.66(m，1H)，7.75(d，1H)。
EXAMPLE 5 preparation of 2- (1- ((2 '-cyano- [1, 1' -biphenyl ] -4-yl) methyl) -2-butyl-4-methyl-6-carbonyl-1, 6-dihydropyrimidin-5-yl) -N, N-dimethylacetamide (III) with lithium carbonate as base
362.57 g (1.443mol) of 2- (2-n-butyl-4-hydroxy-6-methylpyrimidine obtained in example 1Pyridin-5-yl) -N, N-dimethylacetamide was dispersed in a mixed solvent of 2100mL of toluene and 70mL of DMF (v/v ═ 30:1), and 117.26 g (1.587mol) of Li was added to the reaction mixture at room temperature under nitrogen protection2CO3And then heating to 80-85 ℃ for reaction for 1 hour. 392.70 g (1.443mol) of 2-cyano-4' -bromomethylbiphenyl were put into the reaction solution, and then the reaction was carried out at 80 to 85 ℃ for 48 hours. The reaction solution was concentrated, and then 2000mL of ice water was added to the residue and stirred rapidly to precipitate a white solid. Filtration, washing of the filter cake with 1000mL of purified water and subsequent drying, and recrystallization of the resulting white solid from ethanol gave 324.41 g of a white solid (yield 50.8%, purity 99.5%).
1H-NMR(600MHz，CDCl3):δ0.89(t，3H)，1.31～1.43(m，2H)，1.62～1.72(m，2H)，2.34(s，3H)，2.65(t，2H)，2.97(s，3H)，3.17(s，3H)，3.63(s，2H)，7.28(s，2H)，7.41～7.53(m，4H)，7.61～7.66(m，1H)，7.75(d，1H)。
EXAMPLE 6 preparation of 2- (1- ((2 '- (1H-tetrazol-5-yl) - [1, 1' -biphenyl ] -4-yl) methyl) -2-butyl-4-methyl-6-carbonyl-1, 6-dihydropyrimidin-5-yl) -N, N-dimethylacetamide (II) using zinc chloride as catalyst
442.55 g (1.00mol) of 2- (1- ((2 '-cyano- [1, 1' -biphenyl ] -4-yl) methyl) -2-butyl-4-methyl-6-carbonyl-1, 6-dihydropyrimidin-5-yl) -N, N-dimethylacetamide obtained in example 3 and 272.60 g (2.00mol) of zinc chloride were dissolved in 400mL of DMF, stirred and heated to 80-85 ℃ under nitrogen protection to dissolve the substrate, 195.03 g (3.00mol) of sodium azide were added in portions, and the mixture was reacted at 125-130 ℃ for 28 hours under heat preservation. The reaction solution was cooled to 80 ℃, 1000mL of purified water was added thereto, the mixture was stirred further and cooled to normal temperature, 3000mL of methylene chloride was added to dissolve the reaction solution, and 138.00 g (2.00mol) of sodium nitrite was added. And (3) placing the solution in an ice water bath, cooling to 0-5 ℃, and then dropwise adding concentrated hydrochloric acid into the solution until yellow smoke is generated in the reactor. The organic phase was separated and washed with 3X 1000mL of purified water and 200mL of saturated brine, respectively. The organic phase was concentrated to remove the solvent, the residue was dissolved by heating in 1500mL of ethanol and decolorized with 14 g of activated carbon, and the filtrate was recrystallized to obtain 388.50 g of a white solid (yield 80%, purity 99.5%).
1H-NMR(600MHz，d6-DMSO):δ0.82(t，3H)，1.22～1.34(m，2H)，1.50～1.60(m，2H)，2.16(s，3H)，2.61(t，2H)，2.84(s，3H)，3.10(s，3H)，3.55(s，2H)，5.28(s，2H)，7.08(s，4H)，7.53～7.71(m，4H)
EXAMPLE 7 preparation of 2- (1- ((2 '- (1H-tetrazol-5-yl) - [1, 1' -biphenyl ] -4-yl) methyl) -2-butyl-4-methyl-6-carbonyl-1, 6-dihydropyrimidin-5-yl) -N, N-dimethylacetamide (II) using triethylamine hydrochloride as catalyst
442.55 g (1.00mol) of 2- (1- ((2 '-cyano- [1, 1' -biphenyl ] -4-yl) methyl) -2-butyl-4-methyl-6-carbonyl-1, 6-dihydropyrimidin-5-yl) -N, N-dimethylacetamide obtained in example 3, 412.95 g (3.00mol) of triethylamine hydrochloride, 195.03 g (3.00mol) of sodium azide and 1500mL of toluene were charged in a 3000mL reaction flask, and the mixture was stirred under heating and reflux for 30 hours under nitrogen protection. The solvent was removed by concentration (not spin-drying to avoid explosion of unreacted sodium azide), and 1000mL of purified water and 3000mL of methylene chloride were added thereto, and the residue was dissolved by stirring, and 138.00 g (2.00mol) of sodium nitrite was then added thereto. And (3) placing the solution in an ice water bath, cooling to 0-5 ℃, and then dropwise adding concentrated hydrochloric acid into the solution until yellow smoke is generated in the reactor. The organic phase was separated and washed with 3X 1000mL of purified water and 200mL of saturated brine, respectively. The organic phase was concentrated to remove the solvent, the residue was dissolved by heating in 1500mL of ethanol and decolorized with 14 g of activated carbon, and the filtrate was recrystallized to obtain 330.19 g of a white solid (yield 68%, purity 99.5%).
1H-NMR(600MHz，d6-DMSO):δ0.82(t，3H)，1.22～1.34(m，2H)，1.50～1.60(m，2H)，2.16(s，3H)，2.61(t，2H)，2.84(s，3H)，3.10(s，3H)，3.55(s，2H)，5.28(s，2H)，7.08(s，4H)，7.53～7.71(m，4H)。
EXAMPLE 8 preparation of fimasartan (I) Using toluene as solvent
A3000 mL reaction flask was charged with 485.58 g (1.00mol) of 2- (1- ((2 ' - (1H-tetrazol-5-yl) - [1,1 ' -biphenyl ] -4-yl) methyl) -2-butyl-4-methyl-6-carbonyl-1, 6-dihydropyrimidin-5-yl) -N, N-dimethylacetamide obtained in example 6, 242.68 g (0.60mol) of Lawson's reagent and 2000mL of toluene, and refluxed for 3 hours. Concentrating under reduced pressure to remove toluene to obtain yellow viscous substance, adding 2000mL of dichloromethane, stirring at normal temperature to crystallize, precipitating a large amount of yellow solid, filtering, and washing the filter cake with 500mL of dichloromethane to obtain white solid. The white solid was dissolved in 1500mL of ethanol under reflux and decolorized with 15 g of activated carbon, and the filtrate was recrystallized to obtain 401.32 g of a white solid (yield 80%, purity 99.9%).
1H-NMR(600MHz，d6-DMSO):δ0.81(t，3H)，1.20～1.32(m，2H)，1.49～1.59(m，2H)，2.16(s，3H)，2.58(t，2H)，3.41(s，3H)，3.45(s，3H)，3.78(s，2H)，5.27(s，2H)，7.02～7.09(q，4H)，7.51～7.69(m，4H)。
EXAMPLE 9 preparation of fimasartan (I) Using acetonitrile as solvent
A3000 mL reaction flask was charged with 485.58 g (1.00mol) of 2- (1- ((2 ' - (1H-tetrazol-5-yl) - [1,1 ' -biphenyl ] -4-yl) methyl) -2-butyl-4-methyl-6-carbonyl-1, 6-dihydropyrimidin-5-yl) -N, N-dimethylacetamide obtained in example 6, 242.68 g (0.60mol) of Lawson's reagent and 1500mL of acetonitrile, and refluxed for 6 hours. Concentrating under reduced pressure to remove acetonitrile to obtain yellow viscous substance, adding 2000mL of dichloromethane, stirring at normal temperature to crystallize, separating out a large amount of yellow solid, filtering, and washing filter cake with 500mL of dichloromethane to obtain white solid. The white solid was dissolved in 1500mL of ethanol under reflux and decolorized with 15 g of activated carbon, and the filtrate was recrystallized to obtain 391.28 g of a white solid (yield 78%, purity 99.9%).
1H-NMR(600MHz，d6-DMSO):δ0.81(t，3H)，1.20～1.32(m，2H)，1.49～1.59(m，2H)，2.16(s，3H)，2.58(t，2H)，3.41(s，3H)，3.45(s，3H)，3.78(s，2H)，5.27(s，2H)，7.02～7.09(q，4H)，7.51～7.69(m，4H)。
EXAMPLE 10 preparation of fimasartan (I) Using tetrahydrofuran as solvent
A3000 mL reaction flask was charged with 485.58 g (1.00mol) of 2- (1- ((2 ' - (1H-tetrazol-5-yl) - [1,1 ' -biphenyl ] -4-yl) methyl) -2-butyl-4-methyl-6-carbonyl-1, 6-dihydropyrimidin-5-yl) -N, N-dimethylacetamide obtained in example 6, 242.68 g (0.60mol) of Lawson's reagent and 1500mL of THF, and refluxed for 6 hours. The THF was removed by concentration under reduced pressure to give a yellow viscous substance, 2000mL of dichloromethane was added and the mixture was crystallized at room temperature with stirring to precipitate a large amount of yellow solid, which was then filtered, and the filter cake was washed with 500mL of dichloromethane to give a white solid. The white solid was dissolved in 1500mL of ethanol under reflux and decolorized with 15 g of activated carbon, and the filtrate was recrystallized to obtain 381.25 g of a white solid (yield 76%, purity 99.9%).
1H-NMR(600MHz，d6-DMSO):δ0.81(t，3H)，1.20～1.32(m，2H)，1.49～1.59(m，2H)，2.16(s，3H)，2.58(t，2H)，3.41(s，3H)，3.45(s，3H)，3.78(s，2H)，5.27(s，2H)，7.02～7.09(q，4H)，7.51～7.69(m，4H)。
Industrial applicability
Compared with the preparation method of the prior patent, the preparation method of the invention obviously improves the production yield, thereby being very economical and easy for industrial application.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. A method for synthesizing fimasartan, which is characterized by comprising the following steps:
(1) under the action of alkali, the structural formula is
Of (a) a compound
And structural formula is
Of (a) a compound
Reacting in toluene to obtain the compound with the structural formula
Of (a) a compound
(ii) a Wherein R is methyl or ethyl, and X is Cl, Br or I; wherein the compound
The molar ratio of the compound to the alkali is 1: 1-1: 1.5, and the compound is
And compounds
The molar ratio of (A) to (B) is 1: 1-1: 1.5; the alkali in the step (1) is sodium amide, lithium amide, sodium hydride, lithium hydride or calcium hydride;
(2) neutralization of pentamidine hydrochloride with alkali metal hydroxide in alcohol releases pentamidine which is then reacted with compound
Reacting to obtain a compound with a structural formula
Of (a) a compound
(ii) a Wherein the molar ratio of the pentamidine hydrochloride to the alkali metal hydroxide is 1: 1-1: 1.5; pentamidine hydrochloride and compounds
The molar ratio of (A) to (B) is 1: 1-1: 1.5;
(3) compound (I)
Reacting with alkali in a mixed solvent consisting of toluene and DMF, and then reacting with 2-cyano-4' -bromomethyl biphenyl to obtain the compound with the structural formula
Of (a) a compound
(ii) a The volume ratio of toluene to DMF in the mixed solvent is 1: 1-50: 1; said compounds
The molar ratio of the alkali to the 2-cyano-4' -bromomethyl biphenyl is 1:1: 1-1: 2: 1.5;
(4) compound (I)
Reacting with sodium azide in a solvent in the presence of a catalyst to obtain a compound with a structural formula
Of (a) a compound
(ii) a Said compounds
The molar ratio of the catalyst to the sodium azide is 1:1: 1-1: 4: 4;
(5) compound (I)
Carrying out thioamidation reaction with Lawson reagent in solvent to obtain target product
I.e. fimasartan, the structural formula of which is
The solvent is one or two of toluene, acetonitrile and tetrahydrofuran, and the compound
The molar ratio of the lawson reagent to the lawson reagent is 1: 0.5-1: 1.
2. The method of synthesizing fimasartan according to claim 1, wherein the compound in step (1)
Is methyl acetoacetate or ethyl acetoacetate, compound
Is 2-chloro-N, N-dimethylacetamide, 2-bromo-N, N-dimethylacetamide or 2-iodo-N, N-dimethylacetamide.
3. The method of synthesizing fimasartan according to claim 1, wherein the compound in step (1)
The molar ratio of the compound to the alkali is 1:1.05
And compounds
Is 1:1.
4. The method for synthesizing fimasartan according to claim 1, wherein the step (1) is: adding toluene and alkali, nitrogen protection, and dripping the compound at normal temperature
Then stirring for 1 hour at the temperature of 80-85 ℃, stopping heating, and dropwise adding the compound
Controlling the temperature to be 80-90 ℃; after finishing, carrying out heat preservation reaction for 3 hours at the temperature of 80-85 ℃; then, the mixture was concentrated to remove toluene, and water was added to the residue to conduct extraction with methylene chlorideWashing the organic layer with water, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, decolorizing with activated carbon, concentrating to remove dichloromethane, and purifying with chromatography to obtain compound
。
5. The process for the synthesis of fimasartan according to claim 1, wherein the alcohol in step (2) is methanol or ethanol; the alkali metal hydroxide is sodium hydroxide or potassium hydroxide; the molar ratio of the pentamidine hydrochloride to the alkali metal hydroxide is 1:1, and the pentamidine hydrochloride and the compound
Is 1:1.
6. The method for synthesizing fimasartan according to claim 1, wherein the step (2) is: dissolving pentamidine hydrochloride in alcohol, cooling to 0-5 ℃ by using an ice water bath, adding alkali metal hydroxide, stirring for 30 minutes in the ice water bath, and adding a compound
Stirring for 1 hour in ice-water bath, then carrying out heat preservation reaction for 9 hours at the temperature of 25-30 ℃, concentrating to remove the solvent, adding water, adjusting the pH of the solution to about 4 by using concentrated hydrochloric acid in the ice-water bath, and filtering to obtain a compound
。
7. The method for synthesizing fimasartan according to claim 1, wherein the base in step (3) is lithium hydride, lithium amide or lithium carbonate, and the volume ratio of toluene to DMF in the mixed solvent is 30: 1; said compounds
The molar ratio of the alkali to the 2-cyano-4' -bromomethyl biphenyl is 1: 1.1: 1.
8. the method for synthesizing fimasartan according to claim 1, wherein step (3) is performed by first synthesizing the compound
Dispersing in a mixed solvent consisting of toluene and DMF, adding alkali at normal temperature under the protection of nitrogen, gradually heating to 80-85 ℃ for reaction for 1 hour, adding 2-cyano-4' -bromomethyl biphenyl after reaction liquid is clear, then preserving heat at 80-85 ℃ for reaction for 24 hours, concentrating to remove toluene, adding ice water into the concentrate while the concentrate is hot, rapidly stirring, precipitating solid, filtering, washing with water, drying, and recrystallizing with ethanol to obtain a compound
。
9. The method for synthesizing fimasartan according to claim 1, wherein the solvent in step (4) is DMF or toluene; the catalyst is zinc chloride or triethylamine hydrochloride; said compounds
The molar ratio of the zinc chloride to the sodium azide is 1:2: 3; said compounds
The molar ratio of the triethylamine hydrochloride to the sodium azide is 1:3: 3.
10. The method for synthesizing fimasartan according to claim 1, wherein the step (5) is: compound (I)
With Lawson's reagentReacting in a solvent at the temperature of 80-110 ℃ for 3-6 hours in a heat preservation manner, concentrating to remove the solvent after the reaction is finished, adding dichloromethane into the concentrate, stirring the mixture at normal temperature for crystallization, filtering, washing, and recrystallizing tetrahydrofuran to obtain the target compound
。
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