CN107973784A - A kind of synthetic method of Fimasartan - Google Patents
A kind of synthetic method of Fimasartan Download PDFInfo
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- CN107973784A CN107973784A CN201711139742.2A CN201711139742A CN107973784A CN 107973784 A CN107973784 A CN 107973784A CN 201711139742 A CN201711139742 A CN 201711139742A CN 107973784 A CN107973784 A CN 107973784A
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- 0 CCCC/C(/CC(Cc(cc1)ccc1-c1ccccc1-c1nnn[n]1)C1)=N\C(\C)=C(/CC(CCC(C)C)=O)\C1=* Chemical compound CCCC/C(/CC(Cc(cc1)ccc1-c1ccccc1-c1nnn[n]1)C1)=N\C(\C)=C(/CC(CCC(C)C)=O)\C1=* 0.000 description 5
- VOOQEOLOKRTHEB-UHFFFAOYSA-N Cc1c(CC(O)=O)c(O)nc(C)n1 Chemical compound Cc1c(CC(O)=O)c(O)nc(C)n1 VOOQEOLOKRTHEB-UHFFFAOYSA-N 0.000 description 1
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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
- C07D403/02—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
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Abstract
The invention discloses a kind of synthetic method of Fimasartan, is that compound VI and compound VII reacts to obtain compound V in toluene；Compound V is reacted with pentamidine salts hydrochlorate in the presence of alkali metal hydroxide obtains compound IV；Compound IV pulls out hydrogen in toluene and the DMF in the mixed solvent formed with lithium hydride, and N alkylated reactions then, which occur, with 2 cyano group, 4 ' bromomethylbiphenyl obtains compound III；Compound III and the sodium azide reaction in DMF under zinc chloride catalysis obtain compound II；Compound II occurs thioamides with lawesson reagent and reacts to obtain target product I.Present invention process is simple, easy to operate, and raw material is easy to get, economical and efficient, significantly reduces the production cost of Fimasartan, it is easy to accomplish industrialized production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, more particularly it relates to a kind of Fimasartan, that is, 2- butyl-
Thio formyl methyl -6- methyl-the 3- of 5- dimethylaminos [[2'- (1H-TETRAZOLE -5- bases) biphenyl -4- bases] methyl] pyrimidine -4
The new synthetic method of (3H) -one.
Background technology
Fimasartan is the excellent Angiotensin Ⅱ receptor antagonist of a antihypertensive effect (ARB) class hypotensive agent, tool
There is the structural formula shown in formula 1.
Synthetic route in patent WO9608476A1 is using penta amidine as starting material and diacetyl succinic acid diethyl ester condensation
Into 2- normal-butyl -5- ethoxy carbonyl methyl -4- hydroxyl -6- methylpyrimidines (compound 1), compound 1 under NaH effects with
4- [2 '-triphenyl -5- tetrazoles] phenyl-benzyl bromine carries out N- alkylated reactions, obtains 2- normal-butyl -5- ethyoxyl carbonyl first
Base -6- methyl -3- [[2 '-(N- trityl group -5- tetrazole radicals) -4- xenyls] methyl] -4- pyrimidones (compound 2), change
Compound 2 obtains 2- normal-butyl -5- acetic acid -6- methyl -3- [[2 '-(N- trityl group -5- tetrazole radicals) -4- biphenyl through hydrolysis
Base] methyl] -4- pyrimidones (compound 3), compound 3 in the presence of EDCI, HOBt and N-methylmorpholine with dimethylamine occur
Amidation process generation 2- normal-butyl -5- dimethylaminocarbonylmethyl -6- methyl -3- [[2 '-(N- trityl groups -5- four
Oxazolyl) -4- xenyls] methyl] -4- pyrimidones (compound 4), compound 4 carries out thiocarbonylating reaction with lawesson reagent again
Obtain the thio formyl methyl -6- methyl -3- of 2- normal-butyl -5- dimethylaminos [[2 '-(N- trityl group -5- tetrazoles) -
4- xenyls] methyl] -4- pyrimidones (compound 5), compound 5 obtains Fimasartan with sour Deprotection.The synthetic route
It is as follows.The synthetic route includes six reactions steps, and the processing of intermediate and end-product is relatively complicated, compound 1
Carry out inevitably introducing O- alkylate by-products in N- alkylation process under NaH effects, which is chemical combination
The isomer of thing 2, is only 1.28% so causing total recovery relatively low.
Patent CN1558906A improves the synthesis step in patent WO9608476A1.By N- alkylation steps
The hydrogen reagent that pulls out be changed to LiH, substantially increase the selectivity of N- alkylated reactions, overall yield brings up to 28.2%.But carboxylic
The amidation process of acid has selected DCC to react another product dicyclohexylurea (DCU) of generation in general organic phase as condensing agent
Solubility very little but have some slightly solubles, therefore by some common purification process, such as recrystallization, column chromatography are difficult
It is removed very thorough.
Synthetic method in Korean Patent 10-2002-0061850 is as follows, pentamidine salts hydrochlorate and diacetyl succinic acid two
Ethyl ester hydrolysis generation 2- (2- normal-butyl -4- hydroxyl -6- methylpyrimidines -5- while ring closure reaction occurs under the action of alkali
Base) acetic acid (compound 1), compound 1 again DCC catalysis under with dimethylamine carry out amidation process synthesize 2- (2- normal-butyls-
4- hydroxyl -6- methylpyrimidine -5- bases)-n,N-dimethylacetamide (compound 2), compound 2 again alkali effect under with 4-
[2 '-triphenyl -5- tetrazoles] phenyl-benzyl bromine reaction obtain 2- normal-butyl -5- dimethylaminocarbonylmethyl -6- methyl -
3- [[2 '-(N- trityl group -5- tetrazole radicals) -4- xenyls] methyl] -4- pyrimidones (compound 4), compound 4 is through sulphur
In generation, is carbonylated, and Fimasartan is obtained after Deprotection.Although the more above-mentioned route of the route reduces single step reaction, still need
DCC condensing agents are used, the purification to compound 2 brings difficulty.
The defects of for accessory substance urea is produced, patent CN104478811A propose a kind of new by carboxy amidation
Method, it is as follows.2- (2- normal-butyl -4- hydroxyl -6- methylpyrimidine -5- bases) acetic acid and carbonyl dimidazoles are in organic base
In the presence of reaction generation compound 1, then compound 1 again with dimethylamine react, obtain amidated products 2- (2- normal-butyls -4-
Hydroxyl -6- methyl-pvrimidine -5- bases)-DMAC N,N' dimethyl acetamide.Although the synthetic route avoids the generation of accessory substance urea,
But carbonyl dimidazoles is expensive, intermediate 2- (2- normal-butyl -4- hydroxyl -6- methyl-pvrimidine -5- bases)-N can be caused,
The production cost of N- dimethylacetylamides is higher, and the reaction will consume the larger carbonyl dimidazoles of molecular weight, and produces
Largely the reaction waste of the heterocycle containing N, Atom economy be not high.
Two new synthetic routes are described in patent CN102666496A and patent CN104610164A.First prepares
Method is as follows, and methyl acetoacetate and sodium methoxide react in methyl alcohol first removes active hydrogen into salt, then that 2- is chloro-
DMAC N,N' dimethyl acetamide carries out S in being added dropwise into above-mentioned reaction solutionN2- (N, N- dimethylaminocarbonylmethyl) is made in 2 reactions
Methyl acetoacetate (compound 1), then in the presence of KOH, is condensed into intermediate 2- (2- with pentamidine salts hydrochlorate in methyl alcohol
Normal-butyl -4- hydroxyl -6- methyl-pvrimidine -5- bases)-DMAC N,N' dimethyl acetamide.In the route in the building-up process of compound 1
The complete sodium alkoxide of unreacted can produce impurity with the chloro- n,N-dimethylacetamide reactions of 2-, so the reaction product needs to pass through
Chromatography purity, is unfavorable for industrialized production, and yield is relatively low, and only 57.1%.
The second preparation method described in patent CN102666496A and patent CN104610164A is as follows.Penta amidine
Hydrochloride first neutralizes to obtain penta amidine with KOH, and then the condensation water in the presence of excess base solves penta amidine with acetyl dimethyl succinate
To the carboxylic acid shown in compound 1, then compound 1 is reacted with ethyl chloroformate in the presence of triethylamine obtains active ester chemical combination
Thing 2, compound 2 again with dimethylamine occur amidation process obtain intermediate 2- (2- normal-butyl -4- hydroxyl -6- methyl-pvrimidines -
5- yls)-DMAC N,N' dimethyl acetamide.The route uses highly toxic ethyl chloroformate, and raw material is not easy to obtain, and the chemical combination
Thing has strong impulse to eyes, skin and mucous membrane, is unfavorable for shop worker's operation.Moreover secondary amine is to the anti-of compound 2
Should be active not high, it is more difficult to obtain satisfied yield.
In conclusion the optimal synthetic route of the Fimasartan of existing patent report is as follows.But in the route
The synthetic yield of compound 1 is relatively low, and only 57.1%, and it is more, it is necessary to which chromatography purity, is unfavorable for work to react the impurity produced
Industry metaplasia is produced.Secondly, which introduces a larger side chain, i.e. (4 '-bromomethyl joins N- (trityl) -5-
Benzene -2- bases) tetrazole, the side chain is due to the influence of the steric hindrance of trityl, and reactivity is not high, the more difficult reaction of raw material
Completely, it is and longer the time required to the reaction, it is unfavorable for industrialized production.Again, final step need to slough again one compared with
Big trityl-protecting group, Atom economy be not high.
The content of the invention
Based on this, the defects of in order to overcome the above-mentioned prior art, the present invention provides a kind of new synthesis of Fimasartan
Method.The method can significantly improve the Atom economy of Fimasartan synthesis, reduce production cost, be more favorable for industry
Metaplasia is produced.
In order to realize foregoing invention purpose, this invention takes following technical scheme：
A kind of synthetic method of Fimasartan, the described method comprises the following steps：
(1) under the action of alkali, structural formula isCompound VI be with structural formulaCompound VII reacted in toluene, obtaining structural formula isCompound V；Its
Middle R is methyl or ethyl, and X is Cl, Br or I；Wherein, the molar ratio of the compound VI and alkali are 1:1~1:1.5, institute
The molar ratio for stating compound VI and compound VII is 1:1~1:1.5；
(2) pentamidine salts hydrochlorate in alcohol with alkali metal hydroxide and discharging pentamidinum, it is then anti-with compound V
Should obtain structural formula isCompound IV；Wherein, the pentamidine salts hydrochlorate and alkali metal hydrogen-oxygen
The molar ratio of compound is 1:1~1:1.5；The molar ratio of pentamidine salts hydrochlorate and compound V are 1:1~1:1.5；
(3) compound IV is first reacted in toluene and the DMF in the mixed solvent formed with alkali, then with 2- cyano group -4 '-bromine first
Base biphenyl reacts to obtain structural formulaCompound III；The in the mixed solvent toluene and DMF
Volume ratio be 1:1~50:1；The molar ratio of the compound IV and alkali, 2- cyano group -4 '-bromomethylbiphenyl is 1:1:1~1:
2:1.5；
(4) in the presence of a catalyst, obtain structural formula with reaction of sodium azide in a solvent is compound IIICompound II；The molar ratio of the compound III and catalyst, sodium azide is 1:1:1
~1:4:4；
(5) compound II and lawesson reagent occur thioamides and react to obtain target product I in a solvent, as non-
Ma Shatan, its structural formula areThe solvent is toluene, acetonitrile, one kind in tetrahydrofuran or two
Kind, the molar ratio of the compound II and lawesson reagent are 1:0.5~1:1.
In wherein some embodiments, compound VI described in step (1) is methyl acetoacetate or acetoacetate second
Ester, is preferably methyl acetoacetate；Compound VII is the chloro- DMAC N,N' dimethyl acetamides of 2-, the bromo- DMAC N,N' dimethyl acetamides of 2-
Or the iodo- n,N-dimethylacetamide of 2-, it is preferably the chloro- n,N-dimethylacetamide of 2-.
In wherein some embodiments, alkali described in step (1) is Sodamide, lithium amide, sodium hydride, lithium hydride or hydrogen
Change calcium, be preferably Sodamide.
In wherein some embodiments, the molar ratio of compound VI and alkali described in step (1) is 1:1.05, describedization
The molar ratio of compound VI and compound VII is 1:1.
In wherein some embodiments, the step (1) is：Toluene and alkali are first added, nitrogen is protected, and is added dropwise under room temperature
Compound VI, when then insulated and stirred 1 is small at 80~85 DEG C, stops heating, is added dropwise compound VII, control temperature 80~
Between 90 DEG C；Finish, when insulation reaction 3 is small at 80~85 DEG C；Then concentration removes toluene, in residue plus water and with two
Chloromethanes extracts, and organic layer is first washed and then saturated common salt water washing, anhydrous sodium sulfate drying, activated carbon decolorizing, concentration remove again
Dichloromethane is removed, last chromatography purity obtains compound V.
In wherein some embodiments, alcohol described in step (2) is methanol or ethanol.
In wherein some embodiments, alkali metal hydroxide described in step (2) is sodium hydroxide or potassium hydroxide.
In wherein some embodiments, the molar ratio of pentamidine salts hydrochlorate and alkali metal hydroxide is described in step (2)
1:1, the molar ratio of the pentamidine salts hydrochlorate and compound V are 1:1.
In wherein some embodiments, the step (2) is：Pentamidine salts hydrochlorate is first dissolved in alcohol, and is cooled to ice-water bath
0~5 DEG C, alkali metal hydroxide is then added, is stirred in ice-water bath 30 minutes, compound V is then added, is stirred in ice-water bath
Mix 1 it is small when, when then insulation reaction 9 is small at 25~30 DEG C, concentration remove solvent, add water, in ice-water bath with concentrated hydrochloric acid will
PH value of solution is adjusted to 4 or so, and filtering, obtains compound IV.
In wherein some embodiments, alkali described in step (3) is lithium hydride, lithium amide or lithium carbonate, is preferably hydrogenated
Lithium.
In wherein some embodiments, the volume ratio of in the mixed solvent toluene and DMF described in step (3) are 30:1.
In wherein some embodiments, compound IV described in step (3) and alkali, 2- cyano group -4 '-bromomethylbiphenyl
Molar ratio is 1：1.1：1.
In wherein some embodiments, compound IV is first dispersed in the mixing of toluene and DMF compositions by the step (3)
In solvent, nitrogen protection, adds alkali under room temperature, be then progressively warming up to 80~85 DEG C of reactions 1 it is small when, after reaction solution dissolved clarification,
2- cyano group -4 '-bromomethylbiphenyl is added, when then insulation reaction 24 is small at 80~85 DEG C.Concentration remove toluene, while hot to
Frozen water is added in concentrate quickly to stir, solid is separated out, filters, wash, and dry, ethyl alcohol recrystallization obtains compound III.
In wherein some embodiments, solvent described in step (4) is DMF or toluene.
In wherein some embodiments, catalyst described in step (4) is zinc chloride or triethylamine hydrochloride, is preferably
Zinc chloride.
In wherein some embodiments, compound III and the molar ratio of zinc chloride, sodium azide are described in step (4)
1:2:3。
The preparation method of the Fimasartan, compound III described in step (4) and triethylamine hydrochloride, sodium azide
Molar ratio be 1:3:3.
In wherein some embodiments, the step (4) is：First compound III, zinc chloride and DMF are added and reacted
Bottle, 80~85 DEG C are warming up under then stirring, and sodium azide is put into batches after substrate melting, then proceed to be warming up to 125~
130 DEG C, when stirring reaction 28 is small；Then reaction solution is cooled to 80 DEG C, water is added into reaction solution, and stir and be cooled to room temperature；
Dichloromethane is added by reaction solution dissolved clarification, sodium nitrite is then added, above-mentioned solution is cooled to 0~5 DEG C in ice-water bath,
Then concentrated hydrochloric acid is added dropwise thereto until there is the generation of yellow cigarette in reaction bulb；Organic layer is separated, adds water washing three times, is concentrated, it is residual
Thing is stayed to obtain compound II with ethyl alcohol recrystallization；
Or compound III, triethylamine hydrochloride, sodium azide and toluene are added into reaction bulb, under nitrogen protection, add
When thermal agitation back flow reaction 30 is small；Concentration removes toluene (cannot concentrate dry), adds water and dichloromethane stirring and dissolving residual thereto
Thing is stayed, then adds sodium nitrite, above-mentioned solution is cooled to 0~5 DEG C in ice-water bath, concentrated hydrochloric acid is added dropwise until reaction bulb
In have yellow cigarette generation；Organic layer is separated, adds water washing three times, is concentrated, residue obtains compound II with ethyl alcohol recrystallization.
In wherein some embodiments, the molar ratio of compound II and lawesson reagent described in step (5) is 1:0.6.
In wherein some embodiments, the step (5) is：Compound II and lawesson reagent in a solvent, 80~
When insulation reaction 3~6 is small at 110 DEG C, after reaction, concentration remove solvent, then into concentrate add dichloromethane in
Crystalline substance is stirred under room temperature, is filtered, washing, tetrahydrofuran recrystallizes to obtain target compound I.
Compared with prior art, the invention has the advantages that：
1st, the preparation method of Fimasartan provided by the invention improves the synthetic method of compound V so that compound V
Yield greatly improve；
2nd, the preparation method of Fimasartan provided by the invention has used 2- cyano group -4 '-bromomethylbiphenyl to replace existing work
N- (trityl) -5- (4 '-bromomethylbiphenyl -2- bases) tetrazole that skill uses as side chain, not only avoids macoradical three
Benzyl is sloughed, and improves the yield of N- alkylated reactions, largely reduces process costs；
3rd, the preparation method of Fimasartan provided by the invention, post processing is a large amount of by the way of recrystallization, avoids existing
There is the method that the column chromatography that method largely uses purifies, avoid the use of a large amount of silica gel and solvent, meet country and advocate energetically
Clean environment firendly requirement, be easy to industrialized production；
4th, the preparation method technique of Fimasartan provided by the invention is simple, and raw material is easy to get, and total recovery is high.
Embodiment
The present invention is further discussed below with reference to specific embodiment, the present invention does not address part and is suitable for the prior art.Under
Face provides the specific embodiment of the present invention, but embodiment is not intended to limit the present invention merely to the present invention is described in further detail
Claim.
Raw material used in following embodiments, derives from commercially available.
The synthetic route of Fimasartan of the present invention is as follows：
Preparation example 1, make alkali preparation 2- (N, N- dimethylaminocarbonylmethyl) methyl acetoacetate (V) with Sodamide
Under nitrogen protection, 81.92 grams of (2.10mol) Sodamides are added in 2000 milliliters of toluene, stirring are opened, 1
232.22 grams of (2.00mol) methyl acetoacetates are added dropwise in hour thereto, finish, when stirring reaction 1 is small at 80 DEG C, obtain
White suspension.Stop heating, it is interior when 1 is small that 243.14 grams of chloro- N of (2.00mol) 2-, N- dimethylacetamides are added dropwise thereto
Amine, be then refluxed for reaction 3 it is small when.Reaction solution is concentrated and removes toluene, then add thereto 1300 milliliters of dichloromethane and
1300 milliliters of pure water, stir and separate organic layer.Organic layer is concentrated, and with ethyl acetate and the mixed solvent of n-hexane
(v/v=1:5) pale yellow transparent oil 370 grams (yield 92%, purity 99.5%) is obtained by chromatography purity.
1H-NMR (600MHz, CDCl3):δ 2.40 (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, make alkali preparation 2- (N, N- dimethylaminocarbonylmethyl) methyl acetoacetate (V) with lithium hydride
Under nitrogen protection, 16.70 grams of (2.10mol) lithium hydrides are added in 2000 milliliters of toluene, stirring are opened, 1
232.22 grams of (2.00mol) methyl acetoacetates are added dropwise in hour thereto, finish, when stirring reaction 1 is small at 80 DEG C, obtain
White suspension.Stop heating, it is interior when 1 is small that 243.14 grams of chloro- N of (2.00mol) 2-, N- dimethylacetamides are added dropwise thereto
Amine, be then refluxed for reaction 3 it is small when.Reaction solution is concentrated and removes toluene, then adds 1300 milliliters of chloroforms and 1300 millis thereto
Pure water is risen, stirs and separates organic layer.Organic layer is concentrated, and with ethyl acetate and the mixed solvent (v/v=of n-hexane
1:5) pale yellow transparent oil 366.22 grams (yield 91%, purity 99.3%) is obtained by chromatography purity.
1H-NMR (600MHz, CDCl3):δ 2.40 (s, 1H), 2.91 (s, 3H), 3.04 (s, 3H), 3.10-2.75 (m,
2H), 3.75 (s, 1H), 4.15 (m, 1H)
The preparation of preparation example 3,2- (N, N- dimethylaminocarbonylmethyl) ethyl acetoacetates (V)
Under nitrogen protection, 81.92 grams of (2.10mol) Sodamides are added in 2000 milliliters of toluene, under then stirring,
It is interior when 1 is small that 260.28 grams of (2.00mol) methyl acetoacetates are added dropwise thereto, finish, when stirring reaction 1 is small at 80 DEG C,
Obtain white suspension.Stop heating, it is interior when 1 is small that 243.14 grams of (2.00mol) 2- chloro- N, N- dimethyl second are added dropwise thereto
Acid amides, be then refluxed for reaction 3 it is small when.Reaction solution is concentrated and removes toluene, then adds 1300 milliliters of chloroforms and 1300 thereto
Milliliter pure water, stirs and separates organic layer.Organic layer is concentrated, and with ethyl acetate and the mixed solvent (v/v of n-hexane
=1:5) 344.38 grams of colorless transparent oil (yield 80%, purity 99.0%) is obtained by chromatography purity.
1H-NMR (600MHz, CDCl3):δ 1.08 (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)
Embodiment 1, utilize 2- (N, N- dimethylaminocarbonylmethyl) methyl acetoacetate preparation 2- (2- normal-butyls -4-
Hydroxyl -6- methylpyrimidine -5- bases)-DMAC N,N' dimethyl acetamide (IV)
319.69 grams of (2.34mol) pentamidine salts hydrochlorates are dissolved in 2000mL methanol, then add 93.58 grams thereto
(2.34mol) sodium hydroxide, insulation reaction 30 minutes in ice-water bath.Then it is disposable to add 470.8 grams (2.34mol) preparation
2- (N, N- dimethylaminocarbonylmethyl) methyl acetoacetate obtained in example 1, when reaction 1 is small in ice-water bath, then 25
When reaction 9 is small at~30 DEG C.After reaction, reaction solution is concentrated and removes methanol, then add 900mL pure water thereto,
And solution pH value is transferred to 4 or so with concentrated hydrochloric acid, there are a large amount of white solids to separate out.Filtering, the filter cake pure water wash of 300mL,
Obtain 421 grams of white solids (yield 71.7%, purity 99.6%).
1H-NMR (600MHz, CDCl3):δ 0.85 (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)
Embodiment 2：2- (2- normal-butyls -4- are prepared using 2- (N, N- dimethylaminocarbonylmethyl) ethyl acetoacetate
Hydroxyl -6- methylpyrimidine -5- bases)-DMAC N,N' dimethyl acetamide (IV)
319.69 grams of (2.34mol) pentamidine salts hydrochlorates are dissolved in 2000mL ethanol, then add 93.58 grams thereto
(2.34mol) sodium hydroxide, insulation reaction 30 minutes in ice-water bath.Then it is disposable to add 470.8 grams (2.34mol) preparation
2- (N, N- dimethylaminocarbonylmethyl) ethyl acetoacetate obtained in example 3, when reaction 1 is small in ice-water bath, then 25
When reaction 9 is small at~30 DEG C.After reaction, reaction solution is concentrated and removes ethanol, then add 900mL pure water thereto,
And solution ph is transferred to 4 or so with concentrated hydrochloric acid, there are a large amount of white solids to separate out.Filtering, the filter cake pure water wash of 300mL,
Obtain 295.81 grams of white solids (yield 50.3%, purity 99.6%).
1H-NMR (600MHz, CDCl3):δ 0.85 (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)
Embodiment 3, done with lithium hydride alkali prepare 2- (1- ((2 '-cyano group-[1,1 '-biphenyl] -4- bases) methyl) -2- butyl -
4- methyl -6- carbonyl -1,6- dihydro-pyrimidin -5- bases)-DMAC N,N' dimethyl acetamide (III)
2- (2- normal-butyl -4- hydroxyl -6- methylpyrimidines-the 5- that 362.57 grams of (1.443mol) embodiments 1 are obtained
Base)-DMAC N,N' dimethyl acetamide be scattered in 2100mL toluene and 70mL DMF composition mixed solvent (v/v=30:1) in, nitrogen
Gas shielded, 12.62 grams of (1.587mol) LiH are added under room temperature into reaction solution, when stirring reaction 1 is small, then heat to 80~
85 DEG C the reaction was continued 1 it is small when, 392.70 grams of (1.443mol) 2- cyano group -4 '-bromomethylbiphenyls are put into after question response liquid dissolved clarification,
Then when insulation reaction 24 is small at 80~85 DEG C.Reaction solution is concentrated, 2000mL frozen water and fast is then added into residue
Speed stirring, separates out white solid.Filtering, the filter cake pure water washings of 1000mL, are then dried, gained white solid ethanol
Recrystallization, obtains 532 grams of white solids (yield 83%, purity 99.5%).
1H-NMR (600MHz, CDCl3):δ 0.89 (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).
Embodiment 4, done with lithium amide alkali prepare 2- (1- ((2 '-cyano group-[1,1 '-biphenyl] -4- bases) methyl) -2- butyl -
4- methyl -6- carbonyl -1,6- dihydro-pyrimidin -5- bases)-DMAC N,N' dimethyl acetamide (III)
2- (2- normal-butyl -4- hydroxyl -6- methylpyrimidines-the 5- that 362.57 grams of (1.443mol) embodiments 1 are obtained
Base)-DMAC N,N' dimethyl acetamide be scattered in 2100mL toluene and 70mL DMF composition mixed solvent (v/v=30:1) in, nitrogen
Gas shielded, 36.45 grams of (1.587mol) LiNH are added under room temperature into reaction solution2, when stirring reaction 1 is small, then heat to 80
~85 DEG C the reaction was continued 1 it is small when, 392.70 grams of (1.443mol) 2- cyano group -4 '-bromomethyl connection is put into after question response liquid dissolved clarification
Benzene, when then insulation reaction 24 is small at 80~85 DEG C.Reaction solution is concentrated, 2000mL frozen water is then added into residue
And quickly stir, separate out white solid.Filtering, the filter cake pure water washings of 1000mL, are then dried, and gained white solid is used
Ethyl alcohol recrystallization, obtains 450.21 grams of white solids (yield 70.5%, purity 99.5%).
1H-NMR (600MHz, CDCl3):δ 0.89 (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).
Embodiment 5, done with lithium carbonate alkali prepare 2- (1- ((2 '-cyano group-[1,1 '-biphenyl] -4- bases) methyl) -2- butyl -
4- methyl -6- carbonyl -1,6- dihydro-pyrimidin -5- bases)-DMAC N,N' dimethyl acetamide (III)
2- (2- normal-butyl -4- hydroxyl -6- methylpyrimidines-the 5- that 362.57 grams of (1.443mol) embodiments 1 are obtained
Base)-DMAC N,N' dimethyl acetamide be scattered in 2100mL toluene and 70mL DMF composition mixed solvent (v/v=30:1) in, nitrogen
Gas shielded, 117.26 grams of (1.587mol) Li are added under room temperature into reaction solution2CO3, it is small to then heat to 80~85 DEG C of reactions 1
When.392.70 grams of (1.443mol) 2- cyano group -4 '-bromomethylbiphenyls are put into reaction solution, are then kept the temperature at 80~85 DEG C
React 48 it is small when.Reaction solution is concentrated, 2000mL frozen water is then added into residue and is quickly stirred, separates out white solid.
Filtering, the filter cake pure water washings of 1000mL, are then dried, gained white solid ethyl alcohol recrystallization, obtain 324.41 grams in vain
Color solid (yield 50.8%, purity 99.5%).
1H-NMR (600MHz, CDCl3):δ 0.89 (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).
Embodiment 6, make catalyst preparation 2- (1- ((2 '-(1H-TETRAZOLE -5- bases)-[1,1 '-biphenyl] -4- using zinc chloride
Base) methyl) -2- butyl -4- methyl -6- carbonyl -1,6- dihydro-pyrimidin -5- bases)-DMAC N,N' dimethyl acetamide (II)
By the 2- obtained in 442.55 grams of (1.00mol) embodiments 3 (1- ((2 '-cyano group-[1,1 '-biphenyl] -4- bases) first
Base) -2- butyl -4- methyl -6- carbonyl -1,6- dihydro-pyrimidin -5- bases)-DMAC N,N' dimethyl acetamide and 272.60 grams
(2.00mol) zinc chloride is dissolved in 400mL DMF, and under nitrogen protection, stirring, which is warming up to 80~85 DEG C, makes substrate dissolved clarification, in batches
195.03 grams of (3.00mol) sodium azide are put into, when then insulation reaction 28 is small at 125~130 DEG C.Reaction solution is cooled down
To 80 DEG C, 1000mL pure water is added thereto, continues stirring and is down to room temperature, and adding 3000mL dichloromethane makes reaction solution molten
Clearly, then 138.00 grams of (2.00mol) sodium nitrites.Above-mentioned solution is placed in ice-water bath and is cooled to 0~5 DEG C, then to it
Middle dropwise addition concentrated hydrochloric acid is until there is tobacco generation in reactor.Separate organic phase, then respectively with 3 × 1000mL pure water with
200mL saturated common salt water washings.Organic phase concentration removes solvent, and residue adds 1500mL ethanol and dissolves by heating and use 14 grams
Activated carbon decolorizing, filtrate are recrystallized to give 388.50 grams of white solids (yield 80%, purity 99.5%).
1H-NMR (600MHz, d6-DMSO):δ 0.82 (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)
Embodiment 7, make catalyst preparation 2- (1- ((2 '-(1H-TETRAZOLE -5- bases)-[1,1 '-connection using triethylamine hydrochloride
Benzene] -4- bases) methyl) -2- butyl -4- methyl -6- carbonyl -1,6- dihydro-pyrimidin -5- bases)-DMAC N,N' dimethyl acetamide (II)
In the reaction bulb of a 3000ml add 442.55 grams of (1.00mol) embodiments 3 in obtain 2- (1- ((2 '-
Cyano group-[1,1 '-biphenyl] -4- bases) methyl) -2- butyl -4- methyl -6- carbonyl -1,6- dihydro-pyrimidin -5- bases)-N, N- diformazans
Yl acetamide, 412.95 grams of (3.00mol) triethylamine hydrochlorides, 195.03 grams of (3.00mol) sodium azide and 1500mL first
Benzene, under nitrogen protection, when heating stirring back flow reaction 30 is small.Concentration removes solvent and (not be spin-dried for, be folded in order to avoid unreacted is complete
Sodium nitride explodes), and adding 1000mL pure water and the stirring of 3000mL dichloromethane thereto dissolves residue, Ran Houxiang
Wherein add 138.00 grams of (2.00 mol) sodium nitrites.Above-mentioned solution is placed in ice-water bath and is cooled to 0~5 DEG C, Ran Houxiang
Concentrated hydrochloric acid is wherein added dropwise until there is tobacco generation in reactor.Separate organic phase, then respectively with 3 × 1000mL pure water with
200 mL saturated common salt water washings.Organic phase concentration removes solvent, and residue adds 1500mL ethanol and dissolves by heating and use 14 grams
Activated carbon decolorizing, filtrate are recrystallized to give 330.19 grams of white solids (yield 68%, purity 99.5%).
1H-NMR (600MHz, d6-DMSO):δ 0.82 (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).
Embodiment 8, with toluene prepare Fimasartan (I) as solvent
In the reaction bulb of a 3000mL add 485.58 grams of (1.00mol) embodiments 6 in obtain 2- (1- ((2 '-
(1H-TETRAZOLE -5- bases)-[1,1 '-biphenyl] -4- bases) methyl) -2- butyl -4- methyl -6- carbonyl -1,6- dihydro-pyrimidins -5-
Base)-n,N-dimethylacetamide, 242.68 grams of (0.60mol) lawesson reagents and 2000mL toluene, when back flow reaction 3 is small.Subtract
Pressure concentration removes toluene and obtains clear yellow viscous thing, adds 2000mL dichloromethane and stirs crystalline substance under room temperature, has a large amount of yellow solids to analyse
Go out, filter, filter cake is washed with 500mL dichloromethane, obtains white solid.It is heated to reflux dissolving the white admittedly with 1500mL ethanol
Body, and recrystallized with 15 grams of activated carbon decolorizings, filtrate, obtain 401.32 grams of white solids (yield 80%, purity 99.9%).
1H-NMR (600MHz, d6-DMSO):δ 0.81 (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).
Embodiment 9, prepare Fimasartan (I) with acetonitrile as solvents
In the reaction bulb of a 3000mL add 485.58 grams of (1.00mol) embodiments 6 obtain 2- (1- ((2 '-
(1H-TETRAZOLE -5- bases)-[1,1 '-biphenyl] -4- bases) methyl) -2- butyl -4- methyl -6- carbonyl -1,6- dihydro-pyrimidins -5-
Base)-n,N-dimethylacetamide, 242.68 grams of (0.60mol) lawesson reagents and 1500mL acetonitriles, when back flow reaction 6 is small.Subtract
Pressure concentration removes acetonitrile and obtains clear yellow viscous thing, adds 2000mL dichloromethane and stirs crystalline substance under room temperature, has a large amount of yellow solids to analyse
Go out, filter, filter cake is washed with 500mL dichloromethane, obtains white solid.It is heated to reflux dissolving the white admittedly with 1500mL ethanol
Body, and recrystallized with 15 grams of activated carbon decolorizings, filtrate, obtain 391.28 grams of white solids (yield 78%, purity 99.9%).
1H-NMR (600MHz, d6-DMSO):δ 0.81 (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).
Embodiment 10, with tetrahydrofuran prepare Fimasartan (I) as solvent
In the reaction bulb of a 3000mL add 485.58 grams of (1.00mol) embodiments 6 in obtain 2- (1- ((2 '-
(1H-TETRAZOLE -5- bases)-[1,1 '-biphenyl] -4- bases) methyl) -2- butyl -4- methyl -6- carbonyl -1,6- dihydro-pyrimidins -5-
Base)-n,N-dimethylacetamide, 242.68 grams of (0.60mol) lawesson reagents and 1500mL THF, when back flow reaction 6 is small.Subtract
Pressure concentration removes THF and obtains clear yellow viscous thing, adds 2000mL dichloromethane and stirs crystalline substance under room temperature, has a large amount of yellow solids to separate out,
Filtering, filter cake are washed with 500mL dichloromethane, obtain white solid.It is heated to reflux dissolving the white solid with 1500mL ethanol,
And recrystallized with 15 grams of activated carbon decolorizings, filtrate, obtain 381.25 grams of white solids (yield 76%, purity 99.9%).
1H-NMR (600MHz, d6-DMSO):δ 0.81 (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 applicibility
Compared with the preparation method of existing patent, preparation method of the invention significantly improves yield, therefore very
It is economical and be easy to commercial Application.
Each technical characteristic of embodiment described above can be combined arbitrarily, to make description succinct, not to above-mentioned reality
Apply all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited
In contradiction, the scope that this specification is recorded all is considered to be.
Embodiment described above only expresses the several embodiments of the present invention, its description is more specific and detailed, but simultaneously
Cannot therefore it be construed as limiting the scope of the patent.It should be pointed out that come for those of ordinary skill in the art
Say, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to the guarantor of the present invention
Protect scope.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.
Claims (10)
1. a kind of synthetic method of Fimasartan, it is characterised in that the described method comprises the following steps：
(1) under the action of alkali, structural formula isCompound VI be with structural formulaCompound VII reacted in toluene, obtaining structural formula isCompound V；Wherein
R is methyl or ethyl, X Cl, Br or I；Wherein, the molar ratio of the compound VI and alkali are 1:1~1:1.5, the chemical combination
The molar ratio of thing VI and compound VII is 1:1~1:1.5；
(2) then pentamidine salts hydrochlorate reacts to obtain with alkali metal hydroxide and discharging pentamidinum in alcohol with compound V
Structural formula isCompound IV；Wherein, the pentamidine salts hydrochlorate and alkali metal hydroxide
Molar ratio is 1:1~1:1.5；The molar ratio of pentamidine salts hydrochlorate and compound V are 1:1~1:1.5；
(3) compound IV is first reacted in toluene and the DMF in the mixed solvent formed with alkali, then with 2- cyano group -4 '-bromomethylbiphenyl
Reaction obtains structural formula and isCompound III；The volume of the in the mixed solvent toluene and DMF
Than for 1:1~50:1；The molar ratio of the compound IV and alkali, 2- cyano group -4 '-bromomethylbiphenyl is 1:1:1~1:2:1.5；
(4) in the presence of a catalyst, obtain structural formula with reaction of sodium azide in a solvent is compound IIICompound II；The molar ratio of the compound III and catalyst, sodium azide is 1:1:1~
1:4:4；
(5) compound II and lawesson reagent occur thioamides and react to obtain target product I in a solvent, are Fei Masha
Smooth, its structural formula isThe solvent is toluene, acetonitrile, one or both of tetrahydrofuran, institute
The molar ratio for stating compound II and lawesson reagent is 1:0.5~1:1.
2. the synthetic method of Fimasartan according to claim 1, it is characterised in that compound VI described in step (1)
For methyl acetoacetate or ethyl acetoacetate, compound VII is the chloro- n,N-dimethylacetamide of 2-, the bromo- N of 2-, N- diformazans
Yl acetamide or the iodo- DMAC N,N' dimethyl acetamides of 2-.
3. the synthetic method of Fimasartan according to claim 1, it is characterised in that alkali described in step (1) is amino
Sodium, lithium amide, sodium hydride, lithium hydride or calcium hydride.
4. the synthetic method of Fimasartan according to claim 1, it is characterised in that the step (1) is：First add first
Benzene and alkali, nitrogen are protected, and compound VI is added dropwise under room temperature, when then insulated and stirred 1 is small at 80~85 DEG C, stop heating, drop
Add compound VII, control temperature is between 80~90 DEG C；Finish, when insulation reaction 3 is small at 80~85 DEG C；Then concentration removes
Toluene is removed, water is added in residue and is extracted with dichloromethane, then organic layer first washes saturated common salt water washing, anhydrous slufuric acid again
Sodium is dried, activated carbon decolorizing, and concentration removes dichloromethane, and last chromatography purity obtains compound V.
5. the synthetic method of Fimasartan according to claim 1, it is characterised in that alcohol described in step (2) is methanol
Or ethanol；The alkali metal hydroxide is sodium hydroxide or potassium hydroxide；The pentamidine salts hydrochlorate and alkali metal hydroxide
Molar ratio be 1:1, the molar ratio of the pentamidine salts hydrochlorate and compound V are 1:1.
6. the synthetic method of Fimasartan according to claim 1, it is characterised in that the step (2) is：Pentamidine salts acid
Salt is first dissolved in alcohol, and cools to 0~5 DEG C with ice-water bath, then adds alkali metal hydroxide, is stirred 30 minutes in ice-water bath,
Then compound V is added, when stirring 1 is small in ice-water bath, when then insulation reaction 9 is small at 25~30 DEG C, concentration removes solvent,
Add water, pH value of solution is adjusted to 4 or so with concentrated hydrochloric acid in ice-water bath, filtering, obtains compound IV.
7. the synthetic method of Fimasartan according to claim 1, it is characterised in that alkali described in step (3) is hydrogenation
Lithium, lithium amide or lithium carbonate, the volume ratio of the in the mixed solvent toluene and DMF is 30:1；The compound IV and alkali, 2- cyanogen
The molar ratio of base -4 '-bromomethylbiphenyl is 1：1.1：1.
8. the synthetic method of Fimasartan according to claim 1, it is characterised in that the step (3) is first by compound
IV is dispersed in the in the mixed solvent of toluene and DMF compositions, and nitrogen is protected, and is added alkali under room temperature, is then progressively warming up to 80~85
When DEG C reaction 1 is small, after reaction solution dissolved clarification, 2- cyano group -4 '-bromomethylbiphenyl is added, then the insulation reaction at 80~85 DEG C
24 it is small when.Concentration removes toluene, and frozen water is added into concentrate while hot quickly stirs, and separates out solid, filters, washes, dry, second
Alcohol is recrystallized to give compound III.
9. the synthetic method of Fimasartan according to claim 1, it is characterised in that solvent described in step (4) is DMF
Or toluene；The catalyst is zinc chloride or triethylamine hydrochloride, is preferably zinc chloride；The compound III and zinc chloride,
The molar ratio of sodium azide is 1:2:3；The molar ratio of the compound III and triethylamine hydrochloride, sodium azide is 1:3:3.
10. the synthetic method of Fimasartan according to claim 1, it is characterised in that the step (5) is：Compound
With lawesson reagent in a solvent, when insulation reaction 3~6 is small at 80~110 DEG C, after reaction, concentration removes solvent to II, so
Dichloromethane being added in backward concentrate crystalline substance being stirred under room temperature, filtered, washing, tetrahydrofuran recrystallizes to obtain target compound I.
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| CN109485640A (en) * | 2018-12-24 | 2019-03-19 | 合肥创新医药技术有限公司 | A kind of preparation method of Fimasartan impurity |
| WO2021136333A1 (en) | 2019-12-31 | 2021-07-08 | 复星弘创(苏州)医药科技有限公司 | Method for preparing coumarin compound, 3 position of which is substituted with amidoalkyl and products and related intermediates thereof |
| CN113336709A (en) * | 2021-06-25 | 2021-09-03 | 上海立科化学科技有限公司 | Preparation method of N, N-dimethylacetamide |
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