CN103342721B - A kind of method preparing fluvastatin key intermediate - Google Patents
A kind of method preparing fluvastatin key intermediate Download PDFInfo
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Abstract
The invention discloses a kind of method preparing fluvastatin key intermediate.The method for raw material, prepares fluvastatin key intermediate dimethyl (3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-base) methyl phosphorodithioate (compound 4) by halo, methylolation, Phosphation with 3-(4-the fluorophenyl)-1-sec.-propyl-1H-indoles (compound 1) of comparatively easily synthesis.The method process stabilizing, reaction conditions is gentle, and selectivity is good, and post-processing operation is simple, and intermediate is easy to be separated, and products obtained therefrom purity and yield are all very high, for large-scale production fluvastatin key intermediate provides a kind of new thinking and countermeasure.
Description
(1) technical field:
The present invention relates to organic synthesis pharmacy field, particularly a kind of method preparing fluvastatin key intermediate.
(2) background technology:
Fluvastatin, chemistry is by name: [R*, S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indoles-2-base] 3,5-dihydroxy-6-enanthic acid sodium, being a complete synthesis anticholesteremic agent, is hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor.The site of action of this product, at liver, has the synthesis suppressing endogenous cholesterol, reduces the content of liver cell inner cholesterol, stimulates the synthesis of low-density lipoprotein (LDL) acceptor, improves the picked-up of LDL particulate, reduces the effect of total cholesterol density of blood plasma.Because the fluvastatin medicine of listing is raceme, how to construct the key that indole ring is synthesis of fluvastatin.The synthetic method of existing fluvastatin parent nucleus mainly contains several as follows:
1, US Patent No. 5354772 reports and utilizes Fischer-Indole to synthesize the method building indole ring key intermediate, and synthetic route is shown in Fig. 2.The method can build key intermediate, but there is following problem: (1) expensive raw material price; (2) critical materials or intermediate as comparatively dangerous in Arenediazonium salts, do not utilize scale operation; (3) ester group reduction uses DIBAL, and cost price is high.
2, document (TetrahedronLetters, 1985,26,2155-2158) reports and uses Vilsmeier reaction to modify indole ring, thus builds the method for indole ring key intermediate, and synthetic route is shown in Fig. 3.The method synthesizes benzazolyl compounds by Bischler reaction with higher yield, but committed step Vilsmeier reacts because the more reaction preference that causes in active centre on ring is poor, product is difficult to purifies and separates and causes yield very low, is therefore unfavorable for suitability for industrialized production.
3, document (J.Org.Chem.2010,75,7514 – 7518) reports the method (see figure 4) utilizing chiral ligand asymmetric synthesis fluvastatin key intermediate.The method lab scale can obtain good selectivity, but raw materials used and ligand catalyst cost is higher, is not suitable for large-scale production.
4, Chinese patent CN200510022213 and CN200510093297 also successively reports aldehyde radical indoles and phosphonium ylide reagent by witting Reactive Synthesis trans olefins key intermediate (see figure 5).The method reactions steps is longer, and total recovery is lower, is not suitable for more difficult accomplishing scale production.Parent nucleus, as in patent WO2007125547, is made ylide reagent and side chain condensation, is also kept away the shortcoming that unavoidable reaction scheme is longer by similar method.
Therefore, for solving the difficult problem existed in prior art, suddenly wait to find a technique simple, with low cost, selectivity is good, is easy to be separated and the practicable synthetic route of applicable large-scale production.
(3) summary of the invention:
The object of the invention is to the deficiency overcoming prior art existence, a kind of method preparing fluvastatin key intermediate is provided.The method for raw material, prepares fluvastatin key intermediate dimethyl (3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-base) methyl phosphorodithioate by halo, methylolation, Phosphation with 3-(4-the fluorophenyl)-1-sec.-propyl-1H-indoles (compound 1) of comparatively easily synthesis.The method process stabilizing, reaction conditions is gentle, and selectivity is good, and post-processing operation is simple, and intermediate is easy to be separated, and products obtained therefrom purity and yield are all very high, for large-scale production fluvastatin key intermediate provides a kind of new thinking and countermeasure.
Technical scheme of the present invention: a kind of method preparing fluvastatin key intermediate, is characterized in that concrete preparation comprises three-step reaction:
(1) halogenating reaction: generate 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles (compound 2) for initial through halogenating reaction with 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles (compound 1);
(2) hydroxymethylation: with 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles (compound 2) for raw material generates (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol (compound 3) through hydroxymethylation;
(3) phosphating reaction: with (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol (compound 3) for raw material generates dimethyl (3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-base) methyl phosphorodithioate (compound 4) through the reaction of Arbuzov phosphotidic.
The concrete operation step of step described above (1) halogenating reaction is: temperature control 20-30 ° C, halogenated hydrocarbon solvent, main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and halogenating agent is added in reactor, system is back to HPLC detection reaction and terminates at this temperature, then cancellation termination reaction in saturated aqueous solution of sodium bisulfite is joined, leave standstill, separatory, organic phase concentrates, then adds alcoholic solvent recrystallization and obtain product 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles (compound 2); Wherein halo group is chlorine, bromine or iodine, and the amount ratio of main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and halogenated hydrocarbon solvent is 1g/5 ~ 15mL; The mol ratio of main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and halogenating agent is 1:1.0 ~ 1.5; Main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and cancellation use the amount ratio of saturated aqueous solution of sodium bisulfite for 1g/5 ~ 15mL; The amount ratio of the alcoholic solvent that main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and recrystallization use is 1g/2 ~ 15mL.
In above-mentioned steps (1) halogenating reaction, halogenated hydrocarbon solvent is methylene dichloride, 1,2-ethylene dichloride, chlorobenzene, chloroform or tetracol phenixin; Halogenating agent is N-bromosuccinimide, bromine, C5H6Br2N2O2, three pyridine bromides, N-chlorosuccinimide or N-iodosuccinimide; The alcoholic solvent that recrystallization uses is methyl alcohol, ethanol, Virahol or propyl carbinol.
In above-mentioned steps (1) halogenating reaction, optimum condition is: halo group is preferably bromine, halogenated hydrocarbon solvent is methylene dichloride, and main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles is 1g/8 ~ 10mL with the preferable amount ratio of solvent halogenated hydrocarbon solvent; Halogenating agent is three pyridine bromides, and the preferred molar ratio of main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and halogenating agent is 1:1.0 ~ 1.1; The alcoholic solvent that recrystallization uses is methyl alcohol, and the preferable amount of the alcoholic solvent that main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles uses with recrystallization is than being 1g/5 ~ 8mL; Main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and cancellation use the preferable amount of saturated aqueous solution of sodium bisulfite than being 1g/8 ~ 10mL.
The concrete operation step of step described above (2) hydroxymethylation is: temperature control 20-30 ° C, product 2-halo-3-(4-the fluorophenyl)-1-sec.-propyl-1H-indoles of ether solvent and step (1) is added in reactor, system is cooled to-78 ~-70 ° of C, metal reagent is added again in system, finish, system adds paraformaldehyde after insulation reaction 1.5 ~ 2.5h at this temperature, continue insulation reaction to terminate to HPLC detection reaction, then saturated aqueous ammonium chloride cancellation termination reaction is added, leave standstill, separatory, organic phase concentrates, add varsol recrystallization and obtain product (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol (compound 3), wherein the amount ratio of 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and ether solvent is 1g/2 ~ 15mL, the mol ratio of 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and metal reagent is 1:1.5 ~ 4.0, the mol ratio of 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and paraformaldehyde is 1:2.0 ~ 5.0, the amount ratio of 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and saturated aqueous ammonium chloride is 1g/5 ~ 20mL, the amount ratio of 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and varsol is 1g/2 ~ 15mL.
In step described above (2) hydroxymethylation, the metal reagent of reaction is n-Butyl Lithium, s-butyl lithium, zinc ethyl, magnesium chips or magnesium powder; Ether solvent is at least one in tetrahydrofuran (THF), methyl tertiary butyl ether, Isosorbide-5-Nitrae-dioxane, 2-methyltetrahydrofuran, methylcyclopentyl ether or n-butyl ether; The varsol that recrystallization uses is normal hexane, at least one in hexanaphthene or normal heptane.
In step described above (2) hydroxymethylation, optimum condition is: the metal reagent of reaction is preferably n-Butyl Lithium or magnesium powder, and the mol ratio of 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and metal reagent is preferably 1:2.0 ~ 2.5; Ether solvent is preferably tetrahydrofuran (THF) or 2-methyltetrahydrofuran, and the amount ratio of 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and ether solvent is preferably 1g/5 ~ 10mL; The mol ratio of 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and paraformaldehyde is preferably 1:3.0 ~ 4.0; The amount ratio of 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and saturated aqueous ammonium chloride is preferably 1g/10 ~ 12mL; The varsol that recrystallization uses is preferably normal heptane; The amount ratio of 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles varsol is preferably 1g/6 ~ 10mL.
The concrete operation step of step described above (3) phosphating reaction is: temperature control 20-30 ° C, product (3-(4-the fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol of halogenated hydrocarbon solvent and step (2) is added in reactor, then reaction reagent phosphorous acid ester is added, finish, system is reacted to HPLC detection reaction and is terminated at this temperature, then saturated sodium bicarbonate aqueous solution cancellation termination reaction is added, leave standstill, separatory, organic phase concentrates, add varsol recrystallization again and obtain product dimethyl (3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-base) methyl phosphorodithioate (compound 4), wherein (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol and halogenated hydrocarbon solvent amount ratio are 1g/5 ~ 20mL, the mol ratio of (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol and reaction reagent phosphorous acid ester is 1:1.5 ~ 4.0, the amount ratio of 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and cancellation saturated sodium bicarbonate aqueous solution is 1g/5 ~ 20mL, the amount ratio of the varsol that 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and recrystallization use is 1g/5 ~ 20mL.
In step described above (3) phosphating reaction, the halogenated hydrocarbon solvent of reaction is methylene dichloride, chlorobenzene, 1,2-ethylene dichloride, chloroform or tetracol phenixin; Phosphorous acid ester is trimethyl phosphite, triethyl-phosphite, tripropyl phosphite, tributyl phosphate, triisopropyl phosphite or triphenyl phosphite; The varsol that recrystallization uses is sherwood oil, at least one in Skellysolve A, normal hexane, hexanaphthene or normal heptane.
In step described above (3) phosphating reaction, optimum condition is: the halogenated hydrocarbon solvent of reaction is preferably methylene dichloride, and (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol and halogenated hydrocarbon solvent amount ratio are preferably 1g/8 ~ 12mL; Reaction reagent phosphorous acid ester is preferably trimethyl phosphite, and the mol ratio of (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol and reaction reagent phosphorous acid ester is preferably 1:2.0 ~ 3.0; The varsol that recrystallization uses is preferably hexanaphthene, and the amount ratio of the varsol that 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and recrystallization use is preferably 1g/8 ~ 10mL; The amount ratio of the varsol that 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and recrystallization use is preferably 1g/10 ~ 15mL.
Lewis acid catalyst can also be added while interpolation major ingredient in step described above (3) phosphating reaction, the mol ratio of (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol and lewis acid catalyst is 1:1.0 ~ 2.5, is preferably 1:1.0 ~ 1.5.
Lewis acid catalyst described above is zinc chloride, iron trichloride, aluminum chloride or titanium tetrachloride, is preferably zinc chloride.
Superiority of the present invention: 1, using 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles as raw material, avoid using expensive raw material or catalyzer, greatly reduce raw materials cost.2, present method aftertreatment is simple, and each step intermediate is solid, is easy to be separated, is applicable to the needs of suitability for industrialized production.3, the method synthetic route is short, and overall yield is high, and the phosphate intermediate obtained can have well chemistry to select for the synthesis of fluvastatin.
(4) accompanying drawing illustrates:
Fig. 1 is a kind of chemical reaction process figure preparing the method for fluvastatin key intermediate involved by the present invention.
Fig. 2 utilizes Fischer-Indole to synthesize the synthetic route chart building indole ring key intermediate in background technology.
Fig. 3 uses Vilsmeier to react to modify the synthetic route chart that indole ring builds indole ring key intermediate in background technology.
Fig. 4 is the synthetic route chart utilizing chiral ligand asymmetric synthesis fluvastatin key intermediate in background technology.
Fig. 5 is the synthetic route chart by witting Reactive Synthesis trans olefins key intermediate in background technology.
Composition graphs 1 can understand technical scheme of the present invention more intuitively.
(5) embodiment:
In order to absolutely prove essence, the preparation thinking and design of patent of the present invention, verify preparation method of the present invention in the following embodiments, the restriction to the present invention's protection should not explained or be interpreted as to these embodiments only for illustrating and special case representative.
Embodiment 1: a kind of method preparing fluvastatin key intermediate, is characterized in that concrete preparation process is as follows:
(1) halogenating reaction: temperature control 25 ± 5 DEG C, 1 is added in 2000L reactor, 2-ethylene dichloride 504.0kg (5mL/g), main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles 80kg (315.8mol, 1.0equiv.) with N-bromosuccinimide 67.5kg (379.0mol, 1.2equiv.).System is heated to back flow reaction, and HPLC detects to reacting end.System is pressed into (5mL/g) termination reaction in saturated aqueous solution of sodium bisulfite 480.0kg.Leave standstill, separatory, organic phase concentrates, then adds ethanol 126.4kg (2mL/g) recrystallization and obtain the bromo-3-of halides 2-(4-fluorophenyl)-1-sec.-propyl-1H-indoles 89.2kg, and liquid phase purity is 96.0%, and yield is 85.0%.
(2) hydroxymethylation: temperature control 25 ± 5 DEG C, methyl tertiary butyl ether 118.4kg (2mL/g) and the bromo-3-of main raw material 2-(4-fluorophenyl)-1-sec.-propyl-1H-indoles 80kg (240.8mol, 1.0equiv.) is added in reactor.System is cooled to-78 DEG C, then in system, drip metal reagent s-butyl lithium 105.2kg (361.2mol, 1.5equiv., 22%w/w).Finish, system adds paraformaldehyde 43.4kg (481.6mol, 2.0equiv.) after insulation reaction 2h at this temperature, continues insulation reaction and terminates to HPLC detection reaction.Reaction is finished, add saturated aqueous ammonium chloride 460kg (5mL/g) termination reaction, leave standstill, separatory, organic phase concentrates, add normal hexane 105.6kg (2mL/g) recrystallization and obtain (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol (compound 3) 40.9kg, liquid phase purity is 95%, and yield is 60%.
(3) phosphating reaction: temperature control 25 ± 5 DEG C, 1 is added successively in reactor, 2-ethylene dichloride 504.0kg (5mL/g), main raw material (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol 80kg (282.3mol, 1.0equiv.), iron trichloride 68.6kg (423.5mol, 1.5equiv.) and triethyl-phosphite 70.4kg (423.5mol, 1.5equiv.).Finish, system is reacted and is terminated to HPLC detection reaction at this temperature, then joins termination reaction in saturated sodium bicarbonate 440.0kg (5mL/g) aqueous solution.Leave standstill, separatory, organic phase concentrates, then adds normal hexane 264.0kg (5mL/g) recrystallization and obtain dimethyl (3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-base) methyl acid phosphate diethyl ester 91.1kg, purity is 97%, and yield is 80%.
Embodiment 2: a kind of method preparing fluvastatin key intermediate, is characterized in that concrete preparation process is as follows:
(1) halogenating reaction: temperature control 25 ± 5 ° of C, methylene dichloride 665.0kg (10mL/g) is added in 2000L reactor, main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles 50kg (197.4mol, 1.0equiv.) He three pyridine bromide 62.3kg (197.4mol, 1.0equiv.).System is in being heated to back flow reaction, and HPLC detecting and tracking is to reacting end.System is pressed into saturated aqueous solution of sodium bisulfite 600.0kg (10mL/g) termination reaction.Leave standstill, separatory, organic phase concentrates, then adds methyl alcohol 197.5kg (5mL/g) recrystallization and obtain the bromo-3-of halides 2-(4-fluorophenyl)-1-sec.-propyl-1H-indoles 62.3kg, and liquid phase purity is 99.0%, and yield is 95.0%.
(2) hydroxymethylation: temperature control 25 ± 5 ° of C, tetrahydrofuran (THF) 222.5kg (5mL/g) and the bromo-3-of main raw material 2-(4-fluorophenyl)-1-sec.-propyl-1H-indoles 50kg (150.5mol is added in reactor, 1.0equiv.), system is cooled to-78 ° of C, n-Butyl Lithium 87.6kg (301.0mol is dripped again in system, 2.0equiv., 22%w/w), finish, system adds paraformaldehyde 54.2kg (602.0mol at this temperature after insulation reaction 2h, 4.0equiv.), continue insulation reaction, HPLC monitoring is followed the tracks of reaction and is terminated.Reaction is finished, add saturated aqueous ammonium chloride 575.0kg (10mL/g) termination reaction, leave standstill, separatory, organic phase concentrates, adding normal heptane 192.5kg (5mL/g) recrystallization, to obtain (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol (compound 3) 32.0kg, HPLC purity be 98%, and yield is 75%.
(3) phosphating reaction: temperature control 25 ± 5 ° of C, methylene dichloride 655.0kg (10mL/g) is added successively in reactor, main raw material (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol 50kg (176.5mol, 1.0equiv.), Zinc Chloride Anhydrous solid 23.9kg (176.5mol, 1.0equiv.) and trimethyl phosphite 43.8kg (352.9mol, 2.0eq).System is reacted at this temperature, and HPLC monitoring tracks to reaction and terminates.Termination reaction in system press-in saturated sodium bicarbonate aqueous solution 550.0kg (10mL/g).Leave standstill, separatory, organic phase concentrates, then adds hexanaphthene 385.0kg (10mL/g) recrystallization and obtain dimethyl (3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-base) methyl-phosphoric acid dimethyl ester 59.6kg, HPLC purity is 99%, and yield is 90%.
Embodiment 3: a kind of method preparing fluvastatin key intermediate, is characterized in that concrete preparation process is as follows:
(1) halogenating reaction: temperature control 25 ± 5 DEG C, chlorobenzene 499.5kg (15mL/g) is added in 2000L reactor, main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles 30kg (118.4mol, 1.0equiv.) with bromine 28.4kg (177.6mol, 1.5equiv.).System is heated to back flow reaction, and HPLC detecting and tracking is to reacting end.System is pressed in saturated aqueous solution of sodium bisulfite 540.0kg (15mL/g) and stops.Leave standstill, separatory, organic phase concentrates, then adds Virahol 355.5kg (15mL/g) recrystallization and obtain the bromo-3-of halides 2-(4-fluorophenyl)-1-sec.-propyl-1H-indoles (compound 2) 35.4kg, HPLC purity is 97.0%, and yield is 90.0%.
(2) hydroxymethylation: temperature control 25 ± 5 DEG C, tetrahydrofuran (THF) 463.5kg (15mL/g) is added successively in reactor, magnesium powder 4.34Kg(108.6mol, 2.0equiv.), the bromo-3-of main raw material 2-(4-fluorophenyl)-1-sec.-propyl-1H-indoles 3Kg (9.03mol, 0.1equiv.), reflux causes to grignard reagent, then 27kg (81.3mol is dripped, 0.9equiv.), system is back flow reaction 2h at this temperature, then 25 ± 5 DEG C are cooled to, add paraformaldehyde 40.7kg (451.2mol, 5.0equiv.), continue insulation reaction, HPLC detecting and tracking is to reacting end.System is pressed into saturated aqueous ammonium chloride 690kg (20mL/g) termination reaction, leave standstill, separatory, organic phase concentrates, add hexanaphthene 306.0kg (15mL/g) recrystallization and obtain (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol (compound 3) 17.9kg, HPLC purity is 97%, and yield is 70%.
(3) phosphating reaction: temperature control 25 ± 5 DEG C, chlorobenzene 666.0kg (10mL/g) is added successively in reactor, main raw material (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol 30kg (105.9mol, 1.0equiv.), titanium tetrachloride 50.2kg (264.7mol, 2.5equiv.) and triphenyl phosphite 131.4kg (423.5mol, 4.0equiv.).System is reacted at this temperature, and HPLC detecting and tracking, to reacting end, then adds saturated sodium bicarbonate aqueous solution 660.0kg (20mL/g) termination reaction.Leave standstill, separatory, organic phase concentrates, then adds normal heptane 408.0kg (20mL/g) recrystallization and obtain dimethyl (3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-base) methyl acid phosphate diphenyl ester 45.0kg, HPLC purity is 98%, and yield is 85%.
As can be seen here, a kind of method of synthesis of fluvastatin key intermediate disclosed in the present invention, 3-(4-the fluorophenyl)-1-sec.-propyl-1H-indoles adopting comparatively easily synthesis is raw material, prepares fluvastatin key intermediate by halo, methylolation, Phosphation three step.Present invention process is stablized, and reaction conditions is gentle, and selectivity is good, and post-processing operation is simple, and intermediate is easy to be separated, and products obtained therefrom purity and yield are all very high, for large-scale production fluvastatin key intermediate provides a kind of new thinking and countermeasure.
Claims (29)
1. prepare a method for fluvastatin key intermediate, it is characterized in that concrete preparation comprises three-step reaction:
(1) halogenating reaction: be initially generate 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles through halogenating reaction with 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles;
(2) hydroxymethylation: being raw material with 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles generates (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol through hydroxymethylation, wherein, concrete operation step is: temperature control 20-30 DEG C, product 2-halo-3-(4-the fluorophenyl)-1-sec.-propyl-1H-indoles of ether solvent and step (1) is added in reactor, system is cooled to-78 ~-70 DEG C, metal reagent is added again in system, finish, system adds paraformaldehyde after insulation reaction 1.5 ~ 2.5h at this temperature, continue insulation reaction to terminate to HPLC detection reaction, then saturated aqueous ammonium chloride cancellation termination reaction is added, leave standstill, separatory, organic phase concentrates, add varsol recrystallization and obtain product (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol, wherein the amount ratio of 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and ether solvent is 1g/2 ~ 15mL, the amount ratio of 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and saturated aqueous ammonium chloride is 1g/5 ~ 20mL, the amount ratio of 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and varsol is 1g/2 ~ 15mL, the mol ratio of 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and metal reagent is 1:2.0 ~ 2.5, and the mol ratio of 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and paraformaldehyde is 1:3.0 ~ 4.0,
(3) phosphating reaction: being raw material with (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol generates dimethyl (3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-base) methyl phosphorodithioate through the reaction of Arbuzov phosphotidic;
The concrete operation step of described step (3) phosphating reaction is: temperature control 20 ~ 30 DEG C, product (3-(4-the fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol of halogenated hydrocarbon solvent and step (2) is added in reactor, then reaction reagent phosphorous acid ester is added, finish, system is reacted to HPLC detection reaction and is terminated at this temperature, then saturated sodium bicarbonate aqueous solution cancellation termination reaction is added, leave standstill, separatory, organic phase concentrates, add varsol recrystallization again and obtain product dimethyl (3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-base) methyl phosphorodithioate, wherein (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol and halogenated hydrocarbon solvent amount ratio are 1g/5 ~ 20mL, the mol ratio of (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol and reaction reagent phosphorous acid ester is 1:1.5 ~ 4.0, the amount ratio of 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and cancellation saturated sodium bicarbonate aqueous solution is 1g/5 ~ 20mL, the amount ratio of the varsol that 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and recrystallization use is 1g/5 ~ 20mL, described metal reagent is s-butyl lithium, n-Butyl Lithium or magnesium powder.
2. a kind of method preparing fluvastatin key intermediate according to claim 1, it is characterized in that the concrete operation step of described step (1) halogenating reaction is: temperature control 20-30 DEG C, halogenated hydrocarbon solvent is added in reactor, main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and halogenating agent, system is back to HPLC detection reaction and terminates at this temperature, then cancellation termination reaction in saturated aqueous solution of sodium bisulfite is joined, leave standstill, separatory, organic phase concentrates, add alcoholic solvent recrystallization again and obtain product 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles, wherein halo group is chlorine, bromine or iodine, and the amount ratio of main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and halogenated hydrocarbon solvent is 1g/5 ~ 15mL, the mol ratio of main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and halogenating agent is 1:1.0 ~ 1.5, main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and cancellation use the amount ratio of saturated aqueous solution of sodium bisulfite for 1g/5 ~ 15mL, the amount ratio of the alcoholic solvent that main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and recrystallization use is 1g/2 ~ 15mL.
3. a kind of method preparing fluvastatin key intermediate according to claim 2, it is characterized in that in step (1) halogenating reaction, halogenated hydrocarbon solvent is methylene dichloride, 1,2-ethylene dichloride, chlorobenzene, chloroform or tetracol phenixin; Halogenating agent is N-bromosuccinimide, bromine, C5H6Br2N2O2, three pyridine bromides, N-chlorosuccinimide or N-iodosuccinimide; The alcoholic solvent that recrystallization uses is methyl alcohol, ethanol, Virahol or propyl carbinol.
4. a kind of method preparing fluvastatin key intermediate according to claim 2, is characterized in that, in step (1) halogenating reaction, halogenating agent is three pyridine bromides.
5. a kind of method preparing fluvastatin key intermediate according to claim 2, is characterized in that the amount ratio of main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and solvent halogenated hydrocarbon solvent is 1g/8 ~ 10mL.
6. a kind of method preparing fluvastatin key intermediate according to claim 5, is characterized in that described halogenated hydrocarbon solvent is methylene dichloride.
7. a kind of method preparing fluvastatin key intermediate according to claim 2, is characterized in that the mol ratio of main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and halogenating agent is 1:1.0 ~ 1.1.
8. a kind of method preparing fluvastatin key intermediate according to claim 2, is characterized in that the amount ratio of the alcoholic solvent that main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and recrystallization use is 1g/5 ~ 8mL.
9. a kind of method preparing fluvastatin key intermediate according to claim 8, is characterized in that the alcoholic solvent that recrystallization uses is methyl alcohol.
10. a kind of method preparing fluvastatin key intermediate according to claim 2, is characterized in that main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and cancellation use the amount ratio of saturated aqueous solution of sodium bisulfite for 1g/8 ~ 10mL.
11. a kind of methods preparing fluvastatin key intermediate according to claim 1, it is characterized in that in described step (2) hydroxymethylation, the metal reagent of reaction is n-Butyl Lithium, s-butyl lithium, zinc ethyl, magnesium chips or magnesium powder; Ether solvent is at least one in tetrahydrofuran (THF), methyl tertiary butyl ether, Isosorbide-5-Nitrae-dioxane, 2-methyltetrahydrofuran, methylcyclopentyl ether or n-butyl ether; The varsol that recrystallization uses is normal hexane, at least one in hexanaphthene or normal heptane.
12. a kind of methods preparing fluvastatin key intermediate according to claim 1, it is characterized in that in described step (2) hydroxymethylation, the metal reagent of reaction is n-Butyl Lithium or magnesium powder.
13. a kind of methods preparing fluvastatin key intermediate according to claim 1, is characterized in that the amount ratio of 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and ether solvent is 1g/5 ~ 10mL.
14. a kind of methods preparing fluvastatin key intermediate according to claim 1, is characterized in that described ether solvent is tetrahydrofuran (THF) or 2-methyltetrahydrofuran.
15. a kind of methods preparing fluvastatin key intermediate according to claim 1, is characterized in that the amount ratio 1g/10 ~ 12mL of 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and saturated aqueous ammonium chloride.
16. a kind of methods preparing fluvastatin key intermediate according to claim 1, is characterized in that the amount ratio of 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and described varsol is 1g/6 ~ 10mL.
17. according to the method preparing fluvastatin key intermediate a kind of described in claim 16, it is characterized in that the varsol that recrystallization uses is normal heptane.
18. a kind of methods preparing fluvastatin key intermediate according to claim 1, it is characterized in that, in described step (3) phosphating reaction, the halogenated hydrocarbon solvent of reaction is methylene dichloride, chlorobenzene, 1,2-ethylene dichloride, chloroform or tetracol phenixin; Phosphorous acid ester is trimethyl phosphite, triethyl-phosphite, tripropyl phosphite, tributyl phosphate, triisopropyl phosphite or triphenyl phosphite; The varsol that recrystallization uses is sherwood oil, at least one in Skellysolve A, normal hexane, hexanaphthene or normal heptane.
19. a kind of methods preparing fluvastatin key intermediate according to claim 1, it is characterized in that, in described step (3) phosphating reaction, (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol and halogenated hydrocarbon solvent amount ratio are 1g/8 ~ 12mL.
20., according to the method preparing fluvastatin key intermediate a kind of described in claim 19, is characterized in that, the halogenated hydrocarbon solvent of reaction is methylene dichloride.
21. a kind of methods preparing fluvastatin key intermediate according to claim 1, it is characterized in that, the mol ratio of (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol and reaction reagent phosphorous acid ester is 1:2.0 ~ 3.0.
22., according to the method preparing fluvastatin key intermediate a kind of described in claim 21, is characterized in that, described reaction reagent phosphorous acid ester is trimethyl phosphite.
23. a kind of methods preparing fluvastatin key intermediate according to claim 1, it is characterized in that, the amount ratio of the varsol that 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and recrystallization use is 1g/8 ~ 10mL.
24., according to the method preparing fluvastatin key intermediate a kind of described in claim 23, is characterized in that, the varsol that recrystallization uses is hexanaphthene.
25. a kind of methods preparing fluvastatin key intermediate according to claim 1, it is characterized in that, the amount ratio of the varsol that 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and recrystallization use is 1g/10 ~ 15mL.
26. a kind of methods preparing fluvastatin key intermediate according to claim 1, is characterized in that the mol ratio of (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol and lewis acid catalyst is 1:1.0 ~ 2.5.
27. according to the method preparing fluvastatin key intermediate a kind of described in claim 26, it is characterized in that to add lewis acid catalyst while interpolation major ingredient in described step (3) phosphating reaction, the mol ratio of (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-base) methyl alcohol and lewis acid catalyst is 1:1.0 ~ 1.5.
28. according to the method preparing fluvastatin key intermediate a kind of described in claim 26, it is characterized in that described lewis acid catalyst is zinc chloride, iron trichloride, aluminum chloride or titanium tetrachloride.
29. according to the method preparing fluvastatin key intermediate a kind of described in claim 28, it is characterized in that described lewis acid catalyst is zinc chloride.
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| US4870199A (en) * | 1986-04-30 | 1989-09-26 | Sandoz Pharm. Corp. | Processes for the synthesis of diprotected R[R*,S*]-3,5-dihydroxy-6-oxohexanoate esters |
| EP0244364A3 (en) * | 1986-04-30 | 1992-04-01 | Sandoz Ag | Preparation of olefinic compounds |
| CN1430604A (en) * | 2000-05-26 | 2003-07-16 | 西巴特殊化学品控股有限公司 | Process for preparation of indole derivatives and intermediates of the process |
| CN1978428A (en) * | 2005-12-05 | 2007-06-13 | 四川抗菌素工业研究所有限公司 | Method for preparing (3R, %S)-Fluvastatin |
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| US4870199A (en) * | 1986-04-30 | 1989-09-26 | Sandoz Pharm. Corp. | Processes for the synthesis of diprotected R[R*,S*]-3,5-dihydroxy-6-oxohexanoate esters |
| EP0244364A3 (en) * | 1986-04-30 | 1992-04-01 | Sandoz Ag | Preparation of olefinic compounds |
| CN1430604A (en) * | 2000-05-26 | 2003-07-16 | 西巴特殊化学品控股有限公司 | Process for preparation of indole derivatives and intermediates of the process |
| CN1978428A (en) * | 2005-12-05 | 2007-06-13 | 四川抗菌素工业研究所有限公司 | Method for preparing (3R, %S)-Fluvastatin |
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