CN103342721A - Method for preparing fluvastatin key intermediate - Google Patents
Method for preparing fluvastatin key intermediate Download PDFInfo
- Publication number
- CN103342721A CN103342721A CN2013102950682A CN201310295068A CN103342721A CN 103342721 A CN103342721 A CN 103342721A CN 2013102950682 A CN2013102950682 A CN 2013102950682A CN 201310295068 A CN201310295068 A CN 201310295068A CN 103342721 A CN103342721 A CN 103342721A
- Authority
- CN
- China
- Prior art keywords
- propyl
- indoles
- sec
- fluorophenyl
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Abstract
The invention discloses a method for preparing a fluvastatin key intermediate. The method adopts easy-to-synthesize 3-(4-fluorophenyl)-1-isopropyl-1H-indole (compound 1) as a raw material and prepares a fluvastatin key intermediate dimethyl(3-(4-fluorophenyl)-1-isopropyl-1H-indole-2-yl)methyl phosphate (compound 4) through halogenation, hydroxymethylation and phosphate esterification. The method disclosed by the invention has the advantages of stable technology, mild reaction conditions, good selectivity, simple after-treatment operation, easiness for separation of the intermediate and high product purity and yield, and provides a new idea and method for large-scale production of the fluvastatin key intermediate.
Description
(1) technical field:
The present invention relates to the organic synthesis pharmacy field, particularly a kind of method for preparing the fluvastatin key intermediate.
(2) background technology:
Fluvastatin, chemistry is by name: [R*, S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indoles-2-yl] 3,5-dihydroxy-6-enanthic acid sodium, be a complete synthesis anticholesteremic agent, be hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor.The site of action of this product has and suppresses the synthetic of endogenous cholesterol at liver, reduces the content of liver cell inner cholesterol, stimulates the synthetic of low-density lipoprotein (LDL) acceptor, and the picked-up that improves the LDL particulate reduces the effect of total cholesterol density of blood plasma.Because the fluvastatin medicine of listing is raceme, how constructing indole ring is the key of synthesis of fluvastatin.The synthetic method of existing fluvastatin parent nucleus mainly contains following several:
1, US Patent No. 5354772 has been reported and has been utilized the synthetic method that makes up the indole ring key intermediate of Fischer-Indole, and synthetic route is seen Fig. 2.This method can make up key intermediate, but exists following problem: (1) expensive raw material price; (2) critical materials or intermediate such as phenyl diazonium salt are comparatively dangerous, do not utilize scale operation; (3) DIBAL, cost price height are used in the ester group reduction.
2, document (Tetrahedron Letters, 1985,26,2155-2158) reported that use Vilsmeier reaction modifies indole ring, thereby made up the method for indole ring key intermediate that synthetic route is seen Fig. 3.This method can synthesize benzazolyl compounds with higher yield by the Bischler reaction, upward the more reaction preference that causes in active centre is relatively poor but committed step Vilsmeier reaction is owing to ring, product is difficult to purifies and separates and causes yield very low, therefore is unfavorable for suitability for industrialized production.
3, document (J.Org.Chem.2010,75,7514 – 7518) has been reported the method (see figure 4) of utilizing chiral ligand asymmetric synthesis fluvastatin key intermediate.This method lab scale can obtain selectivity preferably, but raw materials used and the ligand catalyst cost is higher, is not suitable for large-scale production.
4, Chinese patent CN200510022213 and CN200510093297 have successively reported that also aldehyde radical indoles and phosphonium ylide reagent are by witting reaction synthesis of trans alkene key intermediate (see figure 5).This method reactions steps is longer, and total recovery is lower, is not suitable for difficulty and accomplishes scale production.Similarly among method such as the patent WO2007125547, parent nucleus is made ylide reagent and side chain condensation, also keep away the long shortcoming of unavoidable reaction scheme.
Therefore, be to solve a difficult problem that exists in the prior art, suddenly wait to find a technology simple, with low cost, selectivity is good, is easy to separate and the practicable synthetic route of suitable large-scale production.
(3) summary of the invention:
The objective of the invention is to overcome the deficiency that prior art exists, a kind of method for preparing the fluvastatin key intermediate is provided.This method is raw material with easily synthetic 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles (compound 1), prepares fluvastatin key intermediate dimethyl (3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl) methyl phosphorodithioate by halo, methylolation, Phosphation.This method process stabilizing, the reaction conditions gentleness, selectivity is good, and post-processing operation is simple, and intermediate is easy to separate, 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 method.
Technical scheme of the present invention: a kind of method for preparing the fluvastatin key intermediate is characterized in that concrete preparation comprises three-step reaction:
(1) halogenating reaction: be initially to generate 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles (compound 2) through halogenating reaction with 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles (compound 1);
(2) hydroxymethylation: being raw material with 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles (compound 2) generates (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-yl) methyl alcohol (compound 3) through hydroxymethylation;
(3) phosphating reaction: being raw material with (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-yl) methyl alcohol (compound 3), reaction generates dimethyl (3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl) methyl phosphorodithioate (compound 4) through the Arbuzov phosphotidic.
The concrete operations step of step described above (1) halogenating reaction is: temperature control 20-30 ° C, in reactor, be added in halogenated hydrocarbon solvent, main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and halogenating agent, system is back to the HPLC detection reaction and finishes under this temperature, join cancellation termination reaction in the saturated aqueous solution of sodium bisulfite then, leave standstill, separatory, organic phase concentrates, and adds the alcoholic solvent recrystallization again and obtains product 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles (compound 2); Wherein the 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 to be 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 bromo pyridines, 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: the halo group is preferably bromine, and 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 bromo pyridines, 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 and recrystallization use is than being 1g/5～8mL; Main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles uses the preferable amount of saturated aqueous solution of sodium bisulfite than being 1g/8～10mL with cancellation.
The concrete operations 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 that adds ether solvent and step (1) in the reactor, system is cooled to-78～-70 ° of C, in system, add metal reagent again, finish, system is in adding Paraformaldehyde 96 behind insulation reaction 1.5～2.5h under this temperature, continuing insulation reaction to HPLC detection reaction finishes, add saturated aqueous ammonium chloride cancellation termination reaction then, leave standstill, separatory, organic phase concentrates, and adds the varsol recrystallization and obtains product (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-yl) 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 96 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 tetrahydrofuran (THF), methyl tertiary butyl ether, 1, at least a in 4-dioxane, 2-methyltetrahydrofuran, methylcyclopentyl ether or the n-butyl ether; At least a as in normal hexane, hexanaphthene or the normal heptane of the varsol that recrystallization uses.
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 96 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 operations 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-yl) methyl alcohol that adds halogenated hydrocarbon solvent and step (2) in the reactor, add the reaction reagent phosphorous acid ester then, finish, system is reacted under this temperature to the HPLC detection reaction and is finished, add saturated sodium bicarbonate aqueous solution cancellation termination reaction then, leave standstill, separatory, organic phase concentrates, and adds the varsol recrystallization again and obtains product dimethyl (3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl) methyl phosphorodithioate (compound 4); Wherein (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-yl) 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-yl) methyl alcohol and reaction reagent phosphorous acid ester is 1:1.5～4.0; 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and cancellation are 1g/5～20mL with the amount ratio of saturated sodium bicarbonate aqueous solution; 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, tricresyl phosphite propyl ester, tributyl phosphate, triisopropyl phosphite or triphenyl phosphite; At least a as in sherwood oil, Skellysolve A, normal hexane, hexanaphthene or the normal heptane of the varsol that recrystallization uses.
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-yl) methyl alcohol and halogenated hydrocarbon solvent amount ratio are preferably 1g/8～12mL; The reaction reagent phosphorous acid ester is preferably trimethyl phosphite, and the mol ratio of (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-yl) 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.
Can also when adding major ingredient, add lewis acid catalyst in step described above (3) phosphating reaction, the mol ratio of (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-yl) 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, with 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 goes on foot intermediate and is solid, is easy to separate, and is fit to need of industrial production.3, this method synthetic route is short, the overall yield height, and the phosphoric acid ester intermediate that obtains can have good chemistry to select for the synthesis of fluvastatin.
(4) description of drawings:
Fig. 1 is the related a kind of chemical reaction process figure for preparing the method for fluvastatin key intermediate of the present invention.
Fig. 2 is for utilizing the synthetic synthetic route chart that makes up the indole ring key intermediate of Fischer-Indole in the background technology.
Fig. 3 uses the Vilsmeier reaction to modify the synthetic route chart that indole ring makes up the indole ring key intermediate in the background technology.
Fig. 4 is for utilizing the synthetic route chart of chiral ligand asymmetric synthesis fluvastatin key intermediate in the background technology.
Fig. 5 is the synthetic route chart that reacts synthesis of trans alkene key intermediate in the background technology by witting.
Can understand technical scheme of the present invention more intuitively in conjunction with Fig. 1.
(5) embodiment:
For essence, preparation thinking and the design that proves absolutely patent of the present invention, verify preparation method of the present invention in the following embodiments, these embodiment only for illustrating and the special case representative, should not explained or be interpreted as the restriction to the present invention's protection.
Embodiment 1: a kind of method for preparing the fluvastatin key intermediate is characterized in that concrete preparation process is as follows:
(1) halogenating reaction: 25 ± 5 ℃ of temperature controls, in the 2000L reactor, be added in 1,2-ethylene dichloride 504.0kg (5mL/g), main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles 80kg (315.8mol, 1.0equiv.) and N-bromosuccinimide 67.5kg (379.0mol, 1.2equiv.).System is heated to back flow reaction, and HPLC detects to the reaction end.System is pressed into (5mL/g) termination reaction among the saturated aqueous solution of sodium bisulfite 480.0kg.Leave standstill, separatory, organic phase concentrates, and adds ethanol 126.4kg (2mL/g) recrystallization again and obtains halides 2-bromo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles 89.2kg, and liquid phase purity is 96.0%, and yield is 85.0%.
(2) hydroxymethylation: 25 ± 5 ℃ of temperature controls, add in the reactor methyl tertiary butyl ether 118.4kg (2mL/g) and main raw material 2-bromo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles 80kg (240.8mol, 1.0equiv.).System is cooled to-78 ℃, drip in the system again metal reagent s-butyl lithium 105.2kg (361.2mol, 1.5equiv., 22%w/w).Finish, system adds Paraformaldehyde 96 43.4kg behind insulation reaction 2h under this temperature (481.6mol 2.0equiv.), continues insulation reaction to HPLC detection reaction and finishes.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-yl) methyl alcohol (compound 3) 40.9kg, liquid phase purity is 95%, and yield is 60%.
(3) phosphating reaction: 25 ± 5 ℃ of temperature controls, in reactor, add 1 successively, 2-ethylene dichloride 504.0kg (5mL/g), main raw material (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-yl) 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 under this temperature to the end of HPLC detection reaction, joins termination reaction in saturated sodium bicarbonate 440.0kg (5mL/g) aqueous solution then.Leave standstill, separatory, organic phase concentrates, and adds normal hexane 264.0kg (5mL/g) recrystallization again and obtains dimethyl (3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl) methyl acid phosphate diethyl ester 91.1kg, and purity is 97%, and yield is 80%.
Embodiment 2: a kind of method for preparing the fluvastatin key intermediate is characterized in that concrete preparation process is as follows:
(1) halogenating reaction: 25 ± 5 ° of C of temperature control, in the 2000L reactor, be added in methylene dichloride 665.0kg (10mL/g), main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles 50kg (197.4mol, 1.0equiv.) and three bromo pyridine 62.3kg (197.4mol, 1.0equiv.).System is in being heated to back flow reaction, and HPLC detects and tracks to the reaction end.System is pressed into saturated aqueous solution of sodium bisulfite 600.0kg (10mL/g) termination reaction.Leave standstill, separatory, organic phase concentrates, and adds methyl alcohol 197.5kg (5mL/g) recrystallization again and obtains halides 2-bromo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles 62.3kg, and liquid phase purity is 99.0%, and yield is 95.0%.
(2) hydroxymethylation: 25 ± 5 ° of C of temperature control, in reactor, add tetrahydrofuran (THF) 222.5kg (5mL/g) and main raw material 2-bromo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles 50kg (150.5mol, 1.0equiv.), system is cooled to-78 ° of C, in system, drip n-Butyl Lithium 87.6kg (301.0mol again, 2.0equiv., 22%w/w), finish, system adds Paraformaldehyde 96 54.2kg (602.0mol behind insulation reaction 2h under this temperature, 4.0equiv.), continuing insulation reaction, the HPLC monitoring is followed the tracks of reaction and is finished.Reaction is finished, add saturated aqueous ammonium chloride 575.0kg (10mL/g) termination reaction, leave standstill, separatory, organic phase concentrates, add normal heptane 192.5kg (5mL/g) recrystallization and obtain (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-yl) methyl alcohol (compound 3) 32.0kg, HPLC purity is 98%, and yield is 75%.
(3) phosphating reaction: 25 ± 5 ° of C of temperature control, in reactor, add methylene dichloride 655.0kg (10mL/g) successively, main raw material (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-yl) 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 under this temperature, and the HPLC monitoring tracks to reaction and finishes.System is pressed into termination reaction among the saturated sodium bicarbonate aqueous solution 550.0kg (10mL/g).Leave standstill, separatory, organic phase concentrates, and adds hexanaphthene 385.0kg (10mL/g) recrystallization again and obtains dimethyl (3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl) methyl-phosphoric acid dimethyl ester 59.6kg, and HPLC purity is 99%, and yield is 90%.
Embodiment 3: a kind of method for preparing the fluvastatin key intermediate is characterized in that concrete preparation process is as follows:
(1) halogenating reaction: 25 ± 5 ℃ of temperature controls, in the 2000L reactor, be added in chlorobenzene 499.5kg (15mL/g), main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles 30kg (118.4mol, 1.0equiv.) and bromine 28.4kg (177.6mol, 1.5equiv.).System is heated to back flow reaction, and HPLC detects and tracks to the reaction end.System is pressed into termination among the saturated aqueous solution of sodium bisulfite 540.0kg (15mL/g).Leave standstill, separatory, organic phase concentrates, and adds Virahol 355.5kg (15mL/g) recrystallization again and obtains halides 2-bromo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles (compound 2) 35.4kg, and HPLC purity is 97.0%, and yield is 90.0%.
(2) hydroxymethylation: 25 ± 5 ℃ of temperature controls, in reactor, add tetrahydrofuran (THF) 463.5kg (15mL/g) successively, magnesium powder 4.34Kg(108.6mol, 2.0equiv.), main raw material 2-bromo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles 3Kg (9.03mol, 0.1equiv.), reflux to grignard reagent causes, drip then 27kg (81.3mol, 0.9equiv.), system is back flow reaction 2h under this temperature, be cooled to 25 ± 5 ℃ then, and adding Paraformaldehyde 96 40.7kg (451.2mol, 5.0equiv.), continue insulation reaction, HPLC detects and tracks to the reaction 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-yl) methyl alcohol (compound 3) 17.9kg, HPLC purity is 97%, and yield is 70%.
(3) phosphating reaction: 25 ± 5 ℃ of temperature controls, in reactor, add chlorobenzene 666.0kg (10mL/g) successively, main raw material (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-yl) 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 under this temperature, and HPLC detects and tracks to the reaction end, adds saturated sodium bicarbonate aqueous solution 660.0kg (20mL/g) termination reaction then.Leave standstill, separatory, organic phase concentrates, and adds normal heptane 408.0kg (20mL/g) recrystallization again and obtains dimethyl (3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl) methyl acid phosphate diphenyl ester 45.0kg, and HPLC purity is 98%, and yield is 85%.
This shows, the method of disclosed a kind of synthesis of fluvastatin key intermediate among the present invention, adopting easily synthetic 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles is raw material, goes on foot and prepares the fluvastatin key intermediate by halo, methylolation, Phosphation three.Process stabilizing of the present invention, the reaction conditions gentleness, selectivity is good, and post-processing operation is simple, and intermediate is easy to separate, 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 method.
Claims (12)
1. method for preparing the fluvastatin key intermediate is characterized in that concrete preparation comprises three-step reaction:
(1) halogenating reaction: be initially to 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-yl) methyl alcohol through hydroxymethylation;
(3) phosphating reaction: being raw material with (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-yl) methyl alcohol, reaction generates dimethyl (3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl) methyl phosphorodithioate through the Arbuzov phosphotidic.
2. according to the described a kind of method for preparing the fluvastatin key intermediate of claim 1, the concrete operations step that it is characterized in that described step (1) halogenating reaction is: temperature control 20-30 ° C, in reactor, be added in halogenated hydrocarbon solvent, main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and halogenating agent, system is back to the HPLC detection reaction and finishes under this temperature, join cancellation termination reaction in the saturated aqueous solution of sodium bisulfite then, leave standstill, separatory, organic phase concentrates, and adds the alcoholic solvent recrystallization again and obtains product 2-halo-3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles; Wherein the 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 to be 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. according to the described a kind of method for preparing the fluvastatin key intermediate of claim 2, it is characterized in that halogenated hydrocarbon solvent is methylene dichloride, 1,2-ethylene dichloride, chlorobenzene, chloroform or tetracol phenixin in step (1) halogenating reaction; Halogenating agent is N-bromosuccinimide, bromine, C5H6Br2N2O2, three bromo pyridines, N-chlorosuccinimide or N-iodosuccinimide; The alcoholic solvent that recrystallization uses is methyl alcohol, ethanol, Virahol or propyl carbinol.
4. according to the described a kind of method for preparing the fluvastatin key intermediate of claim 2, it is characterized in that in step (1) halogenating reaction, optimum condition is: the 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 bromo pyridines, 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 and recrystallization use is than being 1g/5～8mL; Main raw material 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles uses the preferable amount of saturated aqueous solution of sodium bisulfite than being 1g/8～10mL with cancellation.
5. according to the described a kind of method for preparing the fluvastatin key intermediate of claim 1, the concrete operations step that it is characterized in that described step (2) hydroxymethylation is: temperature control 20-30 ° C, product 2-halo-3-(4-the fluorophenyl)-1-sec.-propyl-1H-indoles that adds ether solvent and step (1) in the reactor, system is cooled to-78～-70 ° of C, in system, add metal reagent again, finish, system is in adding Paraformaldehyde 96 behind insulation reaction 1.5～2.5h under this temperature, continuing insulation reaction to HPLC detection reaction finishes, add saturated aqueous ammonium chloride cancellation termination reaction then, leave standstill, separatory, organic phase concentrates, and adds the varsol recrystallization and obtains product (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-yl) 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 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 96 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.
6. according to the described a kind of method for preparing the fluvastatin key intermediate of claim 5, 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 tetrahydrofuran (THF), methyl tertiary butyl ether, 1, at least a in 4-dioxane, 2-methyltetrahydrofuran, methylcyclopentyl ether or the n-butyl ether; At least a as in normal hexane, hexanaphthene or the normal heptane of the varsol that recrystallization uses.
7. according to the described a kind of method for preparing the fluvastatin key intermediate of claim 5, it is characterized in that in described step (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～and 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 96 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.
8. according to the described a kind of method for preparing the fluvastatin key intermediate of claim 1, the concrete operations step that it is characterized in that described step (3) phosphating reaction is: temperature control 20-30 ° C, product (3-(4-the fluorobenzene)-1-sec.-propyl-1H-indoles-2-yl) methyl alcohol that adds halogenated hydrocarbon solvent and step (2) in the reactor, add the reaction reagent phosphorous acid ester then, finish, system is reacted under this temperature to the HPLC detection reaction and is finished, add saturated sodium bicarbonate aqueous solution cancellation termination reaction then, leave standstill, separatory, organic phase concentrates, and adds the varsol recrystallization again and obtains product dimethyl (3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles-2-yl) methyl phosphorodithioate; Wherein (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-yl) 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-yl) methyl alcohol and reaction reagent phosphorous acid ester is 1:1.5～4.0; 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and cancellation are 1g/5～20mL with the amount ratio of saturated sodium bicarbonate aqueous solution; The amount ratio of the varsol that 3-(4-fluorophenyl)-1-sec.-propyl-1H-indoles and recrystallization use is 1g/5～20mL.
9. described a kind of method for preparing the fluvastatin key intermediate according to Claim 8, 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, tricresyl phosphite propyl ester, tributyl phosphate, triisopropyl phosphite or triphenyl phosphite; At least a as in sherwood oil, Skellysolve A, normal hexane, hexanaphthene or the normal heptane of the varsol that recrystallization uses.
10. described a kind of method for preparing the fluvastatin key intermediate according to Claim 8, it is characterized in that in described step (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-yl) methyl alcohol and halogenated hydrocarbon solvent amount ratio are preferably 1g/8～12mL; The reaction reagent phosphorous acid ester is preferably trimethyl phosphite, and the mol ratio of (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-yl) methyl alcohol and reaction reagent phosphorous acid ester is preferably 1: 2.0～and 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.
11. described a kind of method for preparing the fluvastatin key intermediate according to Claim 8, it is characterized in that when adding major ingredient, to add lewis acid catalyst in described step (3) phosphating reaction, the mol ratio of (3-(4-fluorobenzene)-1-sec.-propyl-1H-indoles-2-yl) methyl alcohol and lewis acid catalyst is 1:1.0～2.5, is preferably 1:1.0～1.5.
12. according to the described a kind of method for preparing the fluvastatin key intermediate of claim 11, it is characterized in that described lewis acid catalyst is zinc chloride, iron trichloride, aluminum chloride or titanium tetrachloride, is preferably zinc chloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310295068.2A CN103342721B (en) | 2013-07-15 | 2013-07-15 | A kind of method preparing fluvastatin key intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310295068.2A CN103342721B (en) | 2013-07-15 | 2013-07-15 | A kind of method preparing fluvastatin key intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103342721A true CN103342721A (en) | 2013-10-09 |
| CN103342721B CN103342721B (en) | 2016-04-13 |
Family
ID=49277556
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310295068.2A Active CN103342721B (en) | 2013-07-15 | 2013-07-15 | A kind of method preparing fluvastatin key intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103342721B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0244364A2 (en) * | 1986-04-30 | 1987-11-04 | Sandoz Ag | Preparation of olefinic compounds |
| 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 |
| 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 |
-
2013
- 2013-07-15 CN CN201310295068.2A patent/CN103342721B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0244364A2 (en) * | 1986-04-30 | 1987-11-04 | Sandoz Ag | Preparation of olefinic compounds |
| 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 |
Non-Patent Citations (2)
| Title |
|---|
| ALAN R. KATRITZKY ET AL.: "A General and Facile Synthesis of Heterocyclo[b]-Fused Carbazoles", 《J. ORG. CHEM.》, vol. 60, no. 12, 16 June 1995 (1995-06-16) * |
| TOSHIAKI SUNAZUKA ET AL.: "The first total synthesis and reassignment of the relative stereochemistry of 16-hydroxy-16,22-dihydroapparicine", 《TETRAHEDRON LETTERS》, vol. 53, 3 February 2012 (2012-02-03) * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103342721B (en) | 2016-04-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Müller et al. | Copper mediated carbometalation reactions | |
| Xu et al. | Catalytic asymmetric direct α-alkylation of amino esters by aldehydes via imine activation | |
| Tang et al. | A facile synthesis of α-aminophosphonates catalyzed by ytterbium perfluorooctanoate under solvent-free conditions | |
| Khong et al. | Equilibrium between a vinylogous ylide and a phosphonium dienolate zwitterion: vinylogous Wittig olefination versus vinylogous aldol-type reaction | |
| Madduri et al. | Access to chiral α-bromo and α-H-substituted tertiary allylic alcohols via copper (i) catalyzed 1, 2-addition of Grignard reagents to enones | |
| WO2011047501A1 (en) | 2,4,6- or 2,6-alkoxyphenyl dialkylphosphine, tetrafluoroborate, preparation method and use thereof | |
| CN107011145A (en) | A kind of method that utilization visible light catalytic prepares the derovatives of alkene 1,4 of 2 iodine penta 2 | |
| O'Byrne et al. | Rapid synthesis of the tetrahydroquinoline alkaloids: angustureine, cuspareine and galipinine | |
| Song et al. | Divergent intramolecular reactions between phosphines and alkynes | |
| CN1898255B (en) | Process for the preparation of pyridine derivatives | |
| Zhang et al. | Synthesis and structure of an air-stable bis (isopropylcyclopentadienyl) zirconium perfluorooctanesulfonate and its catalyzed benzylation of 1, 3-dicarbonyl derivatives with alcohols | |
| Chen et al. | Cyclization Accompanied with 1, 2-Phenyl Migration in the Protonation of Ruthenium Acetylide Complex Containing an Allenyl Group | |
| Zhu et al. | PPh 3-mediated intramolecular conjugation of alkyl halides with electron-deficient olefins: facile synthesis of chromans and relevant analogues | |
| JP2017128519A (en) | Dialkyl[2-(pyrenyl)phenyl]phosphine, and catalyst comprising palladium compound and the same | |
| CN103342721B (en) | A kind of method preparing fluvastatin key intermediate | |
| Kobayashi et al. | Zinc borates: functionalized hard nucleophiles for coupling reactions with secondary allylic acetates | |
| Xie et al. | N-Heterocyclic carbene-triggered transition-metal-free synthesis of 2, 3-disubstituted benzofuran derivatives | |
| CN109678901A (en) | A kind of three replace the synthetic method of phosphine oxide compound | |
| CN105152827A (en) | Cross coupling reaction of arenesulphonate substrate and organic titanium | |
| Chen et al. | Highly efficient synthesis of β-amino esters via Mannich-type reaction under solvent-free conditions using ZnCl2 catalyst | |
| Qi et al. | Three-component reaction of triphenylphosphine, dialkyl but-2-ynedioate and arylidene pivaloylacetonitrile for diastereoselective synthesis of densely substituted 2, 3-dihydrofurans | |
| JP5212177B2 (en) | Method for producing γ-ketoacetal compound and pyrrole derivative | |
| Liu et al. | Polymer-supported tertiaryphosphine (JJ–TPP) as a green and recyclable organocatalyst for α-addition of carbon nucleophiles to α, β-unsaturated compounds | |
| CN102260267A (en) | Pyrazolidone-tetrahydropyrazole compounds and synthesis method thereof | |
| CN112876507B (en) | Trisubstituted olefin tertiary phosphine compound and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |