CN102167689B - Preparation method of chiral warfarin and chiral warfarin derivatives - Google Patents
Preparation method of chiral warfarin and chiral warfarin derivatives Download PDFInfo
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- CN102167689B CN102167689B CN 201110060566 CN201110060566A CN102167689B CN 102167689 B CN102167689 B CN 102167689B CN 201110060566 CN201110060566 CN 201110060566 CN 201110060566 A CN201110060566 A CN 201110060566A CN 102167689 B CN102167689 B CN 102167689B
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- warfarin
- acetone
- chiral
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- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention relates to a preparation method of chiral warfarin and chiral warfarin derivatives. The invention aims to provide a preparation method which is simple to operate, has low cost and is is suitable for industrial production. The preparation method comprises the following steps: 1) performing alcohol-aldehyde reaction in a mixed solvent of ethanol and water, wherein the volume ration of ethanol to water in the mixed solvent is 5:2-3 and the dosing molar ratio of substituted benzaldehyde to acetone is 1:2; the aqueous solution is maintained to be alkaline in the reaction process; after the reaction, the product is separated and purified to obtain light yellow solid which is the intermediate product substituted benzalacetone; and 2) in the reaction solvent, performing 1,4-addition reaction between the substituted benzalacetone and 4-hydroxycoumarin under the joint action of chiral catalyst, acetic acid and auxiliary catalyst, wherein the dosing molar ratio of substituted substituted benzalacetone to 4-hydroxycoumarin is 1:1.5-1.6, and the acetic acid is 1-10 times as much as 4-hydroxycoumarin; adjusting the pH value to 7 after the reaction to obtain the chiral warfarin and derivative products of the chiral warfarin.
Description
Technical field
The present invention relates to the preparation method of a class medicine, say more specifically the coumarins anticoagulation---the preparation method of chirality warfarin and derivative thereof.
Background technology
The chemistry of warfarin is called neodicoumarin, the following I formula of its structure:
Warfarin is the coumarins oral anticoagulation, clinical in prevention and treatment thrombotic disease, can prevent thrombosis and development, as treat the thromboembolism induced phlebitis, reduce the M ﹠ M of pulmonary infarction, reduce surgery large operation, the phlebothrombosis sickness rate of rheumatic heart disease, arthrodesis of hip, artificial replacement's heart valve surgery etc.In addition, also can be used for after the treatment operation or post-traumatic venous thrombosis, and can do the adjuvant drug of myocardial infarction.Also must routine take behind multiple surgery, the intervene operation.
Warfarin is metabolism through liver cytochrome P 450 (CYP) enzyme mainly, and the medicine that can suppress the CYP activity all can make the metabolism of warfarin slow down, Increased Plasma Half-life, and anticoagulation strengthens; Vice versa.Warfarin contains 2 kinds of isomer, and the S type is through liver CYP2C9 enzymes metabolism, and the R type is by enzymes metabolisms such as CYP3A4.Thrombocyte plays an important role in the processes such as hemostasis, thrombosis, atherosclerosis.Drug main will be by suppressing arachidonic acid metabolism, increases in the thrombocyte mechanism such as cAMP concentration and suppress platelet adhesion reaction, gathering and secreting function.
This medicine synthesizes prothrombin, VII, IX, X by suppressing vitamin K in liver cell, thus the performance anticoagulation.Carboxylated enzyme in the liver microsomes can become Gla with the glutamic acid rotating of above-mentioned thrombin, the latter again with calcium binding, its blood coagulation activity of competence exertion.The effect of this medicine is to suppress carboxylated enzyme, the synthetic above-mentioned factor be there is no the facedown effect, after must waiting for that these factors are exhausted in vivo relatively, the competence exertion anticoagulant effect, so the onset of this medicine is slow, only effective in vivo, duration of efficacy long (until after the vitamin k-dependent factor returned to finite concentration gradually, anticoagulation just disappeared) after the drug withdrawal.In addition, this medicine still can induce liver to produce the vitamin K-dependent clotting factor precursor substance, and makes it to be released into blood, this material antigenicity is identical with relevant thrombin, but there is no coagulation function, have on the contrary blood coagulation resisting function, and can reduce the platelet aggregation reaction of thrombin induction.Therefore, under the effect of this medicine, prothrombin, VII, IX, X, Protein S and PROTEIN C are synthetic to be reduced, and " false set blood because of " that is " vitamin K antagonistic induced protein " increase, and reaches anticoagulant effect.The pharmacokinetic parameters of this medicine is more stable, is better than other oral anticoagulation (such as anisindione, Marcoumar and temparin etc.).Only have when the patient does not tolerate this medicine, just select other oral anticoagulation.When Atrial fibrillation patient preventing brain stroke, this medication effect obviously is better than acetylsalicylic acid.When treatment or prevention gestational patients thrombus or embolism formation, subcutaneous or intravenous injection heparin curative effect then is better than this medicine (because heparin easily passes through placenta).
This medicine is a kind of of coumarin anticoagulant, and the effect of pair antivitamin K is arranged in vivo.Synthetic at liver that can suppress prothrombin that vitamin K participates in, VII, IX, X.Existing prothrombin, VII, IX, X in the blood be there is no resistant function.Therefore, can not use as external anticoagulation, anti-freezing could be effectively after also must activated consumption of coagulation factors in the body, effect and hold time also longer after the onset.Be mainly used in preventing and treating thrombotic disease.
This medicine is one of coumarins anticoagulation, and the coumarins anticoagulation is the material that a class contains 4 hydroxy coumarin basic structure, and oral participation internal metabolism is just brought into play anticoagulation, therefore claim oral anticoagulation.Temparin (dicoumarol), warfarin (warfarin, neodicoumarin) and Acenocoumarol (acenocoumarol, Syncumar) etc. are arranged.Their pharmacological action is identical.
Pharmacological action: coumarins is vitamin K antagon, suppressing vitamin K at liver is transformed to hydroquinone type by epoxide, thereby stop recycling of vitamin K, impact contains prothrombin, VII, the IX of glutaminic acid residue, the carboxylation of X, make these factors stay in precursor stage without blood coagulation activity, thereby affect coagulation process.To established above-mentioned factor unrestraint effect, so the anticoagulation time of occurrence is slower.Generally need to play a role after 8～12 hours, peaked in 1～3 day, anticoagulation still can be kept a couple of days after the drug withdrawal.The temparin anticoagulation is slow and lasting, continues 4～7 days.The warfarin effect occurs very fast, continues 2～5 days.
Physiological disposition: the warfarin oral absorption is complete, can measure in the blood plasma after 1 hour, reaches the peak in 2～8 hours.With plasma protein binding ratio be 90%～99%.T1/2 is 10～60 hours.Mainly metabolism in liver and kidney.Temparin absorbs irregular.With plasma protein binding ratio be 90%～99%.T1/2 is 10～30 hours.Acenocoumarol t1/2 is 8 hours, and the reduced form meta-bolites still has anticoagulation, and t1/2 is 20 hours.
Clinical application: purposes and heparin are same, can prevent thrombosis and development.Also can be used as the myocardial infarction adjuvant drug.Oral effective, action time is longer.But effect occurs slowly, and dosage is wayward.Also be used for preventing that phlebothrombosis from occuring after the operations such as rheumatic heart disease, arthrodesis of hip, artificial replacement's heart valve.
Drug interaction: 1. vitamin K deficiency or application Broad spectrum antibiotics suppress intestinal bacteria in the food, make vitamin K content in the body, and this class drug effect is strengthened.2. the platelet suppressant drug such as acetylsalicylic acid can act synergistically with this class medicine.3. Chloral Hydrate, crovaril, tolbutamide, Quinidine etc. can be because of the displacement plasma proteinss, and salicylate, imipramine, metronidazole, Cimitidine Type A/AB etc. all make this class drug effect strengthen because suppressing liver drug enzyme.4. barbiturates, phenytoin Sodium predisposition are led liver drug enzyme, and oral contraceptive can make this class drug effect weaken because increasing Blood clotting.
The indication of Anticoagulation of Warfarin:
(1) valvular heart disease and valve replacement: valvular heart disease (especially mitral stenosis) is if merge atrial fibrillation or cerebral embolism has occured, perhaps the left room of ultrasonic cardiography graph discovery diameter obviously increase (＞55mm), answer the Long-term Oral warfarin, keep INR in 2.0～3.0, otherwise oral aspirin is just passable.Strong all mechanical prosthetic valves of recommendation change the lobe patient and accept for a long time (forever) oral anticoagulation thing treatment, generally keep INR in 2.5～3.5.If patient exists in atrial fibrillation or the oral warfarin anti-freezing process simultaneously thromboembolism having occured still, should consider to add and use acetylsalicylic acid.
The risk that thromboembolism occurs in the bioprosthetic valves displacement is significantly less than mechanical prosthetic valve, and general Anticoagulation got final product in 3 months, kept INR in 2.0～3.0.If bioprosthetic valves displacement patient finds thrombus in the room when merging simultaneously atrial fibrillation or operation, answer the Long-term Oral warfarin treatment; If previously the thromboembolism medical history is arranged, the time of anticoagulant therapy should be at 3～12 months.Other situation Long-term Oral acetylsalicylic acid get final product.
(2) non-valve characteristic of disease atrial fibrillation: the meta-analysis of a plurality of random tests shows, non-valve characteristic of disease atrial fibrillation patient, compare with placebo, warfarin makes the danger of cerebral apoplexy descend 68%, the incidence of profuse bleeding does not have significance to increase, and anti-freezing reduces mortality ratio 33%.Acetylsalicylic acid is also effective, and the danger of cerebral infarction descends 21% generally, and effect is not as good as warfarin.The patient of cerebral embolism has occured at atrial fibrillation, oral anticoagulant reduces a year major cardiovascular events (vascular death, non-lethal cerebral apoplexy, non-lethal myocardial infarction or surrounding blood vessel embolism) 47%, Stroke risk descends 66%, and the anti-freezing group does not have patient that hematencephalon occurs.Acetylsalicylic acid only reduces main terminal point event 17%, and cerebral apoplexy descends 14%, compares no difference of science of statistics with the placebo group.
Age is larger, and the risk of thromboembolism is also larger.Age is greater than 75 years old lasting atrial fibrillation, should conventional oral Anticoagulation of Warfarin, and warfarin benefits obviously greater than risk for this class patient.Aged Patients increases for the susceptibility of warfarin, and not only being embodied in hemorrhage risk increases, and also shows same INR level, and therefore the actual anti-bolt higher level that the elderly obtains can consider that with the warfarin dose titration be INR1.6～2.5.
All exist the atrial fibrillation patient of other thrombus Hazard Factor all should accept the anti-bolt treatment of warfarin simultaneously.These Hazard Factor comprise that previous TIA, surrounding blood vessel embolism or cerebral apoplexy, hypertension, left chamber function are low, rheumatic disease of mitral valve, valve replacement.Other comprise that incomplete, the left room of ultrasonic discovery left chamber function increases, left room flow velocity slows down than advanced age, significantly coronary artery disease, diabetes, hyperthyroidism, spontaneous echo in the left room.The patient that cerebral apoplexy or transient ischemic attacks medical history are arranged, a year incidence of stroke can reach 12%.Between 65～75 years old age, if there is no other Hazard Factor, oral warfarin or acetylsalicylic acid can.There were not again other Hazard Factor that cause thromboembolism in age less than 65 years old, and oral aspirin gets final product.
Strong high risk patient's Long-term Oral antithrombotics of recommending to have indication is kept target INR2.5 (2.0～3.0), and the effect of acetylsalicylic acid is not as antithrombotics.The risk of Paroxysmal Atrial Fibrillation generation thromboembolism also increases, and whether uses warfarin and should depend primarily on patient and whether have other Hazard Factor that cause thromboembolism.
(3) electrical conversion: for the patient of atrial fibrillation greater than 48 hours electrical conversions, answer 3 weeks of anti-freezing before the conversion, keep target INR 2.5 (2.0～3.0), in 4 weeks of anti-freezing after the conversion success, in order to avoid shrink delayed recovery because of the auricle position, form new thromboembolism.Therefore it is reported, oral Quinidine conversion embolism incidence is 1.5% in 400 patients, advises that the medicine conversion is the same with electrical conversion, needs the pre-treatment of oral anticoagulation thing, conversion then, the same atrial fibrillation of method.
The warfarin merging uses heparin or Low molecular heparin may be reduced to the time of the front medication of conversion before the conversion, but needs further its effect of discussion.Determine whether need oral 3 weeks of warfarin very unreliable before the conversion with esophagus ultrasound.
(4) coronary heart disease: for primary prevention and the secondary prevention of coronary heart disease, the effect of the warfarin of medium tenacity (INR 2.5～3.5) prevention vascular events is suitable with acetylsalicylic acid at least.If the warfarin of median dose (INR 2.0～3.0) adds acetylsalicylic acid, effect is better than any one medicine to be used separately, but both share and might increase hemorrhage risk.
(5) pulmonary infarction and venous thrombosis: general way is, on the basis of heparin or treatment by Low molecule heparin, gives simultaneously warfarin in 24 hours oral, treats to heparin more than 4～5 days or continuous 2 days INR
1961, West etc. (J.Am.Chem.Soc.1961,81,2676) once used quinine set, the warfarin of isolating single steric configuration of the metal salt compound success of quinine (R and S).Regrettably his productive rate only has 31%.(the J.PHarmcol.Exp.Ther.1979 such as Cook, 210 (3), 391) warfarin is done further derivative with sulphur acyl chloride of camphor, the product post that obtains is separated, then process with the 5%NaOH aqueous solution, obtain respectively R, the warfarin of the single configuration of S, productive rate are respectively 10.5%, 12.2%.Ohta etc. (J.Org.Chem.1995,60.357-363) have reported that a kind of organic phosphine that adopts does catalyzer comes the similar structures of synthesis of chiral by asymmetry catalysis tonka bean camphor and a series of unsaturated annulenones compound.But regrettably the substituting group when unsaturated ketenes is phenyl, when namely product structure is warfarin, does not obtain good experimental result.
Therefore with regard to present technique, the single configuration of suitability for industrialized production is that warfarin and derivative thereof are very difficult things, and this is applied to suitability for industrialized production R/S-warfarin and derivative thereof with regard to requiring us to seek a kind of more simple, efficient, useful synthesis technique.
Summary of the invention
The technical issues that need to address of the present invention are based on the deficiency of existing production technique, to provide a kind of easy and simple to handle, lower-cost synthetic route that is suitable for the suitability for industrialized production warfarin of alternative existing route.
Implement by following synthetic route compound among the present invention (1)-(12): first to contain various substituent phenyl aldehydes and acetone as the benzylidene-acetone of the various replacements of raw material synthetic mesophase product, with the 4 hydroxy coumarin reaction of intermediate product and various replacements, obtain final product warfarin and derivative thereof again.
Particularly, the preparation method of chirality warfarin of the present invention and derivative thereof, as follows:
1) in ethanol and water volume ratio were 5: 2～3 mixed solvent, the phenyl aldehyde of replacement and the molar ratio of acetone were 1: 2, carry out pure aldehyde reaction, and temperature of reaction is 25～30 ℃, and the time is 3～6h; Be that the NaOH aqueous solution of weight 5～15% keeps alkaline environment by adding NaOH in the reaction process; After reaction finishes, through separation and purification (i.e. drying is filtered for extraction, washing, desolventizing, underpressure distillation, cooling), getting faint yellow solid---intermediate product replaces benzylidene-acetone; See reaction formula (III):
2) in reaction solvent, 4 hydroxy coumarin is 1: 1.5～1.6 with the molar ratio that replaces benzylidene-acetone, under at chiral catalyst, with respect to the acting in conjunction of the acetic acid of 1～10 times of amount of 4 hydroxy coumarin and cocatalyst through 1, the 4-addition reaction, temperature of reaction is 25～30 ℃, and the time is 22～24h, and the pH of conditioned reaction liquid was neutral after reaction finished, obtain chirality warfarin and derivative product thereof through aftertreatment, see reaction formula (IV):
R=H in the following formula, CH
3, OC H
3, Cl or Br; X=H, Cl or Br; They are the product of corresponding following structure respectively:
Described chiral catalyst is the chiral primary amine catalyzer, is selected from (R, R) diphenyl ethylene diamine, (S, S)-diphenyl ethylene diamine, (R, R)-cyclohexanediamine or (S, S)-cyclohexanediamine;
Described cocatalyst (for metallic compound) is selected from iron trichloride, magnesium perchlorate, lithium perchlorate, columbium pentachloride;
Described reaction solvent is selected from the ether solvents such as Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF), ether, methyl tertiary butyl ether.
Compare with background technology, that the inventive method has is easy and simple to handle, cost is lower, be more suitable in advantages such as suitability for industrialized production.
Description of drawings
Fig. 1 is the HPLC figure of embodiment 1 racemization warfarin; Fig. 2 is the structural formula figure of racemization warfarin.
Fig. 3 is the HPLC figure of embodiment 1R-warfarin; The structural formula figure of Fig. 4 R-warfarin.
Embodiment
The below is described in detail embodiments of the invention, and the present embodiment is being implemented as prerequisite take the invention technical scheme, has provided detailed embodiment and concrete operating process but protection scope of the present invention is not limited to the following examples.
Embodiment 1
1) intermediate product replaces the preparation of benzylidene-acetone.Reaction formula:
Operation steps:
The 50ml single necked round bottom flask adds phenyl aldehyde (0.02mol) and acetone (0.56mmol).Add again 10% NaOH aqueous solution 0.5ml, add again 2ml H
2O.Stir 3h under the room temperature.Regulating pH with rare HCl after reaction finishes makes solution be neutral.Separation and purification (underpressure distillation) gets the oily liquids of thickness, after the cooling faint yellow solid---benzylidene-acetone (150～160 ℃/3333Pa (7mmHg)).
2) preparation of chirality warfarin.Reaction formula:
Operation steps:
The reaction tube of 10ml, disposable adding 4 hydroxy coumarin (0.1m mol), benzylidene-acetone (0.12m mol), chiral primary amine catalyzer (5m mol%), lithium perchlorate (5mmol%), acetic acid (1mmol, 10eq), add again at last Isosorbide-5-Nitrae-dioxane 2ml.At room temperature stir 24h, add shrend after reaction finishes and go out.Use CH
2Cl
2Extraction (10ml * 3 time), organic phase washes (10ml), anhydrous sodium sulfate drying organic phase with water three times.Be spin-dried for solvent and cross pillar (sherwood oil: ethyl acetate=5: 1) get white solid---formula (1) chirality warfarin.See Fig. 1, Fig. 2, wherein
The peak result
With Fig. 3, Fig. 4, wherein
The peak result
Its characterization of compound data:
1H-NMR(400MHz，CDCl3)：δ(ppm)＝1.68(s，1.60H，CH3，ketal，1.72(s，1.37H，CH3，ketal)，1.97-2.04(t，0.67H，CH2，ketal)，2.30(s，0.46H，CH3，ketal)，2.40-2.60(m，1.65H，CH2，keto)，3.30-3.34(d，J＝19.2Hz，0.29H，CH2，ketal)，3.83-3.39(dd，J＝19.2Hz，0.22H，CH2，keto)，4.14-4.19(m，0.54H，CH，ketal)，4.28-4.30(m，0.43H，CH?ketal)，4.70-4.72(d，J＝9.6Hz，0.20H，CH，keto)，7.23-7.30(m，7.37H，ArH)，7.50(t，0.72H，ArH)，7.80，7.82(d，J＝7.6Hz，0.45H)，7.90，7.91(d，J＝8Hz，0.41Hz，7.94-7.96(d，J＝7.6Hz，0.16H，ArH)，9.50(S，0.21H，OHketo).
13C-NMR(100MHz，CDCl3)：δ(ppm)＝212.318，171.166，162.151，161.384，159.712，158.897，153.023，152.902，143.287，141.410，132.04，131.60，129.27，128.65，128.19，127.99，127.26，127.05，126.97，126.53，123.95，123.65，123.07，122.72，116.69，116.56，104.23，101.13，100.50，98.96，42.51，39.97，35.35，34.13，28.28，27.78.IR(film)：v＝3277.7，1681.5，1617.7，1517.2，1496.2，1451.9，1377.4，1076.0，995.9，763.4，700.1.GC?m/z：309(M
+)，265(bp)，187，120.HR?S(ESI)：calad.for?C
19H
16O
4H
+：[M+H]309.1121；found?309.1125.HPLC(Daicel?AD-H；2-propanol/n-Hexane，20：80；flow?rate＝1.0mL/min；λ＝254nm)：tmajor＝6.3min(major)，tminor＝16.4min(minor).
1) preparation of intermediate product 4-methyl benzylidene-acetone, reaction formula:
Operation steps:
The 50ml single necked round bottom flask adds 4-tolyl aldehyde (0.02mol) and acetone (0.56mmol).Add again 10% NaOH aqueous solution 0.5ml, add again 2ml H
2O.Stir 3h under the room temperature.Regulating pH with rare HCl after reaction finishes makes solution be neutral.Separation and purification (underpressure distillation) gets the oily liquids of thickness, after the cooling faint yellow solid---benzylidene-acetone (150-160 ℃/3333Pa (7mmHg)).
2) preparation of chirality warfarin derivative, reaction formula:
Operation steps:
The reaction tube of 10ml, disposable adding 4 hydroxy coumarin (0.1621g, 0.1mmol, 1eq), intermediate product 4-methyl benzylidene-acetone (0.220g, 0.12mmol, 1.2eq), chiral primary amine catalyzer (5mmol%), lithium perchlorate (5mmol%), acetic acid (1mmol, 10eq), add again at last Isosorbide-5-Nitrae-dioxane 2ml.At room temperature stir 24h, add shrend after reaction finishes and go out.Use CH
2Cl
2Extraction (10ml * 3 time), organic phase washes (10ml), anhydrous sodium sulfate drying organic phase with water three times.Be spin-dried for solvent and cross pillar (sherwood oil: ethyl acetate=5: 1) get white solid---formula (2) chirality warfarin derivative 3-(3-oxo-1-p-methylphenyl butyl)-4-hydroxyl-2H-1-chromen-2-one.
Embodiment 3
1) preparation of intermediate product 2-methoxyl group benzylidene-acetone.Reaction formula:
Operation steps:
The 50ml single necked round bottom flask adds Benzaldehyde,2-methoxy (0.02mol) and acetone (0.56mmol).Add again 10% NaOH aqueous solution 0.5ml, add again 2ml H
2O.Stir 3h under the room temperature.Regulating pH with rare HCl after reaction finishes makes solution be neutral.The cut of separation and purification (underpressure distillation) gets the oily liquids of thickness, after the cooling faint yellow solid---benzylidene-acetone (150-160 ℃/3333Pa (7mmHg))
2) preparation of chirality warfarin derivative, reaction formula:
(3)；
Operation steps:
The reaction tube of 10ml, disposable adding 4 hydroxy coumarin (0.1mmol), intermediate product 2-methoxyl group benzylidene-acetone (0.12mmol), chiral primary amine catalyzer (5mmol%), lithium perchlorate (5mmol%), acetic acid (1mmol, 10eq), add again at last Isosorbide-5-Nitrae-dioxane 2ml.At room temperature stir 24h, add shrend after reaction finishes and go out.Use CH
2Cl
2Extraction (10ml * 3 time), organic phase washes (10ml), anhydrous sodium sulfate drying organic phase with water three times.Be spin-dried for solvent and cross pillar (sherwood oil: ethyl acetate=5: 1) get white solid---formula (3) chirality warfarin derivative 3-(3-oxo-1-2 '-p-methoxy-phenyl butyl)-4-hydroxyl-2H-1-chromen-2-one.
Embodiment 4
1) preparation of intermediate product 3-methoxyl group benzylidene-acetone.Reaction formula:
Operation steps:
The 50ml single necked round bottom flask adds m-methoxybenzaldehyde (0.02mol) and acetone (0.56mmol).Add again 10% NaOH aqueous solution 0.5ml, add again 2ml H
2O.Stir 3h under the room temperature.Regulating pH with rare HCl after reaction finishes makes solution be neutral.Reaction finishes rear separation and purification (underpressure distillation), gets the oily liquids of thickness, gets faint yellow solid---benzylidene-acetone (150-160 ℃/3333Pa (7mmHg)) after the cooling.
2) preparation of chirality warfarin derivative, reaction formula:
Operation steps:
The reaction tube of 10ml, disposable adding 4 hydroxy coumarin (0.1mmol), intermediate product 3-methoxyl group benzylidene-acetone (0.12mmol), chiral primary amine catalyzer (5mmol%), lithium perchlorate (5mmol%), acetic acid (1mmol, 10eq), add again at last Isosorbide-5-Nitrae-dioxane 2ml.At room temperature stir 24h, add shrend after reaction finishes and go out.Use CH
2Cl
2Extraction (10ml * 3 time), organic phase washes (10ml), anhydrous sodium sulfate drying organic phase with water three times.Be spin-dried for solvent and cross pillar (sherwood oil: ethyl acetate=5: 1) get white solid---formula (4) chirality warfarin derivative 3-(3-oxo-1-3 '-p-methoxy-phenyl butyl)-4-hydroxyl-2H-1-chromen-2-one.
Embodiment 5
1) preparation of intermediate product 4-methoxyl group benzylidene-acetone.Reaction formula:
Operation steps:
The 50ml single necked round bottom flask adds 4-methoxybenzaldehyde (0.02mol) and acetone (0.56mmol).Add again 10% NaOH aqueous solution 0.5ml, add again 2ml H
2O.Stir 3h under the room temperature.Regulating pH with rare HCl after reaction finishes makes solution be neutral.Extraction, washing, salt are washed (saturated sodium), dry (anhydrous magnesium sulfate), are removed by filter siccative, are spin-dried for solvent and cross pillar (sherwood oil: ethyl acetate=12: 1) get faint yellow solid.
2) preparation of chirality warfarin derivative, reaction formula:
Operation steps:
The reaction tube of 10ml, disposable adding 4 hydroxy coumarin (0.1mmol), intermediate product 4-methoxyl group benzylidene-acetone (0.12mmol), chiral primary amine catalyzer (5mmol%), lithium perchlorate (5mmol%), acetic acid (1mmol, 10eq), add again at last Isosorbide-5-Nitrae-dioxane 2ml.At room temperature stir 24h, add shrend after reaction finishes and go out.Use CH
2Cl
2Extraction (10ml * 3 time), organic phase washes (10ml), anhydrous sodium sulfate drying organic phase with water three times.Be spin-dried for solvent and cross pillar (sherwood oil: ethyl acetate=5: 1) get white solid---formula (5) chirality warfarin derivative 3-(3-oxo-1 p-methoxyphenyl butyl)-4-hydroxyl-2H-1-chromen-2-one.。
Embodiment 6
1) preparation of intermediate product 4-chlorine benzylidene-acetone.Reaction formula:
(6)，
Operation steps:
The 50ml single necked round bottom flask adds 4-chlorobenzaldehyde (0.02mol) and acetone (0.56mmol).Add again 10% NaOH aqueous solution 0.5ml, add again 2ml H
2O.Stir 3h under the room temperature.Regulating pH with rare HCl after reaction finishes makes solution be neutral.Reaction mixture is changed in the separating funnel, tell organic layer, water layer merges organic phase and toluene extraction liquid with the extraction of 10ml toluene, after the 10ml water washing, uses anhydrous magnesium sulfate drying.Remove by filter siccative, be spin-dried for solvent and cross pillar (sherwood oil: ethyl acetate=10: 1) get faint yellow solid.
2) preparation of chirality warfarin derivative, reaction formula:
Operation steps:
The reaction tube of 10ml, disposable adding 4 hydroxy coumarin (0.1mmol), intermediate product 4-chlorine benzylidene-acetone (0.12mmol), chiral primary amine catalyzer (5mmol%), lithium perchlorate (5mmol%), acetic acid (1mmol, 10eq), add again at last Isosorbide-5-Nitrae-dioxane 2ml.At room temperature stir 24h, add shrend after reaction finishes and go out.Use CH
2Cl
2Extraction (10ml * 3 time), organic phase washes (10ml), anhydrous sodium sulfate drying organic phase with water three times.Be spin-dried for solvent and cross pillar (sherwood oil: ethyl acetate=5: 1) get white solid---formula (6) chirality warfarin derivative 3-(3-oxo-1-rubigan butyl)-4-hydroxyl-2H-1-chromen-2-one.
Embodiment 7
1) preparation of intermediate product 4-bromine benzylidene-acetone.Reaction formula:
Operation steps:
The 50ml single necked round bottom flask adds 4-bromobenzaldehyde (0.02mol) and acetone (0.56mmol).Add again 10% NaOH aqueous solution 0.5ml, add again 2ml H
2O.Stir 3h under the room temperature.Regulating pH with rare HCl after reaction finishes makes solution be neutral.Reaction mixture is changed in the separating funnel, tell organic layer, water layer merges organic phase and toluene extraction liquid with the extraction of 10ml toluene, after the 10ml water washing, uses anhydrous magnesium sulfate drying.Remove by filter siccative, be spin-dried for solvent and cross pillar (sherwood oil: ethyl acetate=10: 1) get faint yellow solid.
2) preparation of chirality warfarin derivative, reaction formula:
Operation steps:
The reaction tube of 10ml, disposable adding 4 hydroxy coumarin (0.1mmol), intermediate product 2-bromine benzylidene-acetone (0.12mmolq), chiral primary amine catalyzer (5mmol%), lithium perchlorate (5mmol%), acetic acid (1mmol, 10eq), add again at last solvent 2ml.At room temperature stir 24h, add shrend after reaction finishes and go out.Use CH
2Cl
2Extraction (10ml * 3 time), organic phase washes (10ml), anhydrous sodium sulfate drying organic phase with water three times.Be spin-dried for solvent and cross pillar (sherwood oil: ethyl acetate=5: 1) get white solid---formula (7) chirality warfarin derivative 3-(3-oxo-1 pair bromo phenyl butyl)-4-hydroxyl-2H-1-chromen-2-one.。
Embodiment 8
1) preparation of intermediate product benzylidene-acetone.Reaction formula:
Operation steps:
The 50ml single necked round bottom flask adds phenyl aldehyde (0.02mol) and acetone (0.56mmol).Add again 10% NaOH aqueous solution 0.5ml, add again 2ml H
2O.Stir 3h under the room temperature.Regulating pH with rare HCl after reaction finishes makes solution be neutral.Separation and purification (underpressure distillation) gets the oily liquids of thickness, after the cooling faint yellow solid---benzylidene-acetone (150-160 ℃/3333Pa (7mmHg)).
2) preparation of chirality warfarin derivative, reaction formula:
Operation steps:
The reaction tube of 10ml, disposable adding 6-bromo-4 hydroxy coumarin (0.1mmol), intermediate product benzylidene-acetone (0.12mmol), chiral primary amine catalyzer (5mmol%), lithium perchlorate (5mmol%), acetic acid (1mmol, 10eq), add again at last Isosorbide-5-Nitrae-dioxane 2ml.At room temperature stir 24h, add shrend after reaction finishes and go out.Use CH
2Cl
2Extraction (10ml * 3 time), organic phase washes (10ml), anhydrous sodium sulfate drying organic phase with water three times.Be spin-dried for solvent and cross pillar (sherwood oil: ethyl acetate=5: 1) get white solid---formula (8) chirality warfarin derivative 3-(3-oxo-1 phenyl butyl)-4-hydroxyl-2H-6-bromo-1-chromen-2-one.
Embodiment 9
1) preparation of intermediate product 4-methyl benzylidene-acetone.Reaction formula:
Operation steps:
The 50ml single necked round bottom flask adds 4-tolyl aldehyde (0.02mol) and acetone (0.56mmol).Add again 10% NaOH aqueous solution 0.5ml, add again 2ml H
2O.Stir 3h under the room temperature.Regulating pH with rare HCl after reaction finishes makes solution be neutral.Separation and purification (underpressure distillation) gets the oily liquids of thickness, after the cooling faint yellow solid---benzylidene-acetone (150-160 ℃/3333Pa (7mmHg))
2) preparation of chirality warfarin derivative, reaction formula:
Operation steps:
The reaction tube of 10ml, disposable adding 6-bromo-4 hydroxy coumarin (0.1mmol), intermediate product 4-methyl benzylidene-acetone (0.12mmol), chiral primary amine catalyzer (5mmol%), lithium perchlorate (5mmol%), acetic acid (1mmol, 10eq), add again at last Isosorbide-5-Nitrae-dioxane 2ml.At room temperature stir 24h, add shrend after reaction finishes and go out.Use CH
2Cl
2Extraction (10ml * 3 time), organic phase washes (10ml), anhydrous sodium sulfate drying organic phase with water three times.Be spin-dried for solvent and cross pillar (sherwood oil: ethyl acetate=5: 1) get white solid---formula (9) chirality warfarin derivative 3-(3-oxo-1 p-methylphenyl butyl)-4-hydroxyl-2H-6-bromo-1-chromen-2-one.
Embodiment 10
1) preparation of intermediate product 4-methoxyl group benzylidene-acetone.Reaction formula:
Operation steps:
The 50ml single necked round bottom flask adds 4-methoxybenzaldehyde (0.02mol) and acetone (0.56mmol).Add again 10% NaOH aqueous solution 0.5ml, add again 2ml H
2O.Stir 3h under the room temperature.Regulating pH with rare HCl after reaction finishes makes solution be neutral.Separation and purification (underpressure distillation) gets the oily liquids of thickness, after the cooling faint yellow solid---benzylidene-acetone (150-160 ℃/3333Pa (7mmHg)).
2) preparation of chirality warfarin derivative, reaction formula:
Operation steps:
The reaction tube of 10ml, disposable adding 6-bromo-4 hydroxy coumarin (0.1mmol), intermediate product 4-methoxyl group benzylidene-acetone (0.12mmol), chiral primary amine catalyzer (5mmol%), lithium perchlorate (5mmol%), acetic acid (1mmol, 10eq), add again at last Isosorbide-5-Nitrae-dioxane 2ml.At room temperature stir 24h, add shrend after reaction finishes and go out.Use CH
2Cl
2Extraction (10ml * 3 time), organic phase washes (10ml), anhydrous sodium sulfate drying organic phase with water three times.Be spin-dried for solvent and cross pillar (sherwood oil: ethyl acetate=5: 1) get white solid---formula (10) chirality warfarin derivative 3-(3-oxo-1 p-methoxyphenyl butyl)-4-hydroxyl-2H-6-bromo-1-chromen-2-one.
Embodiment 11
1) preparation of intermediate product benzylidene-acetone.Reaction formula:
Operation steps:
The 50ml single necked round bottom flask adds phenyl aldehyde (0.02mol) and acetone (0.56mmol).Add again 10% NaOH aqueous solution 0.5ml, add again 2ml H
2O.Stir 3h under the room temperature.Regulating pH with rare HCl after reaction finishes makes solution be neutral.Separation and purification (underpressure distillation) gets the oily liquids of thickness, after the cooling faint yellow solid---benzylidene-acetone (150-160 ℃/3333Pa (7mmHg)).
2) preparation of chirality warfarin derivative, reaction formula:
Operation steps:
The reaction tube of 10ml, disposable adding 6-chloro-4-hydroxyl tonka bean camphor (0.1mmol), intermediate product benzylidene-acetone (0.12mmol), chiral primary amine catalyzer (5mmol%), lithium perchlorate (5mmol%), acetic acid (1mmol, 10eq), add again at last Isosorbide-5-Nitrae-dioxane 2ml.At room temperature stir 24h, add shrend after reaction finishes and go out.Use CH
2Cl
2Extraction (10ml * 3 time), organic phase washes (10ml), anhydrous sodium sulfate drying organic phase with water three times.Be spin-dried for solvent and cross pillar (sherwood oil: ethyl acetate=5: 1) get white solid---formula (11) chirality warfarin derivative 3-(3-oxo-1 phenyl butyl)-4-hydroxyl-2H-6-chloro-1-chromen-2-one.
Embodiment 12
1) preparation of intermediate product 4-methoxyl group benzylidene-acetone.Reaction formula:
Operation steps:
The 50ml single necked round bottom flask adds 4-methoxybenzaldehyde (0.02mol) and acetone (0.56mmol).Add again 10% NaOH aqueous solution 0.5ml, add again 2ml H
2O.Stir 3h under the room temperature.Regulating pH with rare HCl after reaction finishes makes solution be neutral.Reaction mixture is changed in the separating funnel, tell organic layer, water layer merges organic phase and toluene extraction liquid with the extraction of 10ml toluene, after the 10ml water washing, uses anhydrous magnesium sulfate drying.Be spin-dried for solvent and cross pillar (sherwood oil: ethyl acetate=12: 1) get faint yellow solid.
2) preparation of chirality warfarin derivative, reaction formula:
Operation steps:
The reaction tube of 10ml, disposable adding 6-chloro-4-hydroxyl tonka bean camphor (0.1mmol), intermediate product 4-methoxyl group benzylidene-acetone (0.12mmol), chiral primary amine catalyzer (5mmol%), lithium perchlorate (5mmol%), acetic acid (1mmol, 10eq), add again at last Isosorbide-5-Nitrae-dioxane 2ml.At room temperature stir 24h, add shrend after reaction finishes and go out.With CH2Cl2 extraction (10ml * 3 time), organic phase washes (10ml), anhydrous sodium sulfate drying organic phase with water three times.Be spin-dried for solvent and cross pillar (sherwood oil: ethyl acetate=5: 1) get white solid---formula (12) chirality warfarin derivative 3-(3-oxo-1-3 '-p-methoxy-phenyl butyl)-4-hydroxyl-2H-6-chloro-1-chromen-2-one.
Claims (1)
1. the preparation method of a chirality warfarin and derivative thereof is characterized in that as follows:
1) in ethanol and water volume ratio were 5: 2 ~ 3 mixed solvent, the phenyl aldehyde of replacement and the molar ratio of acetone were 1: 2, carry out pure aldehyde reaction, and temperature of reaction is 25～30 ℃, and the time is 3～6h; Be that the NaOH aqueous solution of weight 5 ~ 15% keeps alkaline environment by adding NaOH in the reaction process; Reaction through separation and purification, gets faint yellow solid after finishing---and intermediate product replaces benzylidene-acetone; See the reaction formula III:
2) in reaction solvent, 4 hydroxy coumarin is 1:1.5 ~ 1.6 with the molar ratio that replaces benzylidene-acetone, under at chiral catalyst, with respect to the acting in conjunction of the acetic acid of 1 ~ 10 times of amount of 4 hydroxy coumarin and cocatalyst through 1, the 4-addition reaction, temperature of reaction is 25～30 ℃, and the time is 22 ~ 24h, and the pH of conditioned reaction liquid was neutral after reaction finished, obtain chirality warfarin and derivative product thereof through aftertreatment, see the reaction formula IV:
R=H in the following formula, CH
3, OC H
3, Cl or Br; X=H, Cl or Br;
Described chiral catalyst is the chiral primary amine catalyzer, is selected from (R, R) diphenyl ethylene diamine, (S, S)-diphenyl ethylene diamine, (R, R)-cyclohexanediamine or (S, S)-cyclohexanediamine;
Described cocatalyst is selected from iron trichloride, magnesium perchlorate, lithium perchlorate, columbium pentachloride;
Described reaction solvent is selected from Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF), ether, methyl tertiary butyl ether.
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