CN102670580A - Preparation method for naftidrofuryl stereoisomer and medicine application - Google Patents
Preparation method for naftidrofuryl stereoisomer and medicine application Download PDFInfo
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- CN102670580A CN102670580A CN2011100610494A CN201110061049A CN102670580A CN 102670580 A CN102670580 A CN 102670580A CN 2011100610494 A CN2011100610494 A CN 2011100610494A CN 201110061049 A CN201110061049 A CN 201110061049A CN 102670580 A CN102670580 A CN 102670580A
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Abstract
The invention discloses a preparation method for naftidrofuryl stereoisomer and a medicine application, in particular to an application on preparing the medicines for treating peripheral blood vessel diseases, cardiovascular and cerebrovascular diseases and central nervous system diseases. The invention also relates to a method for preparing four stereoisomers of 2-(1-naphthyl methyl)-3-(tetrahydrofuran base) propionic acid. R-phenylethylamine and S-phenylethylamine are respectively used as resolving agents to respectively resolve 2-(1-naphthyl methyl)-3-(2'R-tetrahydrofuran base) propionic acid and 2-(1-naphthyl methyl)-3-(2'S-tetrahydrofuran base) propionic acid to correspondingly obtain four stereoisomers of the 2-(1-naphthyl methyl)-3-(tetrahydrofuran base) propionic acid. The preparation method related by the invention is convenient to operate and has a strong reproducibility, the resolving yield is improved to a certain degree, a small quantity of resolving agent is used, and the production cost is lowered.
Description
Technical field
The present invention relates to drug world; Be specifically related to four stereoisomers of naftidrofuryl and the method for preparing and the medical usage of pharmaceutically acceptable salt thereof; Particularly be used to prepare treatment peripheral blood vessel, cardiovascular and cerebrovascular disease and and the central nervous system disease medicine aspect purposes, and the synthetic method of key intermediate 2-(1-menaphthyl)-four stereoisomers of 3-(tetrahydrofuran base) propanoic acid.
Background technology
Naftidrofuryl (Nafronyl, NF), chemical name 3-(1-naphthyl)-2-tetrahydrofurfuryl propanoic acid-2-lignocaine ethyl ester is a kind of peripheral vasodilator agent, preparation is the raceme of naftidrofuryl oxalates, i.e. naftidrofuryl oxalate (Naftidrofuryl Oxalate).Abroad release, be used to treat peripheral blood vessel and cerebrovascular disease clinically, like intermittent claudication, vascular occlusive disease, ischemic cerebrovascular etc. in the sixties.Because evident in efficacy, 1992 at Germany, French preceding 15 of the best-selling drugs of being classified as.
5-HT on the main vasoactive bed of naftidrofuryl
2Receptor and playing a role.Zoopery shows that naftidrofuryl is to 5-HT
2The special antagonistic effect of receptor makes naftidrofuryl have and suppresses vasoconstriction and the dual function that suppresses platelet aggregation.Simultaneously, naftidrofuryl can improve RCD, blood viscosity lowering, so naftidrofuryl can play blood vessel dilating when tissue local ischemias such as periphery or brain, improve organ perfusion, the effectively pharmacological action of microcirculation improvement.In addition; Naftidrofuryl also has the cellular metabolism of increasing effect, and its very permeable is crossed blood brain barrier, through stimulating the effect of the succinate dehydrogenase (SDH) in the tricarboxylic acid cycle; Increase aerobic metabolism; ATP is produced to be increased, and lactate levels descends, thereby supplies with the cellular metabolism more energy to improve the aerobic metabolism of brain and blood vessel.This of naftidrofuryl is different to make it at the treatment ischemic cerebrovascular with pharmacological actions other medicament for expanding vascellum, and like vascular dementia, the aspect has unique treatment advantage.After wide clinical application; Some countries have reported the untoward reaction of naftidrofuryl in succession; Common untoward reaction is feeling sick of causing of oral administration, epigastrium pain, erythra etc., and these symptom occurrence probability are up to 10%, but serious in the stage that needs drug withdrawal.The inhibition of spasm, cardiac conduction can appear in the high dose administration.Therefore, when considering intravenous applications heart and the toxic danger of nervous system have been surpassed the benefit that this medicine is used to treat peripheral vascular disease, Britain and European committee on Safety of Drugs announce to stop using the naftidrofuryl injection, but oral formulations still keeps use.
But; The pharmacological action of medicine be through and intravital macromole between strict chiral Recognition and coupling realize; In many cases, there is significant difference in the optical antipode of chemical compound pharmacologically active, metabolic process, metabolic rate and toxicity etc. in vivo.From the sixties in last century, after " thalidomide " incident, the clinical meaning of chiral drug has caused people's extensive concern.21 century more is called as the century of chiral drug.In recent years, the exploitation of chiral drug has become the focus of international medical research.Have 1/3 to be chiral drug approximately in more than the 1200 kind of medicine of exploitation in the world.Have the chirality factor in the chiral drug molecular structure, and by the medicine that the chipal compounds with pharmacologically active is formed, wherein only containing effective enantiomer is main with effective enantiomer perhaps.On the pharmacology, the chiral drug of taking single enantiomer can reduce dosage and metabolism burden, improves the amplitude of dosage and widens purposes, to pharmacokinetics and dosage better control can be arranged.Amplitude is wideer when dosage setting. react less: more confident when dosage is selected.The chiral drug of single enantiomer can reduce the interaction with other drug. and improve activity and reduce dosage, improve specificity and reduce the possible side effect that causes by certain enantiomer.As far as pharmacy corporation, produce chiral drug and can save resource, reduce trash discharge, reduce pollution to environment.Therefore four three-dimensional pure isomers of synthesis of oxalic acid naftidrofuryl, and its pharmacologically active and toxicity difference studied have important significance for theories and using value.
In view of the above, based on present clinical use be the raceme of naftidrofuryl oxalates, the present invention proposes may exist one or several isomer and pharmaceutically acceptable salt thereof to 5-HT in four stereoisomers and the pharmaceutically acceptable salt thereof of naftidrofuryl
2Receptor has than the better antagonism of other isomers, thereby can reduce daily dose, practices thrift cost, and reduces the toxic and side effects of medicine.And four isomers of naftidrofuryl and pharmaceutically acceptable salt thereof add the various pharmaceutical preparatioies that the medicine acceptable carrier is made, and are applicable to following treatment of diseases: cerebral arteriosclerosis, cerebral infarction, cerebral trauma and surgical operation convalescent period, vascular dementia, alzheimer's disease, Combination senile dementia, old abalienation, brain insufficiency, Meniere's disease, intermittent claudication, painful spasm, diabetic vasculitis, Reynolds syndrome, vasculitis, telangiitis and trophic ulcer and early stage gangrene.
The synthesis technique of raceme naftidrofuryl oxalate is comparatively ripe; The synthetic then research of its four stereoisomers is less relatively, and the 2-that is shown in the following figure (1-menaphthyl)-four stereoisomers of 3-(tetrahydrofuran base) propanoic acid (chemical compound 1～4) are the key intermediates in the whole synthetic route.
For synthesizing of chemical compound 1～4, has only one piece of bibliographical information at present.1991; People such as Descours are raw material with the tetrahydrofurfuryl alcohol of R or S type respectively; Through with raceme process route similar methods, obtain two pairs of non-corresponding isomers respectively, i.e. the 2-of intermediate shown in figure below (1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid (chemical compound 5) and 2-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid (chemical compound 6); Be dissolved in the non-corresponding isomer of this two couple in the diisopropyl ether respectively; Can separate out the relatively poor chemical compound of dissolubility, pass through recrystallization again, the promptly corresponding pure article that obtain chemical compound 4 and chemical compound 1.After mother solution reclaimed, use 1 normal R-phenethylamine as resolving agent respectively, separate obtaining the less chirality salt of dissolubility, through recrystallization repeatedly, acid is free again, and recrystallization side obtains other two kinds of stereoisomers once more.(Helv.Chim.Acta，1991.74(8)：1757-1763)。This method complex operation needs the repeated multiple times recrystallization, causes productive rate lower; In addition; The fractionation of chemical compound is that to utilize between the non-corresponding isomer in diisopropyl ether the difference of dissolubility to carry out isolating, because two pairs of non-corresponding isomeric compounds 5 all are to exist with the grease form with 6, making needs a large amount of diisopropyl ether dilution grease that the insoluble matter appearance just can be arranged; And the repeatability of this operation is relatively poor, and productive rate is unstable.Therefore, need develop four stereoisomers of new synthesis technique urgently with the preparation naftidrofuryl.
Summary of the invention
The invention discloses four stereoisomers of naftidrofuryl with medical value and the new prepn process of the acceptable salt of pharmacy thereof.The present invention also aims to provide a kind of is raw material with 2-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid (chemical compound 5) or 2-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid (chemical compound 6) respectively; Pass through chiral separation; Obtain the process of 2-(1-menaphthyl)-four stereoisomers of 3-(tetrahydrofuran base) propanoic acid (chemical compound 1～4); It is high that it splits efficient, and simple to operate.In addition, the present invention also provides four stereoisomers of naftidrofuryl and the medical usage of pharmaceutically acceptable salt thereof, especially for the purposes of preparation treatment peripheral blood vessel, cardiovascular and cerebrovascular disease and central nervous system disease medicine aspect.For example: be applicable to following treatment of diseases: cerebral arteriosclerosis, cerebral infarction, cerebral trauma and surgical operation convalescent period, vascular dementia, alzheimer's disease, Combination senile dementia, old abalienation, brain insufficiency and Meniere's disease, intermittent claudication, painful spasm, diabetic vasculitis, Reynolds syndrome, vasculitis, telangiitis and trophic ulcer or early stage gangrene.
In the pharmaceutical preparation that four stereoisomers by naftidrofuryl of the present invention and its pharmaceutically acceptable salt are processed, can be that single stereoisomers also can be that several stereoisomers mix with arbitrary proportion.
The pharmaceutically acceptable salt of four stereoisomers of naftidrofuryl of the present invention comprises the addition salts that forms with following acid: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid, formic acid, acetic acid, benzoic acid, methanesulfonic acid, fumaric acid, succinic acid, oxalic acid, citric acid, maleic acid, malic acid, tartaric acid, glyoxalic acid or aspartic acid.
Four stereoisomers and the pharmaceutically acceptable salt thereof of naftidrofuryl of the present invention can be carrier with any pharmaceutically acceptable adjuvant, comprising: excipient, diluent, correctives, coloring agent, antiseptic or stabilizing agent.
Of the present inventionly contain four stereoisomers of naftidrofuryl and the pharmaceutical preparation of pharmaceutically acceptable salt can be adopted common capsule, tablet, granule or other oral formulations; Also can carry out parenteral; Can take any conventionally form, for example injection, ointment, percutaneous dosing or inhalant.The various dosage forms of pharmaceutical composition of the present invention can prepare according to the method for knowing in the pharmaceutical field.The dosage of above activating agent will be different because of prescription.
As resolving agent, the process of four stereoisomers (chemical compound 1～4) of preparation 2-(1-menaphthyl)-3-(tetrahydrofuran base) propanoic acid comprises the steps: with R-phenethylamine and S-phenethylamine in the present invention
1. a pair of non-corresponding isomer 2-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid (chemical compound 5) is dissolved in the resolution solvent, adds the S-phenethylamine at ambient temperature.The molar ratio of resolving agent S-phenethylamine and chemical compound 5 can be 0.5～2: 1, and is wherein preferred with 0.5: 1;
2. stir after 10 minutes～24 hours under the room temperature, the adularescent solid is separated out, and sucking filtration is dry;
With the filter cake recrystallization that obtains once after, acidic hydrolysis obtains the bullion of 2S-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid (chemical compound 4);
4. the bullion that step 3 is obtained carries out recrystallization, promptly obtains optical voidness 2S-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid (chemical compound 4);
5. the mother solution in the step 2 is reclaimed; Bullion chemical compound behind the acidic hydrolysis adds the R-phenethylamine at ambient temperature; Resolving agent R-phenethylamine can be 0.5～2: 1 with the molar ratio that reclaims 2-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid (chemical compound 5) that obtains, and is wherein preferred with 0.5: 1;
6. stir after 10 minutes～24 hours under the room temperature, the adularescent solid is separated out, and sucking filtration is dry;
7. with the white solid recrystallization that obtains in the step 62 times,, obtain optical voidness 2R-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid (chemical compound 2) through acidic hydrolysis;
8. a pair of non-corresponding isomer 2-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid (chemical compound 6) is dissolved in the resolution solvent; Add the R-phenethylamine at ambient temperature; The molar ratio of resolving agent R-phenethylamine and chemical compound 6 can be 0.5～2: 1, and is wherein preferred with 0.5: 1;
9. stir after 10 minutes～24 hours under the room temperature, the adularescent solid is separated out, and sucking filtration is dry;
With the filter cake recrystallization that obtains once after, acidic hydrolysis obtains the bullion of 2R-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid (chemical compound 1);
11. the bullion chemical compound that step 10 is obtained carries out recrystallization, promptly obtains optical voidness 2R-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid (chemical compound 1);
12. the mother solution in the step 9 is reclaimed, and the bullion chemical compound behind the acidic hydrolysis adds the S-phenethylamine at ambient temperature, resolving agent S-phenethylamine can be 0.5～2: 1 with the molar ratio that reclaims the chemical compound 6 that obtains, and is wherein preferred with 0.5: 1;
13. stir after 10 minutes～24 hours under the room temperature, the adularescent solid is separated out, sucking filtration is dry;
14.,, obtain optical voidness 2S-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid (chemical compound 3) through acidic hydrolysis with the white solid recrystallization that obtains in the step 13 2 times.
The present invention compared with prior art, its advantage is easy and simple to handle, repeatability is strong, resolution yield improves, and uses the amount of resolving agent less, has reduced production cost.
Description of drawings
Fig. 1 is the proton nmr spectra of 2R-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid (chemical compound 1);
Fig. 2 is the proton nmr spectra of 2R-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid (chemical compound 2);
Fig. 3 is the proton nmr spectra of 2S-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid (chemical compound 3);
Fig. 4 is the proton nmr spectra of 2S-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid (chemical compound 4);
Fig. 5 is 2S-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid-N, the proton nmr spectra of N-lignocaine ethyl ester oxalates;
Fig. 6 is 2R-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid-N, the proton nmr spectra of N-lignocaine ethyl ester oxalates;
Fig. 7 is 2S-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid-N, the proton nmr spectra of N-lignocaine ethyl ester oxalates;
Fig. 8 is 2R-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid-N, the proton nmr spectra of N-lignocaine ethyl ester oxalates.
The specific embodiment
Specify content of the present invention through embodiment below.In the present invention, the instance of the following stated is in order better to set forth the present invention, is not to be used for limiting scope of the present invention.
2S-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid
6.8g 2-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid is dissolved in the 34mL ether, drips S-α-Ben Yian 1.5mL under the room temperature, after continuing to stir 1h; The adularescent solid is separated out, the reactant liquor hold over night, and sucking filtration obtains white solid; Ether/acetone 63mL recrystallization obtains white solid, and white solid is soluble in water, adds dilute hydrochloric acid and regulates pH to acid; Extracted with diethyl ether 4 times merges organic layer, anhydrous Na
2SO
4Dried overnight, steaming removes organic solvent and obtains the bullion chemical compound, and the bullion chemical compound is obtained optical voidness 2S-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid with the isopropyl alcohol recrystallization,
(c 0.49, MeOH) (Lit.
C 8.92, MeOH);
1H-NMR (CDCl
3) δ 1.29-1.33 (m, 1H), 1.71-2.03 (m, 5H), 3.07-3.12 (m, 1H), 3.18-3.23 (m, 1H); 3.53-3.58 (m, 1H), 3.66-3.70 (m, 1H), 3.74-3.79 (m, 1H), 3.90-3.95 (m; 1H), and 7.33-7.39 (m, 2H), 7.45-7.54 (m, 2H), 7.73 (d, J=8.0Hz; 1H), 7.85 (d, J=8.0Hz, 1H), 8.05 (d, J=8.4Hz, 1H); ESI-MS m/z:283.4 [M-H]
-.
2R-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid
Obtaining 2-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid with reclaiming among the embodiment 1, is that resolving agent splits with the R-α-Ben Yian, obtains white solid; Ether/acetone recrystallization secondary obtains pure article chirality salt compound; White solid is soluble in water, add dilute hydrochloric acid and regulate pH to acid, extracted with diethyl ether 4 times; Merge organic layer, anhydrous Na
2SO
4Dried overnight, steaming removes organic solvent and obtains optical voidness 2S-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid,
(c 0.49, MeOH) (Lit.
C 8.69, MeOH);
1H-NMR (CDCl
3) δ 1.33-1.42 (m, 1H), 1.66-2.07 (m, 5H), 2.93-3.03 (m, 1H), 3.14-3.22 (m; 1H), and 3.54-3.60 (m, 1H), 3.67-3.75 (m, 1H), 3.79-3.88 (m, 2H); 7.32-7.40 (m, 2H), 7.45-7.56 (m, 2H), 7.73 (d, J=7.7Hz; 1H), 7.83-7.87 (m, 1H), 8.05 (d, J=8.2Hz, 1H); ESI-MS m/z:283.4 [M-H]
-.
2R-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid
Identical with the method for preparing of 2S-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid; With the R-α-Ben Yian is that resolving agent splits 2-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid; Obtain optical voidness 2R-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid, Mp 103-105 ℃;
(c 0.33, MeOH) (Lit.
C 10.98, MeOH);
1H-NMR (CDCl
3) δ 1.29-1.38 (m, 1H), 1.68-2.10 (m, 5H), 3.07-3.14 (m, 1H), 3.17-3.25 (m; 1H), and 3.51-3.59 (m, 1H), 3.64-3.80 (m, 2H), 3.89-3.95 (m; 1H), and 7.32-7.40 (m, 2H), 7.44-7.56 (m, 2H), 7.72-7.76 (m; 1H), 7.83-7.87 (m, 1H), 8.05 (d, J=8.2Hz, 1H); ESI-MS m/z:283.4 [M-H]
-.
2S-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid
Identical with the method for preparing of 2R-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid; With the S-α-Ben Yian is that resolving agent splits 2-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid that reclaims among the embodiment 3; Obtain optical voidness 2S-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid
(c 0.28, MeOH) (Lit.
C 8.62, MeOH);
1H-NMR (CDCl
3) δ 1.34-1.41 (m, 1H), 1.69-2.06 (m, 5H), 2.94-3.10 (m, 1H), 3.13-3.20 (m; 1H), and 3.55-3.63 (m, 1H), 3.68-3.76 (m, 1H), 3.83-3.89 (m, 2H); 7.32-7.41 (m, 2H), 7.45-7.56 (m, 2H), 7.74 (d, J=7.7Hz; 1H), 7.83-7.87 (m, 1H), 8.05 (d, J=8.2Hz, 1H); ESI-MS m/z:283.4 [M-H]
-.
2R-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid-N, the N-lignocaine ethyl ester
With 2.9 gram K
2CO
3Be dissolved in 25 ml waters, add 1.2 gram N, TMSDEA N diethylamine base ethyl chloride hydrochlorate stirs 1/2h to even.1 gram 2R-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid is dissolved in 30 milliliters of toluene ultrasonic hydrotropy.Above-mentioned aqueous solution and toluene liquid are merged, add 0.5 gram benzyltrimethylammonium chloride, be warming up to 90 ℃ of stirring and refluxing.After reaction finished, ethyl acetate extraction (30 milliliters of X4) merged organic layer, anhydrous Na
2SO
4Dried overnight, steaming removes organic solvent and obtains the bullion chemical compound.Obtain 2R-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid-N through silica gel column chromatography (petrol ether/ethyl acetate/triethylamine: 200: 40: 0.5), N-lignocaine ethyl ester (1.32 gram), productive rate 98%,
1H-NMR (CDCl
3) δ 0.93 (t, J=7.1Hz, 6H), 1.34-1.39 (m, 1H), 1.65-1.70 (m, 1H), 1.80-1.87 (m, 2H); 1.92-1.97 (m, 1H), 2.04-2.10 (m, 1H), 2.41-2.50 (m, 6H), 2.96-2.99 (m, 1H), 3.26-3.30 (m; 1H), and 3.34-3.39 (m, 1H), 3.66-3.70 (m, 1H), 3.79-3.83 (m, 1H), 3.87-3.89 (m, 1H); 4.00 (t, J=6.5Hz, 2H), 7.31-7.37 (m, 2H), 7.44-7.51 (m, 2H), 7.71 (d; J=8.0Hz, 1H), 7.83 (d, J=8.0Hz, 1H), 8.05 (d, J=8.4Hz, 1H); ESI-MS m/z: [M+H]
+384.3.
2R-(1-menaphthyl) 3-(2 ' S-tetrahydrofuran base) propanoic acid-N, N-lignocaine ethyl ester oxalates
With two oxalic acid hydrate (402mg; 3.18mmo1) acetone (8mL) solution and 2R-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid-N, the N-lignocaine ethyl ester (1.22g, acetone 3.18mmo1) (25m1) solution mixes; Reflux 1h places the refrigerator crystallize.Ethanol and re-crystallizing in ethyl acetate, sucking filtration gets white crystal,
1H-NMR (D
2O, 500Hz) δ 0.86 (t, J=7.2Hz, 3H), 0.97 (t, J=7.2Hz, 3H), 1.55-1.60 (m, 1H); 1.86-2.06 (m, 5H), 2.36-2.48 (m, 2H), 2.62-2.71 (m, 3H), 3.01-3.13 (m, 3H), 3.50 (dd; J=4.2Hz, J=13.2Hz, 1H), 3.66-3.76 (m, 2H), 3.86-3.90 (m, 1H), 4.00-4.04 (m, 2H); 7.30 (d, J=7.0Hz, 1H), 7.47 (t, J=7.6Hz, 1H), 7.58-7.63 (m, 2H), 7.87 (d; J=8.2Hz, 1H), 7.98 (d, J=8.0Hz, 1H), 8.08 (d, J=8.2Hz, 1H); ESI-MS m/z: [M+H]
+384.3.
2S-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid-N, the N-lignocaine ethyl ester
Identical with the method for preparing of embodiment 5, with 2S-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid and N, the reaction of TMSDEA N diethylamine base ethyl chloride hydrochlorate obtains 2S-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid-N, the N-lignocaine ethyl ester,
1H-NMR (CDCl
3) δ 0.93 (t, J=7.0Hz, 6H), 1.39-1.46 (m, 1H), 1.70-2.07 (m, 5H), 2.38-2.46 (m; 6H), and 3.09-3.12 (m, 1H), 3.24-3.44 (m, 2H), 3.65-3.84 (m, 3H); 3.95-4.05 (m, 2H), 7.31-7.40 (m, 2H), 7.44-7.55 (m, 2H), 7.72 (d; J=8.0Hz, 1H), 7.82-7.86 (m, 1H), 8.05 (d, J=8.4Hz, 1H); ESI-MSm/z: [M+H]
+384.3.
2S-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid-N, N-lignocaine ethyl ester oxalates
Identical with the method for preparing of embodiment 6, with 2S-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid-N, N-lignocaine ethyl ester and oxalic acid salify make title compound,
(c 0.48, MeOH) (Lit.
C 4.99, MeOH);
1H-NMR (D
2O, 500Hz) δ 0.88 (s, 3H), 0.99 (s, 3H), 1.50-1.57 (m, 1H), 1.84-1.92 (m, 3H); 1.99-2.10 (m, 2H), 2.42-2.47 (m, 2H), 2.66-2.74 (m, 3H), 3.07-3.13 (m, 3H), 3.34-3.40 (m; 1H), and 3.69-3.81 (m, 2H), 3.89-3.95 (m, 2H), 4.05-4.08 (m, 1H), 7.27 (d; J=6.8Hz, 1H), 7.44 (t, J=7.5Hz, 1H), 7.55-7.61 (m, 2H), 7.84 (d; J=8.2Hz, 1H), 7.94 (d, J=7.4Hz, 1H), 8.01 (d, J=7.6Hz, 1H); ESI-MS m/z: [M+H]
+384.3.
2R-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid-N, the N-lignocaine ethyl ester
Identical with the method for preparing of embodiment 5, with 2R-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid and N, the reaction of TMSDEA N diethylamine base ethyl chloride hydrochlorate obtains 2R-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid-N, the N-lignocaine ethyl ester,
1H-NMR (CDCl
3, 500Hz) δ 0.93 (t, J=7.2Hz, 6H), 1.40-1.44 (m, 1H), 1.72-2.04 (m, 5H), 2.39-2.44 (m; 6H), and 3.09-3.11 (m, 1H), 3.24-3.29 (m, 1H), 3.36-3.41 (m, 1H), 3.64-3.68 (m, 1H); 3.74-3.83 (m, 2H), 3.96-4.03 (m, 2H), 7.30-7.37 (m, 2H), 7.46-7.51 (m, 2H), 7.71 (d; J=8.0Hz, 1H), 7.83 (d, J=7.8Hz, 1H), 8.02 (d, J=8.4Hz, 1H); ESI-MS m/z: [M+H]
+384.3.
2R-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid-N, N-lignocaine ethyl ester oxalates
Identical with the method for preparing of embodiment 6, with 2R-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid-N, N-lignocaine ethyl ester and oxalic acid salify make title compound,
(c 0.81, MeOH) (Lit.
C 4.98, MeOH);
1H-NMR (D
2O, 500Hz) δ 0.86 (t, J=6.8Hz, 3H), 0.97 (t, J=6.8Hz, 3H), 1.54-1.58 (m, 1H); 1.83-2.05 (m, 5H), 2.37-2.46 (m, 2H), 2.63-2.71 (m, 3H), 3.01-3.10 (m, 3H), 3.43-3.46 (m; 1H), and 3.68-3.74 (m, 2H), 3.86-3.90 (m, 1H), 3.99-4.04 (m, 2H), 7.28 (d; J=6.8Hz, 1H), 7.44 (t, J=7.7Hz, 1H), 7.55-7.63 (m, 2H), 7.86 (d; J=8.2Hz, 1H), 7.97 (d, J=7.8Hz, 1H), 8.05 (d, J=8.0Hz, 1H); ESI-MS m/z: [M+H]
+384.3.
Embodiment 11
2S-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid-N, the N-lignocaine ethyl ester
Identical with the method for preparing of embodiment 5, with 2S-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid and N, the reaction of TMSDEA N diethylamine base ethyl chloride hydrochlorate obtains 2S-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid-N, the N-lignocaine ethyl ester,
1H-NMR (CDCl
3) δ 0.92 (t, J=7.1Hz, 6H), 1.34-1.40 (m, 1H), 1.40-1.70 (m, 1H), 1.80-1.87 (m; 2H), and 1.92-1.97 (m, 1H), 2.03-2.10 (m, 1H), 2.40-2.50 (m, 6H), 2.95-2.99 (m; 1H), and 3.25-3.39 (m, 2H), 3.66-3.70 (m, 1H), 3.79-3.83 (m, 1H), 3.86-3.89 (m; 1H), 4.00 (t, J=6.4Hz, 2H), 7.30-7.37 (m, 2H), 7.46-7.53 (m, 2H); 7.71 (d, J=8.0Hz, 1H), 7.82-7.84 (m, 1H), 8.05 (d, J=8.4Hz, 1H); ESI-MS m/z: [M+H]
+384.3.
Embodiment 12
2S-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid-N, N-lignocaine ethyl ester oxalates
Identical with the method for preparing of embodiment 6, with 2S-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid-N, N-lignocaine ethyl ester and oxalic acid salify make title compound,
(c 0.41, MeOH) (Lit.
C 4.89, MeOH);
1H-NMR (D
2O, 500Hz) δ 0.86 (t, J=6.8Hz, 3H), 0.97 (t, J=6.8Hz, 3H), 1.54-1.58 (m, 1H); 1.83-2.05 (m, 5H), 2.37-2.46 (m, 2H), 2.63-2.71 (m, 3H), 3.01-3.10 (m, 3H), 3.43-3.46 (m; 1H), and 3.68-3.74 (m, 2H), 3.86-3.90 (m, 1H), 3.99-4.04 (m, 2H), 7.28 (d; J=6.8Hz, 1H), 7.44 (t, J=7.7Hz, 1H), 7.55-7.63 (m, 2H), 7.86 (d; J=8.2Hz, 1H), 7.97 (d, J=7.8Hz, 1H), 8.05 (d, J=8.0Hz, 1H); ESI-MS m/z: [M+H]
+384.3.
Embodiment 13
Naftidrofuryl oxalate and four stereoisomers thereof and 5-HT
2AThe receptors bind experiment
Experimental technique: each combine to contain in hatching pipe of experiment about 50 μ g memebrane proteins, [
3H] and Ketanserine (NEN LifeSciences, Boston, MA, USA), receive reagent thing and buffer (final volume is 250 μ L).With wild-type receptor bonded [
3H] concentration of Ketanserine is 1.0nM, receives reagent thing (competition part) to adopt 5 concentration.Nonspecific combination is confirmed by the mianserin of 10 μ M. for radioligand; Hatched 30 minutes down at 37 ℃; Thereafter, the cessation reaction through quick filtration WhatmanGF/C filter (be immersed in 0.3% PEI in advance, and wash with 10ml ice buffer subsequently).The radioactivity that is trapped on the filter is come detection by quantitative through the liquid scintillation photometer.Experimental result is seen table 1.
Table 1. naftidrofuryl oxalate and four stereoisomers thereof and 5-HT
2AThe receptors bind experiment
| Drugs | K 1(nM) | pK i |
| Naftidrofuryl oxalate | 256.45±10.25 | 6.48±0.04 |
| |
153.00±20.20 | 6.55±0.10 |
| |
972.15±68.85 | 5.77±0.08 |
| |
2073.50±695.50 | 5.64±0.09 |
| Embodiment 12 chemical compounds | 150.40±6.40 | 6.84±0.01 |
Each value is the mean ± S.E.M.of three independent experiments, each performed in duplicate. conclusion: four stereoisomers of naftidrofuryl oxalate and 5-HT
2AReceptor binding capacity has significant difference.Wherein to be that the isomer of S configuration combines better active in the C-2 position, and furan nucleus C '-2 configuration is to combining active contribution less.So the C2 of naftidrofuryl oxalate is that the stereoisomer (embodiment 8 chemical compounds and embodiment 12 chemical compounds) and the related compound thereof of S configuration has good new drug development prospect.
Claims (15)
1. the medical usage of naftidrofuryl stereoisomer or its pharmaceutically-acceptable salts is characterized in that using it for the medicine that preparation prevented or treated peripheral blood vessel, cardiovascular and cerebrovascular disease or central nervous system disease.
2. the naftidrofuryl stereoisomer of claim 1 or its pharmaceutically acceptable salt is characterized in that they are acid-addition salts that the stereoisomer of naftidrofuryl forms with following acid respectively: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid, oxalic acid, formic acid, acetic acid, benzoic acid, methanesulfonic acid, fumaric acid, succinic acid, citric acid, maleic acid, malic acid or tartaric acid.
3. the purposes of claim 1; It is characterized in that naftidrofuryl stereoisomer or its pharmaceutically acceptable salt are used to prepare the medicine of treating following disease, these diseases comprise: cerebral arteriosclerosis, cerebral infarction, cerebral trauma and surgical operation convalescent period, vascular dementia, alzheimer's disease, Combination senile dementia, old abalienation, brain insufficiency and Meniere's disease, intermittent claudication, painful spasm, diabetic vasculitis, Reynolds syndrome, vasculitis, telangiitis and trophic ulcer or early stage gangrene.
One kind the prevention or the treatment peripheral blood vessel, cardiovascular and cerebrovascular disease or central nervous system disease pharmaceutical composition; It is characterized in that, contain naftidrofuryl stereoisomer or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier in the said pharmaceutical composition.
5. the pharmaceutical composition of claim 4 is characterized in that contained naftidrofuryl stereoisomer and pharmaceutically acceptable salt thereof can be any in four stereoisomers of naftidrofuryl, also can be the mixture of several kinds of isomer arbitrary proportions.
6. pharmaceutical composition as claimed in claim 4 is characterized in that, the stereoisomer of said naftidrofuryl or the dosage of its pharmaceutically acceptable salt: during adult's oral administration, the single administration amount is 0.1mg～1000mg; When intravenously administrable, the single administration amount is 0.01mg～500mg.
7. pharmaceutical composition as claimed in claim 4 is characterized in that, when the stereoisomer of said naftidrofuryl or the dosage of its pharmaceutically-acceptable salts were adult's oral administration, the single administration amount was 1mg～500mg; When intravenously administrable, the single administration amount is 0.1mg～250mg.
8. the pharmaceutical composition of claim 4 is characterized in that, said pharmaceutical composition is tablet, capsule, slow releasing tablet, granule, powder, syrup, oral liquid or injection.
9. the pharmaceutical composition of claim 4 is characterized in that, said pharmaceutical composition contains single naftidrofuryl stereoisomer, and it is 2S-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid-N, N-lignocaine ethyl ester or its pharmaceutically acceptable salt.
10. the pharmaceutical composition of claim 4 is characterized in that, said pharmaceutical composition contains single naftidrofuryl stereoisomer, and it is 2S-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid-N, N-lignocaine ethyl ester or its pharmaceutically acceptable salt.
11. the pharmaceutical composition of claim 4; It is characterized in that; Said pharmaceutical composition contains two kinds of blended naftidrofuryl stereoisomers of arbitrary proportion; They are 2S-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid-N, N-lignocaine ethyl ester or its pharmaceutically acceptable salt and 2S-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid-N, N-lignocaine ethyl ester or its pharmaceutically acceptable salt.
12. prepare the method for 2-(1-menaphthyl)-four stereoisomers of 3-(tetrahydrofuran base) propanoic acid: it is characterized in that; Be raw material with 2-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid and 2-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid respectively; Pass through chiral separation; Obtain 2-(1-menaphthyl)-four stereoisomers of 3-(tetrahydrofuran base) propanoic acid, specifically may further comprise the steps:
A. 2-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid is dissolved in the resolution solvent; Add the S-phenethylamine at ambient temperature; The molar ratio of resolving agent S-phenethylamine and 2-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid can be 0.5～2: 1, and is wherein preferred with 0.5: 1;
B. stir after 10 minutes～24 hours under the room temperature, the adularescent solid is separated out, and sucking filtration is dry;
C. with the filter cake recrystallization that obtains once after, acidic hydrolysis obtains the bullion of 2S-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid;
D. the bullion that step c is obtained carries out recrystallization, promptly obtains optical voidness 2S-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid;
E. the mother solution among the step b is reclaimed; Bullion chemical compound behind the acidic hydrolysis adds the R-phenethylamine at ambient temperature; Resolving agent R-phenethylamine can be 0.5～2: 1 with the molar ratio that reclaims 2-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid that obtains, and is wherein preferred with 0.5: 1;
F. stir after 10 minutes～24 hours under the room temperature, the adularescent solid is separated out, and sucking filtration is dry;
G. with the white solid recrystallization that obtains among the step f 2 times,, obtain optical voidness 2R-(1-menaphthyl)-3-(2 ' S-tetrahydrofuran base) propanoic acid through acidic hydrolysis;
H. 2-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid is dissolved in the resolution solvent; Add the R-phenethylamine at ambient temperature; The molar ratio of resolving agent R-phenethylamine and 2-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid can be 0.5～2: 1, and is wherein preferred with 0.5: 1;
I. stir after 10 minutes～24 hours under the room temperature, the adularescent solid is separated out, and sucking filtration is dry;
J. with the filter cake recrystallization that obtains once after, acidic hydrolysis obtains the bullion of 2R-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid;
K. the bullion chemical compound that step j is obtained carries out recrystallization, promptly obtains optical voidness 2R-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid;
L. the mother solution in the step I is reclaimed; Bullion chemical compound behind the acidic hydrolysis adds the S-phenethylamine at ambient temperature; Resolving agent S-phenethylamine can be 0.5～2: 1 with the molar ratio that reclaims 2-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid that obtains, and is wherein preferred with 0.5: 1;
M. stir after 10 minutes～24 hours under the room temperature, the adularescent solid is separated out, and sucking filtration is dry;
N. with the white solid recrystallization that obtains among the step m 2 times,, obtain optical voidness 2S-(1-menaphthyl)-3-(2 ' R-tetrahydrofuran base) propanoic acid through acidic hydrolysis.
13. method as claimed in claim 12; It is characterized in that resolution solvent used among step a, e, h, the l can be any mixed solvent of methanol, ethanol, normal propyl alcohol, isopropyl alcohol, ethyl acetate, n-butyl alcohol, isobutanol, acetonitrile, oxolane, dichloromethane, chloroform, toluene, acetone, ether, diisopropyl ether, propyl ether etc. or above solvent, wherein preferred ether or propyl ether.
14. like the said method of claim 12, it is characterized in that resolution reagent used among step a, e, h, the l and the molar ratio of waiting to split chemical compound can be 0.5～2: 1, wherein preferred with 0.5: 1.
15. like the said method of claim 12; It is characterized in that recrystallization solvent used among step c, d, g, j, k, the n can be any mixed solvent of methanol, ethanol, normal propyl alcohol, isopropyl alcohol, ethyl acetate, n-butyl alcohol, isobutanol, acetonitrile, oxolane, dichloromethane, chloroform, toluene, acetone, ether, diisopropyl ether, propyl ether etc. or above solvent, preferred acetone mixed system or diisopropyl ether.
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| CN104086515A (en) * | 2014-06-13 | 2014-10-08 | 刘博� | Preparation method of naftidrofuryl oxalate |
| CN105418477A (en) * | 2015-12-22 | 2016-03-23 | 爱斯特（成都）生物制药股份有限公司 | Method for reducing content of diastereoisomer impurity in Ledipasvir intermediate |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104086515A (en) * | 2014-06-13 | 2014-10-08 | 刘博� | Preparation method of naftidrofuryl oxalate |
| CN105418477A (en) * | 2015-12-22 | 2016-03-23 | 爱斯特（成都）生物制药股份有限公司 | Method for reducing content of diastereoisomer impurity in Ledipasvir intermediate |
| CN105418477B (en) * | 2015-12-22 | 2018-12-21 | 爱斯特（成都）生物制药股份有限公司 | The method for reducing diastereoisomer impurity content in Lei Dipawei intermediate |
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