CN1182738A - Method for preparing benzene ring nonyl ester - Google Patents
Method for preparing benzene ring nonyl ester Download PDFInfo
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- CN1182738A CN1182738A CN 97125424 CN97125424A CN1182738A CN 1182738 A CN1182738 A CN 1182738A CN 97125424 CN97125424 CN 97125424 CN 97125424 A CN97125424 A CN 97125424A CN 1182738 A CN1182738 A CN 1182738A
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Abstract
The present invention relates to a preparation method of alpha-configurational phenylcyclononyl hydrochloride. Said method includes such process of making methyl (or ethyl) 2 - phenyl - 2 -cyclopentyl - 2 -glycolate or 2 -phenyl -cyclopentyl - 2 - glycolic acid react with 3 - methyl - 3 - azabicyclo (3, 3, 1) nona - 9 alpha - ester.
Description
The present invention relates to the preparation method of 2-phenyl-2-cyclopentyl-2-oxyacetic acid-3-methyl-3-azabicyclo (3,3, the 1) ninth of the ten Heavenly Stems-9 α-ester hydrochloride.
The motion sickness syndrome a kind of special syndrome that to be people take place in motion, the insane device of winnowing with a dustpan or rotating, it mainly shows as dizziness, pale complexion, is in a cold sweat, nausea and vomiting.Motion sickness syndrome is the normal symptom that occurs among space flight, navigation, automobile, train operator and the passenger who takes them, the people that 10-30% is on average arranged in common sea trip according to statistics, in civil aviaton average 1% people is arranged in-flight, in aerospace, on average have the people of 50-60% the different kinematic synthesis of degree all can occur and levy.The syndromic pathogeny of motion sickness is still in continuing research, but the primary pathogeny of generally acknowledging at present is that human body vestibular cholinergic system is hyperfunction because of the be overexcited a series of maincenters and the periphery cholinergic function that produce of irriate in the environment of motion.
People have carried out broad research for preventing and treating motion sickness syndrome for many years, and have developed some medicines.These drug mains will divide maincenter cholinolytic and antihistaminic two classes, and wherein representative drugs is a scopolamine.This two classes medicine is under effective dose, though certain curative effect is all arranged, but exist the side effect of certain degree-drowsy, and drowsy be a kind of very serious potential threat for the space flight of taking such medicine, aviation, navigation and car and boat operator, as the hidden danger of accident; Also can cause inconvenience to passenger or the visitor who takes such medicine, as make people's lassitude.Therefore, develop a kind of curative effect height, the little anti-kinetosis syndrome medicament of side effect is still very necessary.
It is effective to the objective of the invention is to seek a kind of anti-kinetosis syndrome, and the anti-kinetosis syndrome medicine that side effect is little, promptly when keeping anti-kinetosis syndrome curative effect, make the patient still can keep clearheaded, overcome the significant side effects of existing anti-kinetosis syndrome medicine-drowsy.
The present invention is through extensively and profoundly research, unexpectedly find to contain α-configuration phencynonate hydrocloride (2-phenyl-2-cyclopentyl-2-oxyacetic acid-3-methyl-3-azabicyclo (3 of following formula (I), 3,1) ninth of the ten Heavenly Stems-9 α-ester) as the pharmaceutical composition of active ingredient
Have good anti-kinetosis syndrome effect, and side effect is starkly lower than known all anti-kinetosis syndrome medicines.The present invention is based on above-mentioned discovery is accomplished.
In Spain patent NO.549496, reported the preparation method of toluylic acid alcohol derivate, though the compound by this method preparation has comprised 2-cyclopentyl phenylglycollic acid-3-methyl-3-azabicyclo (3,3,1) ninth of the ten Heavenly Stems-the 9-ester, but the steric configuration that does not relate to the bicyclic amino group ester moiety does not point out that it has the effect of treatment anti-kinetosis syndrome yet.In addition, people such as Zhang Qikai are at Acta Pharmaceutica Sinica, and 1984,19, reported the α of a series of 3-methyl-3-azabicyclo (3,3,1) ninth of the ten Heavenly Stems-9-ester class among the 748-754, the synthetic and cholinolytic activity of beta isomer, but do not report compound structure involved in the present invention.
First purpose of the present invention relates to is α-configuration phencynonate hydrocloride of containing formula (I) pharmaceutical composition as active ingredient, it has good anti-kinetosis syndrome effect, and side effect (as drowsy) is starkly lower than all known anti-kinetosis syndrome medicines.
According to the present invention, pharmaceutical composition of the present invention has the good motion sickness syndrome effect of preventing and treating, and its anti-carsick, anti-seasick total effective rate is more than 80%; Alleviating because of quickening that rotation causes that Electronystagmogram changes and Coriolis quickens to cause that the effect that body of stomach and stomach hole electrograph change uses, can obviously alleviate the variation of These parameters, the gained data are learned processing by statistics, pharmaceutical composition P value of the present invention＜0.01, and the placebo group changes no any change to These parameters; Major side effects drowsy aspect, the drowsy incidence the during anti-motion sickness seasick of pharmaceutical composition of the present invention is 10%, the drowsy incidence of diphenidol is 18.7%, P0.05, the drowsy incidence of placebo is 22.4%, P＜0.01.
Further, pharmaceutical composition of the present invention has higher biological activity to maincenter and periphery vagusstoff, and for example, the maincenter that antagonism M agonist methylarecaidin causes on the mouse intensity of trembling is atropinic 1.1 times; On the central convulsion that anti-N agonist nicotine causes, intensity is atropinic 6.7 times; On the convulsions that antagonism anticholinesterase soman causes better effect is arranged, and coromegine there is not this effect; Expand the pupil effect mouse, suppress to be respectively 1/13,1/8 and 1/4 of scopolamine on the intensity of salivation effect and central inhibitory action.
Therefore, pharmaceutical composition of the present invention has tangible anti-kinetosis syndrome effect, and its side effect simultaneously (mainly referring to drowsy) is starkly lower than known drug.
What the present invention's second purpose related to is preparation of pharmaceutical composition of the present invention and preparation method thereof.Pharmaceutical composition of the present invention can be mixed and made into required formulation by vehicle or the carrier that will use always in formula (I) compound and the pharmacy field by the method for the conventional useful in preparing drug formulations in this area.According to the present invention, pharmaceutical composition of the present invention can be made into tablet capsule, slow-release paster, chewing gum and injection, preferred tablet.According to the present invention, pharmaceutical composition of the present invention contains 0.05-7% (weight percent) formula (I) compound.
What the 3rd purpose of the present invention related to is to prevent and treat the syndromic method of motion sickness with pharmaceutical composition of the present invention, and this method comprises the patient who pharmaceutical composition of the present invention is delivered medicine to the need control.That route of administration comprises is oral, paster and intramuscular injection, preferred oral.For example, pharmaceutical composition of the present invention can be before treatment half an hour oral a slice, every contains formula (I) compound 1-4mg, effect continues 4-5 hour.
What last purpose of the present invention related to is the method for preparation formula (I) compound, and this method comprises:
(i) (wherein R is CH with formula (II) compound
3, C
2H
5) with formula (III) compound at basic catalyst
Exist down, in inert solvent, react, add hydrochloric acid subsequently, or (ii) with formula (IV) compound and formula (III) compound at the phosphinylidyne diimidazole
Exist down, in inert solvent, react, add hydrochloric acid subsequently.
Preparation in accordance with the present invention, wherein the basic catalyst in (i) is selected from: sodium hydride, sodium Metal 99.5, sodium methylate or sodium ethylate, formula (II) compound can be prepared by currently known methods (sees U.S.patent No.3,381,017 (1968)), formula (II) compound also can be prepared (seeing HouseH.O.et al:J.org.Chem.28,2407 (1983)) by currently known methods, formula (II) is 1 with the mol ratio of formula (III) reaction: 1-1: 5, and temperature of reaction 50-110 ℃; (i) and the inert solvent (ii) be selected from: anhydrous own heptane, benzene, toluene.In addition, in (ii), the mol ratio of formula (IV) compound and formula (III) compound is 1: 1-1: 5, and temperature of reaction is 20-100 ℃.
The following examples are used for describing in further detail the present invention, but should understand, these embodiment do not mean that any limitation of the invention.
Embodiment 1
Synthesizing of 2-phenyl-2-cyclopentyl-2-oxyacetic acid-9 α-[3-methyl-3-azabicyclo (3,3, the 1) ninth of the ten Heavenly Stems] ester hydrochloride
(1) gets 5 liters of there-necked flasks, add 2-phenyl-2-cyclopentyl-2-hydroxy methyl acetate 228 gram (0.974 mol, n respectively successively
25 D1.5205), 3-methyl-3-azabicyclo (3,3, the 1) ninth of the ten Heavenly Stems-9 α-alcohol 141 grams (0.910 mol, mp 94-5 ℃), 2500 milliliters of anhydrous normal heptanes and sodium hydride (content 80%) 8.2 grams, the oil bath heating is also started stirring, and liquid is slowly steamed.React after 3 hours, removal of solvent under reduced pressure, the room temperature cooling splashes into 2N hydrochloric acid and stirs, and separates out white solid.Filter, the gained solid press dry the back with frozen water washing, airing, with 800 milliliters of recrystallizations of 95% ethanol, gets title compound 232 grams after filter collection, crystallization, the drying, productive rate 65%.Mp 202-5 ℃ (fusion is decomposed simultaneously).
Ultimate analysis: C
22H
31NO
3HCl=393.93
Calculated value %:C 67.07; H 8.19; N 3.56; Cl 9.01
Experimental value %:C 67.00; H 8.08; N 3.46; Cl 8.93 infrared spectras (IR): pressing potassium bromide troche cm
-1
3400; 1730; 1600; 1240 UV spectrum (UV) λ
Max257.6 (ε 234, H2O) proton nmr spectra (
1HNMR), CDCl
3δ, TMS, 10.96 (s, b, 1H), 7.63 (d, 2H, J=7), 7.36 (t, 1H, J=7) 7.28 (m, 2H, J=7) 4.97 (s, 1H), 3.82 (d, 1H, J=12.7), 3.78 (d, 1H, J=12.7) 3.20-3.02 (m, 3H) 2.88 (d, 3H, J=4.4), 2.28-1.36 (m, 16H). carbon-13 nmr spectra (
13CNMR), CDCl3, δ, 175.14 1C 31.58 1C141.18 1C 31.16 1C128.28 2C 26.96 1C127.83 1C 26.64 1C126.00 2C 26.52 1C79.40 1C 26.10 1C72.01 1C 22.90 1C58.59 1C 22.55 1C47.67 1C 17.94 1C46.41 2C mass spectrum (MS) m/z 357 (M+) (2) press the method among the embodiment 1 (1), different is to add 2-phenyl-2-cyclopentyl-2-hydroxy methyl acetate 18 grams (0.0654 mol) successively, 3-methyl-3-azabicyclo (3,3,1) ninth of the ten Heavenly Stems-9 α-alcohol 10 grams (0.0646 mol) and normal heptane are 250 milliliters, replace sodium hydride with 0.2 gram sodium Metal 99.5 (0.0087 mol), get 7.6 gram title compounds, productive rate 29.8%, mp 202-04 ℃ (fusion is decomposed simultaneously), its infrared and spectroscopic data of the nuclear magnetic resonance is with the data among the embodiment 1 (1).
(3) press method among the embodiment 1 (1), different is to add 2-phenyl-cyclopentyl-2-hydroxy methyl acetate 20 gram (0.0858 mol), 3-methyl-3-azabicyclo (3 successively, 3,1) ninth of the ten Heavenly Stems-9 α-alcohol 11 grams (0.0715 mol), normal heptane are 300 milliliters, replace sodium hydride with 0.03 molar sodium methylate 1.62 grams, get 17.2 gram title compounds, productive rate 61%, mp 202-4 ℃ (fusion is decomposed simultaneously), its infrared and spectroscopic data of the nuclear magnetic resonance is with the data among the embodiment 1 (1).
(4) according to the method among the embodiment 1 (1), different is to add 2-phenyl-2-cyclopentyl-2-hydroxy methyl acetate 5 gram (0.0214 mol), 3-methyl-3-azabicyclo (3 successively, 3,1) ninth of the ten Heavenly Stems-9 α alcohol 2.76 grams (0.078 mol), 80% sodium hydride 0.534 gram (0.0178 mol), replace normal heptane for 150 milliliters with dry toluene, get title compound 3.0 grams, productive rate 42.5%, mp 202-4 ℃ (fusion is decomposed simultaneously), its infrared and spectroscopic data of the nuclear magnetic resonance is with the data among the embodiment 1 (1).
(5) according to the method among the embodiment 1 (1), different is to add 2-phenyl-2-cyclopentyl-2-hydroxy methyl acetate 5 gram (0.0214 mol), 3-methyl-3-azabicyclo (3 successively, 3,1) ninth of the ten Heavenly Stems-9 α alcohol 2.76 grams (0.078 mol), 80% sodium hydride 0.534 gram (0.0178 mol), replace normal heptane for 150 milliliters with dry-out benzene, get title compound 4.0 grams, productive rate 57%, mp 202-4 ℃ (fusion can decompose simultaneously), its infrared and spectroscopic data of the nuclear magnetic resonance is with the data among the embodiment 1 (1).
Embodiment 2
The preparation of the phencynonate hydrocloride of α-configuration:
(1) gets 2-phenyl-2-cyclopentyl-2-oxyacetic acid 0.7 gram (0.00318 mol, mp 144-6 ℃), 3-methyl-3-azabicyclo (3,3,1) ninth of the ten Heavenly Stems-9 α-alcohol 0.33 gram (0.00318 mol, 94 ℃-5 ℃ of mp), phosphinylidyne diimidazole 0.515 gram (0.0318 mol), 30 milliliters of anhydrous tetrahydro furans, place altogether in 50 milliliters of reaction flasks, stirred 24 hours decompression and solvent recovery under the room temperature, generate oily matter, separate chloroform with silica gel column chromatography, methyl alcohol, ammoniacal liquor mixed solvent (85: 14: 1) wash-out reclaims solvent, behind the ether dissolution resistates, add an amount of 2N hydrochloric acid again and separate out solid, and with 95% ethyl alcohol recrystallization promptly get 0.639 the gram α-configuration phencynonate hydrocloride, productive rate 51%, mp 203-5 ℃ (fusion is decomposed simultaneously), infrared spectra and spectroscopic data of the nuclear magnetic resonance are with embodiment 1 (1).
Ultimate analysis: C
22H
31NO
3HCl=393.93
Calculated value %:C:67.07; H:8.19; N:3.56;
Experimental value %:C:67.24; H:8.19; N:3.45;
(2) press method described in the embodiment 2 (1), the raw material that adds equivalent weight successively, different is to replace tetrahydrofuran (THF) with anhydrous dimethyl formamide (DMF), then obtain the phencynonate hydrocloride of 0.542 gram α-configuration, productive rate 43.3%, mp 203-5 ℃ (fusion is decomposed simultaneously), the data of its infrared spectra and NMR (Nuclear Magnetic Resonance) spectrum are with embodiment 1 (1).
Embodiment 3
(1) preparation of 2-phenyl-2-cyclopentyl-2-hydroxy methyl acetate:
Get magnesium chips (level Four) 22g (0.90 mol) and anhydrous diethyl ether 250ml, put in the there-necked flask, splash into monobromethane (three grades) 110g (1.0 mol) and 250ml anhydrous ether solution, make Grignard reagent.Feed drying nitrogen, steam ether, temperature rise to 60 ℃ in treating adds dry toluene 200ml, continues the distillation ether, until 95 ℃ of interior temperature.Stir and to drip 60g (0.9 mol) cyclopentadiene (industrial goods, new distillation, boiling point 40-41 ℃) and 250ml anhydrous toluene solution down.Finish, be cooled to 80 ℃, change water distilling apparatus into, add anhydrous diethyl ether 20ml, temperature rise to 100 ℃ in being distilled to.Be cooled to-5-0 ℃, drip the toluene solution of phenyl glyoxilic acid methyl ester 82g (0.50 mol), finish, stirred 10 minutes, remove ice bath, room temperature (21-23 ℃) stirring 50 minutes.Cooling is also stirred dropping 30% acetic acid 300ml and concentrated hydrochloric acid 25ml down, and solid all dissolves.Tell toluene layer, successively through water, sodium hydrogen carbonate solution, water washing.Toluene liquid is put in the hydrogenator, added T-1 type active nickel 20 grams, normal-temperature reaction, significantly slack-off to inhaling hydrogen, discharging.The elimination catalyzer, the filter residue toluene wash, washing lotion and filtrate merge, and boil off toluene, and 82-5 ℃/0.03mmHg fraction is collected in underpressure distillation, gets product 96g, productive rate 82%, n
25 D1.5205, IR:v
OH3525cm
-1, v
C=01725cm
-1
This product thin-layer chromatography controlling quality.Concrete grammar is: silica GF254 thin layer plate, developping agent 1,2-ethylene dichloride, ultraviolet 254nm fluorescence location, principal spot Rf=0.72, inclusion-free spot.
(2) according to the method described in the embodiment 3 (1), add the raw material of identical weight successively respectively, the temperature of reaction when different is the toluene solution that dropping phenyl glyoxilic acid methyl ester 82 restrains in the cyclopentadiene Grignard reagent is-10 °-6 ℃.Get final product to such an extent that 2-phenyl-2-cyclopentyl-2-hydroxy methyl acetate 90 restrains productive rate 76.9%, n
25 D1.5203, boiling point 82-5 ℃/0.03mmHg, silica GF254 thin layer plate, developping agent 1,2-ethylene dichloride, ultraviolet 254nm fluorescence location, principal spot Rf=0.72, inclusion-free spot.
Embodiment four
The preparation of tablet:
Get α-configuration phencynonate hydrocloride 2.0 grams, use anhydrous alcohol solution, slowly add in the starch (35.5 gram) of crossing 80 mesh sieves, dextrin (50 gram) mixture, behind the mixing, cross 20 order nylon mesh, spray into 50% an amount of ethanol and make softwood and cross 20 mesh sieves, use 20 sieve series grains again, 50-60 ℃ of air seasoning, dry granular add magnesium stearate, with the whole grain of 14 mesh sieves, behind the mixing, promptly get α-configuration phencynonate hydrocloride tablet with 6.5 millimeters punching press film-makings, every heavy 88 milligrams.Measure dissolution rate by the RGII of University Of Tianjin type medicament dissolution instrument, its solubility rate promptly reached more than 80% in 20 minutes.
Embodiment five
The biological effect of pharmaceutical composition of the present invention:
One. compare the anti-kinetosis effect and the side effect of pharmaceutical composition of the present invention (with tablet form) with scopolamine, diphenidol:
Adopt reverse syndrome model and the cat motion sickness sample syndrome model of turn-taking of rabbit, observe pharmaceutical composition of the present invention and contrast medicine diphenidol thereof and scopolamine motion sickness sample Syndrome Prevention effect.Experimental technique: rabbit (Japan large rabbit, body weight 1.7-2.6 kilogram) reverse syndrome model is to place clear-headed rabbit right carotid to penetrate into blood reversibility anticholinesterase isopropyl fluophosphate and penetration-assisting agent methyl-sulphoxide, suppress right side brain (containing vestibular) Pseudocholinesterase, destroy west side vestibular equilibrated function, thereby mandatory circus movement left occurs; Cat (domestic cat, body weight 1.4-3.0 kilogram) motion sample syndrome model is that reversibility anticholinesterase Physostol injects clear-headed cat intramuscular, makes it motion sickness sample symptoms such as hydrostomia, gatism, belly subsides ground and nausea and vomiting occur.Under above-mentioned animal model condition, irritate stomach prevention motion sickness sample symptom for respectively rabbit and/or cat pharmaceutical composition of the present invention, diphenidol and scopolamine each minute three dosage groups (8 rabbits of each dosage group or cat), and measure the ED of three medicine preventive effects respectively
60, the results are shown in Table 1.In addition, for assessment pharmaceutical composition side effect of the present invention, above-mentioned three medicines respectively at three models of mouse, are promptly strengthened carbrital subliminal hypnosis amount action model (reflection central inhibitory action); Expand pupil action model (side effect of reflection visual accommodation obstacle), experimentize, test is a Kunming mouse with mouse, and body weight 18-22 restrains, and each medicine divides five dosage groups, and every group with 10 mouse, male and female half and half.Measure the ED of these three medicines
50Value, and calculate pharmaceutical composition ED of the present invention
50Respectively with diphenidol and scopolamine ED
50Ratio, the results are shown in Table 1.
Anti-kinetosis effect and side effect comparisons such as table 1 pharmaceutical composition of the present invention
Dose,equivalent (ED50mg/kg)
Pharmaceutical composition scopolamine diphenidol B/A C/A of the present invention
A B C one, anti-kinetosis effectiveness
1. the anti-reverse syndrome 0.434 0.129＞50 0.30＞115 of turn-taking of rabbit
2. anti-cat motion sickness sample syndrome 0.211 0.059 20.18 0.30 91.3 two, side effect
1. mouse is strengthened penta crust than sodium threshold 4.15 0.99 4.2 0.24 6.9
Following HD effect
2. mouse suppresses salivation 3.74 0.47 8.0 0.13 13.6
3. mouse is expanded pupil 0.911 0.066 13.8 0.072 10.5
Can obviously see by data in the table 1: the ED of scopolamine and diphenidol side effect
50The ED of value and pharmaceutical composition side effect of the present invention
50Ratio (B/A is C/A) less than they two anti-motion disease model effectiveness ED
50With pharmaceutical composition effectiveness ED of the present invention
50Ratio, this shows above-mentioned three medicines under identical anti-kinetosis effective dose, the side effect of pharmaceutical composition of the present invention is less than scopolamine and diphenidol.
Two. the effect that the prevention of pharmaceutical composition of the present invention is seasick, carsick:
Past 90 all there was the volunteer that all there is the medical worker of carsick history in the sailor volunteer of seasick history and past 165, adopt double blinding, parallel, counter point at random, be equally divided into three groups of (seasick 30 people/groups, carsick 55 people/groups), sailing, drove 30 minutes before, take the pharmaceutical composition/people of the present invention who contains 2.0 milligrams of α configuration phencynonate hydroclorides by group respectively, placebo and 25 milligrams/people of diphenidol), ship is in 5 grades in wave, gush 4 grades condition navigation, carryall travels on having, travelled respectively on the road surface of jolting and taking a sudden turn 2-4 hour down, observe preventive effect, the results are shown in Table 2.The effect that the prevention of double blinding parallel check experiments such as table 2 pharmaceutical composition of the present invention is seasick, carsick
Pharmaceutical composition placebo diphenidol preventive effect group n % n % n % total effective rate ship 24 80.0** 00 23 76.7** of the present invention
Car 48 87.3** △ 9 16.4 35 63.6** obvious effective rate ships 20 66.7** 00 20 66.7**
Car 33 60.0** 3 5.5 27 49.1** inefficiency ships 3 10.0** 27 90.0 3 10.0**
Car 5 9.1** 33 60.0 10 18.2** total effective rate=obvious effective rates+efficient * *: compare P＜0.01 with placebo; △: compare P＜0.05 with diphenidol.By table 2 as seen, pharmaceutical composition of the present invention is the same with the positive control drug diphenidol, at total effective rate, compare all difference highly significants (P＜0.01) on obvious effective rate and the inefficiency with placebo, but the anti-carsick total effective rate of pharmaceutical composition of the present invention reaches 87.3%, be higher than 63.6% of diphenidol, statistical procedures P＜0.05.
Three. electronystagmography and Coriolis that pharmaceutical composition prevention swivel chair of the present invention causes quicken to stimulate the clectrogastrogram variation effect that causes:
Adopt the experimental technique of double blinding in (two), equality contrast and, divide 3 groups of experimentize chamber swivel chair whirl test and Coriolis acceleration tests 90 volunteers in preceding 1 hour oral identical drug dose of rotation.Swivel chair is with 1 °/S of acceleration
2Accelerate to 90 °/S by 0
2, observe in the rotation and the postrotatory nystagmus electrograph.The Coriolis acceleration test stimulated after 2 minutes, and body of stomach stomach hole electrograph the results are shown in Table 3 when record stimulated.
Table 3 pharmaceutical composition of the present invention prevention swivel chair cause electronystagmography and
Coriolis quickens to stimulate the clectrogastrogram variation effect that causes
Eye rotation back eye body of stomach clectrogastrogram stomach hole clectrogastrogram medicine group shake in the rotation, (degree/second) shake, (degree/second) amplitude, (μ V) amplitude, (μ V) medicine of the present invention preceding 10.2 ± 3.3 18.5 ± 8.5 540 ± 304 539 ± 301 compositions back 6.6 ± 2.6** 11.2 ± 6.2**, 346 ± 178**, 369 ± 184** placebo of taking medicine of taking medicine takes medicine preceding 8.7 ± 4.1 17.2 ± 5.5 506 ± 212 518 ± 215
Back 7.5 ± 3.9 15.8 ± 5.5 457 ± 246 457 ± 257 diphenidols of taking medicine take medicine preceding 8.9 ± 3.6 15.9 ± 6.2 563 ± 329 559 ± 333
Back 6.9 ± 3.4*, 11.2 ± 6.2*, 396 ± 227*, the 414 ± 265* that takes medicine takes medicine back and the preceding comparison of taking medicine: * P＜0.05; * P＜0.01
By table 3 as seen, pharmaceutical composition of the present invention and positive control drug diphenidol in the anti-rotation test of experiment, alleviating on electronystagmography and the clectrogastrogram change amplitude, all have obvious effects.Pharmaceutical composition group statistical procedures P of the present invention＜0.01, diphenidol group P＜0.05, and placebo take medicine before and after no significant difference P＞0.05.
Claims (3)
1. prepare following formula α-configuration phencyclidine hydrochloride
The ninth of the ten Heavenly Stems ester method, this method comprises:
(i) with formula (II) 2-phenyl-2-cyclopentyl-2-hydroxy methyl acetate or
Ethyl ester in the presence of basic catalyst, in inert organic solvents, at 50-110 ℃, with formula (II) 3-methyl-3-azabicyclo (3,3, the 1) ninth of the ten Heavenly Stems-9 α-ester with 1: 1-1: 5 mol ratios are anti-
Should, add hydrochloric acid then, or
(ii) with formula (IV) 2-phenyl-2-cyclopentyl-2-oxyacetic acid at phosphinylidyne
The diimidazole catalyzer exists down, in inert organic solvents, at 20-100 ℃, with formula (III) 3-methyl-3-azabicyclo (3,3, the 1)-ninth of the ten Heavenly Stems-9 α-alcohol with 1: 1-1: 5 molar ratio reactions add hydrochloric acid then.
2. the method for claim 1 (i), wherein basic catalyst is selected from sodium hydride, sodium Metal 99.5, sodium methylate or sodium ethylate.
3. the process of claim 1 wherein that inert organic solvents is selected from normal heptane, benzene, toluene, tetrahydrofuran (THF) or dimethyl formamide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN97125424A CN1045956C (en) | 1997-12-09 | 1997-12-09 | Method for preparing benzene ring nonyl ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN97125424A CN1045956C (en) | 1997-12-09 | 1997-12-09 | Method for preparing benzene ring nonyl ester |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93119491A Division CN1039623C (en) | 1993-10-22 | 1993-10-22 | Pharmaceutical composition for preventing and treating motion sickness syndrome and preparation method thereof |
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| Publication Number | Publication Date |
|---|---|
| CN1182738A true CN1182738A (en) | 1998-05-27 |
| CN1045956C CN1045956C (en) | 1999-10-27 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN97125424A Expired - Lifetime CN1045956C (en) | 1997-12-09 | 1997-12-09 | Method for preparing benzene ring nonyl ester |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002067933A1 (en) * | 2001-02-28 | 2002-09-06 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences, P.L.A. | New use of phencynonate hydrochloride |
| WO2002067934A1 (en) * | 2001-02-28 | 2002-09-06 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences, P.L.A. | New use of phencynonate hydrochloride |
| CN100341850C (en) * | 2004-11-30 | 2007-10-10 | 中国人民解放军军事医学科学院毒物药物研究所 | Salts of demethyl phencynonate isomer and N-para-methyl-phenyl-sulfuryl glutamic acid optical isomer and their preparing method and use |
| CN100378064C (en) * | 2004-03-26 | 2008-04-02 | 中国人民解放军军事医学科学院毒物药物研究所 | Active metabolic product of phencynonate and its medicinal use |
| CN100434422C (en) * | 2004-03-26 | 2008-11-19 | 中国人民解放军军事医学科学院毒物药物研究所 | Optical isomer of phencynonate and its use in preparing medicine |
-
1997
- 1997-12-09 CN CN97125424A patent/CN1045956C/en not_active Expired - Lifetime
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002067933A1 (en) * | 2001-02-28 | 2002-09-06 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences, P.L.A. | New use of phencynonate hydrochloride |
| WO2002067934A1 (en) * | 2001-02-28 | 2002-09-06 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences, P.L.A. | New use of phencynonate hydrochloride |
| CN100378064C (en) * | 2004-03-26 | 2008-04-02 | 中国人民解放军军事医学科学院毒物药物研究所 | Active metabolic product of phencynonate and its medicinal use |
| CN100434422C (en) * | 2004-03-26 | 2008-11-19 | 中国人民解放军军事医学科学院毒物药物研究所 | Optical isomer of phencynonate and its use in preparing medicine |
| CN100341850C (en) * | 2004-11-30 | 2007-10-10 | 中国人民解放军军事医学科学院毒物药物研究所 | Salts of demethyl phencynonate isomer and N-para-methyl-phenyl-sulfuryl glutamic acid optical isomer and their preparing method and use |
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| CN1045956C (en) | 1999-10-27 |
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