CN102617449A - 4-substituted-4- (N-propionyl) aniline piperidine compounds, preparation method and application - Google Patents
4-substituted-4- (N-propionyl) aniline piperidine compounds, preparation method and application Download PDFInfo
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- CN102617449A CN102617449A CN201210065066XA CN201210065066A CN102617449A CN 102617449 A CN102617449 A CN 102617449A CN 201210065066X A CN201210065066X A CN 201210065066XA CN 201210065066 A CN201210065066 A CN 201210065066A CN 102617449 A CN102617449 A CN 102617449A
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- hydrochloride
- propofol
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- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 34
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- 229960004134 propofol Drugs 0.000 claims abstract description 30
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 claims abstract description 25
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 15
- 230000000202 analgesic effect Effects 0.000 claims abstract description 11
- 230000002936 tranquilizing effect Effects 0.000 claims abstract description 3
- -1 pyridine compound Chemical class 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 28
- 239000002585 base Substances 0.000 claims description 25
- 229940017219 methyl propionate Drugs 0.000 claims description 23
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 6
- 206010002091 Anaesthesia Diseases 0.000 claims description 5
- 230000037005 anaesthesia Effects 0.000 claims description 5
- UKXZWEDNEGGXQX-UHFFFAOYSA-N aniline;piperidine Chemical class C1CCNCC1.NC1=CC=CC=C1 UKXZWEDNEGGXQX-UHFFFAOYSA-N 0.000 claims description 5
- 230000032050 esterification Effects 0.000 claims description 5
- 238000005886 esterification reaction Methods 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- ZTHRQJQJODGZHV-UHFFFAOYSA-N N-phenyl-propionamide Natural products CCC(=O)NC1=CC=CC=C1 ZTHRQJQJODGZHV-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 2
- 230000002557 soporific effect Effects 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 10
- 230000001624 sedative effect Effects 0.000 abstract description 5
- 230000036407 pain Effects 0.000 abstract description 3
- 238000012377 drug delivery Methods 0.000 abstract description 2
- 230000002349 favourable effect Effects 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000000047 product Substances 0.000 description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 239000007789 gas Substances 0.000 description 8
- 239000012141 concentrate Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- ZTVQQQVZCWLTDF-UHFFFAOYSA-N Remifentanil Chemical compound C1CN(CCC(=O)OC)CCC1(C(=O)OC)N(C(=O)CC)C1=CC=CC=C1 ZTVQQQVZCWLTDF-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 229960003394 remifentanil Drugs 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 230000003444 anaesthetic effect Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 230000002980 postoperative effect Effects 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 4
- 230000036592 analgesia Effects 0.000 description 4
- 230000000146 antalgic effect Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 230000028527 righting reflex Effects 0.000 description 3
- 239000000932 sedative agent Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical class BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 2
- 238000012449 Kunming mouse Methods 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- KDPAWGWELVVRCH-UHFFFAOYSA-N bromoacetic acid Chemical compound OC(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 2
- 229960003793 midazolam Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000003533 narcotic effect Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 1
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 1
- IDBPHNDTYPBSNI-UHFFFAOYSA-N N-(1-(2-(4-Ethyl-5-oxo-2-tetrazolin-1-yl)ethyl)-4-(methoxymethyl)-4-piperidyl)propionanilide Chemical compound C1CN(CCN2C(N(CC)N=N2)=O)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 IDBPHNDTYPBSNI-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229960001391 alfentanil Drugs 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- PNZDZRMOBIIQTC-UHFFFAOYSA-N ethanamine;hydron;bromide Chemical compound Br.CCN PNZDZRMOBIIQTC-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229940127240 opiate Drugs 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
4-substituted-4- (N-propionyl) aniline piperidine compounds, and a preparation method and application thereof. The structure of the compound is shown as formula (I) or hydrochloride thereof, wherein R1Is a substituent with a propofol mother nucleus structure, R2Is selected from 3-CCarbomethoxy or benzyl. The compound is soluble in water, has analgesic and sedative effects, is suitable for relieving pain and tranquilizing a patient monitored after an operation, is particularly favorable for realizing the operation of the patient on an automatic control drug delivery system, and can reduce the operation of an anesthesiologist. The basic preparation method of the compound is that propofol (III) and 4-formic acid-4- (N-phenyl propionamido) -N-substituted piperidine compound (II) are condensed to prepare the compound.
Description
Technical field
The present invention relates to a kind of compound, particularly 4-replacement-4-(N-propionyl group) aniline piperidines with general anesthesia and analgesic effect, and the preparation method of this compound and pharmaceutical use.
Background technology
In the curative activity of clinical operation and postoperative care, the operation conformability of having guaranteed patient is used in uniting of analgesia, calmness and anaesthetic.Present clinical anesthesia all is the monitoring anesthesia under the doctor controls, and the anaesthetist need note the patient's life sign at any time and patient's pain impression is handled targetedly, handle main dependence and use various antalgic and sedative medicines and realize these.Analgesic commonly used at present is the opiates agonist, like fentanyl, and remifentanil etc.Remifentanil (Remifentanil, 3 [4 (methoxycarbonyl)-4-(N-Phenylpropionamide base) 1-piperidines] methyl propionate), structure suc as formula (II a) shown in.The common drug of compatibility has Midazolam, Propofol etc. with it.Propofol (Propofol, 2,6-diisopropyl phenol), structure is shown in formula III.Remifentanil and Propofol have all that onset time is rapid, and metabolism is characteristics rapidly, and the drug regimen that these two kinds of medicines form can produce good antalgic and sedative effect, and patient's quick-recovery soon after the drug withdrawal.But because its metabolism is all very rapid, in surgical procedure, the Anesthetist need regulate the dosage of two kinds of medicines at any time; The drug level of remaining valid; Increased the complexity of operation, thereby many clinically doctors is more prone to use long alfentanil of analgesia and calm time and Midazolam etc., the result can make the postoperative recovery of patient slower; Prolonged the residence time, caused the waste of medical resource to a certain extent at Operation theatre.In patient's postoperative care; Because of also continuing to use the antalgic and sedative medicine; At present widely-used by patient-controlled analgesia pump, patient can according to its wish, be infused into Pain relief agents in the patient body by relevant device by simple touching button; Produce analgesic effect, thereby reduced excessive administration or the insufficient situation of administration.But,,, make it all is at present form use, and the great amount of fat breast is not suitable for the long-time administration to postoperative patient with emulsion because of it is water-soluble low though Propofol can produce sedation effect preferably when being lower than anesthetic concentration.
Summary of the invention
To above-mentioned situation, the invention provides a kind of 4-replacement-4-(N-propionyl group) aniline piperidines of new texture, can effectively address the above problem.The present invention further also provides the preparation method of this compound, and the purposes in pharmacy of this compound.
The said 4-replacement-4-of the present invention (N-propionyl group) aniline piperidines, the free alkali of structure such as formula I form or its hydrochloride (I '):
Wherein, the R in the formula
1Be selected from
,
,
Or
R
2Be selected from 3-methyl propionate base or benzyl.
In the above-claimed cpd of the present invention, further preferred compound comprises: R in the formula
1For
Formula (I ') hydrochloride form compound; Or R in the formula
1For
, R
2Formula I free alkali for benzyl; Or R in the formula
1For
, R
2Formula (I ') hydrochloride compound for 3-methyl propionate base; Or R in the formula
1For
, R
2Formula I free alkali for 3-methyl propionate base.
The basic preparation method of above-claimed cpd of the present invention is to be formed by Propofol (III) and 4-formic acid-4-(N-Phenylpropionamide base)-N-substituted pyridine compound (II) condensation with remifentanil mother nucleus structure.For example, but several kinds of typical preparing method's divisions are following:
Method one: in the common solvent of esterifications such as ETHYLE ACETATE or toluene,, after the esterification of reflux dewatering, obtain the formula I product by Propofol (III) and 4-formic acid-4-(N-Phenylpropionamide base)-N-substituted pyridine compound (II); After further in reaction system, feeding HCl gas salify, promptly can obtain corresponding formula (I ') hydrochloride product.Reaction process is following, R in the formula
2Be selected from 3-methyl propionate base or benzyl:
R in the product (I) that obtains by method for preparing
2Can be benzyl (CAS (U.S. chemical abstract): 256507-84-3) or 3-methyl propionate base.R in the preparation formula I
2During for the product of 3-methyl propionate base, remove the above-mentioned R that directly adopts
2For outside the starting compound (II) of 3-methyl propionate base prepares, can also be in the ban with R
2For the compound (II) of benzyl prepares R
2Be the product (I) of benzyl, remove R in usual manner hydrogenation under hydrogenation catalyst effect commonly used such as Pd/C
2After, in the presence of disacidify agent commonly used such as triethylamine, pyridine,, obtain R again with acrylate reactions
2Formula I product for 3-methyl propionate base; After further feeding HCl gas salify, can also obtain corresponding R
2Formula (I ') hydrochloride product for 3-methyl propionate base.
Method two: in the presence of disacidify agent commonly used such as triethylamine, pyridine; By halo acetyl halide compounds such as chloro-acetyl chloride or bromo acetyl bromides; With Propofol (III) under≤0 ℃ through esterification; After preparing corresponding Propofol halogen ester midbody, with the reaction of formula II compound, obtain the formula I product again; After further feeding HCl gas salify, can obtain corresponding formula (I ') hydrochloride product, reaction process is following:
Method three: by the haloformate and the halogen ethanol (or halogen ethamine) of Propofol; After esterification (or amidation) reaction obtains corresponding halogen ester (or halogen acid amide); React in the presence of disacidify agent commonly used such as triethylamine, pyridine with the formula II compound again; Remove hydrogen halide, obtain the formula I product; After further feeding HCl gas salify, obtain corresponding formula (I ') hydrochloride product.Reaction process is following:
Experimental result shows, the compound water soluble of above-claimed cpd of the present invention, particularly hydrochloride form, and possess the characteristics of satisfied analgesia, calmness and anesthetic action etc.Therefore; With above-claimed cpd of the present invention is acceptable auxiliary material in active drug composition and the pharmacy; Usual manner by present relative medicine preparation; Can prepare can supply clinical use have tranquilizing soporific and/or anesthesia and an analgesic medicine, preferably the injection type medicine of administration outside vein or vein is specially adapted to the patient of postoperative care is carried out antalgic and sedative; Be particularly advantageous in and realize the operation of patient, and can reduce Anesthetist's operation the automatic control drug delivery system.
Below in conjunction with the embodiment of embodiment form, foregoing of the present invention is remake further detailed description.But should this be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following instance.Do not breaking away under the above-mentioned technological thought situation of the present invention, various replacements or change according to ordinary skill knowledge and customary means are made all should be included in the present invention) scope in.
Embodiment
Embodiment 1
With equimolar R
2For the compound (II) of benzyl (CAS:256507-84-3) is dissolved in an amount of ETHYLE ACETATE with Propofol (0.016 mol), reflux water-dividing spends the night, and is cooled to room temperature afterwards.Reaction solution is poured in the water; Use dichloromethane extraction, organic layer is used brine wash, uses anhydrous sodium sulfate drying after telling organic layer; Filter; The resistates that the filtrate decompression evaporate to dryness obtains with alumina chromatographic column (developping agent: use cyclohexane/ethyl acetate=2/1 after cyclohexane/ethyl acetate=10/1 instead) purifying after, formula I white solid product 4.5 g, productive rate 53.4%.
Above-mentioned product (I) is dissolved in an amount of anhydrous diethyl ether, and in 0 ℃ of feeding hydrogen chloride gas, reaction 3h salify filters and obtains corresponding formula (I ') hydrochloride product, productive rate 45%.
Formula (I ') product structure detected result:
NMR: Bruker WH-300 (300 MHz) spectrometer, TMS is interior mark, δ unit is ppm.
Mass spectrograph: Agilent 1200 series 6130 mass spectrometer, ESI.(following examples instrument together)
1HNMR(δ)(CD
3OD)：1.289~1.379?(m,?3H),，1.518~1.538(2s,12H)，2.342~2.390(m,2H)，2.542?(s,broad,?1H)，3.148~3.345?(m,?5H)，3.659~3.919(m,?4H)，4.691(s,2H)，7.562~7.607?(m,?3H)，7.833~7.864(d,10H)?。
Ms:527.3（M-HCl+H）。
Embodiment 2
With equimolar R
2For the compound (II) of benzyl (CAS:256507-84-3) is dissolved in an amount of dry toluene with Propofol (0.016 mol), reflux water-dividing 3h is cooled to room temperature afterwards.Reaction solution is poured in the water; Use dichloromethane extraction, organic layer is used brine wash, uses anhydrous sodium sulfate drying after telling organic layer; Filter; The resistates that the filtrate decompression evaporate to dryness obtains gets formula I white solid product 4.0 g, productive rate 47.5% with alumina chromatographic column (developping agent: use cyclohexane/ethyl acetate=2/1 after cyclohexane/ethyl acetate=10/1 instead) purifying.Reaction process is with embodiment 1.
The formula I product of gained is dissolved in an amount of anhydrous diethyl ether, and in 0 ℃ of feeding hydrogen chloride gas, reaction 3h salify filters and obtains corresponding formula (I ') hydrochloride product, productive rate 45%.
Embodiment 3
The formula I product (2.3 g, 4.3 mmol) of embodiment 1 or embodiment 2 is dissolved in the 100ml ETHYLE ACETATE, adds catalytic amount Pd/C, normal pressure hydrogenation spends the night and removes R
2Benzyl filters, and filtrating concentrates, and (developping agent: cyclohexane/ethyl acetate/triethylamine=5:1:1) purifying gets product 1.2g to resistates, productive rate 64% with alumina column chromatography.Product that obtains (1.2 g, 2.7 mmol) and triethylamine (834 mg, 8.2 mmol) are added in the methyl acrylate (465 mg, 5.4 mmol) the reaction solution stirred overnight at room temperature.Concentrate after alumina column chromatography that (developping agent: the purifying of cyclohexane/ethyl acetate=5:1) obtains R in the formula I
2Be the colorless oil product 398mg of 3-methyl propionate base, productive rate 28.2%.
With R in the formula I
2For 3-methyl propionate based products is dissolved in an amount of anhydrous diethyl ether, in 0 ℃ of feeding hydrogen chloride gas, reaction 3h salify filters and obtains corresponding formula (I ') hydrochloride product, productive rate 90%.
Formula (I ') product structure detected result:
1HNMR(δ)(d-DMSO)：0.849~0.941（m,3H），1.068~1.138?(2s,?12H)，1.886~1.958(m,2H)，2.223~2.306(t,1H)，2.502~2.719?(m,?2H)，2.861~3.112?(m,?6H)，3.281~3.418?(m,?4H)，3.573~
3.638(m,4H)，7.211~7.284?(m,?3H)，7.435~7.594(m,5H)，11.153(s,broad,1H)。
Ms：523.3（M-HCl+H）。
Embodiment 4
Bromoacetyl bromide (1.5 g, 7.5 mmol) (or chloroacetyl chloride 0.84 g, 7.5 mmol) and pyridine (790 mg, 10 mmol) are dissolved in the 100ml ether; Dropping adds Propofol (890 mg, 5 mmol), and temperature is controlled at below 0 ℃; Finish the back at room temperature reaction 2h, reaction is also poured in the frozen water, uses ethyl acetate extraction; The organic layer water washing once, brine wash once, anhydrous sodium sulfate drying.Filter, filtrating concentrates, resistates through column chromatography (developping agent: cyclohexane/ethyl acetate=9:1), white solid 1.2g, productive rate 80% (or Propofol chloracetic acid ester products 1.0g, productive rate 67%).
With the Propofol monobromo-acetic acid ester products (0.38 mmol) of gained, Cs
2CO
3(247 mg, 0.76 mmol) and R
2Be the formula II compound of 3-methyl propionate base (CAS numbering: 1044512-35-7) mix stirred overnight at room temperature in (138 mg, 0.38 mmol) and the 20ml acetone.The reaction solution thing concentrates after preparation thin layer purifying (developping agent: cyclohexane/ethyl acetate=1:1), get formula I yellow oil product 60mg, productive rate 27%.
By Propofol monobromo-acetic acid ester products and formula II compound (CAS numbering: 1044512-35-7) after the condensation in kind, obtain formula I yellow oil product 45mg, productive rate 20%.
The product structure detected result:
1HNMR(δ)(CD
3OD)：0.828~0.865?(m,?3H)，1.093~1.109(d,12H)，1.606(t,2H)，1.836~1.854?(m,?2H)，2.276~2.309?(m,?4H)，2.347~2.644(m,6H)，2.927~2.961(m,2H)，3.499(s,3H)，4.998(s,2H)，7.088~7.416(m,8H)。
Ms：581.4（M+H）。
Embodiment 5
After preparing the Propofol chloro-formic ester by the corresponding manner of embodiment 4; Under nitrogen protection, with Propofol chloro-formic ester (1.25 mmol), triethylamine (1.42 mg; 14 mmol) with 4-Dimethylamino pyridine (140 mg; 1.12 mmol) join and contain bromoethanol (625 mg, 5.0mmol) (or glycol chlorohydrin 400mg is in 20ml methylene dichloride 5.0mmol).The reaction solution stirred overnight at room temperature.Reaction solution concentrates after preparation thin layer purifying (developping agent: cyclohexane/ethyl acetate=10:1), Propofol bromoethanol ester midbody 300mg, productive rate 73% (or Propofol chloroethene alcohol ester midbody 245mg, productive rate 69%).
With R
2(the CAS numbering: 1044512-35-7) (55mg, 0.15 mmol) is dissolved in 10ml acetone, adds Propofol bromoethanol ester midbody (100 mg, 0.30 mmol) for the formula II compound of 3-methyl propionate base; Cesium carbonate (83 mg, 0.60 mmol) (or salt of wormwood), refluxing and stirring is spent the night; Be chilled to room temperature, filter, concentrate; Resistates is through preparation thin layer purifying (cyclohexane/ethyl acetate=1:1.5), get formula I yellow oil product 41mg, productive rate 44.8%.
With Propofol chloroethene alcohol ester midbody (85 mg, 0.30 mmol), in kind with R
2Formula II compound (CAS numbering: 1044512-35-7) react, must get formula I yellow oil product yellow oil 33mg, productive rate 36.0% for 3-methyl propionate base.
The formula I product (41 mg, 0.067 mmol) of gained is dissolved in methylene dichloride 10ml, and 0 ℃ feeds hydrogen chloride gas, and behind the reaction 3h salify, enriching soln gets corresponding formula (I ') yellow oily hydrochloride product 46.9mg, productive rate 99%.Reaction process is following:
Product structure inspection result:
1HNMR(δ)(CD
3OD)：0.861~0.897?(m,?3H)，1.073~1.089(d,12H)，1.845~1.914(m,4H)，2.460~2.497?(d,?2H)，2.735~2.767?(t,?2H)，2.880~2.914(m,2H)，3.210~3.470(m,6H)，3.583(s,3H)，4.452(s,4H)，5.563(s,2H)，7.084~7.440(m,8H)。
Ms：611.5(M-HCl+H)。
Embodiment 6
The Propofol chloro-formic ester (480mg, 2 mmol) that embodiment 5 is same, triethylamine (404 mg, 4 mmol) is dissolved in 20ml acetone, stirred overnight at room temperature with 2-bromine ethylamine hydrobromide (410 mg, 2 mmol).Reaction solution concentrates after the preparation thin layer (developping agent: cyclohexane/ethyl acetate=5:1) white solid midbody 65mg, productive rate 19%.
With this midbody 6-1 (65 mg, 0.199 mmol), Cs
2CO
3(129 mg, 0.398 mmol) and R
2(the CAS numbering: 1044512-35-7) (72 mg, 0.199 mmol) is dissolved in 20ml acetone, stirred overnight at room temperature for the formula II compound of 3-methyl propionate base.Reaction solution is through preparation thin layer purifying (developping agent: cyclohexane/ethyl acetate=1:2), get formula I yellow oil product thing 18mg, productive rate 15%.
The product structure detected result:
1HNMR(δ)(CD
3OD)：0.880?(m,?3H)，1.072~1.089(d,12H)，1.585~1.642(t,3H)，1.822~1.877?(m,?2H)，2.222~2.255(d,?2H)，2.385~2.516(m,4H)，2.607~2.679(m,4H)，2.932~2.966(t,3H)，3.439(s,2H)，3.535(s,3H)，4.236(s,2H)，7.042~7.413(m,8H)。
Ms：610.5?(M+H)。
Embodiment 5
The pharmacologically active experiment:
1. narcotic activity experiment:
35 body weight are divided into 7 groups at random at the male mouse of kunming of 20 ~ 30 grams; The compound of hydrochloride form of the present invention is configured to solution with saline water; The compound of non-hydrochloride form is configured to solution with 40% aqueous solution of propylene glycol, and every group of 5 mouse give a kind of compound through tail vein injection; Observe righting response and whether disappear, as the index that whether has anaesthetic effect.The experimental result of narcotic activity is as shown in table 1.
The anaesthesia experiment result of table 1 The compounds of this invention
| Compound | Dosage (mg/kg) | Whether righting reflex disappears |
| Saline water | — | Not |
| Propofol | 15 | Be |
 |
20 | Be |
 |
10 | Be |
 |
10 | Be |
 |
10 | Be |
 |
15 | Be |
Table 1 is the result show, The compounds of this invention has anaesthetic effect, can cause that mouse righting reflex reversibility disappears.
2. analgesic activities:
When 20 ℃ of room temperatures, body weight is placed on 55 ℃ of metal sheets at the female kunming mice of 20 ~ 30 grams, observe it from putting metal sheet to the reaction times of licking metapedes, between negate is seasonable the mouse below 30 seconds more than 10 seconds as suitable subjects.
The kunming mice that 25 warps is sieved in advance stand the test is divided into 5 groups at random, and the compound of hydrochloride form of the present invention is configured to solution with saline water, and the compound of non-hydrochloride form is configured to solution with 40% aqueous solution of propylene glycol; Every group of 5 mouse; Make an experiment for 20 ℃ in room temperature, give a kind of compound, observe its licking the sufficient reaction times on hot plate through tail vein injection; If the reaction times prolongs one times or above person before than administration, has the index of analgesic effect as this medicine.Experimental result is as shown in table 2.
The analgesic experiment result of table 2 compound
| Compound | Dosage (mg/kg) | Whether has analgesic activity |
| Saline water | — | Not |
| Remifentanil | 1 | Have |
 |
5 | Have |
 |
3 | Have |
 |
3 | Have |
 |
3 | Have |
 |
5 | Have |
Table 2 is the result show, The compounds of this invention has analgesic effect, can make the lick sufficient reacting generating time of mouse on hot plate obviously delay
.
Claims (10)
1.4-replacement-4-(N-propionyl group) aniline piperidines, the free alkali of structure such as formula I form or its hydrochloride (I '):
R in the formula
1Be selected from
,
,
Or
R
2Be selected from 3-methyl propionate base or benzyl.
2. compound as claimed in claim 1 is characterized in that being formula (I ') hydrochloride, R in the formula
1For
, R
2Be 3-methyl propionate base or benzyl.
3. compound as claimed in claim 1 is characterized in that being formula I free alkali, R in the formula
1For
, R
2Be benzyl.
4. compound as claimed in claim 1 is characterized in that formula (I ') hydrochloride, R in the formula
1For
, R
2Be 3-methyl propionate base.
5. compound as claimed in claim 1 is characterized in that the formula I free alkali, R in the formula
1For
, R
2Be 3-methyl propionate base.
6. the preparation method of the said compound of claim 1; It is characterized in that by Propofol (III) and 4-formic acid-4-(N-Phenylpropionamide base)-N-substituted pyridine compound (II); After the esterification of reflux dewatering, obtain the formula I product, further feed HCl gas salify after, obtain the hydrochloride product of formula (I '); Reaction process is following, R in the formula
2Be selected from 3-methyl propionate base or benzyl:
。
7. preparation method as claimed in claim 6 is characterized in that earlier with R
2For the compound (II) of benzyl prepares R
2Be the product (I) of benzyl, hydrogenation removes R
2After, in the presence of the disacidify agent and acrylate reactions, obtain R
2Be the formula I product of 3-methyl propionate base, further feed HCl gas salify after, obtain R
2Hydrochloride product for the formula (I ') of 3-methyl propionate base.
8. the preparation method of compound described in claim 1; It is characterized in that in the presence of the disacidify agent, after preparing corresponding Propofol halogen ester midbody under≤0 ℃, react with the formula II compound again by halo acetyl halide and Propofol (III); Obtain the formula I product; After further feeding HCl gas salify, obtain the hydrochloride product of formula (I '), reaction process is following:
9. the preparation method of compound described in claim 1; After it is characterized in that obtaining corresponding ester or acid amides by the haloformate of Propofol and halogen ethanol or the reaction of halogen ethamine; React in the presence of the disacidify agent with the formula II compound again, obtain the formula I product, further feed HCl gas salify after; Obtain the hydrochloride product of formula (I '), reaction process is following:
10. the said compound of one of claim 1 to 5 has the application in tranquilizing soporific and/or anesthesia and the analgesic medicine in preparation.
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|---|---|---|---|---|
| CN101906039A (en) * | 2010-06-23 | 2010-12-08 | 四川大学华西医院 | Hydroxy acid ester compound of substituted phenol, preparation method and application in medicine |
| CN102344408A (en) * | 2011-07-27 | 2012-02-08 | 中国人民解放军第四军医大学 | Double-effect anesthetic |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101906039A (en) * | 2010-06-23 | 2010-12-08 | 四川大学华西医院 | Hydroxy acid ester compound of substituted phenol, preparation method and application in medicine |
| CN102344408A (en) * | 2011-07-27 | 2012-02-08 | 中国人民解放军第四军医大学 | Double-effect anesthetic |
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|---|---|---|---|---|
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