CN102617449B - 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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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 29
- 229960004134 propofol Drugs 0.000 claims abstract description 29
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 claims abstract description 24
- 230000000202 analgesic effect Effects 0.000 claims abstract description 11
- 230000002936 tranquilizing effect Effects 0.000 claims abstract description 3
- -1 halo acetyl halide Chemical class 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 239000002585 base Substances 0.000 claims description 20
- 229940017219 methyl propionate Drugs 0.000 claims description 19
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 206010002091 Anaesthesia Diseases 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 230000037005 anaesthesia Effects 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- UKXZWEDNEGGXQX-UHFFFAOYSA-N aniline;piperidine Chemical class C1CCNCC1.NC1=CC=CC=C1 UKXZWEDNEGGXQX-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
- 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
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 9
- 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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 48
- 239000000047 product Substances 0.000 description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 13
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 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
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-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
- 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
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 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
- 239000012044 organic layer Substances 0.000 description 5
- 230000002980 postoperative effect Effects 0.000 description 5
- 238000012746 preparative thin layer chromatography Methods 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 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
- 230000032050 esterification Effects 0.000 description 4
- 238000005886 esterification reaction Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- ZTHRQJQJODGZHV-UHFFFAOYSA-N N-phenyl-propionamide Natural products CCC(=O)NC1=CC=CC=C1 ZTHRQJQJODGZHV-UHFFFAOYSA-N 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
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 230000028527 righting reflex Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000932 sedative agent Substances 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
- 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
- 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
- 238000012360 testing method Methods 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
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- SWOBPVRHORXNNA-UHFFFAOYSA-N CCC(NC1=CC=CC=C1)=O.C1CCNCC1 Chemical class CCC(NC1=CC=CC=C1)=O.C1CCNCC1 SWOBPVRHORXNNA-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
- 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
- 230000007812 deficiency Effects 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
- 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
- 239000002960 lipid emulsion Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture 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
- 238000012545 processing Methods 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
- 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, R2Selected from methyl 3-propionate 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 with general anesthesia and analgesic effect, particularly 4-replacement-4-(N-propionyl) aniline piperidines, 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 combining of analgesia, calmness and anaesthetic.Current clinical anesthesia is all the monitoring anesthesia under doctor controls, and anaesthetist need to note at any time patient's vital sign and patient's pain impression is processed targetedly, and realize main dependence of these processing, use various antalgic and sedative medicines.Conventional analgesic is opiates agonist at present, as 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, Disoprofol etc. with it.Disoprofol (Propofol, 2,6-Bis(1-methylethyl)phenol), structure is as shown in formula III.Remifentanil and Disoprofol all have that onset time is rapid, and metabolism is feature 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 drug withdrawal.But because its metabolism is all very rapid, in surgical procedure, Anesthetist need to regulate the dosage of two kinds of medicines at any time, the drug level of remaining valid, increased the complexity of operation, thereby many doctors are more prone to use longer alfentanil of analgesia and calm time and Midazolam etc. clinically, result can make the postoperative recovery of patient slower, extend the residence time at Operation theatre, caused to a certain extent the waste of medical resource.In patient's postoperative care, because also needing to continue to use antalgic and sedative medicine, by patient-controlled analgesia pump, be widely used at present, patient can be by simply touching button according to its wish, by relevant device, Pain relief agents is infused in patient body, produce analgesic effect, thereby reduced the situation of excessive administration or administration deficiency.But although Disoprofol can produce good sedation effect when lower than anesthetic concentration, because it is water-soluble low, making is all at present the form use with emulsion, and a large amount of high-fat emulsion is not suitable for the long-time administration to postoperative patient.
Summary of the invention
For above-mentioned situation, the invention provides a kind of 4-replacement-4-(N-propionyl) 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) aniline piperidines, structure is as the free alkali of formula I form or its hydrochloride (I '):
，
Wherein, the R in formula
1be selected from
,
,
or
; R
2be selected from 3-methyl propionate base or benzyl.
In above-claimed cpd of the present invention, further preferred compound comprises: R in formula
1for
formula (I ') hydrochloride form compound; Or R in formula
1for
, R
2formula I free alkali for benzyl; Or R in formula
1for
, R
2formula (I ') hydrochloride compound for 3-methyl propionate base; Or R in 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 Disoprofol (III) and 4-formic acid-4-(N-Phenylpropionamide base)-N-substituted pyridine compound (II) condensation with remifentanil mother nucleus structure.For example, several typical preparation methods can be described below:
Method one: in the common solvent of the esterifications such as ethyl acetate or toluene, by Disoprofol (III) and 4-formic acid-4-(N-Phenylpropionamide base)-N-substituted pyridine compound (II), after the esterification of reflux dewatering, obtain formula I product; Further in reaction system, pass into after HCl gas salify, can obtain corresponding formula (I ') hydrochloride product.Reaction process is as follows, R in formula
2be selected from 3-methyl propionate base or benzyl:
。
R in the product being prepared by aforesaid method (I)
2can be benzyl (CAS (U.S. chemical abstract): 256507-84-3) or 3-methyl propionate base.R in preparing formula I
2during for the product of 3-methyl propionate base, except the above-mentioned R that directly adopts
2for outside the starting compound (II) of 3-methyl propionate base is prepared, can also be in the ban with R
2for the compound (II) of benzyl prepares R
2for the product (I) of benzyl, in usual manner hydrogenation under the conventional hydrogenation catalyst effect such as Pd/C, remove R
2after, under the conventional disacidify agent such as triethylamine, pyridine exists, then with acrylate reactions, obtain R
2formula I product for 3-methyl propionate base; Further pass into after HCl gas salify, can also obtain corresponding R
2formula (I ') hydrochloride product for 3-methyl propionate base.
Method two: under the conventional disacidify agent such as triethylamine, pyridine exists, by halo acetyl halide compounds such as chloro-acetyl chloride or bromo acetyl bromides, with Disoprofol (III) at≤0 ℃ through esterification, prepare after corresponding Disoprofol halogen ester intermediate, react with formula II compound again, obtain formula I product; Further pass into after HCl gas salify, can obtain corresponding formula (I ') hydrochloride product, reaction process is as follows:
。
Method three: by haloformate and the halogen ethanol (or halogen ethamine) of Disoprofol, through esterification (or amidation) reaction, obtain after corresponding halogen ester (or halogen acid amide), react under the conventional disacidify agent such as triethylamine, pyridine exists with formula II compound again, remove hydrogen halide, obtain formula I product; Further pass into after HCl gas salify, obtain corresponding formula (I ') hydrochloride product.Reaction process is as follows:
。
Experimental result shows, the compound water soluble of above-claimed cpd of the present invention, particularly hydrochloride form, and possess the feature of satisfied analgesia, calmness and anesthetic action etc.Therefore, take above-claimed cpd of the present invention acceptable auxiliary material in active drug composition and pharmacy, by the usual manner of current relative medicine preparation, can prepare and can there is tranquilizing soporific and/or anesthesia and analgesic medicine for clinical, the injection type medicine of administration outside vein or vein preferably, be specially adapted to the patient of postoperative care to carry out antalgic and sedative, be particularly advantageous in and realize the operation of patient to automatic control drug delivery system, and can reduce Anesthetist's operation.
Below in conjunction with the embodiment of embodiment form, foregoing of the present invention is described in further detail again.But this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following example.Without departing from the idea case in the present invention described above, various replacements or the change according to ordinary skill knowledge and customary means, made, all should be included in the present invention) scope in.
Embodiment
embodiment 1
By equimolar R
2for the compound (II) of benzyl (CAS:256507-84-3) is dissolved in appropriate ethyl acetate with Disoprofol (0.016 mol), reflux water-dividing spends the night, and is cooled to afterwards room temperature.Reaction solution is poured in water, with dichloromethane extraction, organic layer salt water washing, after separating organic layer, use anhydrous sodium sulfate drying, filter, after the alumina chromatographic column for resistates that filtrate decompression evaporate to dryness obtains (developping agent: use cyclohexane/ethyl acetate=2/1 after cyclohexane/ethyl acetate=10/1 instead) purifying, obtain formula I white solid product 4.5 g, productive rate 53.4%.
。
Above-mentioned product (I) is dissolved in to appropriate anhydrous diethyl ether, passes into hydrogen chloride gas in 0 ℃, reaction 3h salify, filters and obtains corresponding formula (I ') hydrochloride product, productive rate 45%.
Formula (I ') product structure detected result:
Nuclear magnetic resonance analyser: 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 is same)
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
By equimolar R
2for the compound (II) of benzyl (CAS:256507-84-3) is dissolved in appropriate dry toluene with Disoprofol (0.016 mol), reflux water-dividing 3h, is cooled to room temperature afterwards.Reaction solution is poured in water, with dichloromethane extraction, organic layer salt water washing, after separating organic layer, use anhydrous sodium sulfate drying, filter, the alumina chromatographic column for resistates that filtrate decompression evaporate to dryness obtains (developping agent: use cyclohexane/ethyl acetate=2/1 after cyclohexane/ethyl acetate=10/1 instead) purifying, obtains formula I white solid product 4.0 g, productive rate 47.5%.Reaction process is with embodiment 1.
The formula I product of gained is dissolved in to appropriate anhydrous diethyl ether, passes into hydrogen chloride gas in 0 ℃, reaction 3h salify, filters and obtains corresponding formula (I ') hydrochloride product, productive rate 45%.
embodiment 3
The formula I product of embodiment 1 or embodiment 2 (2.3 g, 4.3 mmol) is dissolved in 100ml ethyl acetate, adds catalytic amount Pd/C, normal pressure hydrogenation spends the night and removes R
2benzyl, filters, and filtrate is concentrated, alumina column chromatography for resistates (developping agent: cyclohexane/ethyl acetate/triethylamine=5:1:1) purifying obtains product 1.2g, productive rate 64%.The product obtaining (1.2 g, 2.7 mmol) and triethylamine (834 mg, 8.2 mmol) are added in methyl acrylate (465 mg, 5.4 mmol) to reaction solution stirred overnight at room temperature.Concentrated by alumina column chromatography (developping agent: cyclohexane/ethyl acetate=5:1) purifying, obtains R in formula I
2for the colorless oil product 398mg of 3-methyl propionate base, productive rate 28.2%.
By R in formula I
2for 3-methyl propionate based products is dissolved in appropriate anhydrous diethyl ether, pass into hydrogen chloride gas in 0 ℃, 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
By bromoacetyl bromide (1.5 g, 7.5 mmol) (or chloroacetyl chloride 0.84 g, 7.5 mmol) and pyridine (790 mg, 10 mmol) be dissolved in 100ml ether, dropping adds Disoprofol (890 mg, 5 mmol), and temperature is controlled at below 0 ℃, after finishing at room temperature reaction 2h, reaction is also poured in frozen water, is extracted with ethyl acetate, and organic layer water washing once, salt water washing once, anhydrous sodium sulfate drying.Filter, filtrate is concentrated, and resistates is through column chromatography (developping agent: cyclohexane/ethyl acetate=9:1), obtain white solid 1.2g, productive rate 80%(or Disoprofol chloracetic acid ester products 1.0g, productive rate 67%).
By the Disoprofol monobromo-acetic acid ester products (0.38 mmol) of gained, Cs
2cO
3(247 mg, 0.76 mmol) and R
2formula II compound (CAS numbering: 1044512-35-7) (138 mg, 0.38 mmol) mixes stirred overnight at room temperature with 20ml acetone for 3-methyl propionate base.Reaction solution thing is concentrated by Preparative TLC purifying (developping agent: cyclohexane/ethyl acetate=1:1), obtain formula I yellow oil product 60mg, productive rate 27%.
By Disoprofol monobromo-acetic acid ester products and formula II compound (CAS numbering: 1044512-35-7) after in kind condensation, obtain formula I yellow oil product 45mg, productive rate 20%.
。
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
By the corresponding manner of embodiment 4, prepare after Disoprofol chloro-formic ester; under nitrogen protection; by Disoprofol chloro-formic ester (1.25 mmol); triethylamine (1.42 mg; 14 mmol) with DMAP (140 mg; 1.12 mmol) join in the 20ml methylene dichloride containing bromoethanol (625 mg, 5.0mmol) (or chloroethanol 400mg, 5.0mmol).Reaction solution stirred overnight at room temperature.Reaction solution is concentrated by Preparative TLC purifying (developping agent: cyclohexane/ethyl acetate=10:1), obtain Disoprofol bromoethanol ester intermediate 300mg, productive rate 73%(or Disoprofol chloroethene alcohol ester intermediate 245mg, productive rate 69%).
。
By R
2formula II compound (CAS numbering: 1044512-35-7) (55mg, 0.15 mmol) is dissolved in 10ml acetone, adds Disoprofol bromoethanol ester intermediate (100 mg for 3-methyl propionate base, 0.30 mmol), cesium carbonate (83 mg, 0.60 mmol) (or salt of wormwood), return stirring spends the night, be chilled to room temperature, filter, concentrated, resistates is through Preparative TLC purifying (cyclohexane/ethyl acetate=1:1.5), obtain formula I yellow oil product 41mg, productive rate 44.8%.
With Disoprofol chloroethene alcohol ester intermediate (85 mg, 0.30 mmol), in kind with R
2formula II compound (CAS numbering: 1044512-35-7) reaction, must obtain formula I yellow oil product yellow oil 33mg, productive rate 36.0% for 3-methyl propionate base.
The formula I product of gained (41 mg, 0.067 mmol) is dissolved in to methylene dichloride 10ml, and 0 ℃ passes into hydrogen chloride gas, and after reaction 3h salify, concentrated solution, obtains corresponding formula (I ') yellow oily hydrochloride product 46.9mg, productive rate 99%.Reaction process is as follows:
。
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
By the same Disoprofol chloro-formic ester of embodiment 5 (480mg, 2 mmol), 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 is concentrated by Preparative TLC (developping agent: cyclohexane/ethyl acetate=5:1) obtain white solid intermediate 65mg, productive rate 19%.
By this intermediate 6-1 (65 mg, 0.199 mmol), Cs
2cO
3(129 mg, 0.398 mmol) and R
2formula II compound (CAS numbering: 1044512-35-7) (72 mg, 0.199 mmol) is dissolved in 20ml acetone, stirred overnight at room temperature for 3-methyl propionate base.Reaction solution is through Preparative TLC purifying (developping agent: cyclohexane/ethyl acetate=1:2), obtain formula I yellow oil product thing 18mg, productive rate 15%.
。
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
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 physiological saline, the compound of non-hydrochloride form is configured to solution with 40% aqueous solution of propylene glycol, every group of 5 mouse, through tail vein injection, give a kind of compound, observe righting response and whether disappear, as the index whether with 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 |
| Physiological saline | — | No |
| Disoprofol | 15 | Be |
| 20 | Be | |
| 10 | Be | |
| 10 | Be | |
| 10 | Be | |
| 15 | Be |
Table 1 result shows, 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, get the reaction times the more than 10 seconds mouse below 30 seconds as suitable subjects.
The kunming mice that 25 warps is sieved in advance to stand the test is divided into 5 groups at random, the compound of hydrochloride form of the present invention is configured to solution with physiological saline, the compound of non-hydrochloride form is configured to solution with 40% aqueous solution of propylene glycol, every group of 5 mouse, in 20 ℃ of room temperatures, test, through tail vein injection, give a kind of compound, observe its licking the sufficient reaction times on hot plate, if the reaction times extends one times or above person before compared with administration, as this medicine, there is the index of analgesic effect.Experimental result is as shown in table 2.
The analgesic experiment result of table 2 compound
| Compound | Dosage (mg/kg) | Whether there is analgesic activity |
| Physiological saline | — | No |
| Remifentanil | 1 | Have |
| 5 | Have | |
| 3 | Have | |
| 3 | Have | |
| 3 | Have | |
| 5 | Have |
Table 2 result shows, the compounds of this invention has analgesic effect, can make the lick sufficient reacting generating time of mouse on hot plate obviously delay
.
Claims (6)
1.4-replacement-4-(N-propionyl) aniline piperidines, structure is as the free alkali of formula I form or its hydrochloride (I '):
R in formula I and formula (I ')
1independently selected from
,
or
; R in formula I and formula (I ')
2independently selected from 3-methyl propionate base.
2. compound as claimed in claim 1, is characterized in that formula (I ') hydrochloride, R in formula
1for
, R
2for 3-methyl propionate base.
3. compound as claimed in claim 1, is characterized in that formula I free alkali, R in formula
1for
, R
2for 3-methyl propionate base.
4. the preparation method of compound described in claim 1, it is characterized in that under disacidify agent exists, by halo acetyl halide and Disoprofol (III), at≤0 ℃, prepared after corresponding Disoprofol halogen ester intermediate, react with formula II compound again, obtain formula I product, further pass into after HCl gas salify, obtain the hydrochloride product of formula (I '), reaction process is as follows:
。
5. the preparation method of compound described in claim 1, it is characterized in that reacting and obtaining after corresponding ester or acid amides with halogen ethanol or halogen ethamine by the haloformate of Disoprofol, react under disacidify agent exists with formula II compound again, obtain formula I product, further pass into after HCl gas salify, obtain the hydrochloride product of formula (I '), the M' in formula is OH or NH
2, M is O or NH, reaction process is as follows:
。
6. the described compound of one of claims 1 to 3 has the application in tranquilizing soporific and/or anesthesia and 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 |
-
2012
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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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