CN1281607C - Novel monopiperazine quaternary ammonium compounds with analgesic effect - Google Patents
Novel monopiperazine quaternary ammonium compounds with analgesic effect Download PDFInfo
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- CN1281607C CN1281607C CN 01142111 CN01142111A CN1281607C CN 1281607 C CN1281607 C CN 1281607C CN 01142111 CN01142111 CN 01142111 CN 01142111 A CN01142111 A CN 01142111A CN 1281607 C CN1281607 C CN 1281607C
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Abstract
The invention relates to a novel piperazine quaternary ammonium salt compound which has obvious analgesic and sedative effects and is not found to have addiction.
Description
Invention field
The present invention relates to have the novel piperazine quaternary ammonium compound of analgesic activity.
Technical background
Anodyne (analgesics) mainly acts on central nervous system, can optionally alleviate or alleviating pain sensation, and the fear that causes because of having an intense pain, anxiety, offending mood such as anxious are eased.Analgesic has potent anodyne and antipyretic and analgesic two classes.Here only the progress of potent analgesic is summarized.
German pharmacist Sert ü rner in 1805 from opium first extraction separation obtain morphine (morphine), but after nineteen fifty-two complete synthesis finishing, just determine its structure.
Morphine has stronger analgesic activity, but side effects such as serious habituation, tolerance, respiration inhibition are arranged.In order to strengthen the specificity of its analgesic activity, reduce its side effect, particularly habituation, carried out many-sided structural modification and transformation with the morphine for guide's thing.
Nineteen thirty-nine finds that Pethidine (Pethidine) not only has spasmolysis, and analgesic activity is arranged that though analgesia is renderd a service not as good as morphine, dependency is little than morphine in the process of research spasmolytic coromegine (Atropine) surrogate.
Analyze relatively morphine, coromegine and Pethidine three's chemical structure, can find that their chemical structure has similar going out, a piperidine ring is all arranged, all be connected with methyl on the nitrogen.But the structure of Pethidine is compared simple widely really with morphine, and this research to the synthetic anodyne of replacement morphine has played very big prograding.
Although in research to morphine class medicine, make structure simplify greatly, analgesic activity improves greatly, and addicted problem is never solved so far clinically at all.The medicine scholar is consistent with pharmacologists to be thought, the analgesic compounds that the discovery structure is brand-new or the compound of new role mechanism are the fundamental ways that solves this problem of habituation.
1974, people such as Daly separate the alkaloid that obtains a kind of trace from the skin of the Ecuador three look ground sour jujube frogs (Epipedobates tricolor), generation Straub sticks up end reaction after giving injected in mice, and this is the characteristic reaction that the morphine compounds produces analgesic activity.In two years subsequently, they have extracted this alkaloid of about 1mg from 750 frog skins.Because the restriction of means of purification and authentication method at that time, the structure of this compound is not determined always.Up to the nineties, the raising that the sensitivity of various analytical instrument is big, its structure just obtains deduction, and is determined by complete synthesis, in reported first in 1992, called after Epibatidine, structure is as follows:
Epibatidine
This compound structure novelty is the natural product that contains 7-azabicyclo [2.2.1] heptane bridged ring system that occurring in nature is found first.Haloperidid group in the molecule is also very rare in animal kingdom.More noticeable is that analgesic activities is 200-500 times of morphine, and is not blocked by the opiate receptor antagonist Narlan.Scientists is inferred, might find the efficient no habituation analgesia new drug that people seek for many years always to the further further investigation of Epibatidine.Therefore, the discovery of this compound has caused Pharmaceutical Chemist and pharmacologists' very big interest.Become one of focus of Recent study.
There are two shortcomings in Epibatidine, and the one, occurring in nature content is extremely low, and the 2nd, toxicity is too big, produces during mouse systemic injection 40-80 μ g/kg to faint from fear and dead (ED
50Be 3-28 μ g/kg).Therefore, the target that Epibatidine is studied mainly contains two, and one is to seek simple and effective complete synthesis route; Another is its structure activity relationship of research, reduces toxicity.
In addition, the researchist of Abbott company has synthesized a large amount of 3-pyridyl ethers compounds, therefrom filters out an oral potent analgesic agent ABT-594.Compare with Epibatidine, the analgesic activities of ABT-594 is 1/6 of Epibatidine, but toxic side effect reduces greatly, and therapeutic index increases substantially, and might solve the problem such as respiration inhibition, constipation, habituation of opium type anodyne.Be one have very much the symptom of a trend by Epibatidine chemical structure deutero-new type analgesic.
Summary of the invention
The purpose of this invention is to provide brand-new non-habituation analgesic compounds one piperazine quaternary ammonium salt compound of a class formation, they have significant analgesic activity, make to substitute the habituation morphine class analgesic that uses clinically at present.
The piperazine quaternary ammonium salt compound of general formula I is provided according to an aspect of the present invention:
R wherein
1Be selected from-(CH
2)
4-OC
6H
5,-CH
2CH=CHC
6H
4-Cl-o ,-CH
2CH=CHC
6H
4-Cl-m ,-CH
2CH=CHC
6H
4-Cl-p ,-CH
2CH=CHC
6H
4-NO
2-m ,-CH
2CH=CHC
6H
4-NO
2-p,
-CH
2CH
2(OH) CH
2Cl ,-CH
2CH
2OH ,-C
2H
5,-CH
2CH=CH
2,-C
6H
5CH
2CH
2,-COCH
2CH
2Br ,-COCH
2CH
2Cl etc.;
R
2And R
3Independent separately expression hydrogen or methyl.
R
4And R
5Common expression-(CH
2)
3-,-(CH
2)
4-,-(CH
2)
5-,-(CH
2)
6-or
R
6Represent various substituting groups, as hydroxyl, methyl, ethyl, propyl group, nitro, halogen etc.
X represents Cl, Br, I etc.
The piperazine quaternary ammonium salt compound of general formula I I is provided according to a second aspect of the invention:
R wherein
2, R
3, R
4, R
5Reach X as the definition in the general formula I, Ar represents the aryl of aryl or replacement.
The piperazine quaternary ammonium salt compound of general formula III is provided according to a third aspect of the present invention:
R wherein
2, R
3, R
4, R
5Reach X as the definition in the general formula I, A=-(CH
2)
x-, wherein x is 3-6,
Wherein y is 3-6;
P is 1-6, R
9Expression hydrogen or acyl group, R
7And R
8Independently represent alkyl separately, or constitute ring amino jointly with N, as
Or
Deng.
The piperazine quaternary ammonium salt compound of general formula I V is provided according to a fourth aspect of the present invention:
R
10 and R
11Common expression-(CH connects together
2)
3-,-(CH
2)
4-,-(CH
2)
5-,-(CH
2)
6-or
R
12And R
13Common expression-(CH
2)
3-,-(CH
2)
4-,-(CH
2)
5-,-(CH
2)
6-or
R wherein
6As defined in the general formula I, represent various substituting groups.
R
14, R
15, R
16And R
17Represent hydrogen or methyl separately, X represents Cl, Br or I, and a represents 2-10.
The piperazine quaternary ammonium salt compound of general formula V is provided according to a fifth aspect of the invention:
R
10, R
11, R
12, R
13, R
14, R
15, R
16And R
17Reach X as defining among the formula IV, b is 0-10.
The piperazine quaternary ammonium salt compound of formula VI is provided according to a sixth aspect of the invention:
R wherein
18And R
19Can be identical or different, the benzyl of independent separately expression alkyl, various replacements; R
20And R
21Can be identical or different, independent separately expression H, R
30(CH
2)
d-, d=1-4, R
30The aryl of expression aryl or replacement, R
31CH=CHCH
2-, R
31The aryl of expression hydrogen, alkyl or various replacements; R
22, R
23, R
24, R
25, R
26, R
27, R
28And R
29Independent separately expression methyl or hydrogen; C is 2-10.
The synthetic method of the compound of general formula I is:
(A) the 1-position of the piperazine of piperazine or replacement is carried out the acidylate protection, generate corresponding N-acyl piperazine;
(B) N-acyl piperazine and halohydrocarbons reaction replace;
(C) under acidity or alkaline condition, slough acyl group, become volution again, promptly make the compound of general formula I of the present invention.
Perhaps, its synthetic method is:
(A) piperazine of N-acyl substituted and α, ω-dihalo hydrocarbon reflux under alkaline condition and generate spirocyclic compound;
(B) slough acyl group, neutralization;
(C) carry out substitution reaction with halohydrocarbon again, be the compound of general formula I of the present invention.
The preparation method of the compound of general formula I I is:
(A) piperazine of acyl substituted alkaline condition next time stream be carried out to volution reaction, slough acyl group then, salify;
(B) carry out the Mannich reaction with the ethanoyl arone of formaldehyde and various replacements again, promptly obtain the compound of general formula I I of the present invention.
The preparation method of the compound of general formula III is:
(A) piperazine of N-acyl substituted and 1,3-epoxy chloropropane or α, ω-dihalo hydrocarbon or Br (CH
2)
yCOX or X (CH
2)
pCHOH (CH
2)
pX reacts (wherein X is halogen (Cl, Br, I), and y and p are as defined in the above general formula III);
(B) and then with dialkylamine or cyclic amine reaction, generate corresponding amine;
(C) slough acyl group then, carry out the spirocyclization reaction, choose into the compound that ester promptly obtains general formula III of the present invention again wantonly.
The preparation method of the compound of general formula I V is: the piperazine of N-acyl substituted and α, ω-dihalo hydrocarbon reaction form two piperazines, then alkaline condition next time stream be carried out to the volution reaction, promptly get the compound of general formula I V of the present invention.
The preparation method of the compound of general formula V is: the piperazine of piperazine or replacement and α, the reaction of ω-two carboxylic acid halides or alpha, omega-dicarboxylic acid generates the two piperazine compounds of two acyl groups, again in alkaline condition next time stream carry out the spirocyclization reaction, promptly get the compound of general formula V of the present invention.
The preparation method of the compound of general formula VI is: the piperazine of N-acyl substituted and α; ω-dihalo hydrocarbon reaction forms two piperazines; in the presence of acetone or acetonitrile with halide reaction; form the two piperazine quaternary ammonium salts of two acyl groups; under the effect of acid, slough acyl group; neutralization is carried out the N-substitution reaction then in the presence of acid or carbonate/alcohol, promptly make the compound of general formula VI of the present invention.
Specific embodiment
Embodiment 1
Synthetic (method one) of compound of Formula I
With the piperazine is raw material, and the synthetic route of compound of Formula I is as follows:
| 3，4，I | R | 3，4，I | R |
| a | -(CH 2) 4-OC 6H 5 | b | CH 2CH＝CHC 6H 4-Cl-o |
| c | CH 2CH＝CHC 6H 4-Cl-m | d | CH 2CH＝CHC 6H 4-Cl-p |
| e | CH 2CH＝CHC 6H 4-NO 2-m | f | CH 2CH＝CHC 6H 4-NO 2-p |
Laboratory apparatus
The micro-fusing point instrument of X-4 type; Perkin-Elmer 298 type infrared spectrometers; VXR 300 type nuclear magnetic resonance analyser, solvent is D
2O, TMS are interior mark; ST-20, Carlo Erba 1106 and PE-2400 type elemental analyser, reagent is the commercial reagent.Post layer post, with silica gel H or G (Haiyang Chemical Plant, Qingdao), TLC GF
254(Haiyang Chemical Plant, Qingdao), 0.5%CMC shop system forms, and colour developing detects down with iodine or ultraviolet lamp.
Synthetic (1) of 1-benzoyl-piperazine
Thermometer is being housed, in the there-necked flask of dropping funnel, is adding the anhydrous piperazine of sending of 19.3g (0.225mol), the 150ml Glacial acetic acid stirs and makes it dissolving, drips 31.6g (0.225mol) Benzoyl chloride down at 30-40 ℃ then, added in about 1 hour, room temperature was placed 3 hours, pressure reducing and steaming part acetic acid, be neutralized to pH=9-10 with alkali lye, suction filtration, washing, filtrate is used dichloromethane extraction (100ml * 3), and the Anhydrous potassium carbonate drying boils off solvent, get light yellow viscous liquid 30.0g, yield 70.8%.
The preparation of 1-benzoyl-4-(4 '-benzene oxygen-butyl) piperazine (3a)
With benzoyl-piperazine 1.90g (10mmol), 1-bromo-4-phenoxy group butane 2.29g (10mmol), sodium bicarbonate 1.68g (20mmol), dehydrated alcohol 40ml add in the reaction flask, stirring and refluxing 19 hours, TLC detects (GF
254, ethyl acetate is launched, the iodine colour developing), react completely, cooling is filtered, and ethanol is washed, and steams solvent, gets faint yellow viscous liquid 4.12g, yield 95%.
The preparation of 3b
The same 3a of preparation method only is to use the Chloro-O-Phenyl allyl bromide 98 by the usual way preparation to replace 1-bromo-4-phenoxy group butane.
The preparation of 3c
The same 3a of preparation method only is to use by chloro-phenyl-allyl bromide 98 between the usual way preparation to replace 1-bromo-4-phenoxy group butane.IR(liq.)cm
-1：3404，2918，1627，1429，1278，1017，787。
The preparation of 3d
The same 3a of preparation method only is to use the rubigan allyl bromide 98 by the usual way preparation to replace 1-bromo-4-phenoxy group butane.IR(liq.)cm
-1：3449，3021，1628，1427，1290，997，856。
The preparation of 3e
The same 3a of preparation method only is to use the m-nitro base allyl bromide 98 by the usual way preparation to replace 1-bromo-4-phenoxy group butane.
The preparation of 3f
The same 3a of preparation method only is to use the p-nitrophenyl allyl bromide 98 by the usual way preparation to replace 1-bromo-4-phenoxy group butane.
The preparation of 3g
With 2-methyl-5 nitroimidazole 3.2g (25mmol), 1,3-dibromopropane 15.1g (75mmol), Anhydrous potassium carbonate 6.9g (50mmol), TBAB 0.15g (0.47mmol), acetonitrile 60ml, add with reaction flask in, 70-80 ℃ of following vigorous stirring 6 hours, TLC detected (GF
254, ethyl acetate: methyl alcohol=3: 1, iodine colour developing), the completely dissolve of raw material point, cooling is filtered, the acetonitrile washing, steam solvent, column chromatography (sherwood oil: ethyl acetate=1: 1), tell 3.5g white plates crystallization 1-(3-bromopropyl)-2-methyl-5-nitro imidazoles (2g), yield 56%, mp.68-69 ℃, IR (KBr) cm
-1: 3136,1530,1488,1327,1254,1150,865.)
After this same 3a of preparation method only is to use 1-(3-bromopropyl)-2-methyl-5-nitro imidazoles (2g) to replace 1-bromo-4-phenoxy group butane.IR(liq.)cm
-1：3425，2924，1624，1430，1159，1074，789；
1HNMR(δppm，CD
3OD)：2.00(2H，t，CH
2N)，2.37-2.51(9H，m，CH
3，NCH
2 and pip)，3.44(2H，br，pip)，3.75(2H，br，pip)，4.10(CH
2CH
2CH
2)，7.42(5H，m，Ar)，8.10(1H，s，CH)。
The preparation of 3h
The same 3a of preparation method only is to use the furans allyl bromide 98 to replace 1-bromo-4-phenoxy group butane.
Method is led in 4 preparation
3a (0.01mol) and 10% hydrochloric acid 36ml are added in the reaction flask, stirring and refluxing 3 hours, cooling is filtered, and water-based is neutralized to pH＞10 with saturated aqueous sodium hydroxide solution, uses ethyl acetate extraction, and the Anhydrous potassium carbonate drying is filtered, and steams solvent, gets product 4a.
The preparation of 4b: method is the same, uses 3b to replace 3a.
The preparation of 4c: method is the same, uses 3c to replace 3a.
The preparation of 4d: method is the same, uses 3d to replace 3a.
The preparation of 4e: method is the same, uses 3e to replace 3a.
The preparation of 4f: method is the same, uses 3f to replace 3a.
The preparation of 4g: method is the same, uses 3g to replace 3a.
The preparation of 4h: method is the same, uses 3h to replace 3a.
8-(4 '-phenoxy group) butyl-5,8-diaza spiro [4,5] decane bromide (Ia)
With 4a 400mg (1.7mmol), 1,4-dibromobutane 367mg (1.7mmol), sodium bicarbonate 285mg (3.4mmol), dehydrated alcohol 20ml add in the reaction flask, stirring and refluxing, TLC detects (GF
254, methyl alcohol: 2%NH
4NO
3=10: 1, iodine colour developing), disappear until raw material point, need 6 hours, cooling is filtered, and ethanol is washed, and steams solvent, thick yellow liquid, with Virahol-re-crystallizing in ethyl acetate, the 530mg faint yellow solid, Ia because of suction too soon survey do not go out fusing point, yield 84%.
Ib-g all makes with this method, just replaces 4a with 4b-4g respectively.
The physical data of table 2 Compound I a-Ie
| I | m.p./℃ (solvent) | Yield (%) | Structural formula | (Calcd.) % is formed in ultimate analysis | ||
| C | H | N | ||||
| Ia * | (propanol-AcOEt) | 84 | C 18H 29BrN 2O.H 2O | 55.66 (55.94) | 8.12 (7.83) | 7.23 (7.25) |
| Ib | 144-146 (ethanol) | 98 | C 12H 24BrClN 2 | 54.54 (54.92) | 6.59 (6.51) | 7.43 (7.54) |
| Ic * | (propanol-AcOEt) | 77 | C 17H 24BrClN 2 | 54.45 (54.92) | 6.61 (6.51) | 7.65 (7.54) |
| Id | 135-138 (propanol-AcOEt) | 85 | C 17H 24BrClN 2 | 54.72 (54.92) | 6.40 (6.51) | 7.47 (7.54) |
| Ie | 164-166 (propanol-AcOEt) | 95 | C 17H 24N 3O 2. 0.5H 2O | 52.65 (52.18) | 6.09 (6.44) | 10.76 (10.74) |
*Compound I a and Ic water-absorbent are too strong, and fusing point can not surveyed
The spectral data of table 3 Compound I a-If
| I | IR(KBr or liq.film)cm -1 | 1H NMR(δppm，D 2O) |
| Ia | 3410，1594， 1488，1242， 1030，759 | 1.67(2H，m，NCH 2CH 2)，1.76(2H，m，CH 2CH 2O)，2.16(2H，br， NCH 2)，2.55(2H，t，CH 2O)，2.84(4H，br，a)，3.44(4H，t，b)， 3.57(4H，t，d)，4.09(4H，t，c)，7.36(2H，t，Ar)，7.05(2H，m， J＝7.5，Ar)，7.01(1H，d，J＝8.7，Ar) |
| Ib | 3424，3031， 1462，1364， 1157，1050， 960，789 | 2.01(4H，br，NCH 2)，2.70(4H，br，a)，3.13(2H，d，d)，3.29 (4H，br，b)，3.40(4H，br，c)，6.08(1H，CH 2CH)，6.83(1H，d， CHAr)，7.48(1H，d，J＝7.2，Ar)，7.27(1H，d，J＝7.2，Ar)， 7.14(2H，m，Ar) |
| Ic | 3420，1635， 1590，1447， 1156，988， 775 | 2.01(4H，br，NCH 2)，2.75(4H，br，a)，3.18(2H，d，d)，3.32(4H， t，b)，3.40(4H，m，c)，6.25(1H，q，CH 2CH)，6.57(1H，d，CHAr)， 7.37(1H，d，Ar)，8.10(1H，s，Ar)，7.93(1H，d，J＝8.4，Ar)， 7.63(1H，d，J＝7.2，Ar) |
| Id | 3339，1726， 1587，1359， 1158，1086， 818 | 2.03(4H，br，NCH 2)，2.76(4H，br，a)，3.16(2H，d，d)，3.33- 3.45(8H，d，b and pip)，6.12(1H，m，C 2HCH)，6.51(1H，d， CHAr)，7.29(2H，d，J＝8.4，Ar)，7.22(2H，d，J＝8.4，Ar) |
| Ie | 3410，2969， 1526，1343， 962，737 | 2.04(2H，br，CH 2)，2.79(4H，br，a)，3.20-3.46(12H，m，b and pip)， 6.27(1H，m，CH 2CH)，6.61(1H，d，CHAr)，8.13(1H，s，Ar)， 7.97(1H，d，J＝7.8，Ar)，7.67(1H，d，J＝7.2，Ar)，6.61(1H，dd， J＝7.5，Ar) |
| If | 3474，3139， 1781，1356， 835，725 | 2.78(6H，br，a am NCH 2)，3.33(12H，m，b and pip)， 6.29(1H，m，C2HCH)，6.56(1H，d，CHAr)，7.39(2H，d，J＝7.8， Ar)，7.94(2H，d，J＝7.5，Ar) |
Synthetic (method two) of compound of Formula I
| I | R | X | n | I | R | X | n |
| i | CH 2CH 2(OH)CH 2Cl | Br | 0 | n | CH 2CH＝CH 2 | Br | 1 |
| j | CH 2CH 2(OH)CH 2Cl | Cl | 0 | o | CH 2CH＝CH 2 | Cl | 1 |
| k | CH 2CH 2OH | Br | 0 | p | C 6H 5CH 2CH 2 | Br | 0 |
| l | CH 2CH 2OH | Cl | 0 | q | COCH 2CH 2Br | Br | 0 |
| m | C 2H 5 | Br | 0 | r | COCH 2CH 2Cl | Br | 0 |
8-benzoyl-8-nitrogen-5-nitrogen spiral shell [4,5] decane halogenide 5
5b is 1-benzoyl-piperazine 19g (0.1mol), and 1,4-dichlorobutane 12.7g (0.1mol), anhydrous sodium bicarbonate 25.2g (0.3mol) and dehydrated alcohol 60ml add in the reaction flask, stirring and refluxing, TLC detects, and until raw material point disappearance, approximately needs 18 hours.Filtered while hot, absolute ethanol washing (15ml * 2), merging filtrate and washing lotion boil off solvent, obtain thick weak yellow liquid.Place in refrigerator and spend the night, solidify, add ethyl acetate 50ml, stirring at room 30 minutes is filtered the ethyl acetate washing lotion, and drying obtains white powder solid 24.1g, yield 83.14%, mp.243-244 ℃, ultimate analysis: C
15H
21ClN
2O.0.5H
2O, measured value %, C62.06, H7.57, N9.80; Calculated value %, C62.17, H7.65, N9.67.IR(KBr)cm-1，3445，2960，2919，1628，1447，1422，1282，991，792，731，714。
1H NMR (D
2O, δ ppm), 2.40 (4H, br, CH
2), 3.62-3.93 (8H, m, N
+CH
2), 4.26,4.03 (each 2H, br, CH
2NCO), and 7.60-7.78 (5H, m, Ar).
The same 5b of 5a preparation method only is to use 1, and the 4-dibromobutane replaces 1, the 4-dichlorobutane.
8-nitrogen-5-nitrogen spiral shell [4,5] decane halide salts hydrochlorate 6
6b adds in the reaction flask stirring and refluxing 3h, pressure reducing and steaming solvent with 5b 5.12g (1.8mmole) and 10%HCl 15mL, get faint yellow viscous liquid,, get white crystals with the mixed solvent recrystallization of dehydrated alcohol and methyl alcohol, yield 82%, mp.231-233 ℃, ultimate analysis C
8H
17ClN
2.HCl.0.3H
2O, measured value %, C43.85, H8.71, N13.06; Calculated value %, C43.97, H8.31, N12.82.IR(KBr)cm-1，3392，2995，2962，2142-2613，1582，1460，1090，1019，931。
1H NMR(D
2O，δppm)，2.43(4H，br，CH
2)，3.86-4.00(12H，m，NCH
2)。
The same 6b of 6a uses 5a to replace 5b.
8-nitrogen-5-nitrogen spiral shell [4,5] decane halogenide 7
7b is with 6b 1.7g (9.2mmole), and lithium hydroxide 0.4g (9.2mmole) and distilled water 10mL add in the reaction flask, stirring at room 0.5h, and the pressure reducing and steaming solvent gets the white powder solid, with methyl alcohol-Virahol recrystallization, gets pure product.
The same 7b of 7a uses 6a to replace 6b.
8-(3-chloro-2-hydroxyl) propyl group-8-nitrogen-5-nitrogen spiral shell [4,5] decane halide salts hydrochlorate Ii and Ij
Ij is with 7b 0.56g (3.4mmole), methyl alcohol 10mL and epoxy chloropropane 0.37g (4.0mmole) add in the reaction flask, room temperature reaction, and TLC detects, up to reacting completely, boil off solvent, add an amount of Virahol dissolving, logical hydrogen chloride gas, place, separate out white crystals, filtration, dry pure product, the yield 84% of getting.
Ii only is to use 7a to replace 7b by synthetic with quadrat method.
8-(beta-hydroxy) ethyl-8-nitrogen-5-nitrogen spiral shell [4,5] decane bromide Ik
With 7a 0.44g (2mmol), chloroethanol 0.5g (6mmol), Anhydrous potassium carbonate 0.83g (6mmol) and dehydrated alcohol 15ml add in the reaction flask, stirring and refluxing, TLC detects (propyl carbinol: acetic acid: pyridine: water=2: 1: 1: 1, the iodine vapor colour developing), filter absolute ethanol washing, merging filtrate and washing lotion, slough solvent, obtain viscous liquid, (use eluent ethyl acetate earlier, use ethyl acetate again: purifying dehydrated alcohol=1: 1 mixed solvent wash-out) through silica gel G post layer, obtain white solid Ik, yield 70%.
8-(beta-hydroxy) ethyl-8-nitrogen-5-nitrogen spiral shell [4,5] decane muriate Il
With 7b 0.56g (3.4mmol), chloroethanol 0.5g (6mmol), Anhydrous potassium carbonate 1.0g (7.2mmol) and dehydrated alcohol 15ml add in the reaction flask, stirring and refluxing, TLC detects (propyl carbinol: acetic acid: pyridine: water=2: 1: 1: 1, the iodine vapor colour developing), reacted completely in about 12 hours, filter, dehydrated alcohol is washed, merging filtrate and washing lotion are sloughed solvent, obtain viscous liquid, add a small amount of anhydrous alcohol solution, drip ethyl acetate until becoming turbid, cooling is left standstill, and separates out precipitation, filter, vacuum-drying obtains white solid Il, yield 71%.
8-ethyl-8-nitrogen-5-nitrogen spiral shell [4,5] decane muriate Im
Method 1 is with 7b 0.71g (4mmol), and monobromethane 0.55g (5mmol), anhydrous sodium bicarbonate 0.84g (10mmol) and dehydrated alcohol 15ml add in the reaction flask, at 35-40 ℃ of following stirring reaction, the TLC detection (propyl carbinol: acetic acid: pyridine: water=4: 2: 2: 1, the iodine vapor colour developing), reacted for 1 week approximately, filter, dehydrated alcohol is washed, merging filtrate and washing lotion, slough solvent, obtain viscous liquid, use Virahol: dehydrated alcohol=10: 1 recrystallizations, obtain white solid Im, yield 39%.
Method 2 is with 7a 0.44g (2mmol), monobromethane 0.55g (5mmol), Anhydrous potassium carbonate 1.1g (8mmol) and dehydrated alcohol 15ml add in the reaction flask, at 40 ℃ of following stirring reactions, TLC detects (propyl carbinol: acetic acid: pyridine: water=4: 2: 2: 1, the iodine vapor colour developing), reacted completely in about 20 hours.Aftertreatment gets white solid Im, yield 51% with method 1.
8-allyl group-8-nitrogen-5-nitrogen spiral shell [4,5] decane muriate Io
With 7b 0.53g (3mmol), propenyl chloride 0.38g (5mmol), Anhydrous potassium carbonate 1.1g (8mmol) and dehydrated alcohol 15ml add in the reaction flask, at 35 ℃ of following stirring reactions, the TLC detection (propyl carbinol: acetic acid: pyridine: water=4: 2: 2: 1, the iodine vapor colour developing), primitive reaction was complete in about 30 hours, filtered, and dehydrated alcohol is washed, merging filtrate and placement, separate out white, needle-shaped crystals, filter vacuum-drying, get product Io, yield 65%.
In only is to use 7a to replace 7b by with the quadrat method preparation.
8-(beta-phenyl) ethyl-8-nitrogen-5-nitrogen spiral shell [4,5] decane muriate Ip
With 7a 0.44g (2mmol), β-bromine ethylbenzene 0.74g (4mmol), Anhydrous potassium carbonate 1.1g (8mmol) and dehydrated alcohol 15ml add in the reaction flask, and stirring and refluxing 3 days is filtered, and dehydrated alcohol is washed, and merging filtrate and washing lotion are sloughed solvent and got viscous liquid.(use eluent ethyl acetate earlier, use ethyl acetate again: purifying dehydrated alcohol=5: 2 mixed solvent wash-outs) gets white solid Ip, yield 53.1% through silica gel G post layer.
8-(β-bromine propionyl) ethyl-8-nitrogen-5-nitrogen spiral shell [4,5] decane bromide Iq
With 7a 0.88g (5mmol), anhydrous sodium bicarbonate 0.67g (8mmol) and water 5ml add in the reaction flask, stir cooling, are slowly dripping β-bromo propionyl chloro 0.86g (5mmol) below 5 ℃.Naturally be warming up to 15 ℃ then, under this temperature, continue reaction 4 hours, add 40ml acetone, there is precipitation to separate out, filter, acetone is washed, merging filtrate and washing lotion, slough solvent and obtain viscous liquid, add an amount of Virahol dissolving, a small amount of insoluble inorganic salt of elimination take off most solvent, obtain dope Iq, yield 91%.
Ir only is to use β-bromo propionyl chloro to replace with β-chlorpromazine chloride by with the quadrat method preparation.
The nuclear magnetic resonance data of Compound I i-r
| Compound | H NMR (δ ppm, D 2O) * |
| Ii | 2.27 (4H, br, a), 3.45-3.82 (8H, m, e, d and f), 3.90 (8H, br, b and c), 4.30-4.55 (1H, m, CH 2OH) |
| Ij | 2.23 (4H, br, a), 3.89 (8H, br, b and c), 3.79 (4H, m, d), 3.70 (2H, m, CH 2Cl), 3.45-3.55 (2H, m, CH 2CHOH), 4.43 (1H, m, CHOH) |
| Ik | 2.69 (2H, t, NCH), 3.73 (2H, t, CH 2OH), 2.19 (4H, br, a), 3.48 (4H, m, b), 3.60 (4H, m, c), 2.91 (4H, br, d) |
| Il | 2.69 (2H, t, NCH), 3.73 (2N, t, CH 2OH), 2.19 (4H, br, a), 3.47 (4H, m, b), 3.60 (4H, m, c), 2.92 (4H, br, d) |
| Im | 1.07 (3H, t, CH 3), 2.55 (2H, q, CH 2CH 3), 2.18 (4H, br, a), 3.47 (4H, m, b), 3.60 (4H, m, c), 2.87 (4H, br, d) |
| In | 2.26 (4H, br, a), 3.77 (4H, m, b), 3.83 (4H, m, c), 2.90 (4H, br, d), 3.90 (2H, d, CH 2CH=), 5.69 (2H, m, CH=), 5.93 (1H, m ,-CH=) |
| Io | 2.28 (4H, br, a), 3.70-3.80 (4H, m, b), 3.81-3.90 (4H, m, c), 2.93 (4H, br, d), 3.92 (2H, d, CH 2CH=), 5.68 (2H, m, CH 2=), 5.95 (1H, m ,-CH=). |
| Ip | 2.10(4H，br，a)，3.48(4H，m，b)，3.80(4H，m，c)，2.90-3.05(8H，m，d and NCH 2CH 2Br)，7.30-7.42(5H，m，Ar) |
| Iq | 2.20(4H，br，a)，3.39-3.74(10H，m，b，d and CH 2Br)，3.92(4H，br，c)， 3.06(2H，t，COCH 2) |
| Ir | 2.25(4H，br，a)，3.70(4H，m，b)，3.98(4H，br，c)，3.54，3.59(2H，m，d and e)，3.03(2H，t，COCH 2，J＝6.09)，3.85(2H，t，BrCH 2，J＝6.09) |
Embodiment 2 Compound I I's is synthetic
With the 1-benzoyl-piperazine is raw material, and synthetic route is as follows:
The structure of table 5 IIa-k compound
2.4. experimental section
Used instrument is the same.Methyl phenyl ketone, parahydroxyacet-ophenone, 2,4-resacetophenone and p-nitroacetophenone are the commercial reagent.
8-benzoyl-5, the preparation (8) of 8-diaza nitrogen spiral shell [4.5] decane bromide
With 1-benzoyl-piperazine 4.80g (0.025mol); Carbon Dioxide hydrogen 5.30g (0.0625mol), 1,4-dibromobutane 5.40g (0.025mol) and dehydrated alcohol 15ml add in the reaction flask; stirring and refluxing 6 hours; filtered while hot, a small amount of dehydrated alcohol is washed, cooling; separate out white crystals; filter, drying is used the dehydrated alcohol recrystallization.Get white solid 5.70g, yield 80%, mp.219-220 ℃.
5,8-diaza spiro [4.5] decane bromide hydrochloride (9)
With 819.5g (0.06mol), 10% HCl 216ml adds in the reaction flask, stirring and refluxing 3 hours, cooling is filtered, washing, merging filtrate and washing lotion are sloughed water under the decompression, add an amount of Virahol, stir evenly, separate out solid, filter, acetone is washed, drying, Virahol recrystallization, get the 25.0g white solid, yield 99%, mp.235.5-237.5 ℃.
The preparation of p-methyl aceto phenone (10f)
With toluene 50ml and the anhydrous AlCl of 20.0g that handled
3Add in the reaction flask, and dripping acetyl chloride under the cold water cooling (14.0g, 14ml), at 70-80 ℃, reacted 45 minutes then, solution is dark red, cooling, reactant is poured in the beaker of 75.0g water and ice, with extracted with diethyl ether (15ml * 4), combining extraction liquid, water successively, 10%NaOH solution, water washing, anhydrous MgSO
4Drying is filtered, and steams solvent, underpressure distillation, and the cut of collection 98-101 ℃/1862 Pa (226 ℃ of lit) gets product 9.20g, yield 38%.IR(liq)cm
-1：3026，1674，1602，1266，815。
The preparation of 2-acetyl thiophene (10g)
With thiophene 16.8g, (0.2mol) add in the reaction flask with diacetyl oxide 10.7g (0.1mol), add H down at 70-75 ℃
3PO
41g, thermopositive reaction begins behind several minutes, reaction flask is invaded cool off in the cooling bath with the control reaction, reheats after question response is steady and refluxes 2 hours, until reacting completely, cools off, and mixture is water successively, 5%Na
2CO
3Washing, washing, anhydrous Na
2SO
4Drying is filtered, and steams unreacted thiophene under the normal pressure, the residuum underpressure distillation, and the fraction of 88-90 ℃/1330Pa of collection (214 ℃ of Lit bp) gets 2-acetyl thiophene 4.6g, yield 37%.IR(liq)cm
-1：3086，1657，1514，1410，1271，725。
The preparation of 2-acetofuran (10h)
Furans 34g (0.5mol) is mixed under ice-water bath with diacetyl oxide 107 (1mol), add ZnCl
22g, 0-5 ℃ of reaction 1 hour, then 15-20 ℃ of reaction 3 hours, underpressure distillation, collect 45-48 ℃/665Pa (Lit.67 ℃/1330Pa) cut, product 13.0g, productive rate 24%.IR(liq)cm
-1：3003，1672，1464，1200，765。
8-alpha-oxo-hydrocinnamyl-5,8-diaza spiro [4,5] decane bromide hydrochloride (IIa)
With 10 515mg (2mmol), formalin 10ml, methyl phenyl ketone 196mg (2mmol), 15ml methyl alcohol adds in the reaction flask, and in 50 ℃ of following stirring reactions, TLC detects (GF
254Plate, methyl alcohol: 2%NH
4NO
3Solution=launch at 10: 1, the iodine colour developing), until reacting completely cooling, steam solvent, remove not tolerantly with Virahol-ethanol heating for dissolving, filter, dry crude product, use methyl alcohol: water=10: 1 recrystallizations gets white crystal 230mg, yield 51%, mp.198-202 ℃.
IIb-i all by the method for making preparation of IIa, just replaces methyl phenyl ketone to get final product with corresponding substituted acetophenone respectively.Wherein 2,4-resacetophenone and spiro piperazine quaternary ammonium salt hydrochloride and formalin reaction, gained compound structure warp
1HNMR and ultimate analysis conclusive evidence are not the target compound IId that we wish, but the aminomethylation reaction takes place on phenyl ring, and what obtain is compound 11.This be since on the phenyl ring existence of two hydroxyls make the benzene ring hydrogen than the hydrogen on the methyl more active due to.
The physical data of table 6 Compound I I
| II | Mp.(℃) (solvent) | Yield (%) | Temperature (℃) | (Calcd.) % is formed in ultimate analysis | Formula | ||
| C | H | N | |||||
| IIa | 198-202 (MeOH∶H 2O) | 51 | 50 | 49.71 (50.07) | 6.58 (6.92) | 6.67 (6.87) | C 17H 25BrN 2O .HCl.H 2O |
| IIb | 174-178 (MeOH) | 30 | 70 | 45.54 (45.29) | 6.63 (6.93) | 6.38 (6.22) | C 17H 26BrN 2O 2 HCl.2.5H 2O |
| IIc | 166-169 (MeOH-AcOEt) | 50 | 70 | 46.38 (46.21) | 6.55 (6.84) | 6.27 (6.34) | C 17H 25BrN 2O 2 HCl.2H 2O |
| IIe | 176-180 (MeOH∶H 2O) | 46 | 90 | 48.84 (49.10) | 6.55 (6.64) | 6.76 (6.36) | C 18H 27BrN 2O .2HCl |
| IIf | 201-204 (MeOH∶H 2O) | 42 | 50 | 42.50 (42.60) | 6.29 (6.43) | 6.30 (6.63) | C 15H 23BrN 2OS .HCl.H 2O |
| IIg | 194-200 (MeOH∶H 2O) | 18 | 40 | 43.73 (43.27) | 5.44 (6.01) | 6.21 (6.73) | C 15H 23BrN 2O 2 .HCl |
| IIh | 155-157 (MeOH) | 19 | 70 | 41.45 (41.73) | 5.57 (5.77) | 8.62 (8.59) | C 17H 24BrN 3O 3 2HCl.H 2O |
| IIi | 180-185 (MeOH) | 39 | 100 | 41.40 (41.73) | 5.55 (5.77) | 8.60 (8.59) | C 17H 24BrN 3O 5 .2HCl.H 2O |
* number numerical value is theoretical value in
The spectral data of table 7 Compound I I
| II | IR(KBr)cm -1 | 1H NMR(δppm，D 2O) |
| IIa | 3495，2893，2438， 1671，1221，754， 666. | 2.26(4H，br，e and f)，3.72-3.86(16H，m，a ，b，and pip)，8.02(2H，d，J＝7.8，Ar)，7.72(1H，dd，J＝7.8，Ar)，7.57 (2H，dd，J＝7.2，Ar). |
| IIb | 3548，3412，2425， 1691，1252，784. | 2.11(4H，br，e and f)，3.52(4H，m，a)，3.60-3.70(12H，m，b and pip)，7.42(1H，d，J＝7.8，Ar)，7.32(1H，s，Ar)，7.28(1H， m，J＝7.8，Ar)，7.06(1H，d，J＝8.1，Ar). |
| IIc | 3415，3198，2428， 1666，1510，1220， 801. | 2.25(4H，br，e and f)，3.62(4H，q，a)，3.76(4H，br，d)，3.81- 3.84(8H，m，b and c)，7.95(2H，d，J＝8.7，Ar)， 6.97(2H，d，J＝9.3，Ar) |
| IIe | 3318，2975，2470， 1659，1208，847. | 2.25(4H，br，e and f)，2.41(3H，s，CH 3)，3.67(4H，m，a)，3.77- 3.83(12H，m，band pip)，7.91(2H，d，J＝8.1，Ar)， 7.39(2H，d，J＝7.5，Ar). |
| IIf | 3425，2963，2423， 1659，1410，1226. | 2.25(4H，br，e and f)，3.63(4H，br，a)，3.75(4H，m，d)， 3.81(8H，d，b andc)，7.97(1H，d，J＝3.9，Ar)， 7.93(1H，d.J＝4.8，Ar)，7.25(1H，dd，J＝9.0，Ar). |
| IIg | 3545，3496，2959， 1640，1448，1004. | 2.10(4H，br，e and f)，3.47-3.62(16H，m，a，b and pip)，7.77(1H，d，Ar)，7.36(1H，d，J＝3.6，Ar)，6.58 (1H，dd，J＝5.4，Ar). |
| IIh | 3326，3242，2968， 2449，1685，1353， 809. | 2.13(4H，br，e and f)，3.65-3.75(16H，d，a，b and pip)，8.66(1H，s，Ar)，8.37(1H，d，J＝7.8，Ar)， 8.24(1H，d，J＝7.8，Ar)，7.66(1H，dd，Ar). |
| IIi | 3500，3413，3264， 1690，1528，1216. | 2.12(4H，br，e and f)，3.63-3.72(16H，d，a，b and pip)，8.23(2H，d，J＝8.1，Ar)，8.05(2H，d，J＝8.4，Ar) |
Synthesizing of embodiment 3 compound III
Following 4 compound III a-d have been synthesized in the present embodiment design.
Synthetic route
The synthetic route of compound III
The preparation of 1-benzoyl-4-(2-hydroxyl-3-chloro-propyl group) piperazine (12)
With benzoyl-piperazine 9.5g (0.05mol), 1,3-epoxy chloropropane 6.0g (0.065mol), dehydrated alcohol 50ml adds in the reaction flask, stirring and refluxing 11 hours, TLC detects (GF
254, methyl alcohol launches, the iodine colour developing), react completely, cooling steams solvent, and column chromatography (ethyl acetate) gets yellow viscous liquid 7.9g, yield 56%.
1HNMR(δppm，D
2O)：2.48(6H，br，pip and CH
2CHOH)，3.41-3.60(4H，m，pip)，3.89(2H，t，CH
2Cl)，4.06(1H，m，CHOH)，7.24-7.38(5H，m，Ar)。
1, the preparation of 3-two [1-(4-benzoyl) piperazinyl]-2-propyl alcohol (13)
Method 1 is the compound 12900mg (3.18mmol) of above preparation, 1-benzoyl-piperazine 605mg (3.18mmol), and dehydrated alcohol 20ml adds in the reaction flask, stirring and refluxing 11 hours, TLC detects (GF
254, methyl alcohol launches, the iodine colour developing), react completely, cooling steams solvent, yellow viscous liquid 1.20g, not purifiedly be directly used in next step reaction.
Method 2: with 1-benzoyl-piperazine 3.8g (0.02mol), 1,3-two chloro-2-propyl alcohol 1.3g (0.01mol), Anhydrous potassium carbonate 2.8g (0.02mol), dehydrated alcohol 30ml adds in the reaction flask, stirring and refluxing 6 hours, TLC detects (GF
254, methyl alcohol launches, the iodine colour developing), react completely, cooling steams solvent, column chromatography (ethyl acetate: methyl alcohol=7: 1), get yellow viscous liquid 3.9g, yield 89.4%.
1HNMR(δppm，D
2O)：2.37-2.63(6H，m，pip and NCH
2)，3.44-4.13(5H，m，pip and CHOH)，7.24-7.37(5H，m，Ar)。
1,3-two (1-piperazinyl)-2-propyl alcohol (14)
With the above compound that makes 13 5.0g (0.01mol), 10% hydrochloric acid 36ml adds in the reaction flask, stirring and refluxing 3 hours, and cooling is filtered, and washing is regulated P with saturated sodium hydroxide solution
H7-8, decompression steams most of water, adds ethanol, removes insolubles, concentrates, and uses ethyl alcohol recrystallization, gets white solid 2.5g, yield 95.8%, mp.212-214 ℃.IR(cm
-1)3402，2933，2810，2476，1589，1454.
1HNMR(δppm，D
2O)2.37(4H，d，c)，2.68(8H，br，b)，3.11(8H，br，a)，3.91(1H，m，d).
The preparation of IIIa
Make compound 141.65g (7mmol) more than inciting somebody to action, 1,4-dibromobutane 3.0g (14mmol), anhydrous sodium bicarbonate 1.76g (21mmol), dehydrated alcohol 40ml adds in the reaction flask, stirring and refluxing 21 hours, TLC detects (GF
254, propyl carbinol: acetic acid: pyridine: water=4: 2: 2: 1, the iodine colour developing), reacting completely, cooling steams solvent, with Virahol-re-crystallizing in ethyl acetate, gets white solid 4.0g, yield 80%, mp: it is too fast to absorb water, and can not survey; IR (KBr) cm
-1: 3374,2961,2850,1623,1462,1170;
1HNMR (δ ppm, D
2O): (1.99 (8H, br, CH
2CH
2N
+), 2.35 (4H, m, NCH
2CH), 2.73 (6H, br, pip), 3.29 (8H, t, CH
2N
+), 3.40 (8H, t, N
+CH
2); 3.85 (1H, m, CHOH); Ultimate analysis C
19H
38Br
2N
4O.8H
2O, measured value %:C 46.73, N6.09, H6.25; Theoretical value %:C46.21, N6.34, H6.39.
The preparation of 16b
With 122.8g (0.01mol), Dimethylammonium chloride 815mg (0.01mol), anhydrous sodium bicarbonate 2.5g (0.03mol), dehydrated alcohol 50ml adds in the reaction flask, stirring and refluxing 6 hours, TLC detects (GF
254, methyl alcohol launches, the iodine colour developing), react completely, cooling is filtered, and steams solvent, column chromatography (ethyl acetate: methyl alcohol=5: 1), get viscous liquid 2.1g, yield 72.4%.IR(KBr)cm
-1：3420，2935，2813，1625，1429，1074；
1HNMR(δppm，CD
3OD)：2.28(6H，s，CH
3)，3.77(2H，br，pip)，3.44(2H，br，pip)，3.90(1H，m，CHOH)，7.37-7.48(5H，m，Ar)。
16c-d presses the method preparation of 16b, only is to use piperidines and 4-methyl piperidine to replace dimethylamine.
Method is led in 17 preparation
With 16b-d (0.01mol), 10% hydrochloric acid 36ml adds in the reaction flask, stirring and refluxing 3 hours, cooling respectively, filter, washing is regulated pH7-8 with saturated sodium hydroxide solution, and decompression steams most of water, adds ethanol, remove insolubles, concentrate, recrystallization gets compound 17.
17b mp.178-179℃；IR(cm
-1)3403，2918，2818，2471，1454，995.
1HNMR(δppm，D
2O)：2.35(2H，m，e)，2.70(6H，s，CH
3)，2.62(4H，m，b and c)，2.95-3.10(6H，m，pip)，4.05(1H，m，d).
17c mp.226-229℃；IR(cm
-1)3198，2943，2821，2658，1446，1096..
1HNMR(δppm.D
2O)：1.59-1.71(6H，br，NCH
2CH
2)，2.36(2H，m，e)，2.63(4H，m，f)，2.84-2.89(2H，m，c)，3.07(6H，m，pip)，3.14-.45(2H，br，a)，4.09(1H，m，a).
17d mp.223-225℃；IR(cm
-1)3197，2920，2787，2698，2465，1347.
1HNMR(δppm，D
2O)：0.79(3H，d，CH
3)，1.24(1H，m，CHCH
3)，1.74(2H，m，NCH
2CH
2)，2.36(2H，m，NCH
2CH
2)，2.56-2.86(8H，m，c，e，f and g).
The preparation of IIIc
With 17c 670mg (2.95mmol), 1,4-dibromobutane 637mg (2.95mmol), anhydrous sodium bicarbonate (496mg, 14mmol), dehydrated alcohol 20ml adds in the reaction flask, stirring and refluxing 18 hours, TLC detects (GF
254, propyl carbinol: acetic acid: pyridine: water=4: 2: 2: 1), the iodine colour developing reacts completely, and cooling is filtered, and steams solvent, with methyl alcohol-re-crystallizing in ethyl acetate, gets white solid 960mg, yield 90%, mp:190-192 ℃, IR (KBr) cm
-1: 3343,2940,2723,1416,1080;
1HNMR (δ ppm, D
2O): 1.64-1.72 (6H, br, CH
2CH
2CH
2), 2.01 (4H, br, CH
2CH
2N
+), 2.41 (2H, m, CH CH
2N), 2.73-3.10 (8H, m, pip and NCH
2CH), 3.32 (2H, t, CH
2N), 3.43 (8H, t, CH
2N
-), 4.11 (1H, m, CHOH); Ultimate analysis C
19H
32BrN
3O.6.5H
2O, measured value %:C 40.04, N8.78, H7.11; Theoretical value %:C40.08, N8.76, H6.73.
IIIb and III
dThe same IIIc of preparation, just use 17b, 17d to replace 17c respectively.
IIId yield 86%,
1HNMR (δ ppm, D
2O): 0.76 (3H, d, CH
3), 1.04 (2H, m, CH
2CHCH
3), 1.10 (1H, m, CHCH
3), 1.56 (2H, m, CH
2CHCH
3), 2.04 (4H, br, CH
2CH
2N
+), 2.42 (4H, m, NCH
2), 2.80-2.91 (6H, m, NCH
2CH), 3.48 (6H, t, pip), 3.35 (6H, t, pip and CH
2N
+), 3.98 (1H, m, CHOH).
Some synthetic examples of embodiment 4 IV compounds
Synthetic route is as follows:
Method is led in the preparation of compound IV
1. α, the preparation of ω-two [1-(4-benzoyl) piperazinyl] alkane (18)
With benzoyl-piperazine 19g (0.1mol), 1,3-dibromopropane (0.05mol); sodium bicarbonate 21g (0.25mol) and dehydrated alcohol 60mL add in the reaction flask, stirring and refluxing, and TLC detects up to react completely (about 6-10h); cooling, filtration, dehydrated alcohol is washed, and boils off solvent and gets faint yellow viscous liquid; add 60mL water, shake up freezing leaving standstill; separate out white solid product, use the alcohol-water recrystallization, get pure product 18b; mp.104-105 ℃, yield 80%.
The 18c method for making is the same, only is to use α, and ω-dibromobutane replaces 1,3-dibromopropane, mp.135-136 ℃, yield 32%.
The 18e method for making is the same, only is to use α, and ω-dibromo-hexane replaces 1,3-dibromopropane, mp.113-115 ℃, yield 70%.
The 18h method for making is the same, only is to use α, and ω-two bromooctane replaces 1,3-dibromopropane, mp.101-103 ℃, yield 95%.
The 18j method for making is the same, only is to use α, and ω-dibromo-decane replaces 1,3-dibromopropane, mp.64-65 ℃, yield 66%.
2. the preparation of two (1-piperazinyl) alkane (19)
With 18b (5.6mmole), 10%HCl 20mL adds in the reaction flask, stirring and refluxing 3h, and cooling is filtered, washing, the aqueous solution is neutralized to pH=10 with aqueous sodium hydroxide solution, uses dichloromethane extraction, and anhydrous magnesium sulfate drying boils off solvent, gets product 19b.Yield 73%.
19c is the same, uses 18c to replace 18b, yield 81%.
19e is the same, uses 18e to replace 18b.Yield 86%.
19h is the same, uses 18h to replace 18b, yield 87%.
19j is the same, uses 19j to replace 18b, yield 62%.
3. the preparation of compound IV
With 19b (1mmole), 1,4-dibromobutane 432mg (2mmole), sodium bicarbonate 500mg (6mmole) and dehydrated alcohol 20mL add in the reaction flask, stirring and refluxing, and TLC detects, up to react completely (about 6-10h), cooling is filtered, ethanol is washed, boil off solvent, get dope, with Virahol-re-crystallizing in ethyl acetate, get pure product IVb, yield 55%.mp.236-238 ℃; Ultimate analysis C
19H
38Br
2N
4, measured value %:C 47.08, N 11.46, and H 8.13; Theoretical value %:C 47.31, and N 11.62, and H 7.94.
IVe is the same, uses 19e to replace 19b, yield 58%mp.205-230 ℃; Ultimate analysis C
22H
44Br
2N
43H
2O, measured value %:C 45.49, N 9.47, and H 8.32; Theoretical value %:C 45.68, and N 9.69, and H 8.71.
IVh is the same, uses 19h to replace 19b, yield 57%mp.230-240 ℃; Ultimate analysis C
24H
48Br
2N
4, measured value %:C 51.80, N 9.94, and H 9.04; Theoretical value %:C 52.17, and N 10.14, and H 8.76.
IVj is the same, only is to use 19j to replace 19b, yield 91%mp.248-250 ℃; Ultimate analysis C
26H
52Br
2N
44.5H
2O, measured value %:C 47.32, N 8.35, and H 9.42; Theoretical value %:C 47.20, and N 8.47, and H 9.29.
Some synthetic examples of embodiment 5 V compounds
Synthetic route is as follows:
X＝Br，Cl，I
Method is led in the preparation of compound V
1. α, ω--the preparation of diacyl piperazine (21)
The suberoyl piperazine (21, n=6) add piperazine 3.44g (0.04mol) in the there-necked flask, water 15ml, acetone 15ml transfers to pH=4.5 with dense HCl.The CH of parallel dropping suberoyl chlorine
2Cl
2Solution 21.76ml (0.02mol) and 10%NaOH keep reaction solution PH=4.5.Drip and finish, the stirring at room reaction is spent the night.10%NaOH transfers to PH=10-11, pressure reducing and steaming H
2O and organic solvent.Alcohol reflux, heat filtering, elimination insolubles.Get crude product 5.32g, yield 85.8%.Crude product is crossed silicagel column, eluent: ethyl acetate: methyl alcohol: ammoniacal liquor=7: 3: 1 gets pure product.
1H NMR(δppm，CDC
13)1.02(t，4H)，1.40(m，4H)，1.84(s，2H)，2.09(t，2H)，2.60(m，8H)，3.19-3.36(m，8H)。
13C NMR(δppm，CDCl
3)171.02，45.87，42.04，32.64，28.74，24.67.
Can make other as stated above about 21 compound:
(21, n=2): method for making as above just replaces suberoyl chlorine, yield: 85% with succinic chloride to the succinyl piperazine.
1H NMR(δppm，D
2O)1.98(s，4H)，2.15-2.20(m，8H)，2.84-2.95(m，8H)。
13C NMR(δppm，CDCl
3)170.18，45.62(t)，42.25，27.67。
(21, n=3): method for making is as above just replaced suberoyl chlorine, yield: 86% with the glutaryl chloro to the glutaryl piperazine.
1H NMR(δppm，D
2O)1.19(s，2H)，1.89-1.98(m，4H)，2.79(m，8H)，3.41-3.53(m，8H)。
13CNMR(δppm，CDCl
3)171.05，46.25(t)，42.49，32.44，29.56。
(21, n=4): method for making is as above just replaced suberoyl chlorine, yield: 83.2% with the hexanedioyl chloro to the hexanedioyl piperazine.
1H NMR(δppm，D
2O)1.22(s，2H)，1.65(s，4H)，2.33(m，4H)，2.78-2.84(m，6H)，3.39-3.57(m，8H)。
13C NMR(δppm，CDCl
3)171.24，46.32(t)，42.59，32.97，25.01。
2 α, ω--the preparation of diacyl spiro piperazine quaternary ammonium salt (V)
Suberoyl spiro piperazine quaternary ammonium salt (V, n=6): add suberoyl piperazine 0.50g (1.61mmol), 1,4-dibromobutane 0.38ml (3.23mmol), NaHCO in the 100ml eggplant-shape bottle
30.54g (6.45mmol), dehydrated alcohol 20ml, reflux 8 hours.Heat filtering, solid is washed with hot ethanol, merging filtrate, evaporate to dryness.Crude product gets product 0.83g, yield 88% with methyl alcohol-re-crystallizing in ethyl acetate.
1H NMR(δppm，D
2O)1.21(s，4H)，1.44(t，4H)，2.09(s，8H)，2.34(t，4H)，3.35-3.52(m，16H)，3.77-3.81(m，8H)。
13C NMR(δppm，CDCl
3)178.05，65.46，61.37(d)，43.83，39.77，35.04，30.76，27.17，23.78
Can make other compound as stated above about V.
Succinyl spiro piperazine quaternary ammonium salt (V, n=2): yield, 87%.
1H NMR(δppm，D
2O)2.14(s，8H)，2.69(s，4H)，3.41-3.59(m，16H)，3.81-3.90(m，8H)。
13C NMR(δppm，CDCl
3)175.98，65.65，61.50，43.70，40.12，30.26，23.98。
Glutaryl spiro piperazine quaternary ammonium salt (V, n=3): yield, 85.3%.
1H NMR(δppm，D
2O)1.70-1.75(m，2H)，2.08(s，8H)，2.37-2.42(t，4H)，3.35-3.52(m，16H)，3.78(m，8H)。
13C NMR(δppm，CDCl
3)176.72，65.46，61.37，43.66，39.81，34.34，23.78，22.66。
Hexanedioyl spiro piperazine quaternary ammonium (V, n=4): yield, 87%.
1H NMR(δppm，D
2O)1.49(s，4H)，2.10(s，8H)，2.40(s，4H)，3.37-3.54(m，16H)，3.79-3.83(m，8H)。
13C NMR(δppm，CDCl
3)177.49，65.55，61.52，43.85，39.89，34.87，26.90，23.87。
Some synthetic examples of embodiment 6 VI compounds
Synthetic route is as follows:
The preparation of compound VI
1, dihalide-α, ω-two [1-(4-benzoyl-1-alkyl) piperazinyl] alkane (22)
Dibrominated-α, and ω-two [1-(4-benzoyl-1-methyl) piperazinyl] hexane (22, R=Me, preparation n=6)
With α; ω-two [1-(4-benzoyl) piperazinyl] hexane (0.05mol); chloroform (5mL), acetone (7mL) add in the reaction flask, slowly add about 30% methane acetone soln (6.5mL) under the cooling and stirring; room temperature was placed 3-5 days; filter, acetone is washed, solid vacuum-drying; the Virahol recrystallization gets pure product.Yield 86%, mp.270-271 ℃.
Dibrominated-α, and ω-two [1-(4-benzoyl-1-methyl) piperazinyl] decane (22, R=Me, preparation n=10)
Method for making is the same, only is to use α, and ω-two [1-(4-benzoyl) piperazinyl] decane replaces α, ω-two [1-(4-benzoyl) piperazinyl] hexane.
Dibrominated-α, and ω-two [1-(4-benzoyl-1-benzyl) piperazinyl] decane (22, R=C
6H
5CH
2-, preparation n=10)
With α, ω-two [1-(4-benzoyl) piperazinyl] decane (0.03mol), bromobenzyl (0.10mol), acetonitrile (10mL) add in the reaction flask, stirring and refluxing, the TLC detection reaction disappears up to raw material point.The pressure reducing and steaming solvent gets thick crude product, adds the 20mL ethyl acetate, and stirring at room 1h inclines and desolvates, and washes 2 times with ethyl acetate again, and evaporated under reduced pressure gets the spumescence product.Yield 61%, mp.151-153 ℃.
Dibrominated-α, and ω-two [1-(4-benzoyl-1-(4-nitro-phenmethyl)) piperazinyl] decane (22, R=4-NO
2-C
6H
5CH
2-, preparation n=10)
Same dibrominated-the α of method for making, ω-two [1-(4-benzoyl-1-benzyl) piperazinyl] decane just replaces bromobenzyl with 4-nitro-bromobenzyl.
Dichloride-α, and ω-two [1-(4-benzoyl-1-(4-nitro-phenmethyl)) piperazinyl] decane (22, R=4-NO
2-C
6H
5CH
2-, preparation n=10)
Same dibrominated-the α of method for making, ω-two [1-(4-benzoyl-1-benzyl) piperazinyl] decane just replaces bromobenzyl with 4-nitro-benzyl chloride.
Dibrominated-α, and ω-two [1-(4-benzoyl-1-(4-fluoro-phenmethyl)) piperazinyl] decane (22, R=4-F-C
6H
5CH
2-, preparation n=10)
Same dibrominated-the α of method for making, ω-two [1-(4-benzoyl-1-benzyl) piperazinyl] decane just replaces bromobenzyl with 4-fluoro-bromobenzyl.
Dichloride-α, and ω-two [1-(4-benzoyl-1-(4-fluoro-phenmethyl)) piperazinyl] decane (22, R=4-F-C
6H
5CH
2-, preparation n=10)
Same dibrominated-the α of method for making, ω-two [1-(4-benzoyl-1-benzyl) piperazinyl] decane just replaces bromobenzyl with 4-fluoro-benzyl chloride.
Dichloride-α, and ω-two [1-(4-benzoyl-1-(3,5-dinitrobenzene-phenmethyl)) piperazinyl] decane (22, R=3,5-(NO
2)
2-C
6H
5CH
2-, preparation n=10)
Same dibrominated-the α of method for making, ω-two [1-(4-benzoyl-1-benzyl) piperazinyl] decane, just with 3,5-dinitrobenzene-benzyl chloride replaces bromobenzyl.
Dibrominated-α, and ω-two [1-(4-benzoyl-1-(2-methoxyl group-5-nitro-phenmethyl)) piperazinyl] decane (22, R=3,5-(NO
2)
2-C
6H
5CH
2-, preparation n=10)
Same dibrominated-the α of method for making, ω-two [1-(4-benzoyl-1-benzyl) piperazinyl] decane just replaces bromobenzyl with 2-methoxyl group-5-nitro-bromobenzyl.
Dibrominated-α, and ω-two [1-(4-benzoyl-1-(3-nitro-phenmethyl)) piperazinyl] decane (22, R=3-NO
2-C
6H
5CH
2-, preparation n=10)
Same dibrominated-the α of method for making, ω-two [1-(4-benzoyl-1-benzyl) piperazinyl] decane just replaces bromobenzyl with 3-nitro-bromobenzyl.
Dichloride-α, and ω-two [1-(4-benzoyl-1-(2-methoxyl group-phenmethyl)) piperazinyl] decane (22, R=2-CH
3O-C
6H
5CH
2-, preparation n=10)
Same dibrominated-the α of method for making, ω-two [1-(4-benzoyl-1-benzyl) piperazinyl] decane just replaces bromobenzyl with 2-methoxyl group-benzyl chloride.
Dichloride-α, and ω-two [1-(4-benzoyl-1-(3-methoxyl group-phenmethyl)) piperazinyl] decane (22, R=3-CH
3O-C
6H
5CH
2-, preparation n=10)
Same dibrominated-the α of method for making, ω-two [1-(4-benzoyl-1-benzyl) piperazinyl] decane just replaces bromobenzyl with 3-methoxyl group-benzyl chloride.
Dichloride-α, and ω-two [1-(4-benzoyl-1-(2-methyl-phenmethyl)) piperazinyl] decane (22, R=2-CH
3-C
6H
5CH
2-, preparation n=10)
Same dibrominated-the α of method for making, ω-two [1-(4-benzoyl-1-benzyl) piperazinyl] decane just replaces bromobenzyl with 2-methyl-benzyl chloride.
2, dihalide-α, method is led in the preparation of ω-two [1-(1-alkyl) piperazinyl] alkane dihydrochloride (23)
Compound 22 (0.03mol) and 10%HCl (40mL) are added in the reaction flask, stirring and refluxing 3h, cooling, filtration, washing, the pressure reducing and steaming solvent adds proper amount of acetone, stirs evenly, filter fast, vacuum-drying, recrystallization gets pure product 23.
Dibrominated-α, and ω-two [1-(1-methyl) piperazinyl] hexane two hydrochloric acid (23, R=Me, preparation n=6)
Compound 22 is dibrominated-α, ω-two [1-(4-benzoyl-1-methyl) piperazinyl] hexane, Virahol-water recrystallization, yield 98%, mp.205-206 ℃.
Dibrominated-α, and ω-two [1-(1-methyl) piperazinyl] decane two hydrochloric acid (23, R=Me, preparation n=10)
Compound 22 is dibrominated-α, ω-two [1-(4-benzoyl-1-methyl) piperazinyl] decane, Virahol-water recrystallization, yield 88%, mp.139-141.5 ℃.
Dibrominated-α, and ω-two [1-(1-benzyl) piperazinyl] decane two hydrochloric acid (23, R=Me, preparation n=10)
Compound 22 is dibrominated-α, ω-two [1-(4-benzoyl-1-benzyl) piperazinyl] decane, Virahol-water recrystallization, yield 69%, mp.167-170 ℃.
Adopt same quadrat method,, make successively by changing compound 22:
Dibrominated-α, and ω-two [1-(1-(4-nitro-phenmethyl)) piperazinyl] decane two hydrochloric acid (23, R=4-NO
2-C
6H
5CH
2-, n=10)
Dichloride-α, and ω-two [1-(1-(4-nitro-phenmethyl)) piperazinyl] decane two hydrochloric acid (23, R=4-NO
2-C
6H
5CH
2-, n=10)
Dibrominated-α, and ω-two [1-(1-(4-fluoro-phenmethyl)) piperazinyl] decane two hydrochloric acid (23, R=4-F-C
6H
5CH
2-, n=10)
Dichloride-α, and ω-two [1-(1-(4-fluoro-phenmethyl)) piperazinyl] decane two hydrochloric acid (23, R=4-F-C
6H
5CH
2-, n=10)
Dichloride-α, and ω-two [1-(1-(3,5-dinitrobenzene-phenmethyl)) piperazinyl] decane two hydrochloric acid (23, R=3,5-(NO
2)
2-C
6H
5CH
2-, n=10)
Dibrominated-α, and ω-two [1-(1-(2-methoxyl group-5-nitro-phenmethyl)) piperazinyl] decane two hydrochloric acid (23, R=2-CH
3O-5-NO
2-C
6H
5CH
2-, n=10)
Dibrominated-α, and ω-two [1-(1-(3-nitro-phenmethyl)) piperazinyl] decane two hydrochloric acid (23, R=3-NO
2-C
6H
5CH
2-, n=10)
Dichloride-α, and ω-two [1-(1-(2-methoxyl group-phenmethyl)) piperazinyl] decane two hydrochloric acid (23, R=2-CH
3O-C
6H
5CH
2-, n=10)
Dichloride-α, and ω-two [1-(1-(3-methoxyl group-phenmethyl)) piperazinyl] decane two hydrochloric acid (23, R=3-CH
3O-C
6H
5CH
2-, n=10)
Dichloride-α, and ω-two [1-(1-(2-methyl-phenmethyl)) piperazinyl] decane two hydrochloric acid (23, R=2-CH
3-C
6H
5CH
2-, n=10)
3. dihalide-α, method is led in the preparation of ω-two [1-(1-alkyl) piperazinyl] alkane (24)
With above-mentioned equimolar 23 and lithium hydroxide be dissolved in the suitable quantity of water, stirring at room 30 minutes, the pressure reducing and steaming solvent, spumescence or thick product dihalide-α, ω-two [1-(1-alkyl) piperazinyl] alkane 24, the not purified the next step that is directly used in.
4. method is led in the preparation of compound VI
With above-mentioned each 24 (0.003mol), halogenide (0.01mol), Anhydrous potassium carbonate (0.012mol) and dehydrated alcohol (20mL) add in the reaction flask, stirring and refluxing, TLC detects, up to reaction finish (＞20h), filter, ethanol is washed, and boils off solvent and gets dope.Dope is dissolved in the Virahol, and logical dry hydrogen chloride gets white crystals, filters, and Virahol is washed, and acetone is washed, and gets crude product, gets pure product VI with the appropriate solvent recrystallization.
Adopt different compound 24 and halogenide respectively, prepared following compounds:
VIa 4,4 '-two styroyls-1, and 1 '-dimethyl-1,1 '-hexane-two piperazine quaternary ammonium salt dibromide (R '=C
6H
5CH
2CH
2-, R=Me, n=6, X=Br)
Wherein compound 24 is dibrominated-α in the aforesaid method, ω-two [1-(1-methyl) piperazinyl] hexane, and halogenide is styroyl chlorine, Virahol-recrystallizing methanol, yield 51%, mp.＞200 ℃.
VIb 4,4 '-diallyl-1, and 1 '-dimethyl-1,1 '-decane-two piperazine quaternary ammonium salt dibromide (R '=CH
2=CHCH
2-, R=Me, n=10, X=Br)
Wherein compound 24 is dibrominated-α in the aforesaid method, ω-two [1-(1-methyl) piperazinyl] decane, and halogenide is chlorallylene, Virahol-recrystallizing methanol, yield 43%, mp.114-116 ℃.
VIc 4,4 '-diallyl-1, and 1 '-dibenzyl-1,1 '-decane-two piperazine quaternary ammonium salt dibromide (R '=CH
2=CHCH
2-, R=C
6H
5CH
2-, n=10, X=Br)
Wherein compound 24 is dibrominated-α in the aforesaid method, ω-two [1-(1-benzyl) piperazinyl] decane, and halogenide is chlorallylene.
VId 4,4 '-diallyl-1, and 1 '-two (4-nitro-phenmethyls)-1,1 '-decane-two piperazine quaternary ammonium salt dibromide (R '=CH
2=CHCH
2-, R=4-NO
2-C
6H
5CH
2-, n=10, X=Br)
Wherein compound 24 is dibrominated-α in the aforesaid method, and ω-two [1-(1-(4-nitro-phenmethyl) piperazinyl] decane, halogenide is chlorallylene.
VIe 4,4 '-diallyl-1, and 1 '-two (4-nitro-phenmethyls)-1,1 '-decane-two piperazinyl quaternary ammonium salt dichloride (R '=CH
2=CHCH
2-, R=4-NO
2-C
6H
5CH
2-, n=10, X=Cl)
Wherein compound 24 is dichloride-α in the aforesaid method, and ω-two [1-(1-(4-nitro-phenmethyl) piperazinyl] decane, halogenide is chlorallylene.
VIf 4,4 '-diallyl-1, and 1 '-two (4-fluoro-phenmethyls)-1,1 '-decane-two piperazinyl quaternary ammonium salt dibromide (R '=CH
2=CHCH
2-, R=4-F-C
6H
5CH
2-, n=10, X=Br)
Compound 24 is dibrominated-α, ω-two [1-(1-(4-fluoro-phenmethyl)) piperazinyl] decane, and halogenide is styroyl chlorine.
VIg 4,4 '-diallyl-1, and 1 '-two (4-fluoro-phenmethyls)-1,1 '-decane-two piperazinyl quaternary ammonium salt dichloride (R '=CH
2=CHCH
2-, R=4-F-C
6H
5CH
2-, n=10, X=Cl)
Compound 24 is dichloride-α, ω-two [1-(1-(4-fluoro-phenmethyl)) piperazinyl] decane, and halogenide is chlorallylene.
VIh 4,4 '-diallyl-1, and 1 '-two (3,5-dinitrobenzene-phenmethyl)-1,1 '-decane-two piperazinyl quaternary ammonium salt dichloride (R '=CH
2=CHCH
2-, R=3,5-(NO
2)
2-C
6H
5CH
2-, n=10, X=Cl)
Compound 24 is dichloride-α, ω-two [1-(1-(3,5-dinitrobenzene-phenmethyl)) piperazinyl] decane, and halogenide is chlorallylene.
VIi 4,4 '-diallyl-1, and 1 '-two (2-methoxyl groups-5-nitro-phenmethyl)-1,1 '-decane-two piperazinyl quaternary ammonium salt dibromide (R '=CH
2=CHCH
2-, R=2-CH
2O-5-NO
2-C
6H
5CH
2-, n=10, X=Br)
Compound 24 is dibrominated-α, ω-two [1-(1-(2-methoxyl group-5-nitro-phenmethyl)) piperazinyl] decane, and halogenide is chlorallylene.
VIj 4,4 '-diallyl-1, and 1 '-two (3-nitro-phenmethyls)-1,1 '-decane-two piperazinyl quaternary ammonium salt dibromide (R '=CH
2=CHCH
2-, R=3-NO
2-C
6H
5CH
2-, n=10, X=Br)
Compound 24 is dibrominated-α, ω-two [1-(1-(3-nitro-phenmethyl)) piperazinyl] decane, and halogenide is chlorallylene.
VIk 4,4 '-diallyl-1, and 1 '-two (2-methoxyl group-phenmethyls)-1,1 '-decane-two piperazinyl quaternary ammonium salt dichloride (R '=CH
2=CHCH
2-, R=2-CH
3O-C
6H
5CH
2-, n=10, X=Br)
Compound 24 is dichloride-α, ω-two [1-(1-(2-methoxyl group-phenmethyl)) piperazinyl] decane, and halogenide is chlorallylene.
VIl 4,4 '-diallyl-1, and 1 '-two (3-methoxyl group-phenmethyls)-1,1 '-decane-two piperazinyl quaternary ammonium salt dichloride (R '=CH
2-=CHCH
2-, R=3-CH
3O-C
6H
5CH
2-, n=10, X=Br)
Compound 24 is dichloride-α, ω-two [1-(1-(3-methoxyl group-phenmethyl)) piperazinyl] decane, and halogenide is chlorallylene.
VIm 4,4 '-diallyl-1, and 1 '-two (2-methyl-phenmethyls)-1,1 '-decane-two piperazinyl quaternary ammonium salt dichloride (R '=CH
2=CHCH
2-, R=2-CH
3-C
6H
5CH
2-, n=10, X=Br)
Compound 24 is dichloride-α, ω-two [1-(1-(2-methyl-phenmethyl)) piperazinyl] decane, and halogenide is chlorallylene.
Biological activity test
Adopt mouse writhing method (subcutaneous administration), above-mentioned synthetic compound has been carried out biological activity test, the result shows, the analgesic activities that such compound exhibits is certain, and the analgesic activities of some compound is quite strong.As when dosage is 20mg/kg, the calmness of Compound I c and analgesic activities are respectively 51.4% and 41.7%, and the calmness of Ib compound and analgesic activities are respectively 59.3% and 27.3%; The analgesic activities of Compound I Ic be 100% and sedative activity be 84.9%, the analgesic activities of IIh is 59.3%; The analgesic activities of IIIa is 91%; The analgesic activities of VIa is 88%.When dosage was 10mg/kg, the analgesic activities of IVb was 96%.
Adopt the perpendicular tail test of mouse (subcutaneous administration), carry out the test of compound habituation, the result shows that the more weak or habituation of this compounds habituation is much smaller than morphine.
Claims (5)
1, the piperazine quaternary ammonium salt compound or pharmaceutically acceptable salt thereof of general formula I-III:
Wherein
R
1For-(CH
2)
4-OC
6H
5,-CH
2CH=CHC
6H
4-Cl-o ,-CH
2CH=CHC
6H
4-Cl-m ,-CH
2CH=CHC
6H
4-Cl-p ,-CH
2CH=CHC
6H
4-NO
2-m ,-CH
2CH=CHC
6H
4-NO
2-p,
-CH
2CH(OH)CH
2Cl、-CH
2CH
2OH、-C
2H
5、-CH
2CH＝CH
2、C
6H
5CH
2CH
2-、-COCH
2CH
2Br、-COCH
2CH
2Cl，
R
2And R
3Independent separately expression hydrogen or methyl,
R
4And R
5Common expression-(CH
2)
3-,-(CH
2)
4-,-(CH
2)
5-,-(CH
2)
6-or
R
6Expression hydroxyl, methyl, ethyl, propyl group, nitro or halogen atom,
X represents Cl, Br or I,
But can not meet the following conditions simultaneously: R
2And R
3Be hydrogen, R
4And R
5Common expression-(CH
2)
5-, R
1For-COCH
2CH
2Br, or R
2And R
3Be hydrogen, R
4And R
5Common expression-(CH
2)
5-, R
1For-CH
2CH (OH) CH
2Cl;
R wherein
2, R
3, R
5, R
5And X is respectively as the definition in the general formula I in the above, and Ar represents
R wherein
2, R
3, R
4, R
5Reach X as the definition in the general formula I, A=-(CH
2)
x-, wherein x is 3-6, or
Wherein y be 3-6 or
P is 1-6, R
9Expression hydrogen, R
7And R
8Independently represent methyl separately, or constitute ring amino jointly with N.
2, piperazine quaternary ammonium salt compound or pharmaceutically acceptable salt thereof according to claim 1, wherein in the general formula III, R
7And R
8Constitute jointly with N
Or
3, a kind of method for preparing the described general formula I I of claim 1 compound, this method comprises:
(A) piperazine of acyl substituted alkaline condition next time stream be carried out to volution reaction, slough acyl group then, salify;
(B) carry out the Mannich reaction with the ethanoyl arone of formaldehyde and various replacements again, promptly obtain the compound of general formula I I of the present invention.
4, a kind of method for preparing the described compound of formula III of claim 1, this method comprises: (A) piperazine of N-acyl substituted and 1,3-epoxy chloropropane or α, ω-dihalo hydrocarbon or Br (CH
2)
yCOX or X (CH
2)
pCHOH (CH
2)
pThe X reaction, wherein defined in X, y and p such as the claim 1 to X, y and p;
(B) product and then with dialkylamine or cyclic amine reaction, generate corresponding amine;
(C) slough acyl group then, carry out the spirocyclization reaction, choose into the compound that ester promptly obtains general formula III of the present invention again wantonly.
5, the application of the compound or pharmaceutically acceptable salt thereof of the described general formula I-III of claim 1 in the preparation analgesic.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101089000B (en) * | 2006-06-16 | 2011-01-05 | 北京大学 | Spiro piperazine quaternary ammonium salt compound and its preparation method and application |
| CN102718801A (en) * | 2011-03-30 | 2012-10-10 | 北京大学 | A method for preparing derivative of cyclophosphamide quaternary ammonium salt |
| CN102491957A (en) * | 2011-12-14 | 2012-06-13 | 天津市筠凯化工科技有限公司 | Method for preparation, refining and detection of N-benzoyl piperazidine |
| CN102898428B (en) * | 2012-09-20 | 2015-04-22 | 常州大学 | Microwave synthesis method of spirocyclopiperazinium compound |
| CN102827157A (en) * | 2012-09-20 | 2012-12-19 | 北京哈三联科技股份有限公司 | Method for preparing lurasidone |
| CN105012309A (en) * | 2014-04-15 | 2015-11-04 | 北京大学 | Applications of spiro piperazine quaternary ammonium salt compound LXM-10-M in preparation of anti-inflammatory drugs |
| CN107021940A (en) * | 2017-05-03 | 2017-08-08 | 天津国际生物医药联合研究院 | A kind of BISPIP class compound and its application |
| CN114907531A (en) * | 2022-06-28 | 2022-08-16 | 西南石油大学 | Preparation method of a salt-responsive hydrophobically associating polymer and application in fracturing fluid |
-
2001
- 2001-09-12 CN CN 01142111 patent/CN1281607C/en not_active Expired - Fee Related
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