CN1018453B - Process for preparation of new diaryl compounds - Google Patents
Process for preparation of new diaryl compoundsInfo
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- CN1018453B CN1018453B CN 85107987 CN85107987A CN1018453B CN 1018453 B CN1018453 B CN 1018453B CN 85107987 CN85107987 CN 85107987 CN 85107987 A CN85107987 A CN 85107987A CN 1018453 B CN1018453 B CN 1018453B
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- phenyl
- formula
- piperidine
- diphenyl
- group
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Abstract
The present invention discloses a new method for preparing a diaryl compound. Substituents in the formula are defined in the specification. The diaryl compound is used as a medicament.
Description
The invention relates to the preparation method of new diaryl compounds.This compound is used for preparing medicine in pharmaceutical industry.
Known some that replaces in every way 1, the 4-dihydrogen pyridine derivative has useful characteristic on pharmacology.Can european patent application book 88,903,94,159 and 106,276 as an example.Be surprised to find that now the new compound and the compound of the prior art that describe in detail hereinafter differ widely, have on its 4-position by the disubstituted piperidine ring, this new compound has significant especially pharmacology characteristic, and the difference of they and compound of the prior art is these pharmacology characteristics.
The invention relates to the preparation method of new diaryl compounds He its salt of formula I,
In the formula:
Ar represents the ring of following formula
Wherein Y represents oxygen (O), sulphur (S), vinylene (CH=CH-), the azomethine base (CH=N-), or the base of following formula
R
1, R
2And R
3Identical or different, represent hydrogen, C
1-C
6-alkyl, C
3-C
7-alkoxyalkyl, aryl, aryl-C
1-C
6-alkyl or alkoxy-C
1-C
6-alkyl,
R
4And R
5Identical or different, represent hydrogen, hydroxyl, halogen, nitro, cyano group, trifluoromethyl, C
1-C
4-alkyl, C
1-C
4-alkoxyl group, by the C of all or part of replacement of fluorine
1-C
4-alkoxyl group, C
1-C
4-alkoxy carbonyl, C
2-C
5-acyl group, amino, or list-C
1-C
4-alkylamino or two-C
1-C
4-alkylamino,
R
6, R
7, R
8And R
9Identical or different, represent hydrogen, hydroxyl, halogen, C
1-C
4-alkyl, C
1-C
4-alkoxyl group, amino, list-C
1-C
4-alkylamino or two-C
1-C
4-alkylamino, or by the C of all or part of replacement of fluorine
1-C
4-alkoxyl group,
A represents the C of straight or branched
2-C
5-alkylidene group, it can be by C
1-C
4-alkoxyl group or aryl replace.
C
1-C
6-alkyl is a straight or branched, typical example such as hexyl, neo-pentyl, isopentyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, propyl group, sec.-propyl, perhaps particularly ethyl or methyl.
C
3-C
7-alkoxyl group typical example such as methoxy ethyl, ethoxyethyl group, propoxy-ethyl, isopropoxy ethyl, butoxyethyl group, methoxy-propyl, 2-methoxyl group-1-methylethyl or 2-oxyethyl group-1-methylethyl.
Aryl general proxy phenyl or the phenyl of using one or two substituting group in the group base of forming by following groups to replace: halogen, hydroxyl, nitro, cyano group, trifluoromethyl, C
1-C
4-alkoxyl group, C
1-C
4-alkoxy carbonyl, C
2-C
5-acyl group, amino and single C
1-C
4-alkylamino or two C
1-C
4-alkylamino.
Aryl-C
1-C
6The C that-alkyl is replaced by aryl
1-C
6-alkyl.Aryl-C
1-C
6Alkyl is for example styroyl, 3-(4-chloro-phenyl-)-propyl group, perhaps benzyl particularly.
Aryloxy-C
1-C
6The C that-alkyl is replaced by aryloxy
1-C
6-alkyl.Aryloxy-C
1-C
6-alkyl is a phenoxy group ethyl for example.
Halogen is represented bromine and particularly fluorine and chlorine.
C
1-C
4-alkyl is a straight or branched, typical example such as butyl, isobutyl-, sec-butyl, the tertiary butyl, propyl group, sec.-propyl, ethyl, perhaps methyl particularly.
Except that Sauerstoffatom, C
1-C
4-alkoxyl group also contains above-mentioned C
1-C
4A base the in-alkyl.Methoxyl group is preferred.
By the C of all or part of replacement of fluorine
1-C
4-alkoxyl group is for example 1,1,2,2-tetrafluoro oxyethyl group, trifluoromethoxy, 2,2,2-trifluoro ethoxy, or difluoro-methoxy.
Except that carbonyl, C
1-C
4-alkoxy carbonyl also contains above-mentioned C
1-C
4A base in the alkoxyl group.Methoxycarbonyl and ethoxy carbonyl are preferred.
Except that carbonyl, C
2-C
5-acyl group also contains above-mentioned C
1-C
4A base the in-alkyl.Ethanoyl is preferred.
Except that nitrogen-atoms, single C
1-C
4-alkylamino or two C
1-C
4-alkylamino also contains above-mentioned C
1-C
4One or two alkyl in-the alkyl.Two C
1-C
4-alkylamino is preferred, particularly two methylaminos, two ethylamino or two sec.-propyl amino.
The C of straight or branched
2-C
5-alkylidene group is a tetramethylene, 1 for example, 2-dimethyl-ethylene, 1,1-dimethyl-1,2-ethylidene, 2,2-dimethyl-ethylene, isopropylidene, 1-methyl isophthalic acid, 2-ethylidene, 2-ethyl-1,2-propylidene, perhaps particularly ethylene or propylene.
By C
1-C
4The C that-alkoxyl group replaces
2-C
5Alkylidene group is for example 1-methoxyl group-propylene, 2-oxyethyl group-propylene, or 1,2-dimethoxy-ethylene.
The C that is replaced by aryl
2-C
5-alkylidene group is a 1-styrolene for example, or the 2-(4-chloro-phenyl-)-propylene.
Possible salt all is the salt that generates with acid.Being generally used for mineral acid qualified on the pharmacology of medicine industry and organic acid salt can narrate especially.Underproof salt on the pharmacology, for example when preparing compound of the present invention with technical scale as the available salt of the product of technological process, change into salt qualified on the pharmacology by the known method of professional and technical personnel.The example of the salt that this type is suitable is water miscible and water-insoluble acid salt; hydrochloride for example; hydrobromide; hydriodide; phosphoric acid salt; nitrate; vitriol; acetate; Citrate trianion; gluconate; benzoate; diphenic acid salt (hibenzate); fendizoate; butyrates; sulfosalicylate; maleate; lauroleate; the Pingguo hydrochlorate; fumarate; succinate; oxalate; tartrate; 4; 4 '-diaminostilbene-2; 2 '-sulfonate; 4; 4 '-methylene bis 3-hydroxyl-2-bitter edible plant hydrochlorate; 3-methoxyl group-2-bitter edible plant hydrochlorate; stearate; benzene methanesulfonic acid salt; 2-hydroxyl-3-bitter edible plant formate; 3-hydroxyl-2-bitter edible plant formate; or mesylate (mesylate); with the additive salt that generates with following acid; the 3-(amino-sulfonyl)-5-(butyl amino)-4-phenoxy group benzoic acid; the 5-(amino-sulfonyl)-4-chloro-2 ((2-furyl methyl) amino) phenylformic acid; 2-chloro-5-(IH-tetrazolium-5-yl)-4-((2-thienyl methyl) amino) benzsulfamide (azosemide); galosemide; besunide, the 4-(amino-sulfonyl)-4-phenoxy group-5(1-pyrrolidyl) phenylformic acid; Uregit; Tienilic Acid (tienilicacid) or 4-chloro-sulfamoylbenzoic acid.
The Ar base of picking out is a phenyl, the 3-fluorophenyl, the 2-chloro-phenyl-, the 3-chloro-phenyl-, the 4-chloro-phenyl-, 2, the 3-dichlorophenyl, the 2-cyano-phenyl, the 3-cyano-phenyl, the 2-p-methoxy-phenyl, the 3-p-methoxy-phenyl, the 2-trifluoromethyl, the 3-trifluoromethyl, 3-(1,1,2,2-tetrafluoro oxyethyl group)-phenyl, 2-difluoro-methoxy phenyl, 3-difluoro-methoxy phenyl, the 2-tolyl, the 3-tolyl, the 4-tolyl, the 2-pyridyl, the 3-pyridyl, 2,1,3-benzodiazole-4-base (2,1,3-benzoxdiazol-4-y), 5-methyl-2-thienyl and particularly 2-nitrophenyl and 3-nitrophenyl.
The compound of formula I has a chiral centre 1 on the 4-position of 4-dihydropyridine.Therefore, product of the present invention comprises two enantiomorphs, and if have another chiral centre to exist, also comprise diastereomer and their mixture and racemoid.
The feature of present method is:
A) cinnamic acid derivative of formula II
With the enamine derivates reaction of formula III,
B) β of the cinnamic acid derivative of formula II and ammonia and formula IV-keto carboxylic acid derivatives reaction,
C) enamine of formula (V)
（Ⅴ）
With the benzylidene carboxylic acid derivative reaction of formula VI,
（Ⅵ）
D) ketone compound of formula (VII)
With the benzylidene carboxylic acid derivative reaction of ammonia and formula VI,
E) aldehyde of formula (VIII)
With the enamine of formula (V) and the β of formula IV-keto carboxylic acid derivatives reaction,
F) ketone compound of the enamine derivates of the aldehyde of formula (VIII) and formula III and formula (VII) reaction,
G) 1 of formula (IX), the 4-dihydrogen pyridine derivative
（Ⅸ）
With biaryl compound or its reactant salt of formula (X),
If desired, the salt that obtains changes into free alkali then.The alkali that perhaps obtains transforms salify, in the formula: Ar, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, Y and A have above-mentioned implication, Z and carbonyl representation carboxy that is connected with it or active carboxylic acid derivative (for example carboxylic acid halide).
In The suitable solvent, carry out preferred inert organic solvents to the method for f according to a.The example that can narrate has alcohol, for example ethanol, methyl alcohol, Virahol, the trimethyl carbinol, ether, for example: diox, ether, tetrahydrofuran (THF), ethylene glycol monomethyl ether and glycol dimethyl ether; Perhaps other solvents, as polar solvent, for example dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile or hexamethyl phosphoric triamide (hexamethylphosphoricacid triamide), perhaps, particularly chlorinated hydrocarbon, for example methylene dichloride, chloroform or zellon.
Temperature of reaction can change-depend on the reactivity of educt in wide scope.Reaction is generally carried out for 20 ℃ to 150 ℃ in temperature, preferred 20 ℃ to 100 ℃, particularly carries out under the solvent for use boiling temperature.
Technological process can or add at normal pressure to depress carries out, and based on the reaction under normal pressure, application of pressure also is possible, particularly for the reaction with ammonia.
A participates in the material of reaction and generally uses with molar weight in all cases in the method for f according to the present invention implementing, but can use excessive reactant (for example ammonia among method b and the d)-depend on reaction conditions when needed.
In the method for implementing g according to the present invention, use with a to the similar reaction conditions of f method, still additional when appropriate measure be necessary-depend on the character of substituting group Z.For example, when substituting group Z was hydroxyl, reaction was preferably carried out in the presence of condensing agent, and condensing agent separates or combination water (for example dicyclohexyl carbodiimide).When Z is halogen atom (for example chlorine atom), again when needed, is reflected at alkali and carries out (trimethylamine for example is as triethylamine, or inorganic carbonate, for example yellow soda ash) under existing.
Material according to the present invention for example goes out solvent with vacuum distilling with known method segregation and purification, and the resistates that recrystallization obtains from The suitable solvent is purified with a kind of common method of purification again, for example carries out column chromatography and separate on suitable carrier substance.
Acid salt obtains by free alkali is dissolved in the The suitable solvent, and for example in chlorinated hydrocarbon such as methylene dichloride or chloroform, perhaps in lower molecular weight Fatty Alcohol(C12-C14 and C12-C18) (ethanol or Virahol), acid or this acid of containing needs in the solvent are adding thereafter.
Salt is by filtration, redeposition, obtain with non-solvent precipitation or solvent evaporation additive salt.
The salt that obtains can be by making them become alkalescence with ammonia soln, thereby make it change into free alkali, and these alkali itself can change into acid salt.Underproof acid salt can change into acid salt qualified on the pharmacology with this method on the pharmacology.
Be known in the initial compounds document, known method similar methods preparation in available and the document.Cinnamic acid derivative (II) and benzylidene carboxylic acid derivative (VI) are for example available to be prepared with G.Jones method similar methods (" the Nuo Wengeer condensation, organic reaction (Org.Reactions), X V volume, 204(1967)).Enamine derivates (III) and enamine (V) are for example available to be obtained with A.C.Cope method similar methods (U.S. chemical institute magazine (J.Amer.Chem.Soc.), 67,1017(1945)).β-keto carboxylic acid derivatives (IV) and ketone compound (VII) can be according to the preparation of D.Borrmann method (" reactions of diketene and alcohol, phenol and mercaptan ", organic chemistry method (Methods of Organic Chemistry), the VII volume, 4,230(1968)), perhaps according to the preparation of people's such as Y.Oikawa method (organic chemistry magazine (JOrgChem.), 43,2087(1978)).Compound (IX) can be used with a from corresponding initial compounds and obtain to the method similar methods of f.The compound X can obtain with corresponding piperidines (referring to for example German patent specification 1,936,452) and ω-halo reaction of alkanol.
Just to explanation, narrated above-mentioned preparation method, the preparation of formula I compound is not limited to these methods according to the present invention.Or rather, these methods any improves one's methods and similarly is applicable to preparation according to The compounds of this invention.
Preferable methods is method a and c.
Below preparation embodiment be used for the present invention is described in more detail but be not limited.M.p. represent fusing point, b.p. represents boiling point.
Embodiment
1. 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-methyl 5-(3-(4,4-diphenyl-piperidine-1-yl)-propyl group) the ester hydrochloride
Method e)
With the 4.53g3-nitrobenzaldehyde, amino methyl crotonate of 3.45g3-and 11.38g etheric acid 3-(4,4-diphenyl-piperidine-1-yl)-propyl diester is in 100ml 2-propyl alcohol, at one night of boiling point reflux.The refrigerative solution concentration is to dry, and the resistates that stays carries out chromatographic separation with ethyl acetate as elutriant in silicagel column.Concentrate the uniform product cut in back and stay the solid foam residue, this resistates is dissolved in the methyl alcohol, and adds the hydrochloride of ether.Concentrated solution, the solid residue that stays is dissolved in the small amount of methanol, and title substance comes out with the adding petroleum ether precipitation.Fusing point: since 135 ℃ (decomposition); Output: 9.3g.
Initial compounds is prepared as follows:
A) etheric acid 3-(4,4-diphenyl-piperidine-1-yl)-propyl diester
With 23.6g3-(4,4-diphenyl-piperidine-1-yl)-propyl alcohol is dissolved in the 100ml dry toluene, under agitation adds the acetone soln of 16ml concentration 50% diketene.Mixture is at room temperature placed after several days and (is controlled with thin-layer chromatography), concentrates, and resistates is dry under high vacuum, and the light yellow sticking oily matter that stays is used for next step and need not purifies again.
B) 3-(4,4-diphenyl-piperidine-1-yl)-propyl alcohol
At 500ml1: in the mixture of 1 diox and 1-butanols, under boiling temperature and vigorous stirring, with 40g4,4-diphenyl-piperidine, 24.7g3-bromopropyl alcohol, about 48 hours of 116.4g potassium carbonate powder and about 1g potassiumiodide reflux.The cooled and filtered mixture, concentrated filtrate.The oily resistates is dissolved in the ethyl acetate, and solution refilters.After filtrate is concentrated into drying, obtain faint yellow oily product, be solidified into wax lentamente.Output: 44.8g.Handle with the hydrochloride of ether, obtain hydrochloride, and from the 2-propyl alcohol recrystallization.Fusing point: 226-7 ℃.
Obtain initial compounds b with another kind of method): under boiling temperature with 352g4, the 4-diphenyl-piperidine, the 128g sodium hydrate particle, 2.5l methylene dichloride, 500ml water, the phase-transfer catalyst of 218g3-bromo-1-propyl alcohol and catalytic activity amount (for example zephiran chloride trimethyl ammonium) reflux 10 hours.Isolate organic phase and wash the water dichloromethane extraction of collection with water.The blended organic phase with dried over sodium sulfate after, transparent brown solution is evaporated to drying.The resistates that arborescens is brown is dissolved in the 4.5l ebullient sherwood oil (boiling range 100-140 ℃), and insoluble resistates heating and filtering from solution is come out, cooling filtrate.Obtaining title compound after placing a night, is the free alkali of colourless coarse crystallization.Fusing point: 97 ℃; Output: 303g.
Obtain following initial compounds with similar methods:
4-(4,4-diphenyl-piperidine-1-yl)-and the fusing point of butanols hydrochloride: 209-212 ℃,
2-(4,4-diphenyl-piperidine-1-yl)-the 2-methylpropanol, fusing point: 115-116 ℃,
3-(4,4-two-(4-p-methoxy-phenyl) piperidines-1-yl)-propyl alcohol, the fusing point of hydrochloride: 130-134 ℃ (in crystallization, containing 1 equivalent methyl alcohol),
3-(4,4-diphenyl-piperidine-1-yl)-2-methyl-2-propyl alcohol, the fusing point of hydrochloride: 181-183 ℃,
2-(4,4-diphenyl-piperidine-1-yl)-ethanol, the fusing point of hydrochloride: 197-199 ℃.
With making above-mentioned alcohol and diketene solution reaction, obtain corresponding acetylacetic ester, the further reaction of just need not purifying with embodiment 1a similar methods.
Method c)
Under boiling temperature, with 15.38g2-ethanoyl-3-(3-nitrophenyl)-vinylformic acid 3-(4,4-diphenyl-piperidine-1-yl)-the amino methyl crotonate of propyl diester and 3.45g3-one night of reflux in 100ml 2-propyl alcohol.The refrigerative solution evaporation is to dry, and foamed solid residue is dissolved in a small amount of methylene dichloride, and adds the hydrochloride of ether.Again after being concentrated into drying, solid residue is dissolved in a small amount of methylene dichloride, adds ethyl acetate till slight turbidity is constant.Mixture is placed a night in refrigerator after, title compound is with meticulous little yellow thin slice crystal structure come out (at microscopically).Fusing point: 230-231 ℃ (decomposition); Output: 13.6g.
Other solvents that are used for condensation reaction are: trimethyl carbinol, diox, tetrahydrofuran (THF) and chlorinated hydrocarbon.The output of product is the 60-80% of theoretical amount.
Other salt of the title compound 1 of preparation are:
Hydrobromide: fusing point: 229-230 ℃ (decomposition), meticulous platelet (recrystallization from ethyl acetate and diisopropyl ether);
Fumarate: fusing point: 144-145 ℃ (decomposition), meticulous thin slice (recrystallization from ethyl acetate);
Maleate: fusing point: 151-152 ℃ (decomposition), bodkin shape crystal (recrystallization from ethyl acetate).
When condensation product is concentrated into drying, when the foam solid resistates is dissolved in a spot of methylene dichloride, obtain the free alkali of title compound 1; Add diisopropyl ether up to keeping thin turbidity to end, after placing in refrigerator, alkali crystallizes out with meticulous platelet form.Fusing point: 145-147 ℃.
Initial compounds 2-ethanoyl-3-(3-nitrophenyl) vinylformic acid 3-(4,4-diphenyl-piperidine-1-yl) propyl diester (suitable/the trans isomer mixture) is prepared as follows:
In 300ml benzene,, 4-diphenyl-piperidine-1-yl) with 40.14g etheric acid 3-(4-and propyl diester, 15.97g3-nitrobenzaldehyde, 8.0ml acetate and 0.5ml piperidines heat under boiling temperature and when water separator is arranged.1.9ml after water sepn was come out, refrigerative solution washed with water then with saturated sodium hydrogen carbonate solution washing.Organic phase with dried over sodium sulfate after, the solution with transparent reddish-brown under high vacuum contracts to constant weight.The sticking resistates of the reddish brown property that obtains need not be purified again and is directly used in condensation.Output: 52g crude product.Other suitable entrainers are: toluene and chlorinated hydrocarbon.The output of crude product is the 90-100% of theoretical amount.
With the fumaric acid reaction of free alkali and equimolar amount, obtain the fumarate of initial compounds; Fusing point: since 128 ℃ (decomposition), meticulous needle-like crystal, recrystallization from ethyl acetate.
Obtain hydrochloride with the hydrochloride reaction of ether; Fusing point: 152-155 ℃ (meticulous platelet, recrystallization from ethyl acetate and ether).
Method a)
In boiling temperature and under backflow and nitrogen atmosphere; with 134.6g2-ethanoyl-3-(3-nitrophenyl)-methyl acrylate; 204.5g3-amino Ba Dousuan 3-(4,4-diphenyl-piperidine-1-yl)-propyl diester and 4.5ml acetate heated 20 hours in the no Shui diox of 2.7l.After the cooling 45ml concentrated hydrochloric acid (37%) is added in this mixture, add the crystal seed of title compound 1, this mixture was at room temperature placed 24 hours.The throw out suction filtration, Yong diox and diisopropyl ether washing are then 75 ℃ of vacuum-dryings.Product (270g) distributes in 1.5 liters of methylene dichloride and ammonia soln (PH11), and organic phase is dry on sodium sulfate, and vacuum distilling goes out solvent then.Resistates is dissolved in the 2.5l diox, adds 35ml concentrated hydrochloric acid (concentration 37%), introduces crystal seed in the mixture, places 40 hours.The product suction filtration that crystallization goes out, the washing of Yong diox is then with the diisopropyl ether washing, 100 ℃ of vacuum-dryings.Obtain pale yellow powder shape title substance (at microscopically: little needle-like crystal).Fusing point: 198-200 ℃; Output: 246g.
The amino Ba Dousuan 3-(4 of initial compounds 3-, 4-diphenyl-piperidine-1-yl)-propyl diester is prepared as follows:
260.5g etheric acid 3-(4 in the 1.6l2-propyl alcohol, 4-diphenyl-piperidine-1-yl)-propyl diester mixes the back and stirs a night with the 260ml concentrated ammonia solution.Isolated meticulous little band ochreous throw out suction filtration with cold 2-propyl alcohol, ether washing, is used petroleum ether at last.Fusing point: 144-150 ℃; Output: 225g adds the 100ml concentrated ammonia solution again in filtrate, mixture is placed after several days in refrigerator, the product 12g that gets back and have identical fusing point.
Can obtain initial compounds with another kind of method: under agitation, ammonia is fed etheric acid 3-(4,4-diphenyl-piperidine-1-yl)-the 2-propanol solution of propyl diester in, till no longer including throw out and separating.Output: be about 90% of theoretical amount.
2. 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-methyl 5-(2-(4,4-diphenyl-piperidine-1-yl)-ethyl) the ester hydrochloride
Title compound 1 similar methods,, amino methyl crotonate of 3.45g and 11g etheric acid 2-(4,4-diphenyl-piperidine-1-yl from the 4.53g3-nitrobenzaldehyde the 100ml2-propyl alcohol with embodiment)-ethyl ester obtains.Fusing point: since 137 ℃ (decomposition); Output: 8.5g.
3. 4-(3-cyano-phenyl)-1,4-dihydro-2,6-lutidine-3,5-dicarboxylic acid 3-methyl 5-(3-(4,4-diphenyl-piperidine-1-yl)-propyl group) the ester hydrochloride
Title compound use with embodiment 1 similar methods from the 3.93g3-cyanobenzaldehyde the 80ml trimethyl carbinol, amino methyl crotonate of 3.45g3-and 11.38g etheric acid 3-(4,4-diphenyl-piperidine-1-yl)-propyl diester obtains.Fusing point: 136-146 ℃ (slow deliquescence, amorphous material, sedimentary in sherwood oil); Output: 5.9g.
4. 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-methyl 5-(2-(4,4-diphenyl-piperidine-1-yl)-2-methyl-propyl group) the ester hydrochloride
Title compound use with embodiment 1 similar methods from the ethanoyl of the 15.8g2-the 100ml tetrahydrofuran (THF)-3-(3-nitrophenyl)-vinylformic acid 2-(4,4-diphenyl-piperidine-1-yl)-the amino methyl crotonate reaction of 2-methyl-propyl ester and 3.45g3-obtains after 12 hours.Fusing point: since 155 ℃ (slow deliquescence, amorphous substance, sedimentary from sherwood oil); Output: 13.6g.
5. 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-ethyl 5-(3-(4,4-diphenyl-piperidine-1-yl)-propyl group) the ester hydrochloride
Title compound 1 similar methods with embodiment; from the ethanoyl of the 13.16g2-the 100ml tetrahydrofuran (THF)-3-(3-nitrophenyl)-the amino Ba Dousuan 3-(4 of ethyl propenoate and 18.91g3-, 4-diphenyl-piperidine-1-yl)-the propyl diester reaction obtains after 6 hours.Fusing point: 230-232 ℃ (meticulous dihedral crystal, from acetonitrile and ether recrystallization); Output: 29.7g
6. 1,4-dihydro-2,6-dimethyl-4-(3-(1,1,2,2-tetrafluoro oxyethyl group)-phenyl)-pyridine-3,5-dicarboxylic acid 3-methyl 5-(3-(4,4-diphenyl-piperidine-1-yl)-propyl group) the ester hydrochloride
Title compound 1 similar methods with embodiment; from the 40.33g2-ethanoyl-3-(3-(1 400ml tetrahydrofuran (THF) and 0.5ml Glacial acetic acid; 1; 2; 2-tetrafluoro oxyethyl group)-phenyl)-the amino Ba Dousuan 3-(4 of methyl acrylate and 37.85g3-, 4-diphenyl-piperidine-1-yl)-the propyl diester reaction obtains after 14 hours.Fusing point: 189-192 ℃; Output: 57g.
7. 1,4-dihydro-2,6-dimethyl-4-(3-(1,1,2,2-tetrafluoro oxyethyl group)-phenyl)-pyridine-3,5-dicarboxylic acid 3-methyl 5-(2-(4,4-diphenyl-piperidine-1-yl)-ethyl) the ester hydrochloride
Title compound 1 similar methods with embodiment; from 4.03g2-ethanoyl-3-(3-(1,1,2 the 80ml2-propyl alcohol; 2-tetrafluoro oxyethyl group)-phenyl)-the amino Ba Dousuan 2-(4 of methyl acrylate and 3.4g3-, 4-diphenyl-piperidine-1-yl)-the ethyl ester reaction obtains after 8 hours.Fusing point: 130-140 ℃ (slow deliquescence, amorphous material, sedimentary from 1: 1 sherwood oil and ether); Output: 6.2g.
8. 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-(2-methoxy ethyl) 5-(2-(4,4-diphenyl-piperidine-1-yl)-ethyl) the ester fumarate
Title compound 1 similar methods with embodiment; from the 4.99g2-ethanoyl-3-(3-nitrophenyl 60ml tetrahydrofuran (THF) and 0.5ml Glacial acetic acid)-vinylformic acid 2-(4,4-diphenyl-piperidine-1-yl)-the amino Ba Dousuan 2-(2-of ethyl ester and 1.6g3-ethoxyethyl group) the ester reaction obtains after 4 hours.Fusing point: since 130 ℃ (slow deliquescence, meticulous platelet, recrystallizations from ethyl acetate and ether); Output: 3.7g.
9. 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-(2-methoxy ethyl) 5-(3-(4,4-diphenyl-piperidine-1-yl)-propyl group) the ester fumarate
Title compound 1 similar methods with embodiment; from the ethanoyl of the 5.12g2-the 80ml trimethyl carbinol-3-(3-nitrophenyl)-vinylformic acid 3-(4,4-diphenyl-piperidine-1-yl)-the amino Ba Dousuan 2-(2-of propyl diester and 1.6g3-methoxy ethyl) the ester reaction obtains after 5 hours.Fusing point: 184-185 ℃ (dihedral thin slice, from ethyl acetate and ether recrystallization); Output: 5.3g.
10. 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-methyl 5-{ 3-(4,4-two-(4-p-methoxy-phenyl) piperidines-1-yl)-propyl group } ester hydrochloride
Title compound 1 similar methods with embodiment, from the 4.4g etheric acid 3-(4 the 60ml trimethyl carbinol, 4-two-(4-p-methoxy-phenyl)-piperidines-1-yl)-and propyl diester, amino methyl crotonate of 1.15g3-and 1.51g3-nitrobenzoyl aldehyde reaction obtained after 12 hours.Fusing point: since 138 ℃ (slow deliquescence, amorphous material, sedimentary in sherwood oil); Output: 4.9g.
11. 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-methyl 5-(4-(4,4-diphenyl-piperidine-1-yl) butyl) the ester fumarate
Title compound 1 similar methods with embodiment, from the 3.94g etheric acid 4-(4 the 80ml trimethyl carbinol, 4-diphenyl-piperidine-1-yl)-butyl ester, 1.15g3-amino methyl crotonate and 1.51g3-nitrobenzoyl aldehyde reaction obtained after 6 hours, fusing point: 123-126 ℃ (meticulous needle crystal, from ethyl acetate and methylene dichloride recrystallization); Output: 3.9g.
12. 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-methyl 5-(1,1-dimethyl-2-(4,4-diphenyl-piperidine-1-yl)-ethyl) the ester hydrochloride
Title compound 1 similar methods with embodiment; from the ethanoyl of the 15.8g2-the 120ml2-propyl alcohol-3-(3-nitrophenyl)-vinylformic acid 1; 1-dimethyl-2-(4,4-diphenyl-piperidine-1-yl)-ethyl ester and the amino methyl crotonate reaction of 3.45g3-obtain after 15 hours.Fusing point: since 148 ℃ (slow deliquescence, amorphous material, sedimentary from sherwood oil); Output: 11.3g.
13. 1,4-dihydro-2,6-dimethyl-4-(2-difluoro-methoxy phenyl)-pyridine-3,5-dicarboxylic acid 3-ethyl 5-(3-(4,4-diphenyl-piperidine-1-yl) propyl group) the ester hydrochloride
Title compound 1 similar methods with embodiment; from the ethanoyl of the 3.8g2-the 60ml trimethyl carbinol-3-(2-difluoro-methoxy phenyl)-vinylformic acid 3-(4,4-diphenyl-piperidine-1-yl)-the amino ethyl crotonate reaction of propyl diester and 1.3g3-obtains after 20 hours.Fusing point: since 126 ℃ (slow deliquescence, amorphous material, sedimentary from 1: 1 sherwood oil and ether); Output: 2.8g.
14. 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-(3-(4,4-diphenyl-piperidine-1-yl)-propyl group) ester
At room temperature, with 6.8g1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-(2-cyano ethyl) 5-(3-(4,4-diphenyl-piperidine-1-yl)-propyl group) the ester hydrochloride stirred 3 hours with 40ml0.5N sodium hydroxide solution and 100ml diox.After most of diox steams, 15ml2N hydrochloric acid is added in the resistates.The solution of milkiness is used 100ml chloroform/propyl carbinol (3: 1) extraction 4 times at every turn, and the blended organic phase is washed with the saturated sodium chloride solution of 50ml.Organic phase is concentrated into drying, and solid residue is recrystallization from chloroform/methanol (1: 1).Fusing point: 192-195 ℃ (decomposition); Output: 5.4g.
Initial compounds 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-(2-cyano ethyl) 5-(3-(4,4-diphenyl-piperidine-1-yl)-propyl group) ester is prepared as follows:
In boiling temperature with under refluxing; in 120ml2-propyl alcohol and 0.5ml Glacial acetic acid; with 8.1g2-ethanoyl-3-(3-nitrophenyl)-the amino Ba Dousuan 3-(4 of vinylformic acid 2-cyano methyl ester and 10.6g3-, 4-diphenyl-piperidine-1-yl)-propyl diester heating 4 hours.Most of solvent steams the back and adds 2 parts of 50ml toluene, and resistates is concentrated into drying.The resistates that becomes the solid foam shape is dissolved in the Virahol, and ether is added in the transparent solution till initial turbidity is constant.After mixture was placed in refrigerator, initial compounds crystallized out with meticulous platelet.Fusing point: 158-160 ℃; Output: 14.3g.
Handle with the hydrochloride of ether, obtain the hydrochloride of initial compounds, and from methylene chloride recrystallization.Fusing point: 184-194 ℃ (slowly deliquescence).
15. 1,4-dihydro-2,6-dimethyl-4-(3-(1,1,2,2-tetrafluoro oxyethyl group)-phenyl)-pyridine-3,5-dicarboxylic acid 3-ethyl 5-(3-(4,4-diphenyl-piperidine-1-yl)-propyl group) the ester hydrochloride
Title compound 1 similar methods with embodiment is from the 22.2g3-(1 the 280ml trimethyl carbinol, 1,2,2-tetrafluoro oxyethyl group) phenyl aldehyde, amino ethyl crotonate of 12.9g3-and 37.9g etheric acid 3-(4,4-diphenyl-piperidine-1-yl)-the propyl diester reaction obtains after 14 hours.Fusing point: 196-197 ℃ (decompose, from methylene dichloride and diisopropyl ether recrystallization); Output: 48.9g.
16. 1,4-dihydro-2,6-dimethyl-4-(3-difluoro-methoxy phenyl)-pyridine-3,5-dicarboxylic acid 3-ethyl 5-(3-(4,4-diphenyl-piperidine-1-yl)-propyl group) the ester hydrochloride
Title compound 1 similar methods with embodiment, from the 1.6g3-difluoro-methoxy phenyl aldehyde the 80ml tetrahydrofuran (THF), 1.3g3-amino ethyl crotonate and 3.8g etheric acid 3-(4,4-diphenyl-piperidine-1-yl)-propyl diester reaction obtains after 4 hours, fusing point: 197-198 ℃ (meticulous platelet, from methylene dichloride and ethyl acetate recrystallization); Output: 5.1g.
17. 4-(2, the 3-dichlorophenyl)-1,4-dihydro-2,6-lutidine-3,5-dicarboxylic acid 3-methyl 5-(3-(4,4-diphenyl-piperidine-1-yl)-propyl group) the ester hydrochloride
Title compound 1 similar methods with embodiment; from the 2.72g2-ethanoyl-3-(2 the 100ml2-propyl alcohol; the 3-dichlorophenyl)-and the amino Ba Dousuan 3-(4 of methyl acrylate and 3.79g3-, 4-diphenyl-piperidine-1-yl)-the propyl diester reaction obtains after 7 hours.Fusing point: 228-230 ℃ (the meticulous needle-like crystal that recrystallization goes out from methyl alcohol and ethyl acetate); Output: 4.2g.
18. 4-(2,1,3-benzodiazole-4-yl)-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl 5-(3-(4,4-diphenyl-piperidine-1-yl)-propyl group) the ester hydrochloride
Title compound 1 similar methods with embodiment; from the 2.5g2-ethanoyl-3-(2 60ml tetrahydrofuran (THF) and 0.5ml acetate; 1,3-benzodiazole-4-yl)-and methyl acrylate and the amino Ba Dousuan 3-(4 of 3.8g3-, 4-diphenyl-piperidine-1-yl)-the propyl diester reaction obtains after 4 hours.Fusing point: 208-210 ℃ (the meticulous bulk crystals that recrystallization goes out from ethyl acetate and methylene dichloride); Output: 4.1g.
19. 1,4-dihydro-2,6-dimethyl-4-(3-fluorophenyl)-pyridine-3,5-dicarboxylic acid 3-methyl 5-(3-(4,4-diphenyl-piperidine-1-yl)-propyl group) the ester hydrochloride
Title compound 1 similar methods with embodiment is from the ethanoyl of the 2.44g2-the 50ml tetrahydrofuran (THF)-3-(3-fluorophenyl)-the amino Ba Dousuan 3-(4 of methyl acrylate and 4.39g3-, 4-diphenyl-piperidine-1-yl)-the propyl diester reaction obtains after 5 hours.Fusing point: 213-216 ℃ (the meticulous dihedral crystal of recrystallization from methylene dichloride and diisopropyl ether); Output: 4.8g.
20. 1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethyl)-pyridine-3,5-dicarboxylic acid 3-methyl 5-(3-(4,4-diphenyl-piperidine-1-yl)-propyl group) the ester hydrochloride
Title compound use with embodiment 1 similar methods from the ethanoyl of the 2.7g2-the 60ml trimethyl carbinol-3-(2-trifluoromethyl)-the amino Ba Dousuan 3-(4 of methyl acrylate and 4.4g3-, 4-diphenyl-piperidine-1-yl)-the propyl diester reaction obtains after 4 hours.Fusing point: 158-162 ℃ (the meticulous cubic system of recrystallization from methylene dichloride and diisopropyl ether); Output: 4.2g.
21. the 4-(2-cyano-phenyl)-1,4-dihydro-2,6-lutidine-3,5-dicarboxylic acid 3-ethyl 5-(3-(4,4-diphenyl-piperidine-1-yl)-propyl group) the ester hydrochloride.
Title compound 1 similar methods,, amino methyl crotonate of 3.45g3-and 11.38g etheric acid 3-(4,4-diphenyl-piperidine-1-yl from the 3.93g2-cyanobenzaldehyde the 80ml2-propyl alcohol with embodiment)-the propyl diester reaction obtains after 10 hours.Fusing point: 178-181 ℃ (the meticulous needle-like crystal that recrystallization goes out from ethyl acetate and methylene dichloride); Output: 8.4g.
22. the 4-(2-chloro-phenyl-)-1,4-dihydro-2,6-lutidine-3,5-dicarboxylic acid 3-methyl 5-(3-(4,4-diphenyl-piperidine-1-yl)-propyl group) the ester hydrochloride
Title compound 1 similar methods with embodiment; from the 3.6g2-ethanoyl-3-(2-chloro-phenyl-60ml tetrahydrofuran (THF) and 0.5ml acetate)-the amino Ba Dousuan 3-(4 of methyl acrylate and 5.7g3-, 4-diphenyl-piperidine-1-yl)-the propyl diester reaction obtains after 8 hours.Fusing point: 150 ℃ (decomposition) (meticulous needle-like crystal of recrystallization from methylene dichloride and diisopropyl ether); Output: 3.3g.
Industrial applicibility
Has industrial applicibility according to chemical compounds I of the present invention and its salt.They particularly have the active vasodilator of coronary vasodilator treatment characteristic.The pharmacologic activity of this compound combines with hypotoxicity, show especially bring high blood pressure down slowly on, and be powerful and for a long time.And compound according to the present invention has the end slightly, coronal, vasodilation characteristic brain and kidney and saline diuretic (Salidiuretic) characteristic.
The pharmacology test
Antihypertensive active according to The compounds of this invention can prove by enough typical natural high pressure mouse.
In order to measure antihypertensive active, the compound that is listed in the table below was supplied with the dosage of mentioning with the stomach tube method in continuous 4 days once a day, (male SHR/N/Ibm/Bm mouse, 250-350g), these mouse have the hypertension (RR＞180mmHg) of genetic origin to 6 mouse of every kind of situation.Every kind of situation is surveyed 6 blood pressures, when appropriate, supplies with the back at compound and surveys once in 2 or 24 hours.
In the table below, the sequence number mark of the compound of test according to embodiment number.
Table 1 show according to the The compounds of this invention sample according to oral supply mouse after the percentage ratio that reduces of blood pressure (BP).
Table 1
According to continuous four days oral once a day supplying compounds (N=6/ dosage), the percentage ratio % that hereditary hypertension rat blood pressure (BP) changes; Dosage (mg/kg) is pressed free alkali and is calculated.
Preface dosage blood pressure (the variation % of relative comparison group)
Micromole/kilogram mg/kg shown in the measured mean value of minute
2 hours 6 hours 24 hours
(the 1st day+the 1st day the-the 1st day+
Number the 4th day) the 4th day the 3rd day
1 5 3.05 -47 -30 -7
10 6.09 -50 -37 -9
25 15.24 -48 -45 -25
2 25 14.89 -51 -36 -2
3 25 14.74 -48 -41 -19
4 25 15.60 -51 -44 -25
5 10 6.24 -51 -41 -20
6 25 17.02 -21 -21 -10
8 25 15.99 -44 -33 0
9 25 16.34 -48 -28 -5
10 10 6.70 -53 -45 -14
11 10 6.24 -40 -18 -2
12 5 3.12 -54 -33 -15
13 5 3.22 -15 -8 -3
16 25 16.12 -41 -29 -6
17 25 15.84 -49 -43 -30
Table before continuous
18 25 15.17 -49 -41 -16
19 25 14.57 -46 -38 -7
20 25 15.82 -44 -30 -17
21 25 15.09 -37 -25 -1
22 25 14.98 -43 -28 -2
Claims (2)
1, the compound of logical formula I and the preparation method of its salt,
(Ⅰ)
In the formula:
Ar represents phenyl, 2-nitrophenyl, 3-nitrophenyl, 2-cyano-phenyl, 3-cyano-phenyl, 2-(1,1,2,2-tetrafluoro oxyethyl group)-phenyl, 3-(1,1,2,2-tetrafluoro oxyethyl group)-phenyl, 2-difluoro-methoxy phenyl, 3-difluoro-methoxy phenyl, 2-chloro-phenyl-, 3-chloro-phenyl-, 2,3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-trifluoromethyl or 3-trifluoromethyl
R
1Represent methylidene, R
2Represent methylidene, R
3Represent methylidene, ethyl or methoxy ethyl,
R
6Represent hydrogen, R
7Represent hydrogen or methoxyl group, R
8Represent hydrogen, R
9Represent hydrogen or methoxyl group,
A represents ethylene, propylene, butylidene, 1,1-dimethyl-ethylene or 2, and 2-dimethyl-ethylene,
The method is characterized in that:
A) cinnamic acid derivative of formula II
(Ⅱ)
With the enamine derivates reaction of formula III,
Or
B) enamine of formula (V)
(Ⅴ)
With the benzylidene carboxylic acid derivative reaction of formula VI,
(Ⅵ)
Or
C) aldehyde of formula (VII)
(Ⅶ)
With the enamine of formula (V) and the β of formula IV-keto carboxylic acid derivatives reaction,
If desired, then the salt that obtains is changed into free alkali, perhaps the alkali that obtains is transformed salify,
In the formula: Ar, R
1, R
2, R
3, R
6, R
7, R
8, R
9Has top given implication with A.
2,, it is characterized in that preparing 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl according to the method for claim 1)-pyridine-3,5-dicarboxylic acid 3-methyl 5-(3-(4,4-diphenyl-piperidine-1-yl)-propyl group) ester or its salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 85107987 CN1018453B (en) | 1984-09-28 | 1985-09-26 | Process for preparation of new diaryl compounds |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH465384 | 1984-09-28 | ||
| CN 85107987 CN1018453B (en) | 1984-09-28 | 1985-09-26 | Process for preparation of new diaryl compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN85107987A CN85107987A (en) | 1987-05-20 |
| CN1018453B true CN1018453B (en) | 1992-09-30 |
Family
ID=25695998
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 85107987 Expired CN1018453B (en) | 1984-09-28 | 1985-09-26 | Process for preparation of new diaryl compounds |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1018453B (en) |
-
1985
- 1985-09-26 CN CN 85107987 patent/CN1018453B/en not_active Expired
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| Publication number | Publication date |
|---|---|
| CN85107987A (en) | 1987-05-20 |
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