CN85105643A - The preparation of heterogeneous ring compound - Google Patents
The preparation of heterogeneous ring compound Download PDFInfo
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- CN85105643A CN85105643A CN85105643.1A CN85105643A CN85105643A CN 85105643 A CN85105643 A CN 85105643A CN 85105643 A CN85105643 A CN 85105643A CN 85105643 A CN85105643 A CN 85105643A
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Abstract
This invention is the method for the compound of relevant preparation chemical structural formula (I).
In the structural formula: R
1Expression methyl, third-2-base, propylene-2-base or cyclopentyl and qualified physiology salt and solvate (as hydrate) thereof.
These compounds to " neuronic " serotonine receptor be effectively, antagonist selectively, to the treatment migraine with to resemble the mental patient of schizophasia one class effective in cure.
Description
The present invention is the preparation about pharmaceutical novel heterocyclic compound.The present invention provides the method for the logical formula I compound of preparation in more detail.
(in the structural formula: R represents methyl, 2-propenyl, cyclopentyl or 2-propyl group) and qualified physiology salt and solvate thereof.
A kind of compound of preferentially selecting for use is 1,2,3,9-tetrahydrochysene-9-methyl-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-4H-carbazole-4-ketone.
According to the present invention, these compounds with this method preparation, it is effective, selectable serotonine (being called for short 5HT) antagonist, it can induce the reaction of the isolating vagus nerve preparation of mouse, therefore, it is as the effectively selectable antagonist of " neural unit " 5HT receptor, and this class receptor is on afferent main nerve.
This compound can be used as anodyne, for example treats migrainous pain; Also can treat the psychotic psychiatric disorder that resembles schizophasia one class.In addition, also effective in cure to treatment anxiety, obesity and mania.
This compound can be with common equipment by formulation.This compound of the present invention, dosage varies with each individual, the people that body weight is about 70 kilograms, dosage is 0.05 to 20 milligram, the significant quantity of per unit dosage is advisable with 0.1 to 10 milligram, for example takes 1 to 4 time on the one by this dosage.The dosage size depends on instructions about how to take medicine and patient's body weight.Dosage depends on the severity of patient's age, body weight and the state of an illness, stipulates that various doses commonly used are necessary.
Prepare according to first method (A).The compound of logical formula I, qualified physiology salt or solvate and this type of material thereof can prepare with the reaction of logical formula II compound.
(in the structural formula: R
1With preceding identical, Y represents the substituted in reaction base), protected derivative and this type of material or salt and this type of material thereof that contains chemical structure formula III imidazoles.
The sample of chemical structure formula II compound can be used as the starting material (comprising compound) of method (A).In the structural formula: Y represents from alkylene=CH
2Base of selecting or chemical formula CH
2The base of Z.Z represents that easy metathetical resembles the atom or the base of halogen atom (as a chlorine or bromine) class; Acidic group, for example acetoxy group, trifluoromethane sulphonyl hydroxyl, right-sulfonyloxy methyl or sulfonyl methane;-
R
2R
3R
4X
-Base, in the formula, R
2, R
3And R
4Be identical or different base, each basis representation contains the alkyl (as methyl) of low-carbon (LC), aryl (as phenyl), aralkyl (as phenmethyl); R
2, R
3Link together with nitrogen-atoms, can form 6 joint rings (as pyrrolidine ring) from 5 joint rings, X represents to resemble the negatively charged ion of halide ions (as muriate, a bromide or iodide) class;-NR
2R
3Base, in the formula, R
2And R
3With preceding identical, for example-N(CH
3)
2
When Y represents=CH
2During base, this preparation method is preferably in the suitable solvent and carries out, and suitable solvent comprises water; Ester (as vinyl acetic monomer); Ketone (as acetone); Methyl iso-butyl ketone (MIBK); Acid amides (as DIMETHYL FORMAMIDE); Alcohol (as ethanol); Ether (such as diox or tetrahydrofuran (THF)); This class mixture and this type of material thereof.This method is carried out under (as 20 ° to the 100 ℃) condition of heating.
When Y represents CH
2During the Z base, Z is a halogen atom or acidic group in the formula.Can prepare in suitable solvent, these solvents are acid amides (as dimethyl formamides); Alcohol (as methyl alcohol or industrial methylated alcohol); Halogenation alkane (as methylene dichloride).During preparation, temperature is (for example, can in+20 ° to+100 ℃ scopes) between-10 ° to 150 ℃.
The chemical reaction of the compound of chemical structure formula II.Y represents CH in the formula
2Z base, Z be-
R
2R
3R
4X
-Base in suitable solvent, reacts in 20 ° to 150 ℃ scopes of temperature, and these solvents have: water; Acid amides (as DIMETHYL FORMAMIDE); Ketone (as acetone); Ether (such as diox).
The chemical reaction that comprises chemical structure formula II compound, in the structural formula, Y represents-CH
2Z base, Z are-NR
2R
3Base in the suitable solvent that resembles water, alcohol (as methyl alcohol) or this type of mixture one class, reacts in 20 ° to 150 ℃ temperature ranges.
Prepare according to another usual way (B).The compound of chemical structure formula I can be produced by the oxygenizement of chemical structure formula IV compound.
(A represents hydrogen atom or hydroxyl, R in the formula
1With preceding identical) or salt or protected derivative and this type of material thereof.
Adopt common method and general reagent can realize oxidising process, also can select not cause really the reaction conditions of indyl oxidation, therefore, oxidising process preferably adopts weak oxidant.
When chemical structure formula IV compound carried out oxidation, A represented hydrogen atom in the formula, and suitable oxygenant comprises the quinone (as 2,3-two chloro-5,6-dicyano-1,4-benzoquinones or 2,3,5,6-tetrahydrochysene-1,4-benzoquinones) that is placed in the water; Tin anhydride; Resemble cerium (IV) oxygenant of high cerium one class of ammonium nitrate; Chromium (VI) oxygenant (as chromic acid solution in acetone (as Jones reagent) or the chromium trioxide in pyridine).
When chemical structure formula IV compound carried out oxidation, A represented hydroxyl in the formula, and suitable oxygenant comprises the quinone (as 2,3-two chloro-5,6-dicyano-1,4-benzoquinones or 2,3,5,6-tetrachloro-1,4-benzoquinones) in water; Ketone (as acetone, methyl ethyl ketone or pimelinketone) in alkali (as t-fourth oxygen aluminium); Chromium (VI) oxide compound (as chromic acid solvent (as Jones reagent) or the chromium trioxide in pyridine in acetone); N-halo succinimide (as N-chlorosuccinimide or N-bromosuccinimide); Dialkyl sulfoxide in promoting agent (as dimethyl sulfoxide (DMSO)), promoting agent has N, N '-dicyclohexyl carbodiimide or acyl halide (as oxalyl chloride or toluene sulfonyl chloride); Pyridine-sulphur trioxide complex compound; Resemble the dehydrogenation catalyst of copper chromite, zinc oxide, copper or a silver-colored class.
From ketone (as acetone or butanone), ether (as tetrahydrofuran (THF) Huo diox), acid amides (as DIMETHYL FORMAMIDE), alcohol (as methyl alcohol), hydrocarbon polymer (as benzene or toluene), halogenated hydrocarbon (as methylene dichloride) and water or mixture like that, pick out suitable solvent.
This preparation method is adapted at carrying out in-70 ° to+50 ℃ temperature ranges, it is said that the selective oxidation agent will change preferred temperature of reaction.
Prepare according to another usual way (C).According to the present invention, chemical structure formula I compound, salt or protected derivative and this type of material thereof can be produced by the alkylating of chemical structural formula (V) compound, salt or protected derivative and this type of material thereof.
The suitable alkylating agent that employing is selected from chemical formula RaXa compound carries out alkanisation, and Ra represents methyl, 2-propyl group, 2-propenyl or cyclopentyl in the formula, and Xa represents residual base (as halogenide), acidic group (Y is with preceding identical) or chemical formula (Ra)
2SO
4In vitriol.
Alkylation reaction is suitable for carrying out in inert organic solvents.These solvents have acid amides (as DIMETHYL FORMAMIDE), ether (as tetrahydrofuran (THF)) and aromatic hydrocarbon (as toluene), are preferably in the alkali and carry out.Suitable alkali comprises alkalimetal hydride (as sodium hydride), alkali metal amide (as sodium amide), alkaline carbonate (as yellow soda ash), alkali metal alcoholates (as methylate, ethylate or the t-butoxide of sodium or potassium).Alkylation reaction carries out in-20 ° to+100 ℃ temperature ranges (being preferably in 0 ° to 50 ℃).
Differentiating that in above some conversion responsive base is necessary in any compound of protection, also is desired, in order to avoid undesirable side reaction occurs.Used protecting group is the ideal base in preparation chemical structure formula I compound; these bases in the suitable stage, are preferably in the easy cracking of terminal stage, for example in reaction sequence; during above-mentioned any reaction sequence, must protection ketone group (as ketone acetal or thioketones acetal).
Logical formula I compound can prepare according to another usual way (D).This compound comprises from the protected structure formation of chemical structure formula I compound removes any protecting group.Adopt general technology can remove protecting group, for example refer to this problem in " vitochemical protecting group " book, this book is write by J.F.W.McOmie, and Plenum published in 1973.Therefore, handle, can remove the ketone acetal that resembles alkylene ketal radical one class with mineral acid (example hydrochloric acid).The thioketones acetal can divide with the mercury salt (as mercury chloride) that is placed in the suitable solvent that resembles ethanol one class.
The compound of chemical structure formula I can change into the qualified physiology salt of these compounds according to usual way.Therefore, the free alkali of logical formula I can preferably select for use suitable equivalent solvent (as aqueous ethanol) to handle with suitable acid treatment.
Qualified physiology salt in the chemical structure formula I compound, can prepare according to the present invention, these salt comprise the acid salt additive, and they generate with organic acid or mineral acid, for example have: hydrochloride, hydrobromide, vitriol, phosphoric acid salt, Citrate trianion, fumarate and maleate.The solvate of chemical structure formula I compound is produced according to the present invention (comprising hydrate).
Indivedual enantiomers of compound of the present invention, the mixture that can adopt usual way (as the optically-active dissolving acid) to decompose enantiomer (as the mixture of racemization) obtains.Referring to " stereochemistry of a carbon compound " book, write by E.L.Eliel, Mc Graw Hill published in 1962; " solvating agent catalogue " book is write by S.H.Wilen.
The sample of optically-active dissolving acid can be used as and generates the salt have racemoid, comprises (R) and (S) organic carboxyl acid and the sulfonic acid (as tartrate, two-right-toluoyl tartrate, camphorsulfonic acid and lactic acid) of type.The mixture of the isomery salt that obtains, if necessary, the way of available fractional crystallization is separated into diastereoisomer, and required optically active isomer changes into free alkali.
The method of above-indicated preparation compound of the present invention can be as last main phase in the preparation order.Identical usual way in progressively generating required compound, can be used for the intermediate stage to introduce desired base, these usual ways in multistage preparation process in every way connection get up.In multistage preparation process, to select reaction sequence certainly, make used reaction conditions not change base in the molecule really, and these bases needed base in the finished product just.
In the starting material of chemical structure formula II, Y represents=CH
2Base can be produced from the compound of chemical structure formula II, and in compound, Y represents CH
2 R
2R
3R
4X
-Base, by with suitable solvent in alkali react acquisition.The sample of alkali comprises alkali metal hydroxide (as potassium hydroxide), alkaline carbonate or hydrogen carbonate (as sodium bicarbonate).
If select suitable solvent (as DIMETHYL FORMAMIDE), quaternary salt can be produced by reacting the corresponding tertiary amine that obtains with alkylating agent (as methyl-iodide or Dimethylsulfate).Tertiary amine is produced with the reaction of the tetrahydro-carbazolone in the logical formula VI.
If necessary, in the suitable solvent that resembles a pure class (as ethanol), can have formaldehyde and corresponding secondary amine.
The method preparation that the paper that logical formula VI compound can adopt people such as H.Lida to deliver proposes.This paper publication is at " organic chemistry magazine " in 1980 the 45th volumes the 15th phase 2938-2942 page or leaf.
Y in the logical formula II starting material represents-CH
2Z, Z are halogen atom or acidic group, can produce from the corresponding hydroxymethyl derivative of general formula (VII).
Tetrahydro-carbazolone with logical formula VI reacts this starting material of acquisition with formaldehyde, is preferably in the suitable solvent that resembles a pure class (as ethanol) and carries out in alkali.
Therefore, this compound (Z is a halogen atom in the chemical formula) reacts acquisition by the compound of chemical structural formula (VII) with the halogenating agent (as phosphorus trichloride) that resembles trihalid one class.
This compound (Z is sour benzene in the chemical formula) reacts and produces by the compound of chemical formula (VII) and suitable acylating agent (as acid anhydride) or halogen sulphonyl (as the chlorination sulphonyl).
(Y represents-CH chemical structure formula II compound in the formula
2Z, Z are halogen atoms), (Y represents=CH compound that also can be by chemical formula II in the formula
2Base) produces with suitable hydrogen halide (as hydrochloride) reaction, be preferably in suitable resembling in this kind solvent of ether (as diethyl ether) and produce.
The compound of logical formula IV can be produced with the reaction of general formula (VIII) compound.
In the structural formula, R
1With A with preceding identical, Z
1Represent that easy metathetical resembles halogen atom and acidic group this class atom or base, and-
R
2R
3R
4X
-Base.
The compound of chemical structural formula (VIII) can reduce chemical formula II compound with Li-Al hydrogen thing or sodium borohydride thing and produce.
The compound (A represents hydroxyl in the formula) of the also available chemical formula of compound (A represents hydrogen atom in the formula) (VIII) of chemical structural formula (VIII) is produced with tolylsulfonyl halogenide (as tolylsulfonyl chlorination thing) reaction, then the tolylsulfonyl salt that generates with the reduction of Li-Al hydrogen thing.
Following example explanation the present invention.Temperature with degree centigrade (℃) expression.Use excessive N a
2SO
4Drying solution; With excessive P
2O
5Under 50 ℃ of temperature and place in a vacuum one night dry solids.Adopt the technology (publication is at " organic chemistry magazine " in 1978 the 43rd phase 2923-2925 pages or leaves) of people's propositions such as W.C.Still to carry out chromatography.
Preparation 1
2,3,4,9-tetrahydrochysene-N, N, N-trimethylammonium-4-oxo-1H-carbazole-3-methane amine iodide
3-in methyl iodide (15 milliliters) ((dimethylin) methyl)-1,2,3,9-tetrahydrochysene-4H-carbazole-4-ketone (0.53 gram) solution, reflux 5 hours is evaporated to drying then, obtains white solid product (0.84 gram), fusing point 202-205 ℃.
Preparation 2
2,3,4,9-tetrahydrochysene-N, N, N, 9-tetramethyl--4-oxo-1H-carbazole-3-methane amine iodide.
With the 3-in the methyl iodide (100 milliliters) ((dimethylin) methyl)-1,2,3,9-tetrahydrochysene-9-methyl-4H-carbazole-4-ketone (3.80 gram) suspensoid, reflux and stirred 57 hours, concentrate in a vacuum, obtain 192 °-195 ℃ of solid phase prod (5.72 gram) fusing points.
Preparation 3
1,2,3,9-tetrahydrochysene-9-methyl-3-methylene-4H-carbazole-4-ketone
The solution that will prepare 2 products (5.0 gram) leaves (20 milliliters) in the water in, handle with 2 equivalent concentration yellow soda ash (6.55 milliliters), heating is 45 minutes under 35 ℃ of temperature, the soup compound of gained is cooled to 0 ℃, filter out solid matter, wash with water, dry then, obtain product (2.8 gram), 127 °-129 ℃ of fusing points.
Preparation 4
2,3,4,9-tetrahydrochysene-9-methyl-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-1H-carbazole maleate
Sodium borohydride (90 milligrams) is when inflated with nitrogen stirs, be added in sample 6 products (500 milligrams) solution in methyl alcohol (3 milliliters) and chloroform (3 milliliters) mixture, continuously stirring 48 hours (the more sodium borohydride (250 milligrams) of adding after 17.5 hours and 42 hours) is separated suspensoid in the middle of 2 equivalent concentration hydrochloric acid (15 milliliters) and chloroform (3 * 10 milliliters) then.Alkalizing with solid sodium carbonate in the waterbearing stratum, uses chloroform (3 * 10 milliliters) to extract again, and water (2 * 10 milliliters) and salt solution (10 milliliters) washing extract are dry and concentrated under vacuum condition then; Remaining foam (557 milligrams) with methylene dichloride, ethanol and 0.88 ammoniacal liquor (300: 10: 1) mixture elution stratography post, obtain solid matter (200 milligrams), this material of dissolving refluxes in dehydrated alcohol (3 milliliters), in dehydrated alcohol (1 milliliter), reflux again and add toxilic acid (80 milligrams) solution, filter the solution of heat, stir, use anhydrous diethyl ether (40 milliliters) dilution then, obtain product (240 milligrams), 138.5 °-140 ℃ of fusing points.
Preparation 5
2,3,4,9-tetrahydrochysene-9-methyl-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-1H-carbazole-4-alcohol
Be added in the suspensoid of Li-Al hydrogen thing (7.75 gram) stirring in anhydrous tetrahydro furan (750 milliliters) during with sample 6 products (30.0 gram) inflated with nitrogen.This mixture refluxes and stirred 1 hour, uses water cooling, with aqueous tetrahydrofuran (THF) (15%H
2O; 100 milliliters) and water (100 milliliters) dilute suspension body, concentrate in a vacuum, use methylene dichloride (2 * 500 milliliters) to extract residual solids then, concentrate organic extraction in a vacuum, use methylene dichloride, ethanol and 0.88 ammonia water mixture (150: 10: 1) elution again, (Kieselgel 60 with silica; Merck 7747; 500 grams) short distance stratography post purification residual solids material (16.4 gram) obtains spumescence product (13.4 gram).
Thin layer stratography post silica, methylene dichloride/ethanol/0.88 ammoniacal liquor (150: 10: 1) Rf0.34 and two pairs of diastereoisomers of 0.36(), calibrating u.v. and iodo platinic acid.
Nucleus magnetic resonance δ (CDCl
3+ CD
3OD(1 drips)) 1.6～2.3 and 2.6～3.0(5H, m), 2.32 and the Me of 2.40(3H, s+s, two different isomerization things), 3.32(3H, S, NMe), 3.65～4.3(2H, m, CHCH
2N), 4.75～4.85(1H, m, CH-OH), 6.8-7.8(CH, m, perfume compound).
Preparation 6
1,2,3,9-tetrahydrochysene-3-(2-methyl isophthalic acid H-imidazoles-1-base-methyl)-4H-carbazole-4-ketone
The solution of glyoxal ethyline in DIMETHYL FORMAMIDE (75 milliliters) (17.00 gram) and preparation 1 product (6.60 gram) 100 ℃ of heating 17.25 hours, adds entry after the cooling, use six times of ethyl acetate extraction then.Washing and dry extract obtain solid matter after the evaporation; Use sulfonic acid ethyl ester/ethanol (4: 1) elution again, purify with silica post (Merck 7734), evaporation product obtains solid matter.Suspend in hot ethanol then, and handle with toxilic acid, the cooling solvent filters out crystalline solid, obtains product maleate (0.4 gram) after the drying, fusing point 155-156 ℃.
Sample 1
1,2,3,9-tetrahydrochysene-9-methyl-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-4H-carbazole-4-ketone hydrochloride.
At the solution of anhydrous dimethyl for methylimidazole in the methane amide (30 milliliters) (5.0 gram) and preparation 2 products (2.0 gram), inflated with nitrogen stirs, heating is 16.75 hours under 95 ℃ of temperature, cooled and filtered goes out crystalline solid, water, anhydrous dimethyl are for methane amide (3 * 2 milliliters) and anhydrous diethyl ether (2 * 10 milliliters) washing, and be dry then.At dehydrated alcohol (30 milliliters) with contain in the mixture of alcoholic acid hydrochloride (1 milliliter), the solid matter (0.60 gram) that suspends and obtain, slowly heating is filtered in heat-processed to obtain solution.Dilute filtrate with anhydrous diethyl ether then, with precipitated solid material (0.6 gram); This solid matter of recrystallize in dehydrated alcohol obtains solid phase prod (0.27 gram), 186 °-187 ℃ of fusing points.
Analyze component result: C61.9; H6.4; N11.8
C
18H
19N
2O.HCl.H
2O needs C62.3; H6.1; N12.1%
Sample 2
1,2,3,9-tetrahydrochysene-9-methyl-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-4H-carbazole-4-ketone maleate
In the ethanol (5 milliliters) of heat, suspend 1,2,3,9-tetrahydrochysene-9-methyl-4H-carbazole-4-ketone (300 milligrams) is handled cooling solution with toxilic acid (116 milligrams), carry out drying after filtering out white crystalline solid, obtain product (300 milligrams), fusing point is 132.3 ℃.
Sample 3
1,2,3,9-tetrahydrochysene-9-methyl-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-4H-carbazole-4-ketone
Replace 1 in the methane amide at anhydrous dimethyl, 2,3,9-tetrahydrochysene-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-4H-card azoles-4-ketone (1.0 gram) solution is added to anhydrous dimethyl dropwise and (contains 80% in oil for stirring, refrigerative sodium hydride in the methane amide (5 milliliters) in nitrogen; 0.11 gram) in the suspensoid.Add methyl-sulfate (0.34 milliliter) after half an hour, stirred solution is 4 hours at ambient temperature.Filter out the solid resultant, for methane amide (2 * 5 milliliters) and anhydrous diethyl ether (3 * 15 milliliters) washing, draw solid phase prod (0.25 gram) after the drying, fusing point 223-224 ℃ (dec) with ice-cold anhydrous dimethyl.Thin layer stratography post silica, chloroform/methanol (93: 7) Rf0.27 calibrating u.v. and iodo platinic acid are identical with sample 1 product.
Sample 4
9-cyclopentyl-1,2,3,9-tetrahydrochysene-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-4H-carbazole-4-ketone-maleate
Anhydrous dimethyl is replaced 1 in the methane amide (9 milliliters), 2,3,9-tetrahydrochysene-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-4H-card azoles-4-ketone (1.20 gram) solution, be added in the ice-cold hydrogen sodium thing suspensoid of stirring, this sodium hydride (contains 80% in oil; 0.14 gram) be placed down in anhydrous dimethyl in the methane amide (2 milliliters) filling the nitrogen condition, continuously stirring 0.25 hour adds bromocyclopentane (0.51 milliliter), in 100 ℃ of temperature the solution that stirred is heated 18.5 hours.Cooling solution separates in water (100 milliliters) and vinyl acetic monomer (3 * 70 milliliters) then.With 2 equivalent concentration yellow soda ash (2 * 50 milliliters), water (2 * 50 milliliters) and salt solution (50 milliliters) washing organic extraction, evaporation is done after super-dry, use methylene dichloride, ethanol and 0.88 ammoniacal liquor (150: 10: 1) elution again, purify, obtain oily mater (0.27 gram) with the stratography post.This oil of dissolving refluxes in dehydrated alcohol (7 milliliters), in backflow dehydrated alcohol (0.5 milliliter), add maleic acid solution again, filter, stir and, use anhydrous diethyl ether (7 * 25 milliliters) and mother liquor washing yellow gummy at last with the solution of anhydrous diethyl ether (20 milliliters) heat of dilution.Filter out the solid that crystallizes out from solution,, obtain white crystalline solid product (0.058 gram) after the drying, fusing point 104.5-106 ℃ with anhydrous diethyl ether (3 * 5 milliliters) washing.
Analyze component result: C65.95; H6.4; N8.6
C
22H
25N
2O.C
4H
4O
4.O.6H
2O needs C65.8; H6.4; N8.9%
Sample 5
1,2,3,9-tetrahydrochysene-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-9-(2-propenyl)-4H-carbazole-4-ketone-maleate
Anhydrous dimethyl is replaced 1 in the methane amide (6 milliliters), 2,3,9-tetrahydrochysene-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-4H-carbazole-4-ketone (1.0 gram) solution is added at anhydrous dimethyl and replaces in the ice-cold sodium hydride suspensoid that stirred in the methane amide (2 milliliters).Add allyl bromide 98 after 0.25 hour,, deposited 20 hours in room temperature earlier, be placed on then that water (75 milliliters) and vinyl acetic monomer (3 * 50 milliliters) are middle to be separated 0 ℃ of stirred solution of temperature 0.25 hour.Water (2 * 50 milliliters) and salt solution (50 milliliters) washing organic extraction, drying concentrates in a vacuum, uses the mixture diluted of methylene dichloride, ethanol and 0.88 ammoniacal liquor (200: 10: 1) then, purify with the stratography post, obtain solid matter (0.43 gram).
The dissolving that in dehydrated alcohol (2 milliliters), refluxes of this solid matter, be added in toxilic acid (0.18 gram) solution that in anhydrous diethyl ether, refluxes, filter the solution of heat, use anhydrous diethyl ether (4 milliliters) dilution again, filter out the crystalline solid then, use anhydrous diethyl ether (3 * 5 milliliters) washing at last, obtain white solid matter (0.48 gram) after the drying, 150.5 ℃-151 ℃ of fusing points.
Analyze component result: C66.3; H5.75; N9.6
C
20H
21N
3O.C
4H
4O
4Need C66.2; H5.8; N9.65%.
Sample 6
1,2,3,9-tetrahydrochysene-9-methyl-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-4H-carbazole-4-ketone
Handle the 3-((dimethylin) methyl)-1 of in water (17 milliliters) with glyoxal ethyline (1.4 gram), 2,3,9-tetrahydrochysene-9-methyl-4H-carbazole-4-ketone hydrochloride (1.7 gram) solution, reflux 20 hours filters the refrigerative mixture, then water (3 * 15 milliliters) washing filter residue, obtain thick product (1.7 gram), 221 °～221.5 ℃ of fusing points.This material recrystallize in methyl alcohol obtains product (1.4 gram), 231 °-232 ℃ of fusing points, and it is identical with sample 3 products to record product with the thin layer chromatography.
Sample 7
1,2,3,9-tetrahydrochysene-9-methyl-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-4H-carbazole-4-ketone
The suspensoid of glyoxal ethyline in water (5 milliliters) (0.4 gram) and preparation 3 products (0.5 gram), reflux 20 hours, filter the refrigerative reaction mixture, water (3 * 10 milliliters) washing filter residue, drying, recrystallize in methyl alcohol (18 milliliters) obtains product (0.3 gram), fusing point 232-234 ℃ (dec), the product that measures with the thin layer chromatography is identical with sample 3 products.
Sample 8
1,2,3,9-tetrahydrochysene-9-(2-propyl group)-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-4H-carbazole-4-ketone hydrochloride
In DIMETHYL FORMAMIDE (35 milliliters) 1,2,3, in the solution that 9-tetrahydrochysene-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-4H-carbazole-4-ketone (1.93 gram) has stirred, in the time of 0 ℃, add sodium hydride (80% is dispersed in the oil, 0.208 gram).Stirring suspension body 0.25 hour in the time of 0 ℃ adds 2-N-PROPYLE BROMIDE (0.78 milliliter) again, and at ambient temperature one night of continuously stirring, restir is 4 hours in the time of 40 ℃.The mixture of reaction is in yellow soda ash (2 equivalent concentration; 200 milliliters) separate with vinyl acetic monomer (2 * 150 milliliters) is middle.Organic extraction used water (3 * 75 milliliters) washing, drying, methylene dichloride/ethanol/ammoniacal liquor (100: 8: 1) dilution is used in evaporation in a vacuum again, purifies with the stratography post, obtains oily mater.This oil dissolves in ethanol (3 milliliters), with the hydrochloride acidifying of ether, at last with the anhydrous diethyl ether dilution, is settled out white solid product (0.13 gram), fusing point 230-232 ℃.
Analyze component result: C65.3; H6.6; N11.1
C
20H
23N
3O.HCl.O.5H
2O needs C65.4; H6.9; N11.45%.
Sample 9
1,2,3,9-tetrahydrochysene-9-methyl-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-4H-carbazole-4-ketone hydrochloride dihydrate.
Be placed on 1 in hot Virahol (90 milliliters) and water (18.3 milliliters) mixture with concentrated hydrochloric acid (6.25 milliliters) processing, 2,3,9-tetrahydrochysene-9-methyl-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-4H-carbazole-4-ketone (18.3 gram), filter the mixture of heat,, at room temperature stirred 17 hours with Virahol (90 milliliters) dilution filtrate, be cooled to 2 ℃, filter out solid matter (21.6 gram).Recrystallize goes out sample (6 gram) from water (6 milliliters) and Virahol (10 milliliters) mixture, obtains white crystalline solid product (6 gram), and fusing point is 178.5 °-179.5 ℃.
Analyze component result: C59.45; H6.45; N11.5
C
12H
19N
3O.HCl.2H
2O needs C59.1; H6.6; N11.5%
Water is ordered the method result for a trial: 10.23%
C
18H
19N
3O.HCl.2H
2O needs 9.85%
Sample 10
1,2,3,9-tetrahydrochysene-9-methyl-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-4H-carbazole-4-ketone phosphoric acid salt (1: 1)
In the hot mixt of phosphoric acid (90%, 0.13 milliliter) and water (10 milliliters), dissolve 1,2,3,9-tetrahydrochysene-9-methyl-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-4H-carbazole-4-ketone (0.61 gram) filters by Hyflo, obtain product (0.5 gram) after the crystallization, 225 ℃ of fusing points.
Analyze component result: C55.1; H5.6; N10.55
C
18H
19N
3OH
3PO
4Need C55.2; H5.7; N10.7%
Sample 11
1,2,3,9-tetrahydrochysene-9-methyl-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-4H-carbazole-4-ketone Citrate trianion (2: 1)
Dissolve 1,2,3 in citric acid in ethanol (20 milliliters) (0.58 gram) hot solution, 9-tetrahydrochysene-9-methyl-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-4H-carbazole-4-ketone (0.89 gram), crystallization then.The crystalline solid that generates with acetone (20 milliliters) dilution, obtains product (0.6 gram), 162 ℃ of fusing points again by dissolved way recrystallize in acetone (2: 1,2 milliliters).
Sample 12
1,2,3,9-tetrahydrochysene-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-9-propyl group-4H-carbazole-4-ketone maleate
Replace in methane amide (5 milliliters) mixture at dehydrated alcohol (20 milliliters) and anhydrous dimethyl, platinum on the carbon of employing excessive 5% under room temperature and the normal pressure (0.1 gram, reduction earlier in dehydrated alcohol (10 milliliters)), went back original sample 5 products (0.86 gram) solution 1 hour.Filter out catalyzer, use washing with alcohol, concentrated filtrate is into about 15 milliliters in a vacuum.Stir residual solution, water (50 milliliters) dilution filters out precipitated solid, water (3 * 15 milliliters) washing again, and drying obtains flour (0.73 gram).The dissolving that in dehydrated alcohol (7 milliliters), refluxes of this material, filter, refluxing in dehydrated alcohol (1 milliliter) adds maleate (0.25 gram) solution, with anhydrous diethyl ether (50 milliliters) agitation and dilution solution, draw product (0.84 gram), 150 °-151 ℃ of fusing points.
Analyze component result: C65.8; H6.1; N9.3
C
20H
23N
3O.C
4H
4O
4Need C65.9; H6.2; N9.6%
Sample 13
1,2,3,9-tetrahydrochysene-9-methyl-3-((2-methyl isophthalic acid H-imidazoles-1-yl)-4H-carbazole-4-ketone
(ⅰ) 3-(chloromethyl)-1,2,3,9-tetrahydrochysene-9-methyl-4H-carbazole-4-ketone.
The hydrochloride of ether (3.0 milliliters) is added in the ice-cold solution of stirring, this solution is preparation 3 products (1.90 gram) that are placed in the chloroform (15 milliliters), at room temperature stir and placed the interior suspensoid of encloses container 16.5 hours, concentrate in a vacuum, dilute with chloroform again, with stratography post purification residual solids material (2.27 gram), draw product (1.75 gram), 109～110.5 ℃ of fusing points.Attempt to go out a part of this material with the vinyl acetic monomer crystallization that obtains in the part decomposition course.
(ⅱ) 1,2,3,9-tetrahydrochysene-9-methyl-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-4H-carbazole-4-ketone
At anhydrous dimethyl for 2-methyl isophthalic acid H-imidazoles in the methane amide (1.60 gram) and 3-(chloromethyl)-1,2,3, in 9-tetrahydrochysene-9-methyl-4H-carbazole-4-ketone (0.50 gram) solution, inflated with nitrogen stirred 3.75 hours under 90 ℃ of temperature, pour in the water (25 milliliters), stirring suspension body 1 hour, filter out solid, water (3 * 20 milliliters) washing, dry under 50 ℃ of temperature and vacuum condition, use methylene dichloride, the solid matter of ethanol and 0.88 ammoniacal liquor (150: 10: 1) mixture diluted stratography post (0.53 gram), obtain product (weighing 0.45 gram), fusing point 228-229 ℃.This product is identical with sample 6 products that record with thin layer chromatography and nuclear magnetic resonance method.
Sample 14
1,2,3,9-tetrahydrochysene-9-methyl-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-4H-carbazole-4-ketone
With 2 in the anhydrous tetrahydro furan (1.5 milliliters), 3-two chloro-5,6-dicyano-1,4-benzoquinones (170 milligrams) solution, be added to dropwise in nitrogen in the ice-cold suspensoid of stirring, this is the suspensoid that places preparation 4 products of tetrahydrofuran (THF) (3.5 milliliters) and water (0.4 milliliter) mixture.Stirred blue solution 1.5 hours, and concentrated in a vacuum then, the residual solids material with methylene dichloride, ethanol and 0.88 ammoniacal liquor (150: 10: 1) mixture diluted stratography post obtains product (45 milligrams), 227 °-228.5 ℃ of fusing points.This material is identical with sample 6 products that record with thin layer chromatography and nuclear magnetic resonance method.
Sample 15
1,2,3,9-tetrahydrochysene-9-methyl-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-4H-carbazole-4-ketone
With 2 in the anhydrous tetrahydro furan (1.5 milliliters), 3-two chloro-5,6-dicyano-1,4-benzoquinones (80 milligrams) solution is added to the ice-cold suspensoid of the stirring of preparation 5 products (100 milliliters) in tetrahydrofuran (THF) (3.5 milliliters) and water (0.4 milliliter) mixture dropwise in nitrogen.Stirred blue solution 1.5 hours, concentrate suspensoid then in a vacuum, with the residual solids material of methylene dichloride, ethanol and 0.88 ammoniacal liquor (150: 10: 1) mixture diluted stratography post, obtain white solid product (0.47 gram), fusing point is 227.5 °-229 ℃.This material is identical with sample 6 products that record with thin layer chromatography and nuclear magnetic resonance method.
Sample 16
3S-1,2,3,9-tetrahydrochysene-3-((glyoxal ethyline-1-yl) methyl)-9-methyl-4H-carbazole-4-ketone maleate.
Dissolved samples 6 products in hot methanol (30 milliliters) (0.5 gram) solution, be used in (ten)-two-right-toluoyl-dextrorotation-tartrate-hydrate in the methyl alcohol (10 milliliters) (0.7 gram) hot solution again and handle, make solution crystallization obtain desired salt (0.68 gram) one night.This salt dissolves in hot DIMETHYL FORMAMIDE (20 milliliters), dilute with hot water (10 milliliters), one night of crystallization then, filtering product, dry in a vacuum, the enantiomorph that obtains is about (ten)-two-right-toluoyl-dextrorotation-tartrate (0.23 gram) of 90% purity (representing with nucleus magnetic resonance), fusing point 231-233 ℃.
The sample of this salt (0.15 gram) separates in 8% sodium bicarbonate (25 milliliters) and chloroform (2 * 25 milliliters).Dry extract, evaporation in a vacuum obtains pure free alkali (0.07 gram).This alkali is placed on dissolving in toxilic acid (0.03 gram) the acidifying methyl alcohol (5 milliliters), is precipitated out with adding excessive anhydrous diethyl ether (80 milliliters), obtains product (0.062 gram), fusing point 142-145 ℃.
Thin layer stratography post silica, methylene dichloride/ethanol/0.88 ammoniacal liquor (100: 8: 1) Rf, 0.3 calibrating u.v. and iodo platinic acid are identical with sample 6 products.Measure enantiomorph with ' H magnetic nuclear resonance method, its ratio is 93: 7(s: R).The maleate sample shows that its opticity is not obvious in methyl alcohol, measures (α) from maleate regenerated free alkali
25 D-14 ° (C0.19, MeOH).
Sample 17
3R-1,2,3,9-tetrahydrochysene-9-methyl-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-4H-carbazole-4-ketone maleate
Dissolved samples 6 products in hot methanol (30 milliliters) (0.5 gram) solution, the hot solution that is used in (-)-two-right-toluoyl-left-handed-tartrate-hydrate (0.7 gram) in the methyl alcohol (10 milliliters) is handled, make one night of solution crystallization, obtain desired salt (0.8 gram).This salt is placed on dissolving in the hot DIMETHYL FORMAMIDE (20 milliliters), dilute with hot water (10 milliliters), crystallization three days, filter out product, dry in a vacuum then, obtain (representing) (-)-two-right-toluoyl-left-handed-tartrate (0.26 gram) of about 95% purity of enantiomorph, 170 °-172 ℃ of fusing points with nucleus magnetic resonance.
The sample of this salt (0.2 gram) separates in 8% sodium bicarbonate (25 milliliters) and chloroform (2 * 25 milliliters).Dry extract, evaporation in a vacuum obtains pure free alkali (0.12 gram).This alkali is placed on dissolving in toxilic acid (0.045 gram) the acidifying methyl alcohol (5 milliliters).And be settled out this salt by adding excessive anhydrous diethyl ether (80 milliliters), obtain product (0.08 gram), fusing point 142-145 ℃.
Thin layer stratography post silica, methylene dichloride/ethanol/0.88 ammoniacal liquor (100: 8: 1) Rf0.3 calibrating u.v. and iodo platinic acid are identical with sample 6 products.Measure enantiomorph with ' H magnetic nuclear resonance method, its ratio is＞95: 5.The maleate sample shows that its opticity is not obvious in methyl alcohol, measures (α) from maleate regenerated free alkali
24 D+ 16 ° (C0.34, MeOH).
Errata
Errata
Errata
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Errata
Claims (3)
1, the preparation method of logical formula I compound
In the structural formula: R
1Expression methyl, third-2-base, propylene-2-base or cyclopentyl or qualified physiology salt or its solvate.They comprise:
(A) logical formula II compound or a kind of imidazoles of its protected derivative and logical formula III or the chemical reaction of its a kind of salt
(in the structural formula: Y represents the substituted in reaction base)
Perhaps
(B) oxygen of chemical structure (IV) compound or its a kind of salt or its a kind of protected derivative
(in the structural formula: A represents hydrogen atom or hydroxyl); Perhaps
(C) alkylation of chemical structural formula (V) compound or salt or a kind of protected derivative
(D) remove protecting group or other base from the protected structure formation of chemical structure formula I compound; Resolve the racemic compound of chemical structure formula I selectively, to obtain the optically-active enantiomer; And/or the compound of its chemical structure formula I exists with free alkali form, selectively free alkali transformed salify.
2, according to the preparation method of claim the first, preparation 1,2,3,9-tetrahydrochysene-9-methyl-3-((2-methyl isophthalic acid H-imidazoles-1-yl) methyl)-4H-carbazole-4-ketone or its a kind of qualified physiology salt or its solvate.
3, according to the preparation method who requires in claim the first or second patent, in method (A), Y represents thiazolinyl=CH
2Or chemical formula CH
2The base of Z, the Z in the chemical formula are represented easy metathetical atom or base.
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| CN 85105643 CN1011237B (en) | 1984-01-25 | 1985-07-24 | Preparation of heterocyclic compounds |
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|---|---|---|---|
| GB848401888A GB8401888D0 (en) | 1984-01-25 | 1984-01-25 | Heterocyclic compounds |
| CN 85105643 CN1011237B (en) | 1984-01-25 | 1985-07-24 | Preparation of heterocyclic compounds |
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| CN1011237B CN1011237B (en) | 1991-01-16 |
Family
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1035672C (en) * | 1994-08-08 | 1997-08-20 | 上海医科大学 | Preparation method of 3-(methyl-imidazolyl) methyl-tetrahydro-carbazolone |
| CN1040644C (en) * | 1994-04-29 | 1998-11-11 | 北京天衡时代科技集团 | Method for prepn. of 4-hydrocarbzaolone derivative |
| CN1052979C (en) * | 1992-10-14 | 2000-05-31 | 格德昂·理查德化学工厂股份公司 | Carbazolone derivatives and process for preparing the same |
| CN114302721A (en) * | 2019-08-06 | 2022-04-08 | 加利福尼亚大学董事会 | Scalable preparation of polyketones |
| CN115611864A (en) * | 2022-11-01 | 2023-01-17 | 常州兰陵制药有限公司 | Ondansetron compound and preparation method and application thereof |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1045437C (en) * | 1994-12-29 | 1999-10-06 | 中国科学院上海有机化学研究所 | Anthratancitone and its physiological saline synthesis |
| CN1045438C (en) * | 1994-12-29 | 1999-10-06 | 中国科学院上海有机化学研究院 | 4H carbazoleone Mannich base and its synthesizing method and application |
-
1985
- 1985-07-24 CN CN 85105643 patent/CN1011237B/en not_active Expired
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1052979C (en) * | 1992-10-14 | 2000-05-31 | 格德昂·理查德化学工厂股份公司 | Carbazolone derivatives and process for preparing the same |
| CN1083430C (en) * | 1992-10-14 | 2002-04-24 | 格德昂·理查德化学工厂股份公司 | Carbazolone derivatives |
| CN1040644C (en) * | 1994-04-29 | 1998-11-11 | 北京天衡时代科技集团 | Method for prepn. of 4-hydrocarbzaolone derivative |
| CN1035672C (en) * | 1994-08-08 | 1997-08-20 | 上海医科大学 | Preparation method of 3-(methyl-imidazolyl) methyl-tetrahydro-carbazolone |
| CN114302721A (en) * | 2019-08-06 | 2022-04-08 | 加利福尼亚大学董事会 | Scalable preparation of polyketones |
| CN115611864A (en) * | 2022-11-01 | 2023-01-17 | 常州兰陵制药有限公司 | Ondansetron compound and preparation method and application thereof |
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| Publication number | Publication date |
|---|---|
| CN1011237B (en) | 1991-01-16 |
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