CN1113234A - Anthratancitone and its physiological saline synthesis - Google Patents

Abstract

The present invention relates to a method for preparing compound of the invented chemical constitutional formula (I) and its correspondent free alkali (II). In its constitutional formula A represents chlorhydric acid, sulfuric acid, hydrobromic acid, oxalic acid, maleic acid and perchloric acid, the inorganic and organic acid which can be mathched with (II) to produce acceptable physiological salts, and S represents water solvent. The chemical name of said compound (I) is the solvate of physiological salt of 1,1,2,2,3-pentahydrogen-9-methyl-3 (2-methyl-imidazole-1-radical) methyl]-4-oxocarbazole, and is effective 5-HT3 receptor antagonist, and clinically it has the strong therapeutic effect for treating nausea and vomiting due to cis-platinum and noncis-platinum chemotherapy and radiotherapy.

Description

Anthratancitone and its physiological saline synthesis

The present invention relates to pharmaceutical a kind of organic bases and qualified physiology salt thereof and the preparation of solvate, the chemical structure of general formula of this kind compound is represented with formula I:

In the structural formula: A represents hydrochloric acid, sulfuric acid, Hydrogen bromide, oxalic acid, toxilic acid, mineral acid or organic acid; S represents water solvent; R ₁Expression C ₁～C ₆Straight chain or alicyclic ring shape alkyl.At its hydrochloride two hydrates (X) customs commodity muriatic ondansetron by name pharmaceutically.

Chemistry is called 1,1,2,2,3-pentahydro--9-methyl-3-[(2 '-Methylimidazole-1-yl)-methyl]-4-oxo-carbazole.Structural formula is represented with (II):

This organic bases prepared in accordance with the present invention and qualified physiology salt thereof and solvate are as selectivity serotonine (5-HT ₃) antagonist of acceptor is effectively strong.Be called 5-HT now ₃Acceptor comprises and is called 5-HT ₃, 5-HT ₃M ' or 5-HT ₃' M-formula ' acceptor, the past is to the existing more detailed description of this receptoroid.For example in following some papers: Fozard, et al Eur.J.pharmacol., 1979.59,195～210; Irelard, Straughan, Typers, Brit.J.pharmacol., 1982,75 16p; Humphrey, Neuropharm 1984,23, and 1503～1570; Richardson et al, Nature 1985,316, and 126～131; Bradlay et al, Neuropharm 1986,25, and 563～576.Found that chemical compound lot is 5-HT ₃Effective antagonist of acceptor, they are azabicyclic derivatives normally, and benzoic acid derivative or imdazole derivatives have disclosed the chemical structural formula of these compounds in following patent; They are United States Patent (USP)s: 2,100,259 2,125,398 2,131,420 2,132,189 2,145,416 2,152,049 2153821 and 2169292.European patent: 111,608 116,255 158,265 191,562 210,840 214,772 219,103 221,702 226,267 227,215 230,718 235,878 242,973 225,545 220,011 275669.Australian Patent: 8767121.Germany's publication: 3740352.Day disclosure special permission: clear 61-212521, clear 62-77380, clear 62-77381.Chinese patent application numbers 85105643.

This research is intended to invent the novel method of producing ondansetron and qualified physiology salt thereof in batches, provides the production technique of practical value and economic benefit.

The first method (A) of the logical formula I compound of the preparation that provides according to this patent, general formula is optionally acted on weak-acid ion exchange resin or silicic acid G(≤100 orders for the compound of (II) or content greater than 30% mixture) or perlon-1 powder or diatomite or positive alumina supporter on and the mineral acid or the organic acid soln of suitable concn, react on solid-liquid interface, highly selective obtains logical formula I compound.

The second method (B) of the logical formula I compound of the preparation that provides according to this patent, general formula joins in the water-alcohol solvent for the compound of (II) or content greater than 30% mixture continuously, feed simultaneously gases such as hydrogenchloride continuously, can be through obtaining the compound of general formula continuously for (I).

The preparation method (E) of the logical formula II of the preparation that provides according to this patent, chemical structure formula IV compound is an aromatic ketone compounds, glyoxal ethyline is an aromatic amine compounds, they are under common Mannich reaction conditions, the main condensation reaction that amine aldehyde takes place, generate the arborescens polycondensate, and, the logical formula IV compound of fragrant ketone belonged to

3 hydracids are strong inadequately, but under the effect of Lewis acid catalyst, shift to the part of the cationic imide of aldimine condensation by Lewis acid negative ion center charge, for example through possible intermediate structure formula (XI), promoted the generation of cationic imide intermediate (XII), the enol form midbody compound of chemical structure formula IV (X III) is finished logical formula II with the addition of imine intermediate (XII)

The preparation of compound, R in structural formula (X III) ₁Expression C ₁～C ₆Straight chain or alicyclic ring shape alkyl.

The preparation method (C) of the logical formula II compound of preparation is provided according to this patent, in aqueous proton type mixed solvent, chemical structure formula III compound is dissociated into unstable intermediate and the chemical structural formula that the possibility structural formula is (an X IV) rapidly under the Lewis acid catalysis be the heterocyclic amine molecule of (VII), in the chemical structural formula: R ₁Expression C ₁～C ₆Straight chain or alicyclic ring shape alkyl; R ₂, R ₃, R ₄, R ₅Expression C ₁～C ₃Positive alkyl of short chain or iso-alkyl.

Intermediate (X IV) at first generates the compound of chemical structural formula (X VII), the C of (X VII) through 1,4 addition middle transition attitude (X VI) of glyoxal ethyline ₃, C ₄Between two keys be in cis position, therefore, change into trans position more stable on the energy immediately, also be the ketone form structure of (X VII), to be exactly structural formula be the compound of (II) to this ketone form structure.

The preparation method (D) of the preparation chemical structure formula II that provides according to this patent, the compound of chemical structure formula IV compound and chemical structural formula (V) or (VI) is being heated in tart proton type solvent, and (as 25～100 ℃) take place under the condition

The ketone permutoid reaction, reaction can separate obtaining succinimide (X VIII) or benzimidazolyl (X IX), so the first step of this permutoid reaction is most probably after finishing

The decomposition reaction of proton-induced takes place in (V) or (VI), removes the generation (X VIII) or (X IX), generates also that important cationic imide intermediate (XII) and (IV) immediately addition reaction take place and the compound that generates the chemical structure formula II.When implementing preparation method (D), reaction intermediate does not need separation and purification, promptly is that one kettle way is synthetic.(V) that in preparation method (D), needs or (VI) from N-chloromethyl-glyoxal ethyline (XX) of being easy to get respectively with amber imines or benzimidazolyl reacting by heating and get.

The preparation method (F) of the preparation chemical structure formula III compound that provides according to this patent, carbazole-4-ketone (IV), the catalyzing and condensing reaction of Paraformaldehyde 96 and structural formula (VII) compound, for adding fast response, in the reaction with as AgNO ₃, Cu ₂X ₂(X=Cl, Br, I), Cu(OAc) ₂, Al ₂O ₃Deng mineral acids such as solid Lewis acid catalyst or their mixed type composite catalyst or hydrochloric acid, when implementing preparation method (F), can be that three kinds of components add simultaneously, can not add (IV) and acid earlier yet, allow the aminated compounds of Paraformaldehyde 96 and structural formula (VII), the aldimine condensation reaction takes place earlier, and it is 1: 2 condenses (X XI) that this condensation reaction only may generate aldehyde amine molecule ratio, and (X XI) can react generating structure formula III compound with (IV) equally under acidic conditions.

The preparation method (G) of the preparation structure formula III compound that provides according to this patent, the reactive ketone of chemical structure formula IV compound and chemical structural formula (VIII) or (IX) compound, permutoid reaction is preferably under the condition of heating carries out (for example 30～150 ℃), and used chemical structural formula (VIII) or (IX) compound are got by chemical structural formula compound (X XII) and succinimide (X VIII) or benzimidazolyl (X IX) reacting by heating respectively among the preparation method (G).

In the structural formula: R ₂, R ₃, R ₄, R ₅Expression C ₁～C ₃The positive alkyl of short chain or iso-alkyl or hydrogen atom.

In the ondansetron of this patent preparation and numerous intermediate, to mention 1,1 especially, 2,2,3-pentahydro--9-methyl-3-[(morphine quinoline base-N)-methyl]-4-oxo carbazole, 1,1,2,2,3-pentahydro--9-methyl-3-[(2 ', 6 '-dimethyl-morphine quinoline base-N)-methyl]-4-oxo carbazole, the chemical structure of above-mentioned two kinds of carbazoles by ¹HNMR, IR, MS, ¹³CNMR and results of elemental analyses are confirmed ,-CH ₂CH ₂The chemical shift of CH-is at 1.80～3.00ppm, 9 N-CH ₃The unimodal chemical shift of characteristic at 3.68ppm, 3 methyne bridge hydrogens exists ¹Find out on the HNMR spectrum two bimodal, the characteristic spectrogram of morphine quinoline portion also appears on spectrogram, on mass spectrum, except that the molecular ion peak that occurs estimating, M/Z198(

) be the common base peak of above-mentioned two kinds of carbazoles.On the IR spectrogram, remove the 1640cm of carbonyl ^-1Outside the peak, also generally have 1580,1480cm ^-1The phenyl ring peak.1,1,2,2,3-pentahydro--9-methyl-3-[(2 '-Methylimidazole-1) methyl]-the structural difference proof of 4-oxo carbazole and it and silica gel compound is on infrared spectra, and the characteristic absorption spectrum of the phenyl ring base of mixture is displacement 30～40cm respectively ^-1Illustrate that this mixture is stacking plate-like structure, this carbazole is as center of negative charge, forms hydrogen bond between the hole of unsaturated link(age) and silicon oxide, has guaranteed that acid and solvent molecule are from the attack of another side to the carbazole molecule.

This patent relates to the novel method through synthetic ondansetron of new reaction midbody compound and qualified physiology salt thereof, the reflection intermediate is through the new compound of spectroscopic techniques and ultimate analysis affirmation structure, has raw material and is easy to get, the reaction conditions gentleness, advantage easy and simple to handle, that product is easy to purify.

Following Example explanation the present invention is measuring fusing point through the corrected kapillary of known compound, and infrared, proton magnetic spectrum and mass spectrum are measured on Simadzu IR-440 type, Bruker AM300 type and HP 5989A type spectrograph respectively.

Example A ₁:

Hydrochloric acid 1,1,2,2,3-pentahydro--9-methyl-3[(2 '-Methylimidazole-1-yl) methyl]-4-oxo carbazole two hydrates (X) and monohydrate.

By 5g(0.017mol) example C, the compound (II) and the 50ml ethyl acetate Hybrid Heating of D or E preparation make into short grained suspension, and add while hot and be equipped with in the tlc silica gel post, column diameter 5cm, column length 15cm feeds small amount of N ₂Atmospheric pressure is used the 300ml eluent ethyl acetate earlier, and the elutriant of collection boils off ethyl acetate, residual 100mg yellow mucus, thin plate chromatography detect and are forward position impurity, collect liquid with the 200ml eluent ethyl acetate then and concentrate, residue is a white solid, detects to be example F, and G prepares compound (III), promptly reclaim raw material 0.8g, use 1N HCl aqueous solution wash-out then, use the 1000ml water elution then, the aqueous solution merges concentrated, cooling, crystallization, suction filtration, crystallisate are dry infrared, get 4.75g title compound (X), productive rate 90.54%, mp.176～178 ℃, analytic sample, the water recrystallization once and has P ₂O ₅Vacuum-drying in the moisture eliminator obtains monohydrate, ultimate analysis: C ₁₈H ₁₉N ₃OHClH ₂O, MW, 347.83, measured value (calculated value) %:C62.44(62.16), H6.12(6.38), N12.12(12.08), Cl10.46(10.19); IR:v _Max3200-3400(OH), 1630(C=C), 1620(C=0), 1580,1480,760cm ^-1, MS:M/Z,

55（

）; ¹HNMR：DMSO-d ₆，δ _1H，1.90～2.25，2.96～3.25，（5H，m，-CH ₂-CH ₂-CH-），2.65（3H，S，C-CH ₃），3.74（3H，S，N-CH ₃），4.23～4.31，4.63～4.69（2H，dd-dd，-CH ₂-），7.55～7.69（2H，d，d CH＝CH），7.19～7.29，7.50～7.55（3H，m，ArH），7.97～8.05（1H，m，ArH）; ¹³CNMR：δ _13C，191.18，152.83，144.44，137.41，124.05，122.65，122.26，122.20，122.01，117.71，110.60，110.26，46.87，45.36，29.76，26.20，20.64，10.42.

Example A ₂:

Hydrochloric acid 1,1,2,2,3-pentahydro--9-methyl-3-[(2 '-Methylimidazole-1-yl) methyl]-4-oxo carbazole two hydrates (X) and-hydrate.

By 5g(0.017mol) example C, the compound (II) of D or E preparation is suspended in the 40ml ethanol, adds the 30g hydrogen type cation exchange resin, after stirring half an hour, suspended substance disappears, and continues to stir half an hour, leach resin, and use washing with alcohol, dry adsorbent, be put back in the beaker, add 40ml 0.1N HCl, stirred 1～2 hour, leach acid solution, add fresh 40ml 0.1N HCl in the resin again and stir, so repeatable operation repeatedly, leaching acid solution merges, concentrate cooling, crystallization, leach, drying gets 4.5g title compound (X), productive rate 72.05%, tool P is put in mp.176～178 ℃ ₂O ₅Vacuum-drying in the moisture eliminator gets monohydrate, ultimate analysis: C ₁₈H ₁₉N ₃OHClH ₂O, MW, 374.83, measured value (calculated value) %:C62.46(62.16), H6.24(6.12), N12.04(12.07), Cl10.41(10.19); IR, MS, ¹HNMR, ¹³CNMR spectrum and example A ₁Product is identical.

Example A ₃:

10mg1,1,2,2,3-pentahydro--9-methyl-3[(2 '-Methylimidazole-1-yl) methyl]-4-oxo carbazole is dissolved in and makes the thin plate chromatography in the 5ml ethyl acetate on the thin-layer silicon offset plate, makes the echelon developping agent with 5～10% ethyl acetates-normal hexane, the deployment conditions of hand-held ultraviolet lamp detection reagent, with the reflective NICOLET IR of twin-beam spectrograph, measure infrared spectra, find that former ownership is that the absorption peak of C=C is from 1630cm ^-1Be displaced to 1675cm ^-1The place, and former ownership is that the C=0 absorption peak is only from 1620cm ^-1Be displaced to 1625cm ^-1The place shows the formula absorption in an overlapping on silica gel of this oxo carbazole, and the hole that intermolecular hydrogen bonding is made electronics knot body and silica gel by the two keys of C=C is made electron acceptor(EA) and formed, and C ₄The C=0 key of position then not with indole ring and imidazole ring at grade, so the shift value of C=0 key is minimum, 1,1,2,2,3-pentahydro--9-methyl-3-[(2 '-Methylimidazole-1-yl) methyl]-4-oxo carbazole is at SiO ₂Be following structure on the surface:

HYPETCHEM three types quantize to calculate and to show that the π system of molecule gets copline, carbonyl is positioned at outside the plane, two methyl also are positioned at out-of-plane configuration, and molecule can obtain the stabilization energy of 3.214 KJ (kilojoule)/moles, and calculate (E=hv) molecule πDian Zi and SiO from the infrared displacement value of two keys ₂Interaction energy between the hole is 0.5382 KJ (kilojoule)/mole.

Example B:

Hydrochloric acid 1,1,2,2,3-pentahydro--9-methyl-3-[(2 '-Methylimidazole-1-yl) methyl]-4-oxo carbazole two hydrates (X)

Example C, the compound (II) of D or E preparation is used recrystallizing methanol 2 times, after the drying, get 0.25g(0.85mmol) (II) be dissolved in the 5ml ethanol, feed to do HCl gas, when treating pH3, stop cooling, crystallization filters out solid, the water recrystallization, get 220mg white title compound (X), productive rate 70.45%, mp.176～178 ℃, IR, MS, ¹HNMR, ¹³CNMR spectrum and example A ₁Product is identical.

Implement C:

1,1,2,2,3-pentahydro--9-methyl-3-[(2 '-Methylimidazole-1-yl) methyl]-4-oxo carbazole (II)

Example C ₁:

2.5g2-Methylimidazole is dissolved in the 20ml ethanol, cools off in water-bath, adds the dense H of equivalent ₂SO ₄Stir, remove ice bath, add 2.98g(10mmol) compound (III) of example F or G preparation, about 90 ℃, stirred 5 hours, and boiled off most of alcohol solvent, cooling adds 100ml water, separate out solid, suction filtration is filtered and is washed with water, drying, 2.5g title compound (II), mp.220～223 ℃, content 85%, analytic sample: use recrystallizing methanol, drying gets 2.2g white meal, mp.227～228 ℃, productive rate 75.1%, ultimate analysis: C ₁₈H ₁₉N ₃O, MW, 293.35, measured value (calculated value) %:C73.45(73.70), H6.54(6.53), N14.01(14.32); IR, MS measurement result and example C ₂Identical; ¹HNMR:CDCl ₃, δ _1H1.80～1.94,2.04～2.25,2.82～3.02(5H, m ,-CH ₂-CH ₂CH-), 2.46(3H, S, C-CH ₃), 3.68(3H, S, NCH ₃), 4.07～4.14,4.62～4.69(2H, dd-dd ,-CH ₂-), 6.91～6.95(2H, d-d, CH=CH), and 7.31～7.33(3H, m, ArH), and 8.22～8.26(1H, m, ArH).

Example C ₂:

In the 250ml there-necked flask, add 3 gram (0.01mol) 1,1,2,2, the methyl of 3-pentahydro--9-methyl-3[(morphine quinoline base-N-)]-4-oxo carbazole, be adjusted to pH6 with 3N hydrochloric acid, then, add 40ml n-propyl alcohol and 5 gram (0.06mol) glyoxal ethylines, be stirred to reactants dissolved, heated 35 hours down, cooling at 95 ℃, leach solid, decolouring and recrystallization in methyl alcohol obtain 2.62 gram white powder solids, mp.227～228 ℃, productive rate 85.9%, ultimate analysis C ₁₈H ₁₉N ₃O, MW, 293.35, experimental value (calculated value) %:C73.45(73.72), H6.54(6.58), N14.01(14.22); IR:v _Max3050,2920,2850,1630,1620,1580,1480,1280,1200,760cm ^-1; MS:M/Z293(M ⁺), 211,198,183,149,144,55; δ _1H(CDCl ₃) 8.23～8.26(1H, m, ArH), and 7.33～7.31(3H, m, ArH), and 6.95～6.91(2H, dd, CH=CH), and 4.69～4.62,4.14～4.07(2H, dd, dd ,-CH ₂-), 3.68(3H, S, NCH ₃), 2.46(3H, S, C-CH ₃), 3.02～2.82,2.25～2.04,1.94～1.80(5H, m ,-CH ₂-CH ₂CH-) ppm.

Example C ₃:

Experimental procedure is similar to example C ₂, difference only is reinforced order, free and carbazole Mannich base and glyoxal ethyline are dissolved in earlier in the n-propyl alcohol, use 3N hydrochloric acid conditioned reaction mixture to pH6 again, 95 ℃ down heating press example C after 35 hours ₂The method purified product, amine exchange productive rate reaches 81.3%.

Example C ₄:

In the 250ml there-necked flask, add 7.1 gram (0.06mol) glyoxal ethyline hydrochlorides, 3 gram (0.01mol) 1,1,2,2, the methyl of 3-pentahydro--9-methyl-3-[(morphine quinoline base-N-)]-4-oxo carbazole and 40ml n-propyl alcohol, with 3N hydrochloric acid conditioned reaction mixture to pH6, heated 35 hours down at 95 ℃, subsequently by routine real C ₂Method is done aftertreatment, obtains 2.35 gram title compounds, productive rate 77.01%.

Example D ₁:

1,1,2,2,3-pentahydro--9-methyl-3-[(2 '-Methylimidazole-1-yl) methyl-4-oxo carbazole (II).

14.85g(0.15mol) succinimide and 15ml dimethyl formamide solution be added dropwise to by 13 gram (0.1mol) N-chloromethyl-glyoxal ethylines, 10.6 in the reaction mixture that gram (0.1mol) yellow soda ash and 50ml dimethyl formamide are formed, keeping temperature of reaction during dropping is 60 ℃, after dripping, slowly be warming up to 100 ℃, keep this temperature to stir 2 hours, cooling is poured in the 1000ml frozen water, organic phase benzene extraction 3 * 15ml, extracting solution and organic phase merge, be washed to neutrality, boil off solvent, obtain thick product 15.9 grams, productive rate 92%, product be not purified just to be used for next step reaction.

2.0g(10mol) compound (IV), 2.0g(10.4mmol) N-(2 '-Methylimidazole-1-yl) methyl-succinimide is dissolved in the 25ml ethanol, regulates pH6 with 2N HCl, reflux stirred 10 hours, cooling, add 100ml 1N HCl, leach solid insoluble, water benzene extraction, the washing of benzene layer, divide water outlet, use anhydrous sodium sulfate drying, and boil off benzene recovery compound (IV) 0.8g, water alkalization Na ₂CO ₃, separate out solid, suction filtration, filter is washing also, drying, title compound 1.2gmp.220～223 ℃, productive rate 68.26%.

Example E:

1,1,2,2,3-pentahydro--9-methyl-3-[(2 '-Methylimidazole-1-yl) methyl]-4-oxo carbazole (II)

2.0g(10mmol) compound (IV), 1.2g(40mmol) Paraformaldehyde 96,1.6g(19.5mmol) glyoxal ethyline and 40ml ethanol mix, and add Cu again ₂Cl ₂-HCl catalyzer, reflux stirred 20 hours, cooling, 50ml 1N HCl stirs, and insolubles leaches, water benzene extraction 3 * 3ml, and benzene is also laminated, wash with water, with the anhydrous sodium sulphate alkalization, separate out solid then, cooling, suction filtration leaches the solid washing, and drying gets the 0.85g crude product, recrystallizing methanol ℃ is used in mp.218～222, drying, 0.26g gram product, productive rate 8.87%, mp.228～229 ℃, IR, MS, ¹HNMR is same as example C and prepares compound.

Example F:

1,1,2,2,3-pentahydro--9-methyl-3-[(morphine quinoline-N-yl) methyl]-4-oxo carbazole (II)

2.0g(10mmol) compound (IV), 1.2g(40mmol) Paraformaldehyde 96,1.74g(20mmol) the morphine quinoline is dissolved in the 20ml acetate, stir, heat 70 ℃ and reacted 5 hours cooling down, add 50ml 1N HCl, stir, leach insolubles, water benzene extraction 3 * 3ml, benzene is also laminated, washes with water, benzene layer anhydrous sodium sulfate drying, boil off benzene, residue 0.2g is (IV) that reclaims.Water and washing water merge, and with solid NaOH alkalization, separate out solid, cooling, suction filtration, filter also washes with water, and drying gets 2.2g title compound (II), productive rate 81.21%, analytic sample: use re-crystallizing in ethyl acetate, white crystal, mp.165.5～166.5 ℃, ultimate analysis: C ₁₈H ₂₂N ₂O ₂, MW, 298.37, measured value (calculated value) %:C71.94(72.46), H7.53(7.43), N9.28(9.38); IR:v _Max1640,1620,1580,1480,760cm ^-1; MS:M/Z, 299(M ⁺+ 1), 298(M ⁺), 211( ), 198( ), 183,100(

); ¹HNMR:CDCl ₃, δ _1H, 8.23(1H, m, ArH), and 7.26～7.30(3H, m, ArH), 3.70～3.78(4H, m, CH ₂OCH ₂), 3.86(3H, S, N-CH ₃), 2.20～3.06(11H, m, CH ₂NCH ₂, CH ₂CH ₂CH, CH ₂).

Example G:

1,1,2,2,3-pentahydro--9-methyl-3-[(morphine quinoline-N-yl) methyl]-4-oxo carbazole (III)

14.85g(0.15mol) succinimide and 15ml dimethyl formamide solution be added dropwise in the reaction mixture of being made up of 13 gram (0.1mol) N-chloromethyl-glyoxal ethylines 10.6 gram (0.1mol) yellow soda ash and 50ml dimethyl formamide, keeping temperature of reaction during dropping is 60 ℃, after dripping, slowly be warming up to 100 ℃, keep this temperature to stir 2 hours, cooling, be poured in the 1000ml frozen water, organic phase merges with benzene extraction 3 * 15ml, extracting solution and organic phase, is washed to neutrality, boil off solvent, obtain thick product 15.9 grams, productive rate 92%, product be not purified just to be used for next step reaction.

2.0g(10mmol) compound (IV), 2.0gN-(morphine quinoline-N-yl) methyl-succinimide is dissolved in the ethanol, regulates pH6 with 2N HCl, reflux 20 hours boils off ethanol, adds 50ml 1N HCl, stirring and dissolving leaches insolubles, and filtrate is used benzene extraction, benzene is also laminated, washes anhydrous sodium sulfate drying with water, boil off benzene, residue displaing yellow solid, 0.5g detects the compound (IV) for reclaiming, water alkalizes with NaOH, separate out solid, filter, filter and washing, dry, get the 1.2g title compound, productive rate 53.69%, analytic sample re-crystallizing in ethyl acetate, mp.165.5～166.5 ℃, IR, MS; ¹The HNMR spectroscopic data makes the compound unanimity with example F.

Claims (4)

1, the preparation method of logical formula I:

In the structural formula: A represents hydrochloric acid, sulfuric acid, Hydrogen bromide, oxalic acid, toxilic acid, organic acid or mineral acid; S represents water solvent; R ₁Expression C ₁～C ₆Straight chain or alicyclic ring shape alkyl;

The preparation method of logical formula I comprises:

(A) compound of logical formula II or its protected derivative or content are higher than 30% reaction mixture and the solid-liquid interface salt-forming reaction between the A;

(B) compound of logical formula II or its protected derivative or content are higher than 30% reaction mixture and the liquid-gas interface salt-forming reaction between the A.

2, the preparation method of logical formula II according to claim 1:

(C) compound and glyoxal ethyline or other amine exchange reactions of logical formula III;

In the structural formula: R ₁Expression C ₁～C ₆Straight chain or alicyclic ring shape alkyl, R ₂, R ₃, R ₄, R ₅Expression C ₁～C ₃The positive alkyl of short chain or iso-alkyl or hydrogen atom, R ₂, R ₃, R ₄, R ₅Can be substituting group identical or inequality, or unsubstituted;

(D) the ketone permutoid reaction of chemical structure formula IV compound and chemical structural formula (V) or (VI) compound;

In the structural formula: R ₁Expression C ₁～C ₆Straight chain or alicyclic alkyl;

(E) chemical structure formula IV compound, the catalyzing and condensing reaction of Paraformaldehyde 96 and glyoxal ethyline, used solid catalyst is AgNO in the reaction ₃, Cu ₂X ₂(X=Cl, Br, I), Cu(OAc) ₂, Al ₂O ₃Lewis acid or their hybrid composite catalyst.

3, the method for preparing the chemical structure formula III according to claim 2 comprising:

(F) chemical structure formula IV compound, the catalyzing and condensing reaction of Paraformaldehyde 96 and structural formula (VII) compound, used solid catalyst is AgNO in the reaction ₃, Cu ₂X ₂(X=Cl, Br, I), Cu(OAc) ₂, Al ₂O ₃Lewis acid or their hybrid composite catalyst or hydrochloric acid, sulfuric acid, mineral acid;

In the structural formula: R ₂, R ₃, R ₄, R ₅Expression C ₁～C ₃The positive alkyl of short chain or iso-alkyl or hydrogen atom;

(G) the ketone permutoid reaction of chemical structure formula IV compound and chemical structural formula (VIII) or (IX) compound;

In the structural formula: R ₁Expression C ₁～C ₆Straight chain or alicyclic alkyl, R ₂, R ₃, R ₄, R ₅Expression C ₁～C ₃The positive alkyl of short chain or iso-alkyl or hydrogen atom.

4, in the numerous important intermediate according to the preparation ondansetron of one of claim 1 to 3, useful especially compound is 1,1,2,2,3-pentahydro--9-methyl-3-[(2 '-methylimidazolyl-1)-methyl]-mixture of 4-oxo carbazole and silicon-dioxide or ion exchange resin.