CN1045437C - Anthratancitone and its physiological saline synthesis - Google Patents

Anthratancitone and its physiological saline synthesis Download PDF

Info

Publication number
CN1045437C
CN1045437C CN94114311A CN94114311A CN1045437C CN 1045437 C CN1045437 C CN 1045437C CN 94114311 A CN94114311 A CN 94114311A CN 94114311 A CN94114311 A CN 94114311A CN 1045437 C CN1045437 C CN 1045437C
Authority
CN
China
Prior art keywords
compound
formula
acid
methyl
iii
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN94114311A
Other languages
Chinese (zh)
Other versions
CN1113234A (en
Inventor
吴国生
周文娟
陈国平
金雄民
钱淑芹
陈荣清
王淑芬
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Changzhou Third Pharmaceutical Factory
Shanghai Institute of Organic Chemistry of CAS
Original Assignee
Changzhou Third Pharmaceutical Factory
Shanghai Institute of Organic Chemistry of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Changzhou Third Pharmaceutical Factory, Shanghai Institute of Organic Chemistry of CAS filed Critical Changzhou Third Pharmaceutical Factory
Priority to CN94114311A priority Critical patent/CN1045437C/en
Publication of CN1113234A publication Critical patent/CN1113234A/en
Application granted granted Critical
Publication of CN1045437C publication Critical patent/CN1045437C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to a compound for preparing a chemical structural formula (I) and a method of corresponding free alkali (II) of the compound. In the structural formula, a represents hydrochloric acid, sulphuric acid, hydrogen bromide, oxalic acid dihydrate, maleic acid and perchloric acid, and can generate qualified inorganic and organic acid of physiology salt with (II); S represents a water solvent. The chemical name of the compound (I) is the physiology salt solvate of 1, 1, 2, 2, 3-pentahydro-9-methyl radical-[(2-methyl-imidazole-1-base) methyl]-4-oxocarbazole, is effective 5-HT3, and is a receptor antagonist. The present invention clinically has strong curative effect for nausea and vomitus caused by cisplatin and non-cisplatin chemotherapy and cisplatin and non-cisplatin radiotherapy.

Description

Synthesizing of ondansetron and physiology salt thereof
The present invention relates to the preparation of two hydrates of pharmaceutical a kind of organic bases and physiology salt thereof, the chemical structure of this organic bases is represented with formula (II):
Figure C9411431100041
Chemistry is by name 1,1,2,2,3-pentahydro--9-methyl-3-((2 '-methyl of methylimidazolyl-1-))-4-oxo carbazole, the structural formula of hydrochloride two hydrates of this alkali is represented what formula [I], is called for short muriatic ondansetron.
Figure C9411431100042
This organic bases of the present invention's preparation and qualified physiology monocalcium salt compound thereof are as selectivity serotonine (5-HT 3) antagonist of acceptor is effectively strong.Be called 5-HT now 3Acceptor comprises 5-HT 3, 5-HT 3M ', or 5-HT 3' M-formula ' acceptor, the past is to the existing 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., 1982,75,16; Humphrey, Neuropharm1984,23,1503-1570; Richardson et.al., Nature 1985,316,126-131; Bradlay et.al., Neuropharm 1986,25, and 563-576 has 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 structural formula of these compounds in following patent; They are United States Patent (USP)s: 2100259,2125398,2131420,2132189,2145416,2152049,2153821 and 2169292.European patent: 111608,116255,158265,191562,210840,214772,219103,221702,226267,227215,230718,235878,242973,225545,220011,275669.Australian Patent: 8767121.Germany's publication: 3740352.Day disclosure special permission: clear 61-212521, clear 62-77380, clear 62-77381.Chinese patent application number: 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 method (A) of preparation formula [I] compound is provided according to this patent, mixture by formula [II] compound or the big what 30% of its content optionally is adsorbed on weak-acid ion exchange resin or the silica gel, then adopt hydrochloric acid on solid-liquid interface, to carry out salt-forming reaction, or join continuously in the water-ethanol solvent by the mixture of formula [II] compound or the big what 30% of its content, simultaneously feed hydrogen chloride gas continuously, obtain the compound of formula [I] thus continuously.
Provide the method (B) of preparation formula [II] compound according to this patent, in water type mixed solvent, general formula for [III] compound is dissociated into rapidly under the Lewis acid catalysis may structural formula be
Figure C9411431100051
The unstable intermediate of [VI] and general formula are the heterocyclic amine of [V], in the formula [V]: R1, R2, R3, R4 represents C 1-3Positive alkyl or iso-alkyl or hydrogen atom.Intermediate (VI) is followed and glyoxal ethyline 1,4 addition, the middle transition attitude [VII] of generation, and it at first generates chemical structural formula [VIII] compound,
Figure C9411431100061
The C of formula [VIII] compound 3, C 4Between two keys be in cis position, therefore change into trans position more stable on the energy immediately again, be the ketone form structure thing of [VIII], this ketone form structure promptly is formula [II] compound.
According to the method (C) for preparing general formula [III] compound that this patent provides,,, used as AgNO in the reaction for adding fast response by the condensation reaction of carbazole-4-ketone [IV] and Paraformaldehyde 96 and general formula [V] compound 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 this preparation method, can be that three kinds of components add simultaneously, can not add 4H carbazole ketone [IV] earlier yet, allow Paraformaldehyde 96 and general formula [V] aminated compounds that the aldimine condensation reaction takes place earlier, generation aldehyde amine mole ratio is 1: 2 a condenses [IX], and [IX] compound reacts with 4H carbazole ketone [IV] under acidic conditions equally, generates general formula [III] compound.
Figure C9411431100062
Intermediate according to the ondansetron of this patent preparation is: 1,1,2,2,3-pentahydro--9-methyl-3-((morphine quinoline base-N)-methyl)-4-oxo carbazole [III], the chemical structure of this carbazole ketone Mannich base by 1HNMR, 13CNMR, IR, MS and results of elemental analyses are confirmed.-CH 2CH 2The CH-chemical shift is at 1.80-3.00ppm, 9 N-CH 3The unimodal chemical shift of characteristic absorbance at 3.68ppm, 3 methyne bridge hydrogens exists 1Find on the HNMR spectrum two bimodal, the characteristic spectrogram of morphine quinoline base also appears on spectrogram, on mass spectrum, remove the molecular ion peak (M that prediction occurs +/ Z) outside, also have
Figure C9411431100071
Base peak.On the IR spectrogram, remove carbonyl 1640cm -1The peak also has 1580,1480cm -1The phenyl ring peak.
This patent relates to the method through synthetic ondansetron of novel intermediates compound and qualified physiology salt thereof, and have raw material and be easy to get, the reaction conditions gentleness, easy and simple to handle, product is easy to advantages such as purification.
In the following example, measure the thermometer of fusing point and proofread and correct, infrared spectra, nuclear magnetic resonance spectrum and mass spectrum are used the infrared instrument of Simadzu IR-440 type respectively, Bruker AM300 type nuclear magnetic resonance analyser, and HP 5989A type mass spectrograph is measured.
Example A: preparation 1,1,2,2,3-pentahydro--9-methyl 3-((2 '-methylimidazolyl-1)-methyl)-4-oxo carbazole hydrochloride two hydrates [I] and monohydrate
Example A1
Compound [II] crude product and 50ml ethyl acetate Hybrid Heating by 5g (0.017mol) example B 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 solvent, residual 100mg yellow mucus, the thin plate chromatography detects to forward position impurity, uses the 200ml eluent ethyl acetate then, collects liquid and concentrates, residue is a white solid, detect compound [III], promptly 1,1 of recovery for example C preparation, 2,2, the methyl of 3-pentahydro--9-methyl-3-[(morphine quinoline base-N-)]-4-oxo carbazole raw material 0.8g, use the 1NHCl eluant solution then, then use the 1000ml water elution, the aqueous solution merges concentrated, cooling, crystallization, suction filtration, crystallisate is dry under infrared lamp, gets 4.75g title compound [I] productive rate 90.54%, mp.176-178 ℃, analytic sample water recrystallization once and has P 2O 5Vacuum-drying in the moisture eliminator of siccative obtains mono-hydrate, ultimate analysis: C 18H 19N 3O.HCl.H 2O, MW, 347.83, measured value (calculated value) %:C, 62.44 (62.16), H, 6.12 (6.38), N, 12.12 (12.08), Cl, 10.46 (10.19); IR: υ Max3200-3400 (OH), 1630 (C=C), 1620 (C=O), 1580,1480,760cm 1MS: 55
[H 2CCHC≡0] + 1HNMR:σ 1H(DMSO-d 6),1.90-2.25,2.96-3.25(5H,m,-CH 2CH 2CH-),2.65(2H,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)ppm； 13CNMR:σ 13c(DMSO-d 6),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?ppm。
Example A2.
Compound [II] crude product by 5g (0.017mol) example B preparation is suspended in the 40ml ethanol, adds the 30g hydrogen type cation exchange resin, stirs half an hour, the elimination resin, and use washing with alcohol, dry adsorbent, put into beaker, add 40ml, 0.1N HCl, stirred 1-2 hour, leach acid solution, add fresh 40ml 0.1N HCl in the resin again, so repeatable operation repeatedly, merge the acid solution that leaches, concentrate cooling, crystallization, leach, drying gets 4.5g title compound [I], productive rate 72.05%, mp.176-178 ℃, put into and have P 2O 5Moisture eliminator in, vacuum-drying, monohydrate, ultimate analysis: C 18H 19N 3OHClH 2O, MW.347.83, measured value (calculated value) %; C, 62.46 (62.16), H, 6.24 (6.12), N, 12.04 (12.07), Cl, 10.41 (10.19); IR, MS, 1HNMR, 13CNMR spectrum is identical with example A1 products therefrom.
Example A3:
Compound [II] crude product of example B preparation, use recrystallizing methanol 2 times, after the drying, get 0.25g (0.085mmol) and be dissolved in the 5ml ethanol, feed exsiccant HCl gas, when treating pH3, the stop ventilation, cooling, crystallization, leach solid water recrystallization, get 220mg white title compound [I], productive rate 70.45%, mp.176-178 ℃, IR 1HMR, 13CNMR, MS spectrum is identical with example A1 product.
Example B: preparation 1,1,2,2,3 pentahydro-s-9-methyl-3-((2 '-methylimidazolyl-1-) methyl)-4-oxo carbazole [II]
Example B1
The 2.5g glyoxal ethyline is dissolved in the 20ml ethanol, in water-bath, cools off, add the dense H of equivalent 2SO 4, stir, remove water-bath, add the compound [III] of 2.98g (10mmol) example C preparation, under 90 ℃ of temperature, stirred 5 hours, boil off most of ethanol, cooling, add 100ml water, separate out solid, suction filtration, filter cake washes with water, drying gets the 2.5g title compound, and mp.220-223 ℃, content 85%, analytic sample: use recrystallizing methanol, drying gets the 2.2g white powder, mp.227-228 ℃, productive rate 75.1%, ultimate analysis: C 18H 19N 3O, MW.293.35, measured value (calculated value) %:C, 73.45 (73.70), H, 6.54 (6.53), N, 14.01 (14.32); IR, the MS measurement result is identical with example A1; 1HNMR:, σ 1H(CDCl 3), 1.84-1.94,2.04-2.25,2.82-3.02 (5H, m ,-CH 2CH 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, dd, CH=CH), 7.31-7.33 (3H, m, ArH), 8.22-8.26 (1H, m, ArH) ppm.
Example B2
In the 250ml there-necked flask, add 1,1 of 3g (0.01mol) example c preparation, 2,2,3-pentahydro--9 methyl-3-((morphine quinoline base-N)-methyl)-4-oxo carbazole [III], be adjusted to pH 6 with 3N HCl, then, add 40ml n-propyl alcohol and 5g (0.06mol) glyoxal ethyline, be stirred to the reaction mixture dissolving, 95 ℃ were heated 35 hours cooling down again, leach solid, decolouring and recrystallization obtain the 2.62g white powder in methyl alcohol, mp.227-228 ℃, productive rate 85.9%, ultimate analysis: C 18H 19N 3O, MW.293.35, experimental value (calculated value) %:C, 73.45 (73.72), H, 6.54 (6.58), N, 14.01 (14.32); IR: ν Max3050,2920,2850,1630,1620,1580,1480,1280,1200,760cm 1MS:M +/ Z 293 (M +), 211,198,183,149,144,55; 1HNMR: σ 1H(CDCl 3) 8.23-8.26 (1H, m, ArH), 7.33-7.31 (3H, m, ArH), 6.96-6.91 (2H, dd, CH=CH), 4.69-4.62,4.14-4.07 (2H, dd, dd ,-CH-), 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 2CH 2CH-) ppm.
Example B3
Experimental procedure is similar to example B2, and difference only is reinforced order, and free carbazole ketone Mannich base and glyoxal ethyline are dissolved in the n-propyl alcohol earlier, with 3N hydrochloric acid conditioned reaction thing again to pH6, press example B2 method purified product in heating under 95 ℃ after 35 hours, amine exchange yield 81.3%.
Example B4
In the 250ml there-necked flask, add 7.1g (0.06mol) glyoxal ethyline hydrochloride, 3g (0.01mol) 1,1,2,2,3-pentahydro--9-methyl-3-((morphine quinoline base-N-) methyl)-4-oxo carbazole [III] and 40ml n-propyl alcohol,, heated 35 hours down to pH6 with 3N hydrochloric acid conditioned reaction mixture, do aftertreatment by example B2 method subsequently at 95 ℃, obtain the 2.35g title compound, productive rate 77.01%.
Example C preparation 1,1,2,2,3-pentahydro--9-methyl-3-((morphine quinoline base-N)-methyl)-4-oxo carbazole [III]
2.0g (10mmol) compound [IV], 1.2g (40mmol) Paraformaldehyde 96,1.74g (20mol) morphine quinoline is dissolved in the 20ml acetate, stir, heat 70 ℃ and reacted 5 hours cooling down, add 50ml 1NHCl, stir, leach insolubles, water benzene extraction 3*3ml, benzene is also laminated, washes with water, 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 cake washes with water, and drying gets 2.2g title compound [III], productive rate 81.21%, analytic sample: use re-crystallizing in ethyl acetate, get white crystal, mp.165.5-166.5 ℃, ultimate analysis: C 18H 22N 2O, MW.298.37, measured value (calculated value) %:C, 71.94 (72.46), H, 7.53 (7.43), N, 9.28 (9.38); IR: ν Max1640,1620,1580,1480,760cm 1MS:M +/ Z, 299 (M ++ 1), 298 (M +),
Figure C9411431100121
1HNMR: σ 1H(CDCl 3), 8.23 (1H, m, ArH), 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-) ppm.

Claims (3)

1, the preparation method of chemical formula I compound:
Figure C9411431100021
(A), by formula (II) compound
Figure C9411431100022
Or its content is adsorbed on weak-acid ion exchange resin or the silica gel by selectivity greater than 30% mixture, then adopts hydrochloric acid to carry out salt-forming reaction on solid-liquid interface.
2, method according to claim 1, its Chinese style (II) compound prepares as follows:
(B), carry out amine exchange reaction, with general formula (III) compound and glyoxal ethyline
Figure C9411431100023
R1 in the formula (III), R2, R3, R4 represents C 1～3Positive alkyl or iso-alkyl or hydrogen atom.
3, preparation method according to claim 2, its formula of (III) compound prepares as follows:
(C), with chemical structural formula (IV) compound, AgNO has been used in the catalyzing and condensing reaction of Paraformaldehyde 96 and general formula (V) compound in the reaction 3, Cu 2X 2(X=Cl, Br, I), Cu (OAC) 2, Al 2O 3Solid Lewis acid catalyst or their mixed type composite catalyst or mineral acid, in the general formula (V), R1, R2, R3, R4 represents C 1～3Positive alkyl or iso-alkyl or hydrogen atom.
Figure C9411431100031
CN94114311A 1994-12-29 1994-12-29 Anthratancitone and its physiological saline synthesis Expired - Fee Related CN1045437C (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN94114311A CN1045437C (en) 1994-12-29 1994-12-29 Anthratancitone and its physiological saline synthesis

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN94114311A CN1045437C (en) 1994-12-29 1994-12-29 Anthratancitone and its physiological saline synthesis

Publications (2)

Publication Number Publication Date
CN1113234A CN1113234A (en) 1995-12-13
CN1045437C true CN1045437C (en) 1999-10-06

Family

ID=5037196

Family Applications (1)

Application Number Title Priority Date Filing Date
CN94114311A Expired - Fee Related CN1045437C (en) 1994-12-29 1994-12-29 Anthratancitone and its physiological saline synthesis

Country Status (1)

Country Link
CN (1) CN1045437C (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL366150A1 (en) * 2000-10-30 2005-01-24 Teva Pharmaceutical Industries Ltd. Novel crystal and solvate forms of ondansetron hydrochloride and processes for their preparation
DK1499623T3 (en) 2002-04-29 2007-10-08 Teva Gyogyszerg Ar Zartkoeruee Process for the preparation of 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1011237B (en) * 1984-01-25 1991-01-16 格拉克索公司 Preparation of heterocyclic compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1011237B (en) * 1984-01-25 1991-01-16 格拉克索公司 Preparation of heterocyclic compounds

Also Published As

Publication number Publication date
CN1113234A (en) 1995-12-13

Similar Documents

Publication Publication Date Title
EP3847156B1 (en) Salts of methyl 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylate and preparation process thereof
CN114805314A (en) Synthesis method of Ensaitevir
CN108794351A (en) A kind of preparation method of Mo Fanselin key intermediate
CN104418807A (en) Preparation method of 2-ethoxyl-1-[[2'-(hydroxyl amidino)-biphenylyl]-4-yl]methyl-1H-benzimidazole-7-carboxylic acid and ester derivatives thereof
CN106256825A (en) The synthetic method of his Wei of Dacca
CN103601645B (en) The preparation method of 1-(phenethyl amino) propane-2-alcohol compound or its salt
CN1045437C (en) Anthratancitone and its physiological saline synthesis
CN115667222B (en) Method for preparing GLP-1 receptor agonist
CN107673978B (en) Intermediate of 2, 2-difluorocycloalkyl methylamine and preparation method thereof
CN111100042B (en) Preparation method of 2-methoxy-5-sulfonamide benzoic acid
JP4994772B2 (en) Method for producing piperidin-4-one derivative using bisaminol ether compound
CN114072143A (en) Synthesis of CRAC channel inhibitors
US3644373A (en) Method for the production of 3-substituted-1 2 3 4 5 6-hexahydro-6 11-dimethyl-8-hydroxy-2 6-methano-3-benzazocines
CN108409561B (en) Preparation method of 5-aminolevulinic acid hydrochloride and intermediate
CN105111136B (en) A kind of method for preparing the ketone of 3 methyl, 1 piperidine 4 or the ketone of 1 piperidine 4
WO2006129781A1 (en) Process for production of dibenzoxepin derivative
CN110818677A (en) Process for the preparation of cyclohexane derivatives
CN111100063B (en) Preparation method for synthesizing 2-fluoromethyl substituted pyrrolidine, piperidine and piperazine derivatives
JP2641363B2 (en) Novel phenethyl alcohol and its production method
CN111100111B (en) Method for preparing benzothiophene derivative
CN114380783B (en) Preparation method of olopatadine deuterium labeled metabolite
CN112679405B (en) Preparation method of (S) -7-oxa-2-azaspiro [4.5] decane derivative
CN111333528B (en) Synthesis method of multi-configuration O-phenyl-serine compound
CN117820241A (en) Preparation method of itraconazole intermediate
CN106316954B (en) The method for preparing optical voidness (+)-or (-)-N- demethyl meptazinol

Legal Events

Date Code Title Description
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C06 Publication
PB01 Publication
C14 Grant of patent or utility model
GR01 Patent grant
C19 Lapse of patent right due to non-payment of the annual fee
CF01 Termination of patent right due to non-payment of annual fee