CN1145902A - Preparation of carbazones compounds - Google Patents
Preparation of carbazones compounds Download PDFInfo
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- CN1145902A CN1145902A CN 95111775 CN95111775A CN1145902A CN 1145902 A CN1145902 A CN 1145902A CN 95111775 CN95111775 CN 95111775 CN 95111775 A CN95111775 A CN 95111775A CN 1145902 A CN1145902 A CN 1145902A
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Abstract
In the present invention, using carbazolyl ketone as raw material acid-added salt of carbazolyl ketone-3-imidazolyl methyl compound is produced through the processes of the condensation with carbonate, the condensation with 1-(chloromethyl)-2-methyl imidazole, and removing the carbonyl group with hydrochloric acid. It has less reaction steps and low cost.
Description
The invention relates to a kind of preparation method of carbazones compounds, belong to the technical field of chemical substance preparation.The invention provides hydrazide-3-imidazole methly compound and the general formula thereof that a kind of general formula is (I) especially is the preparation method of the acid salt of (II).
The R here
1Expression hydrogen, methyl, ethyl, propyl group, sec.-propyl or cyclopentyl etc.Work as R
1During for methyl, general formula is also referred to as Ondansetron for the compound of (I), and its hydrochloride dihydrate is a kind of important medicine clinically, the called after muriatic ondansetron.
Muriatic ondansetron is a kind of 5-HT of potent, highly selective
3Receptor antagonist, it is to 5-HT
3The avidity of acceptor is compared other 5-HT
3Receptor subtype (5-HT
1, 5-HT
2) the avidity and the avidity of non-5-HT acceptor (Dopamine HCL, norepinephrine, vagusstoff etc.) high 10000 times.Muriatic ondansetron is by the 5-HT on the blocking-up periphery vagus nerve tip
3Acceptor and produce good antiemetic effect, and do not have the outer side effect of centrum system.Muriatic ondansetron is to having good efficacy because of accepting the nausea and vomiting that chemotherapy such as cis-platinum and radiotherapy causes, side effect is little, thus can improve greatly patient change, during radiotherapy to the tolerance of medicine.
Muriatic ondansetron, i.e. Ondansetron Hydrochloride Dihydrate, chemistry is by name: 1,2,3,9-tetrahydrochysene-9-methyl-3-[(2-methyl isophthalic acid H-1-imidazolyl) methyl]-4H-carbazole keto hydrochloride dihydrate.
About the preparation method of muriatic ondansetronHydrochloride hydrazide-3-imidazole methly compound and acid salt thereof, existing multiple report on the document.For example:
With hydroresorcinol monoene alcohol ether is starting raw material, and imidazolyl-alkyl group side chain is incorporated on the hydroresorcinol monoene alcohol ether on the methylene radical adjacent to the oxo base, and then, this enol ether group is replaced by 2-methyl-2-phenylhydrazine group; The phenylhydrazone of gained carries out Fischer indoles synthetic (EP219929).
And for example: react with imidazolidyl-hydroresorcinol monoene alcohol ether and 2-indole aniline, the enamine of gained is through caproic acid palladium (II) cyclisation, and methylation reaction (EP221629) is carried out in last 9-N position on indole ring.
And for example: with 3-(dimethyl amido) 9-methyl isophthalic acid, 2,3,9-tetrahydrochysene-4H-carbazole-4-ketone is starting raw material, heats with glyoxal ethyline and makes (GB2153821).
And for example: with the 9-methyl isophthalic acid, 2,3,9-tetrahydrochysene-4H-carbazole-4-ketone is starting raw material, with barkite in the condensation of 3-position, introduce methylol then; With the glyoxal ethyline condensation, slough oxalyl group and form (CN1089941) again.
Ondansetron class hydrazide-3-imidazole methly compound, its structure can be divided into carbazole ketone and imidazolyl two parts; Correspondingly, method cited more than also can be divided into two classes:
1) introduce imidazolyl, earlier, the back forms carbazole ketone;
2), be starting raw material with carbazole ketone, imidazolyl is introduced in the back.Carbazole ketone is formed by tricyclic condensed.In carbazole ketone synthetic, in ring-closure reaction, reaction conditions is generally relatively fiercer, harsh especially.Introduce too early as imidazolyl, destroyed easily under above-mentioned reaction conditions, produce more by product; And the steric hindrance of imidazolyl also is unfavorable for the synthetic of carbazole ketone.So the present invention adopts the back to introduce the route of imidazolyl.
Press the described method of GB2153821, because it is starting raw material with the tertiary amine compound, its chemical property is similar to the chemical property of final product, makes both separation relatively more difficult, and the quality and the yield of product had adverse influence.
Press the described method of CN1089941, with the 9-methyl isophthalic acid, 2,3,9-tetrahydrochysene-4H-carbazole-4-ketone is starting raw material, gets muriatic ondansetron through four steps:
(1) with barkite in the condensation of 3-position;
(2) methylol is introduced in the 3-position;
(3) with glyoxal ethyline condensation and slough oxalyl group;
(4) with the hydrochloric acid salify.
The invention provides the another kind of method that more reasonably prepares the muriatic ondansetronHydrochloride hydrazide-3-imidazole methly compound, form by two reactions steps.It below is detailed description to present method.
(1): the present invention is starting raw material with general formula for the carbazole ketone of (III), carries out condensation reaction with carbonic ether under the alkali existence condition, makes the 3-substituent of general formula for (IV).Because the existence of 4-ketone, the hydrogen atom of 3-position is more active, and condensation reaction is carried out easily:
The R here
1Expression hydrogen, methyl, ethyl, propyl group, sec.-propyl or cyclopentyl etc.; R
2Expression methyl or ethyl.Used carbonic ether can be methylcarbonate, diethyl carbonate; Used basic catalyst can be sodium methylate, sodium ethylate etc.Reaction medium is lower alcohol, pyridine, benzene, low alkyl group benzene etc., and general employing is comparatively convenient with used corresponding methyl alcohol of basic catalyst or ethanol.
Here used general formula is the carbazole ketone starting raw material of (III), can begin to make from hydroresorcinol easily: with hydroresorcinol in the presence of ethanol and sodium-acetate, with the phenylhydrazine hydrochloride condensation; Add the trifluoroacetic acid cyclization again and get carbazole ketone (R
1Be hydrogen).By the difference of required product, can on the nitrogen-atoms of carbazole ketone 9-position, carry out common alkylation reaction and introduce required alkyl.For example, be alkylating agent with methyl-sulfate, ethyl sulfate, under alkaline condition, can easily obtain the carbazole ketone that 9-methyl or 9-ethyl replace.
(2): the condenses of step 1 gained is carried out condensation reaction with 1-(chloromethyl)-glyoxal ethyline under alkaline condition; add hydrochloric acid again; slough carbonic acyl radical, while and hydrochloric acid salify, make the acid salt of general formula for the hydrazide-3-imidazole methly compound of (II):
The R here
1Expression hydrogen, methyl, ethyl, propyl group, sec.-propyl or cyclopentyl etc.; R
2Expression methyl or ethyl.Used basic catalyst can be sodium methylate, sodium ethylate etc.Reaction medium is lower alcohol, pyridine, benzene, low alkyl group benzene etc., and general employing is comparatively convenient with used corresponding methyl alcohol of basic catalyst or ethanol.The hydrochloric acid that adds is concentrated hydrochloric acid, under the situation of heating, for example sloughs carbonic acyl radical under the temperature that reaction solvent refluxes, and simultaneously and the hydrochloric acid salify, makes the acid salt of general formula for the hydrazide-3-imidazole methly compound of (II).
Here used 1-(chloromethyl)-glyoxal ethyline is that starting raw material makes by glyoxal ethyline, introduces methylol with formaldehyde in the 1-position of glyoxal ethyline, and with halogenating agents such as sulfur oxychlorides methylol is converted into chloromethyl:
As required, can be easily general formula be carried out neutralization reaction for acid salt and the alkali of the hydrazide-3-imidazole methly compound of (II), make general formula and be the hydrazide-3-imidazole methly compound of (I).Here used alkali can be the oxyhydroxide of alkaline-earth metal such as potassium, sodium, magnesium, calcium or the aqueous solution of its carbonate.
The present invention adopts the back to introduce the route of imidazolyl, compares with the described method of CN1089941, only needs two steps just can obtain the acid salt of general formula for the hydrazide-3-imidazole methly compound of (II).Having the advantage that reactions steps is short, cost is low, is a kind of method that more reasonably prepares muriatic ondansetronHydrochloride carbazole ketone-3-imidazolyl methyl-derivatives.
Following embodiment can further specify method of the present invention, but and unrestricted purposes of the present invention.
Embodiment 1,
One mole of glyoxal ethyline is put in the reactor, adds the benzene of 3-10 part, and the formaldehyde of 2-5 part is heated to backflow, keeps back flow reaction 4-7 hour.Cooling, dripping thionyl chloride 1-3 part.Heat continues reaction about 3-5 hour at 50-70 ℃ a little.Heating, the pressure reducing and steaming sulfur oxychloride obtains 1-(chloromethyl)-glyoxal ethyline crude product.Crystallization gets beige solid 1-(chloromethyl)-glyoxal ethyline in the acetone, and fusing point is 85-87 ℃, yield about 60%.
Embodiment 2,
One mole of hydroresorcinol is put in the reactor, adds ethanol and 1-3 part phenylhydrazine hydrochloride of 3-10 part, and gradation adds 0.6-2 part sodium-acetate under the heated and stirred, reacts 1-3 hour; Drip trifluoroacetic acid, ring-closure reaction 4-6 hour, get 1,2,3,9-tetrahydrochysene-4H-carbazole-4-ketone.Fusing point is 220-223 ℃, yield about 60%.
Embodiment 3,
Add 50 weight part dehydrated alcohols in the dry reactor, 6 weight part sodium Metal 99.5s are made pure sodium solution.Be cooled to subzero 10 ℃ of subzero 5-, add 1,2,3 of 40-50 weight part, 9-tetrahydrochysene-4H-carbazole-4-ketone adds the diethyl carbonate of 35-45 weight part, again in the subzero 10 ℃ of reactions of subzero 5-2-4 hour.Continuation was stirring at room reaction 8-12 hour.With the acetic acid pH value that neutralizes is 7-8, pours elutriation in the frozen water into, products obtained therefrom washing, drying, white solid, promptly 1,2,3,9-tetrahydrochysene-3-carbazole carboxylic acid, ethyl ester-4-ketone.The about 50-60% of yield.
Embodiment 4,
Add 1 mole 1,2,3 in the dry reactor, 9-tetrahydrochysene-3-carbazole carboxylic acid, ethyl ester-4-ketone, 5-10 weight part anhydrous methanol and the sodium methylate made from 1 mole metal sodium.Add 1-1.2 mole 1-(chloromethyl)-glyoxal ethyline, back flow reaction 10-14 hour, be neutral substantially to reaction solution.The pressure reducing and steaming solvent adds about 10 weight parts of 20% hydrochloric acid, heating reflux reaction 6-10 hour.When being cooled to about 40-50 ℃, add 10 weight part acetone, stir diel, get 1,2,3,9-tetrahydrochysene-3-[(2-methyl isophthalic acid H-1-imidazolyl) methyl]-4H-carbazole keto hydrochloride.
Gained crude product recrystallization in acetone-water gets the off-white color crystalline powder.
Embodiment 5,
Add 1 mole 1,2,3 in the reactor, 9-tetrahydrochysene-4H-carbazole-4-ketone, 50% sodium hydroxide 2-3 weight part, acetone 16 weight parts drip methyl-sulfate 1-2 mole, stirring reaction 4-6 hour, get 1,2,3,9-tetrahydrochysene-9-methyl-4H-carbazole-4-ketone crude product.Ethyl alcohol recrystallization, yield about 90%.
Embodiment 6,
Add 50 weight part dehydrated alcohols in the dry reactor, 6 weight part sodium Metal 99.5s are made pure sodium solution.Be cooled to subzero 10 ℃ of subzero 5-, add 1,2,3 of 40-50 weight part, 9-tetrahydrochysene-9-methyl-4H-carbazole-4-ketone adds the diethyl carbonate of 35-45 weight part, again in the subzero 10 ℃ of reactions of subzero 5-2-4 hour.Continuation was stirring at room reaction 8-12 hour.With the acetic acid pH value that neutralizes is 7-8, pours elutriation in the frozen water into, products obtained therefrom washing, drying, white solid, promptly 1,2,3,9-tetrahydrochysene-9-methyl-3-carbazole carboxylic acid, ethyl ester-4-ketone.Fusing point is 132-134 ℃, the about 55-60% of yield.
Embodiment 7,
Add 1 mole 1,2,3 in the dry reactor, 9-tetrahydrochysene-9-methyl-3-carbazole carboxylic acid, ethyl ester-4-ketone, 5-10 weight part anhydrous methanol and the sodium methylate made from 1 mole metal sodium.1-1.2 mole 1-(chloromethyl)-glyoxal ethyline back flow reaction 10-14 hour, is neutral substantially to reaction solution.The pressure reducing and steaming solvent adds about 10 weight parts of 20% hydrochloric acid, heating reflux reaction 6-10 hour.When being cooled to about 40-50 ℃, add 10 weight part acetone, stir diel, get 1,2,3,9-tetrahydrochysene-9-methyl-3-[(2-methyl isophthalic acid H-1-imidazolyl) methyl]-4H-carbazole keto hydrochloride.Fusing point is 168-174 ℃.
Gained crude product recrystallization in acetone-water gets the off-white color crystalline powder.Fusing point is 171-176 ℃.
Claims (4)
1, a kind of with general formula be for the carbazole ketone compound of (III) raw material the preparation general formula for the hydrazide-3-imidazole methly compound of (1) and general formula thereof for the method for the acid salt of (II), it is characterized in that this method comprises the following steps:
(1) general formula is carried out condensation reaction with carbonic ether for the carbazole ketone compound of (III) under the alkali existence condition, make the 3-substituent of general formula for (IV);
The R here
1Expression hydrogen, methyl, ethyl, propyl group, sec.-propyl or cyclopentyl etc.; R
2Expression methyl or ethyl; Used carbonic ether can be methylcarbonate, diethyl carbonate; Used alkali can be sodium methylate, sodium ethylate etc.;
(2) condenses with step () gained carries out condensation reaction with 1-(chloromethyl)-glyoxal ethyline under the alkali existence condition; Add hydrochloric acid, slough carbonic acyl radical, while and hydrochloric acid salify, make the acid salt of general formula for the hydrazide-3-imidazole methly compound of (II);
Here used alkali can be sodium methylate, sodium ethylate etc.;
(3) or, again general formula is carried out neutralization reaction for acid salt and the alkali of the hydrazide-3-imidazole methly compound of (II), make the hydrazide-3-imidazole methly compound that general formula is (I);
Here used alkali can be the oxyhydroxide of alkaline-earth metal such as potassium, sodium, magnesium, calcium or the aqueous solution of its carbonate.
2, by the described method of claim 1, it is characterized in that the R in the step ()
1Be hydrogen or methyl; Carbonic ether is a diethyl carbonate.
3,, it is characterized in that hydrochloric acid in the step (two) is 20% hydrochloric acid by claim 1,2 described methods; The decarburization acyl group carries out under the reflux condition.
4, by claim 1,2,3 described methods, it is characterized in that step () is: add 50 weight part dehydrated alcohols in dry reactor, 6 weight part sodium Metal 99.5s are made pure sodium solution; Be cooled to subzero 10 ℃ of subzero 5-, the general formula that adds the 40-50 weight part is the carbazole ketone compound of (III); The diethyl carbonate that adds the 35-45 weight part was in the subzero 10 ℃ of reactions of subzero 5-2-4 hour; Stirring at room reaction 8-12 hour; With the acetic acid pH value that neutralizes is 7-8, pours elutriation in the frozen water into, products obtained therefrom washing, drying;
Step (two) is: add the condenses of 1 mole of step () gained in dry reactor, 5-10 weight part anhydrous methanol and the sodium methylate made from 1 mole metal sodium; 1-1.2 mole 1-(chloromethyl)-glyoxal ethyline, back flow reaction 10-14 hour; The pressure reducing and steaming solvent adds about 10 weight parts of 20% hydrochloric acid, heating reflux reaction 6-10 hour; Be cooled to about 40-50 ℃, add 10 weight part acetone, stir diel.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 95111775 CN1145902A (en) | 1995-09-22 | 1995-09-22 | Preparation of carbazones compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 95111775 CN1145902A (en) | 1995-09-22 | 1995-09-22 | Preparation of carbazones compounds |
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| Publication Number | Publication Date |
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| CN1145902A true CN1145902A (en) | 1997-03-26 |
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ID=5079023
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 95111775 Pending CN1145902A (en) | 1995-09-22 | 1995-09-22 | Preparation of carbazones compounds |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100360506C (en) * | 2005-08-29 | 2008-01-09 | 浙江工业大学 | 1,2,3,9-tetrahydro-9-methyl-4H-carbazole-4-one preparation method |
-
1995
- 1995-09-22 CN CN 95111775 patent/CN1145902A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100360506C (en) * | 2005-08-29 | 2008-01-09 | 浙江工业大学 | 1,2,3,9-tetrahydro-9-methyl-4H-carbazole-4-one preparation method |
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