CN1733698A - 1,2,3,9-tetrahydro-9-methyl-4H-carbazole-4-one preparation method - Google Patents
1,2,3,9-tetrahydro-9-methyl-4H-carbazole-4-one preparation method Download PDFInfo
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- CN1733698A CN1733698A CN 200510060548 CN200510060548A CN1733698A CN 1733698 A CN1733698 A CN 1733698A CN 200510060548 CN200510060548 CN 200510060548 CN 200510060548 A CN200510060548 A CN 200510060548A CN 1733698 A CN1733698 A CN 1733698A
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Abstract
The invention provides a process for preparing 1,2,3,9-terahydro-methyl-4H-carbazole-4-one comprising the following steps, using HMCM-41 molecular sieve as catalyst, subjecting alpha-methyl-alpha-phenylhydrazine and 1,3-cyclohexanedione to condensation and cyclization reaction in polar organic solvent at 30-65 deg C, then carrying out post-treatment to obtain the outcome yield. The catalyst HMCM-41 can be reused for four times after simple scrubbing and drying without influencing the yield.
Description
(1) technical field
The present invention relates to a kind of 1,2,3, the preparation method of 9-tetrahydrochysene-9-methyl-4H-carbazole-4-ketone.
(2) background technology
1,2,3,9-tetrahydrochysene-9-methyl-4H-carbazole-4-ketone is the key intermediate of synthetic ondansetron (Ondansetron), and this medicine is a kind of 5-HT of potent, highly selective
3Antagonist is used for side effects such as the ameliorate tumor chemotherapy and radiation is causedly felt sick, vomiting.Present 1,2,3, the preparation method of 9-tetrahydrochysene-9-methyl-4H-carbazole-4-ketone is with 1, hydroresorcinol and phenylhydrazine hydrochloride are starting raw material, obtain target product through condensation, cyclisation, the three-step reaction that methylates, and the cyclization catalyst that reported in literature adopted has: 40% sulfuric acid, anhydrous ZnCl
2And CF
3COOH.Adopt the method for vitriol oil cyclisation, though the cyclisation yield reaches 60%, because the vitriolic oxygenizement, the product colour that obtains is dark, is difficult for decolouring, and purity is lower, and 40% sulfuric acid large usage quantity (mass ratio is 17: 1) produces a large amount of three wastes (CN1113239).Adopt anhydrous ZnCl
2The method of cyclisation, the cyclisation yield has only 36%, has environmental problem (CN1113239) equally.Adopt CF
3The method of COOH, though the cyclisation yield reaches 59%, cyclisation product purity height, CF
3The consumption of COOH big (mass ratio is 8: 1) is because CF
3COOH price height, and be difficult for to reclaim makes not only production cost height of this method, and quantity of three wastes big (CN1145902, US3892766).It is that methylating reagent obtains target product that document all adopts methyl-sulfate at last, because the toxicity of methyl-sulfate has increased the unsafe factor of producing.
(3) summary of the invention
The object of the invention is to provide a kind of economy, easy and simple to handle, safe, eco-friendly 1,2,3, the preparation method of 9-tetrahydrochysene-9-methyl-4H-carbazole-4-ketone.
Preparation method of the present invention comprises the steps: that with the HMCM-41 molecular sieve be catalyzer, and Alpha-Methyl-α-phenylhydrazine and hydroresorcinol carry out condensation and cyclization in 30～65 ℃ and react in polar organic solvent, and aftertreatment gets product.
The mass ratio of described Alpha-Methyl-α-phenylhydrazine and HMCM-41 molecular sieve is generally 1: 0.8～5, is preferably 1: 3.
It is one of following that described polar organic solvent is preferably: methyl alcohol, dehydrated alcohol, acetone, acetonitrile most preferably are methyl alcohol.With 1mol Alpha-Methyl-α-phenylhydrazine is benchmark, and the consumption of organic solvent is generally 250～600mol.
Described temperature of reaction is preferably 60～65 ℃.
Preparation method's specific operation process of the present invention can be:
Alpha-Methyl-α-phenylhydrazine is added drop-wise in hydroresorcinol and the HMCM-41 molecular sieve, and dropping temperature is 30～65 ℃, wherein 60～65 ℃ of the bests after dropwising, continue reaction 16～18h, with high performance liquid chromatography reaction is detected, after reaction finishes, be cooled to room temperature, filter molecular sieve, apply mechanically in order to purifying with small amount of methanol drip washing, mother liquor reclaims solvent, and cooling is poured in the frozen water, separate out a large amount of white solids, suction filtration with acetone-water (1+1) recrystallization, gets 1,2,3,9-tetrahydrochysene-9-methyl-4H-carbazole-4-ketone, purity is more than 99%.
After filtering HMCM-41 molecular sieve fully soaks in methyl alcohol and cleans, place 120 ℃ of dryings of baking oven after, be used further to 1,2,3,9-tetrahydrochysene-9-methyl-4H-carbazole-4-ketone synthetic reused more than four times, the cyclisation yield does not have obvious decline.
The present invention also provides the preparation method of a kind of Alpha-Methyl-α-phenylhydrazine, and described preparation method comprises: with the Zn powder is reductive agent, and N-nitroso-group-methylphenylamine carries out reduction reaction in 80～85 ℃ in aqueous acetic acid, and aftertreatment gets product.The mol ratio of described N-nitroso-group-methylphenylamine and Zn powder is preferably 1: 1.5～and 4, the best is 1: 3.Concrete operating process can be: at room temperature the mixing solutions with N-nitroso-group-methylphenylamine and Glacial acetic acid is added drop-wise in the mixture of Zn powder and water, dropwises, and is warming up to 80～85 ℃, continue reaction 1h, after reaction finishes, filtered while hot, filter cake washes with 5%HCl, treat that mother liquor is cooled to room temperature, add 40%NaOH solution and make resolution of precipitate, isolate oil reservoir, the water extracted with diethyl ether, merge oil reservoir and ether extraction liquid, through anhydrous Na
2SO
4Drying, distillating recovering solvent, 106～109 ℃/13mmHg cut is collected in the raffinate underpressure distillation, gets Alpha-Methyl-α-phenylhydrazine.
The present invention also provides a kind of preparation method of N-nitroso-group-methylphenylamine, and described preparation method comprises: with NaNO
2Be nitrosification agent, methylphenylamine carries out nitrosation reaction in 5～10 ℃ in 10% hydrochloric acid, and aftertreatment gets product.Described methylphenylamine and NaNO
2Mol ratio be preferably 1: 1～1.3, the best is 1: 1.15.Concrete operating process can be: with 20%NaNO
2In the mixing solutions of methylphenylamine that the aqueous solution is added drop-wise to and 10% hydrochloric acid, dropping temperature is 5～10 ℃, dropwises, at 5～10 ℃ of following insulation reaction 1h, reaction finishes, and divides oil-yielding stratum, water layer extracts with toluene, merges oil reservoir and toluene extraction liquid, through anhydrous Na SO
4Drying, toluene is reclaimed in distillation, and 135～137 ℃/13mmHg cut is collected in the raffinate underpressure distillation, gets N-nitroso-group-methylphenylamine.
Net reaction of the present invention is as follows:
The present invention compared with prior art has the following advantages:
1, this technology is starting raw material with the methylphenylamine, has avoided the highly toxic product methyl-sulfate to methylate, and has improved the security of producing, has reduced production cost.
2, this technology is cyclization catalyst with HMCM-41, and reaction can be carried out at a lower temperature, the reaction conditions gentleness, and the cyclisation yield is higher, and separation and purification of products is easy, environmental friendliness.
3, after catalyzer HMCM-41 passes through simple washing, drying, apply mechanically continuously four times, yield is constant substantially.
(4) embodiment
The invention will be further described below in conjunction with embodiment, but protection scope of the present invention is not limited to this.
The preparation of embodiment 1N-nitroso-group-methylphenylamine
In three mouthfuls of round-bottomed flasks of 500ml, add methylphenylamine 42.8g (0.4mol) and 10% hydrochloric acid 210mL, slowly drip 20%NaNO down at 5～10 ℃
2Aqueous solution 158.7g (0.46mol) dropwises, and insulation 1h divides oil-yielding stratum, and water layer merges oil reservoir and toluene extraction liquid, through anhydrous Na with the extraction of 2 * 50mL toluene
2SO
4Drying, normal pressure reclaims toluene, and 135～137 ℃/13mmHg cut is collected in the raffinate underpressure distillation, gets glassy yellow liquid 50.6g, productive rate 93.0%, purity 98.7%.
The preparation of embodiment 2N-nitroso-group-methylphenylamine
Remove 20%NaNO
2The charging capacity of the aqueous solution changes 138.0g (0.4mol), i.e. methylphenylamine and NaNO into
2Mol ratio be outside 1: 1, other operational condition is all identical with embodiment 1, glassy yellow liquid 42.5g, productive rate 78.1%, purity 98.9%.
The preparation of embodiment 3 Alpha-Methyls-α-phenylhydrazine
In three mouthfuls of round-bottomed flasks of 500ml, add Zn powder 78.0g (1.2mol) and 150mL water, at room temperature slowly drip the mixing solutions of N-nitroso-group methylphenylamine 54.4g (0.4mol) and Glacial acetic acid 100g, dropwise, be warmed up to 80～85 ℃, continue reaction 1h, reaction finishes, filtered while hot, filter cake is with the drip washing of 3 * 50mL5% hydrochloric acid, merge mother liquor and leacheate, to be cooled to room temperature, add 300mL40%NaOH solution and make resolution of precipitate, isolate oil reservoir, water merges oil reservoir and ether extraction liquid, through anhydrous Na with 3 * 50mL extracted with diethyl ether
2SO
4Drying, normal pressure reclaims solvent, and 106～109 ℃/13mmHg cut is collected in the raffinate underpressure distillation, gets colourless liquid 31.3g, productive rate 64.1%, purity 98.4%.
The preparation of embodiment 4 Alpha-Methyls-α-phenylhydrazine
The charging capacity of removing the Zn powder changes 39.0g (0.6mol) into, and promptly the mol ratio of N-nitroso-group methylphenylamine and Zn powder is outside 1: 1.5, and other operational condition is all identical with embodiment 3, gets colourless liquid 20.7g, productive rate 42.4%, purity 98.2%.
Embodiment 51,2,3, the preparation of 9-tetrahydrochysene-9-methyl-4H-carbazole-4-ketone
CaCl is being housed
2In three mouthfuls of round-bottomed flasks of the 500mL of drying tube, add hydroresorcinol 22.4g (0.2mol), 200mL methyl alcohol and 73.2g HMCM-41 molecular sieve, be warming up to 60～65 ℃, be added dropwise to Alpha-Methyl-α-phenylhydrazine 24.4g (0.2mol) in the 30min and be dissolved in the solution of 80mL methyl alcohol, after dropwising, continue reaction 16～18h, with high performance liquid chromatography reaction is detected, reaction is cooled to room temperature after finishing, filter, molecular sieve 5mL methyl alcohol drip washing, mother liquor reclaims solvent, cooling, pour in the 100mL frozen water, separate out a large amount of white solids, suction filtration is with acetone-water (1+1) recrystallization, get colourless acicular crystal 26.0g, yield 65.3%.198～199 ℃ of fusing points, purity 99.2%.
Embodiment 61,2,3, the preparation of 9-tetrahydrochysene-9-methyl-4H-carbazole-4-ketone
Except reaction medium changed 80mL acetone into, other operational condition was all identical with embodiment 5, got colourless acicular crystal 18.1g, yield 45.5%, 197～199 ℃ of fusing points, purity 98.6%.
Embodiment 71,2,3,9-tetrahydrochysene-9-methyl-4H-carbazole-4-ketone:
Except reaction medium changed the 80mL acetonitrile into, other operational condition was all identical with embodiment 5, got colourless acicular crystal 6.0g, yield 15.1%, 197～199 ℃ of fusing points, purity 98.2%.
Embodiment 81,2,3,9-tetrahydrochysene-9-methyl-4H-carbazole-4-ketone:
Except reaction medium changed the 80mL dehydrated alcohol into, other operational condition was all identical with embodiment 5, got colourless acicular crystal 3.5g, yield 8.8%, 198～199 ℃ of fusing points, purity 99.3%.
Embodiment 91,2,3,9-tetrahydrochysene-9-methyl-4H-carbazole-4-ketone:
Except temperature of reaction is 30～35 ℃, other operational condition is all identical with embodiment 5, gets colourless acicular crystal 4.1g, yield 10.3%, 198～199 ℃ of fusing points, purity 98.7%.
Embodiment 101,2,3,9-tetrahydrochysene-9-methyl-4H-carbazole-4-ketone
Except the charging capacity of HMCM-41 molecular sieve changes 19.5g into, promptly the mass ratio of Alpha-Methyl-α-phenylhydrazine and HMCM-41 molecular sieve is outside 1: 0.8, and other operational condition is all identical with embodiment 5, get colourless acicular crystal 6.2g, yield 15.6%, 197～199 ℃ of fusing points, purity 97.6%.
Embodiment 111,2,3,9-tetrahydrochysene-9-methyl-4H-carbazole-4-ketone
Except the charging capacity of HMCM-41 molecular sieve changes 39.0g into, promptly the mass ratio of Alpha-Methyl-α-phenylhydrazine and HMCM-41 molecular sieve is outside 1: 1.6, and other operational condition is all identical with embodiment 5, get colourless acicular crystal 13.7g, yield 34.4%, 197～198 ℃ of fusing points, purity 98.7%.
Embodiment 121,2,3,9-tetrahydrochysene-9-methyl-4H-carbazole-4-ketone
Except the charging capacity of HMCM-41 molecular sieve changes 61.0g into, promptly the mass ratio of Alpha-Methyl-α-phenylhydrazine and HMCM-41 molecular sieve is outside 1: 2.5, and other operational condition is all identical with embodiment 5, get colourless acicular crystal 21.3g, yield 53.5%, 198～199 ℃ of fusing points, purity 99.0%.
Claims (10)
1, a kind of 1,2,3, the preparation method of 9-tetrahydrochysene-9-methyl-4H-carbazole-4-ketone comprises the steps: that with the HMCM-41 molecular sieve be catalyzer, Alpha-Methyl-α-phenylhydrazine and 1, hydroresorcinol carries out condensation and cyclization in 30～65 ℃ and reacts in polar organic solvent, aftertreatment gets product.
2, preparation method as claimed in claim 1, the mass ratio that it is characterized in that described Alpha-Methyl-α-phenylhydrazine and HMCM-41 molecular sieve is 1: 0.8～5.
3, preparation method as claimed in claim 2, the mass ratio that it is characterized in that described Alpha-Methyl-α-phenylhydrazine and HMCM-41 molecular sieve is 1: 3.
4, preparation method as claimed in claim 1 is characterized in that described polar organic solvent is one of following: methyl alcohol, dehydrated alcohol, acetone, acetonitrile; With 1mol Alpha-Methyl-α-phenylhydrazine is benchmark, and the consumption of organic solvent is 250～600mol.
5, preparation method as claimed in claim 4 is characterized in that described polar organic solvent is a methyl alcohol.
6,, it is characterized in that described temperature of reaction is 60～65 ℃ as the described preparation method of one of claim 1～5.
7, preparation method as claimed in claim 1, it is characterized in that described Alpha-Methyl-α-phenylhydrazine is got by following step preparation: with the Zn powder is reductive agent, N-nitroso-group-methylphenylamine carries out reduction reaction in 80～85 ℃ in aqueous acetic acid, aftertreatment gets product.
8, preparation method as claimed in claim 7, the mol ratio that it is characterized in that N-nitroso-group-methylphenylamine and Zn powder is 1: 1.5～4.
9,, it is characterized in that described N-nitroso-group-methylphenylamine is got by following step preparation: with NaNO as claim 7 or 8 described preparation methods
2Be nitrosification agent, methylphenylamine carries out nitrosation reaction in 5～10 ℃ in 10% hydrochloric acid, and aftertreatment gets product.
10, preparation method as claimed in claim 9 is characterized in that described methylphenylamine and NaNO
2Mol ratio be 1: 1～1.3.
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| CNB2005100605486A CN100360506C (en) | 2005-08-29 | 2005-08-29 | 1,2,3,9-tetrahydro-9-methyl-4H-carbazole-4-one preparation method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115677560A (en) * | 2022-11-01 | 2023-02-03 | 常州兰陵制药有限公司 | Synthesis method of 1,2,3, 9-tetrahydro-9-methyl-4H-carbazole-4-ketone |
| CN115677561A (en) * | 2022-11-01 | 2023-02-03 | 常州兰陵制药有限公司 | 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone and synthesis method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1145902A (en) * | 1995-09-22 | 1997-03-26 | 上海华联制药公司 | Preparation of carbazones compounds |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115677560A (en) * | 2022-11-01 | 2023-02-03 | 常州兰陵制药有限公司 | Synthesis method of 1,2,3, 9-tetrahydro-9-methyl-4H-carbazole-4-ketone |
| CN115677561A (en) * | 2022-11-01 | 2023-02-03 | 常州兰陵制药有限公司 | 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone and synthesis method thereof |
| CN115677561B (en) * | 2022-11-01 | 2024-04-05 | 常州兰陵制药有限公司 | 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone and synthesis method thereof |
| CN115677560B (en) * | 2022-11-01 | 2024-04-05 | 常州兰陵制药有限公司 | Synthesis method of 1,2,3, 9-tetrahydro-9-methyl-4H-carbazole-4-one |
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