CN1740153A - Prepn process of 7-ethyl tryptophol - Google Patents
Prepn process of 7-ethyl tryptophol Download PDFInfo
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- CN1740153A CN1740153A CN 200510060465 CN200510060465A CN1740153A CN 1740153 A CN1740153 A CN 1740153A CN 200510060465 CN200510060465 CN 200510060465 CN 200510060465 A CN200510060465 A CN 200510060465A CN 1740153 A CN1740153 A CN 1740153A
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Abstract
The preparation process of 7-ethyl tryptophol includes the following steps: hydrolyzing 2, 3-dihydrofuran inside glycol-ether solvent to obtain 4-hydroxy butyraldehyde; reacting 4-hydroxy butyraldehyde and o-ethyl phenylhydrazine hydrohcloride inside glycol-ether solvent in the temperature from -20 deg.c to solvent boiling point for 1-24 hr; and post-treatment. The 7-ethyl tryptophol preparing process of the present invention has high yield, convenient operation and high product purity, and is suitable for industrial production. The product is used in further production of etodolac.
Description
(1) technical field
The present invention relates to a kind of preparation method of 7-ethyl tryptophol.
(2) background technology
The 7-ethyl tryptophol is the key intermediate of non-steroidal anti-inflammatory medicine material R-ETODOLAC, its synthetic method can via: (1) 2, the 3-dihydrofuran is in dioxane under the room temperature, become hydrazone with adjacent ethyl hydrazinobenzene hydrochloride salt, 95 ℃ of down reactions and making then, through chromatographic column separation and purification (US4585877), (2) ethylene glycol bisthioglycolate-(tetrahydrofuran base) ether is in ethylene glycol monomethyl ether, get with adjacent ethyl hydrazinobenzene hydrochloride salt reaction (JP58192867), (3) o ethyl aniline is under the catalysis of Cadmium Sulphate, under the high temperature, with ethylene glycol cyclization 7-ethylindole; Replace lithium hydride reduction and get (CA 1149396) again through chloroacetyl chloride.
In the aforesaid method, method (1) reaction yield is low, and pass through column chromatography separating purification, be not suitable for suitability for industrialized production, method (2) ethylene glycol bisthioglycolate-(tetrahydrofuran base) ether is not a kind of common chemical raw materials, and has used the adjacent ethyl hydrazinobenzene hydrochloride salt of three times of mol ratios, cost is higher, method (3) requires the temperature of reaction height, and the process complexity, is not suitable for suitability for industrialized production.
(3) summary of the invention
Reaction yield is low in the prior art, production cost is high in order to overcome, and the shortcoming of process complexity the invention provides a kind of preparation method of 7-ethyl tryptophol.
Preparation method of the present invention comprises:
(1) 2,3 dihydro furan is under acidic conditions, and hydrolysis obtains the 4-acetaldol in suc as formula the glycol ethers solvent of (IV);
(2) in the temperature range internal reaction of-20 ℃-solvent boiling point 1～24 hour, aftertreatment got the 7-ethyl tryptophol in suc as formula the glycol ethers solvent of (IV) for 4-acetaldol and adjacent ethyl hydrazinobenzene hydrochloride salt;
RO-(CH
2)
2-OR′(IV)
R, R ' are hydrogen or C independently separately in its Chinese style (IV)
1～C
4The saturated fatty alkyl.
Described 2,3 dihydro furan: the mol ratio of adjacent ethyl hydrazinobenzene hydrochloride salt is preferably 1: 1/3～and 3, more preferably 1: 2/3～1.5.
In the described step (1) weight ratio of 2,3 dihydro furan and glycol ethers solvent be preferably 1: 1～20, more preferably 1: 5～10; In the step (2) weight ratio of adjacent ethyl hydrazinobenzene hydrochloride salt and glycol ethers solvent be preferably 1: 1～20, more preferably 1: 5～10.
R, R ' in the described formula (IV) is as hydrogen atom, methyl, ethyl, propyl group, butyl, sec.-propyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopropyl methyl; It is one of following that glycol ethers solvent is preferably: ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol positive propyl ether, glycol isopropyl ether, ethylene glycol n-butyl ether, ethylene glycol ethyl isobutyl ether, ethylene glycol uncle butyl ether, glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol bisthioglycolate positive propyl ether, ethylene glycol bisthioglycolate isopropyl ether, ethylene glycol bisthioglycolate n-butyl ether, ethylene glycol bisthioglycolate ethyl isobutyl ether, ethylene glycol bisthioglycolate uncle butyl ether, more preferably ethylene glycol monomethyl ether or ethylene glycol monoethyl ether.
The described acidic conditions of step (1) can adopt one of following acid: hydrochloric acid, sulfuric acid, tosic acid are preferably hydrochloric acid.Generally select the concentrated hydrochloric acid or the vitriol oil in the actually operating for use.Acid is catalyzer in this preparation method, and its add-on is that general catalyst levels gets final product.
The described temperature of reaction of step (2) is preferably 60～120 ℃.
Among the preparation method of the present invention, 2, the 3-dihydrofuran is under the effect of water, acidic conditions forms 4-acetaldol (VIII) down, the adjacent ethyl hydrazinobenzene hydrochloride salt of the 4-acetaldol Yin of gained forms hydrazone (IX), the gained hydrazone directly carries out indoles without separation and changes into ring reaction formation 7-ethyl tryptophol, and process is as follows:
The formation of 4-acetaldol wherein can be passed through two kinds of methods: 1) elder generation is under acidic conditions, and 2,3 dihydro furan adds entry and makes in solvent; 2) in adjacent ethyl hydrazinobenzene hydrochloride salt, add entry, drip 2,3 dihydro furan and make.
Comply with the 7-ethyl tryptophol that preparation method of the present invention obtains, through making support degree methyl esters (VI) with 3-oxopentanoic acid methyl esters (propionyl methyl acetate V) reaction, make the R-ETODOLAC (VII) that has pharmaceutical use accordingly after the further hydrolysis of gained ester, net reaction is:
Preparation method's yield of 7-ethyl tryptophol of the present invention is good, easy to operate, the product purity height, thus further prepare R-ETODOLAC, be suitable for suitability for industrialized production.
(4) embodiment
The preparation of embodiment 1 7-ethyl tryptophol
In the reaction flask of a 500mL, 350 gram ethylene glycol monomethyl ethers, 18 gram water, 10 gram concentrated hydrochloric acids below 0 ℃, drip the 2,3 dihydro furan of 70 grams, after adding, stir 1 hour, and are stand-by.
In the reaction flask of another 1500mL, add 350 gram ethylene glycol monomethyl ethers, the adjacent ethyl hydrazinobenzene hydrochloride salt of 173 grams stirs down, be heated to 80 ℃, then, above-mentioned ethylene glycol monomethyl ether solution slowly is added drop-wise to this contains in the adjacent ethyl hydrazinobenzene hydrochloride salt reaction solution, finish, reacted 8 hours, concentrate and boil off ethylene glycol monomethyl ether, add water 600 grams, methylene dichloride 300 grams, after stirring layering, methylene dichloride is concentrated, and fraction: 180-200 ℃ (5mmHg) collected in underpressure distillation, get faint yellow solid 104 grams, fusing point: 55-62 ℃, purity: 91.5% (GC), pure yield: 50.3%.
Embodiment 2～12
Change the raw material consumption and the condition of reaction shown in the embodiment 1, thereby the product result who obtains is as shown in table 1.
Table 1
| The embodiment numbering | 2,3 dihydro furan (gram) | 2,3 dihydro furan spent glycol monomethyl ether (gram) | Adjacent ethyl hydrazinobenzene hydrochloride salt (gram) | Adjacent ethyl hydrazinobenzene hydrochloride salt spent glycol monomethyl ether (gram) | Water (gram) | Temperature (℃) | Purity (%) | Output (gram) |
| 2 | 70 | 700 | 173 | 700 | 18 | 80 | 91.3 | 100 |
| 3 | 70 | 350 | 520 | 2500 | 18 | 100 | 89.9 | 104 |
| 4 | 70 | 700 | 173 | 700 | 36 | 80 | 86.5 | 109 |
| 5 | 70 | 700 | 173 | 700 | 36 | 120 | 82.1 | 110 |
| 6 | 105 | 700 | 173 | 700 | 18 | 80 | 90.1 | 102 |
| 7 | 105 | 700 | 173 | 700 | 36 | 80 | 87.9 | 100 |
| 8 | 105 | 700 | 173 | 700 | 36 | 100 | 87.5 | 98 |
| 9 | 210 | 700 | 173 | 700 | 36 | 60 | 90.6 | 103 |
| 10 | 210 | 700 | 173 | 700 | 18 | 80 | 89.4 | 109 |
| 11 | 210 | 700 | 173 | 700 | 18 | 100 | 88.1 | 106 |
| 12 | 210 | 700 | 173 | 700 | 36 | 120 | 86.9 | 107 |
Embodiment 13-20
The kind of acid that change is adopted and consumption thereof, glycol ethers solvent, all with embodiment 1, reaction result is as shown in table 2 for other.
Table 2
| The embodiment numbering | Acid and consumption | Glycol ethers solvent | Temperature (℃) | Purity (%) | Output (gram) |
| 13 | Concentrated hydrochloric acid 15 grams | Glycol dimethyl ether | 80 | 90.8 | 101 |
| 14 | Concentrated hydrochloric acid 8 grams | Ethylene glycol ethyl ether | 80 | 86.1 | 105 |
| 15 | Concentrated hydrochloric acid 15 grams | Glycol isopropyl ether | 100 | 83.5 | 110 |
| 16 | The vitriol oil 10 grams | Ethylene glycol monomethyl ether | 60 | 88.6 | 108 |
| 17 | The vitriol oil 15 grams | Ethylene glycol monomethyl ether | 80 | 90.6 | 103 |
| 18 | Tosic acid 10 grams | Ethylene glycol monomethyl ether | 100 | 88.8 | 99 |
| 19 | Tosic acid 15 grams | The ethylene glycol n-butyl ether | 80 | 85.6 | 96 |
| 20 | Concentrated hydrochloric acid 8 grams | Ethylene glycol diethyl ether | 120 | 80.3 | 108 |
Claims (12)
1, a kind of preparation method of 7-ethyl tryptophol comprises the steps:
(1) 2,3 dihydro furan is under acidic conditions, and hydrolysis obtains the 4-acetaldol in suc as formula the glycol ethers solvent of (IV);
(2) in the temperature range internal reaction of-20 ℃～solvent boiling point 1～24 hour, aftertreatment got the 7-ethyl tryptophol in suc as formula the glycol ethers solvent of (IV) for 4-acetaldol and adjacent ethyl hydrazinobenzene hydrochloride salt;
RO-(CH
2)
2-OR′ (IV)
R, R ' are hydrogen or C independently separately in its Chinese style (IV)
1～C
4The saturated fatty alkyl.
2, the preparation method of 7-ethyl tryptophol as claimed in claim 1 is characterized in that described 2,3 dihydro furan: the mol ratio of adjacent ethyl hydrazinobenzene hydrochloride salt is 1: 1/3～3.
3, the preparation method of 7-ethyl tryptophol as claimed in claim 2 is characterized in that described 2,3 dihydro furan: the mol ratio of adjacent ethyl hydrazinobenzene hydrochloride salt is 1: 2/3～1.5.
4, the preparation method of 7-ethyl tryptophol as claimed in claim 1, it is characterized in that in the described step (1) 2, the weight ratio of 3-dihydrofuran and glycol ethers solvent is 1: 1～20, and the weight ratio of adjacent ethyl hydrazinobenzene hydrochloride salt and glycol ethers solvent is 1: 1～20 in the step (2).
5, the preparation method of 7-ethyl tryptophol as claimed in claim 4, it is characterized in that in the described step (1) 2, the weight ratio of 3-dihydrofuran and glycol ethers solvent is 1: 5～10, and the weight ratio of adjacent ethyl hydrazinobenzene hydrochloride salt and glycol ethers solvent is 1: 5～10 in the step (2).
6, the preparation method of 7-ethyl tryptophol as claimed in claim 1 is characterized in that R, R ' in the described formula (IV) is independent of separately one of following: hydrogen atom, methyl, ethyl, propyl group, butyl, sec.-propyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopropyl methyl.
7, the preparation method of 7-ethyl tryptophol as claimed in claim 6 is characterized in that described glycol ethers solvent is one of following: ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol positive propyl ether, glycol isopropyl ether, ethylene glycol n-butyl ether, ethylene glycol ethyl isobutyl ether, ethylene glycol uncle butyl ether, glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol bisthioglycolate positive propyl ether, ethylene glycol bisthioglycolate isopropyl ether, ethylene glycol bisthioglycolate n-butyl ether, ethylene glycol bisthioglycolate ethyl isobutyl ether, ethylene glycol bisthioglycolate uncle butyl ether.
8, the preparation method of 7-ethyl tryptophol as claimed in claim 7 is characterized in that described glycol ethers solvent is an ethylene glycol monomethyl ether.
9, the preparation method of 7-ethyl tryptophol as claimed in claim 7 is characterized in that described glycol ethers solvent is an ethylene glycol monoethyl ether.
10, the preparation method of 7-ethyl tryptophol as claimed in claim 1 is characterized in that the described acidic conditions of step (1) adopts one of following acid: hydrochloric acid, sulfuric acid, tosic acid.
11, the preparation method of 7-ethyl tryptophol as claimed in claim 10 is characterized in that the acid that the described acidic conditions of step (1) adopts is hydrochloric acid.
12,, it is characterized in that the described temperature of reaction of step (2) is 60～120 ℃ as the preparation method of the described 7-ethyl tryptophol of one of claim 1～11.
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| CN 200510060465 CN1740153A (en) | 2005-08-23 | 2005-08-23 | Prepn process of 7-ethyl tryptophol |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102030696A (en) * | 2010-11-17 | 2011-04-27 | 浙江工业大学 | Method for synthesizing tryptophol compound under catalysis of sulfonated MCM-41 (Mobile Crystalline Material-41) |
| CN113666860A (en) * | 2020-05-14 | 2021-11-19 | 鲁南制药集团股份有限公司 | Preparation method of 7-ethyl tryptophol |
-
2005
- 2005-08-23 CN CN 200510060465 patent/CN1740153A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102030696A (en) * | 2010-11-17 | 2011-04-27 | 浙江工业大学 | Method for synthesizing tryptophol compound under catalysis of sulfonated MCM-41 (Mobile Crystalline Material-41) |
| CN102030696B (en) * | 2010-11-17 | 2012-12-12 | 浙江工业大学 | Method for synthesizing tryptophol compound under catalysis of sulfonated MCM-41 (Mobile Crystalline Material-41) |
| CN113666860A (en) * | 2020-05-14 | 2021-11-19 | 鲁南制药集团股份有限公司 | Preparation method of 7-ethyl tryptophol |
| CN113666860B (en) * | 2020-05-14 | 2024-03-15 | 鲁南制药集团股份有限公司 | Preparation method of 7-ethyl tryptol |
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