CN1740154A - Prepn process of 7-ethyl tryptophol - Google Patents
Prepn process of 7-ethyl tryptophol Download PDFInfo
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- CN1740154A CN1740154A CN 200510060466 CN200510060466A CN1740154A CN 1740154 A CN1740154 A CN 1740154A CN 200510060466 CN200510060466 CN 200510060466 CN 200510060466 A CN200510060466 A CN 200510060466A CN 1740154 A CN1740154 A CN 1740154A
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Abstract
The preparation process of 7-ethyl tryptophol includes the following steps: reacting hydrolyzing 2, 3-dihydrofuran and o-ethyl phenylhydrazine hydrohcloride under the action of water inside glycol-ether solvent at the temperature from -20 deg.c to solvent boiling point; 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.
Described 7-ethyl tryptophol is shown in (III), described preparation method comprises: as (I) 2, the 3-dihydrofuran with as (II) adjacent ethyl hydrazinobenzene hydrochloride salt under the effect of water, suc as formula (react in the temperature range of-20 ℃～solvent boiling point in the glycol ethers solvent of IV, aftertreatment gets described product;
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.
Reaction formula is as follows:
Described 2,3 dihydro furan: adjacent ethyl hydrazinobenzene hydrochloride salt: the mol ratio of water is preferably 1: 1/3～and 3: 1/5～5, more preferably 1: 2/3～1.5: 1/2～2.
The weight ratio of described 2,3 dihydro furan and glycol ethers solvent is preferably 1: 1～and 20, more preferably 1: 5～10.
R, R ' are respectively freely in the described formula (IV): hydrogen atom, methyl, ethyl, propyl group, butyl, sec.-propyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopropyl methyl etc.; 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.
Described temperature of reaction is preferably 60～120 ℃.
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 invention will be further described below in conjunction with specific embodiment, but protection scope of the present invention is not limited to this.
Embodiment 1 7-ethyl tryptophol preparation
In the reaction flask of a 500mL, add the 2,3 dihydro furan of 70 grams, 350 gram ethylene glycol monomethyl ethers stir, and are stand-by.
In the reaction flask of another 1500mL, add 350 gram ethylene glycol monomethyl ethers, 18 gram water, the adjacent ethyl hydrazinobenzene hydrochloride salt of 173 grams, be heated to 80 ℃, then, with above-mentioned 2, the ethylene glycol monomethyl ether solution of 3-dihydrofuran is added drop-wise in this reaction solution, finish, reacted 6 hours, concentrate and boil off ethylene glycol monomethyl ether, add water 600 grams, methylene dichloride 300 grams after the stirring layering, concentrate methylene dichloride, underpressure distillation, collect fraction: 180-200 ℃ (5mmHg), get faint yellow solid 106 grams, fusing point: 55-62 ℃, purity: 91.8% (GC), pure yield: 51.6%.
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 | 90.6 | 101 |
| 3 | 70 | 350 | 520 | 2500 | 18 | 100 | 88.8 | 105 |
| 4 | 70 | 700 | 173 | 700 | 36 | 80 | 85.6 | 110 |
| 5 | 70 | 700 | 173 | 700 | 36 | 120 | 80.3 | 108 |
| 6 | 105 | 700 | 173 | 700 | 18 | 80 | 90.8 | 103 |
| 7 | 105 | 700 | 173 | 700 | 36 | 80 | 86.1 | 99 |
| 8 | 105 | 700 | 173 | 700 | 36 | 100 | 83.5 | 96 |
| 9 | 210 | 700 | 173 | 700 | 36 | 60 | 88.6 | 108 |
| 10 | 210 | 700 | 173 | 700 | 18 | 80 | 89.3 | 110 |
| 11 | 210 | 700 | 173 | 700 | 18 | 100 | 88.0 | 108 |
| 12 | 210 | 700 | 173 | 700 | 36 | 120 | 84.9 | 105 |
Embodiment 13-20
Change the kind of glycol ethers solvent, all with embodiment 1, reaction result is as shown in table 2 for other.
Table 2
| The embodiment numbering | Glycol ethers solvent | Temperature (℃) | Purity (%) | Output (gram) |
| 13 | Ethylene glycol monoethyl ether | 80 | 90.8 | 105 |
| 14 | Ethylene glycol diethyl ether | 80 | 86.1 | 100 |
| 15 | Glycol isopropyl ether | 100 | 83.5 | 102 |
| 16 | Butyl glycol ether | 60 | 88.6 | 108 |
| 17 | The ethylene glycol ethyl isobutyl ether | 80 | 90.6 | 103 |
| 18 | Ethylene glycol uncle butyl ether | 100 | 88.8 | 99 |
| 19 | Glycol dimethyl ether | 80 | 85.6 | 96 |
| 20 | Ethylene glycol diethyl ether | 120 | 80.3 | 108 |
Claims (10)
1, a kind of preparation method of 7-ethyl tryptophol, comprise: 2,3-dihydrofuran and adjacent ethyl hydrazinobenzene hydrochloride salt react in the temperature range of-20 ℃～solvent boiling point in suc as formula the glycol ethers solvent of (IV) under the effect of water, and aftertreatment gets described product;
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: adjacent ethyl hydrazinobenzene hydrochloride salt: the mol ratio of water is 1: 1/3～3: 1/5～5.
3, the preparation method of 7-ethyl tryptophol as claimed in claim 2 is characterized in that described 2,3 dihydro furan: adjacent ethyl hydrazinobenzene hydrochloride salt: the mol ratio of water is 1: 2/3～1.5: 1/2～2.
4, the preparation method of 7-ethyl tryptophol as claimed in claim 1, the weight ratio that it is characterized in that described 2,3 dihydro furan and glycol ethers solvent is 1: 1～20.
5, the preparation method of 7-ethyl tryptophol as claimed in claim 4, the weight ratio that it is characterized in that described 2,3 dihydro furan and glycol ethers solvent is 1: 5～10.
6, the preparation method of 7-ethyl tryptophol as claimed in claim 1 is characterized in that R in the described formula (IV) and R ' are 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,, it is characterized in that described temperature of reaction is 60～120 ℃ as the preparation method of the described 7-ethyl tryptophol of one of claim 1～9.
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|---|---|---|---|
| CN 200510060466 CN1740154A (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 200510060466 patent/CN1740154A/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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