CN1123269A - Method for preparation of ethyl tert-butyl ether and prdouct thereof and application thereof - Google Patents
Method for preparation of ethyl tert-butyl ether and prdouct thereof and application thereof Download PDFInfo
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- CN1123269A CN1123269A CN 94118066 CN94118066A CN1123269A CN 1123269 A CN1123269 A CN 1123269A CN 94118066 CN94118066 CN 94118066 CN 94118066 A CN94118066 A CN 94118066A CN 1123269 A CN1123269 A CN 1123269A
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Abstract
The present invention discloses a preparation method for ethyl tert-butyl ether and its product and medicinal composite containing said product, which can be used as litholytic agent. Advantage and usage: have the good litholytic effects for curing general cholesterol calculus, combination calculus and bile pigment calculus. Its clinical cure rate can be up to 99%.
Description
The present invention relates to the preparation of compound and the purposes of this compound, specifically a kind of preparation method of ether material, product and its clinical application in molten cholelith.
At first, ether once was used for molten cholelith test as organic solvent, and it is on record therefore having solvency action for Biliary Calculi.Owing to toxicity with boiling point is low, the reason of vaporizing easily, be not suitable for clinical application.
Along with growth in the living standard, human food structure's variation, the gallbladdergallstonecholetithiasis disease also increases rapidly, cholesterol type calculus (CS) in three kinds of calculosises that it has been generally acknowledged that, mixed type calculus (MS), pigment type calculus (PS) increases the fastest with the former again.ALLEN in 1985 has reported methyl tertiary butyl ether, and (MethylTertiary Butyl Ether, molten cholelith experiment MTBE) has promoted the experimental study work of this area.Through to the exploration of MTBE actual effect and experiment clinical verification, find that its toxic side effect problem in fact still is difficult to resolve to determine, and it has obvious selectivity to the molten stone performance of dissimilar Biliary Calculis.
(Ethyl Tertisry Butyl Ether ETBE) has the molten cholelith effect same with MTBE to the Ethyl Tertisry Butyl Ether of the present invention's selection and preparation, and is remarkable to the litholytic effect of cholesterol type calculus, and toxic side effect is very little, is fit to very much clinical application.
The objective of the invention is to propose a kind of method for preparing the ethyl tert-butyl ether compound, and the high purity product that obtains with present method and the application of product, comprise the application of this material itself and contain this material pharmaceutical composition, reach the application of pharmaceutical composition.They have the effect more better than methyl tertiary butyl ether, and clinical experiment shows that the treatment that is used for Biliary Calculi is fully feasible.
The structural formula of known substance is shown in general formula (I):
R, R ', R in the formula " all elect a CH as
3
Preparation method comprises makes the trimethyl carbinol shown in the formula (II) and ethanol under the katalysis of dilute sulphuric acid, in 60-90 ℃ of liquid temperature temperature range internal reactions, fractionation 8-12 hours, through washing, dry, remove alcohol after, rectifying obtains the ethyl tert-butyl ether compound shown in (I) under 72-73 ℃ of temperature again:
Above-mentioned reaction is undertaken by the different mol ratio of raw material:
The trimethyl carbinol: ethanol: sulfuric acid: water=1: 1-3: 0.3-0.6: 10-20
Select the water bath with thermostatic control heating method for use, 70-100 ℃ of outer temperature, 60-90 ℃ of liquid temperature (interior temperature) are heated up in a steamer 50-80 ℃ of head temperature, carry out fractionation and collect, and press 0.5-1.5ml/ minute speed, are the fractionation terminal point in this temperature range inner control during to no overhead product; With the gained distillate, with time washing of volume moisture, use Anhydrous potassium carbonate, Calcium Chloride Powder Anhydrous drying then, remove alcohol via sodium Metal 99.5 backflow drying at last, carry out rectifying again and obtain pure product, rectification temperature is 72-73 ℃.
The ethyl tert-butyl ether compound that utilizes above-mentioned preparation method to obtain is colourless transparent liquid, product purity reaches 〉=and 99.5%, boiling point is 72-73 ℃, and its structural formula is shown in (I), and molecular formula is C
6H
14O.
The structure of the compound of the present invention's preparation is by the NMR spectrum, and IR spectrum and ultimate analysis confirm.
With the pharmaceutical composition of the said products preparation, contain the compound of (I) structure that has formula, and preferred and pharmaceutically acceptable molten stone solvent, emulsifying agent, complexing agent.
Pharmaceutical composition is main composition with Ethyl Tertisry Butyl Ether (ETBE), also comprise add the solvent hesperidene, be that complexing agent and Yelkin TTS are emulsifying agent with 1.2 1 cyclohexanediaminetetraacetic acids (CDTA).General CDTA solution: the ETBE that presses: hesperidene=1: 6-10: 1 mixed adds lecithin with the consumption of per 100 milliliter of 2 gram again, makes through emulsify at a high speed 1-5 minutes.
The present invention make suc as formula the ethyl tert-butyl ether compound of structure shown in (I) and contain of the application of the pharmaceutical composition of this compound as molten cholelith agent, comprising making this material solvent and the combination solvent that contains this material contact, soak corrosion with Biliary Calculi or the two alternately pours into corrosion several times.
Method provided by the present invention can prepare the high purity ETBE medicinal compound that satisfies clinical use, its litholytic effect and MTBE are suitable, and toxic side effect is very little, when being applied to the cholesterol type gallbladdergallstonecholetithiasis, its molten stone speed is very fast, can clearly observe molten stone change procedure.The pharmaceutical composition ETBEce that is mixed with has the complementary effect with ETBE, and it slightly reduces the litholytic effect of cholesterol type gallbladdergallstonecholetithiasis on the one hand, and it gains by comparison to the litholytic effect of pigment type gallbladdergallstonecholetithiasis, mixed type gallbladdergallstonecholetithiasis on the other hand.The litholytic effect of described material and the litholytic effect of pharmaceutical composition see Table 1, table 2.
Metal element contents such as detected calcium, magnesium, copper compare than single result who handles with ethyl tert-butyl ether compound (solvent) in the courage mud of discharge after pharmaceutical composition ETBEce handles, and the constituent content of calcium, magnesium, copper obviously reduces (being that colored substance reduces) in its courage mud residue.
Experiment shows that the two is perfusion alternately with clinical effectiveness, and repeatedly the litholytic effect after the vibration is very good, and the clinical total cure rate of litholytic effect of three general class choleliths is reached 99%.
The invention will be further described with the experiment clinical case below in conjunction with embodiment
Embodiment 1
The ethyl tert-butyl ether compound
In the 3000ml three-necked flask of dropping funnel, thermometer and fractional column is housed, add 15.5% dilute sulphuric acid 1160ml, add 95% ethanol 450ml again, and add several zeolites, heating is when bathing 70-100 ℃ of temperature (outer temperature), and 60-90 ℃ of liquid temperature (interior temperature) are when heating up in a steamer 50-80 ℃ of head temperature, add trimethyl carbinol 100ml again, overhead product is collected in fractionation, and remaining 250ml trimethyl carbinol drips via dropping funnel, and its speed is suitable with the speed that distillates, until not having overhead product, be the fractionation terminal point in this temperature range.Overhead product washs 15 times with volume moisture.Washing times is generally more than 15 times or 15 times.Use Anhydrous potassium carbonate, Calcium Chloride Powder Anhydrous drying then, remove alcohol through sodium Metal 99.5 backflow drying more at last, 72-73 ℃ cut is collected in rectifying again, and yield 75% is colourless transparent liquid, and content is 99.5%, and IR spectrogram, NMR spectrogram are consistent with the standard spectrogram.
Embodiment 2
The ethyl tert-butyl ether compound
In reaction flask with embodiment 1, add 10% dilute sulphuric acid 1000ml, add 95% ethanol 450ml again, add several zeolites again, heating is when bathing 70-100 ℃ of temperature (outer warm), 60-90 ℃ of liquid temperature (interior temperature) when heating up in a steamer 50-80 ℃ of head temperature, add trimethyl carbinol 100ml fractionation again, collect overhead product, remaining 250ml trimethyl carbinol drips via dropping funnel, and its speed is suitable with the speed that distillates, until not having overhead product, be the fractionation terminal point in this temperature.Overhead product washs 16 times with volume moisture.Use Anhydrous potassium carbonate then, the Calcium Chloride Powder Anhydrous drying is removed alcohol through sodium Metal 99.5 backflow drying, rectifying more at last again, collect 72-73 ℃ cut, yield 72% is colourless transparent liquid, and special ether flavor is arranged, content＞99.5%, the IR spectrogram, the NMR spectrogram is consistent with standard substance.
Above finished product ultimate analysis:
C
6H
14O: theoretical value measured value
C 70.59 70.605
H 13.73 13.710
O 15.68 15.685
Embodiment 3
Pharmaceutical composition
The main composition of pharmaceutical composition is Ethyl Tertisry Butyl Ether (ETBE), is the good organic solvent of gallbladdergallstonecholetithiasis.Hesperidene is another fine solvent of gallbladdergallstonecholetithiasis for auxiliary composition, and Yelkin TTS is as emulsifying agent, and is fused mutually in order to facilitate between solvent.1,2-cyclohexanediaminetetraacetic acid (CDTA) is a metal chelating agent, utilizes its complexing action, and the net connection that can destroy cholelith promotes its disintegration, quickens corrosion.
With 10ml bi-distilled water and 2gCDTA, add the CDTA solution for standby of the miscible one-tenth 20% of an amount of NaOH solution again;
Again by CDTA solution: ETBE: hesperidene=1: 6: 1 (volume ratio) is made into mixed solution, gets mixed solution 100ml, adds lecithin 2g, puts the stirring of high speed homogenizer high speed and carries out emulsification in 3 minutes, obtains to contain ETBE and is about 75% the molten stone solvent of composition.
Embodiment 4
Pharmaceutical composition
Get content and be 20% CDTA solution, ETBE, hesperidene is made into the mixed solution of 100ml by 1: 10: 1 (volume ratio), adds lecithin 2g, and emulsify at a high speed 5 minutes is made into and contains the molten stone solvent of about 83.3% composition of ETBE.
Utilize compound-Ethyl Tertisry Butyl Ether that the inventive method obtains-can directly apply to clinical, or utilize the composition that contains ETBE (ETBEce) that is mixed with to be applied to clinical.
Be used for once their toxicity toxicity being made a large amount of animal experiments before clinical, the sub-acute toxicity test of its Chinese traditional medicine the results are shown in Table 3.Can see that by comparing ETBE is more much smaller than the toxicity of MTBE in the table.
Through the clinic trial to human body, example suffers from the patient treatment of cholelithiasis surplus 80, and curative ratio is more than 99%.Method is through the hepatic duct puncture and intubation or directly to the gall-bladder puncture and intubation, earlier with the molten stone agent of ETBE, adopts perfusion at regular time and quantity to take out notes again according to detecting to observe, or is used alternatingly with the molten stone agent of ETBEce and achieves the goal.
Embodiment 5
Bavin * *, the woman, 38 years old, the B ultrasonic radiography confirmed, two in calculus is arranged in the gall-bladder, and size is about φ 1.2cm, after intubate, and injection EBTE12-20ml and being vibrated in pipe, changed ETBE once in per 30-45 minutes, and after 2 hours, a large amount of courage mud solutes were arranged from managing interior discharge.B ultrasonic check in 3 hours, the calculus shadow disappears.Check in 3,10 is negative.
Embodiment 6
Slowly * *, the women, calculus is two pieces in the gall-bladder, directly through 1.8cm and 1.6cm, wherein one piece of incarceration is stiff in cystic duct, after the gall-bladder intubate, with ETBE and ETBEce alternately perfusion in per 20 minutes, shade disappears after the wherein free calculus perfusion 4 times, and another is the rim of a cup shape to gall-bladder one end and dwindles, and incarceration is partly failed corrosion, be to add vibration treatment calculus to be loosened take off in the capsule, as above 6 perfusions of method, the calculus shadow all disappears, and has more solute to sneak into courage mud during perfusion and discharges from intubate.
External 12 hours molten stone weight-loss ratio tables 1
24 hours weight-loss ratio tables 2 of molten stone animal experiment in the body (hybridization dog)
The medicine sub-acute toxicity test is comparison sheet 3 as a result
| Dabbling drug and condition | Reaction of animals | Blood | The heart and DM | Liver | Lung | Spleen | Kidney | Gall-bladder |
| 15 days gall-bladder fistulization perfusion 2ml/kg. days MTBE | The few food of survival is few moving, Body weight loss, and ight soil is shapeless | Serum, free hemoglobin, SGBT raise, red blood cell decreased, leucocyte rises | No abnormality seen | Withered apricot Schwann Cells hyperplasia, degeneration of liver cells or double-core or little focal necrosis | Lung tissue extravasated blood, alveolar sepage appear individually | The special mess inflammatory infiltration is arranged individually | Tubularization of cell appears individually | It is rotten to the corn that shallow table takes place mucous membrane, and there is inflammatory cell infiltration in lower floor |
| The same ETBE * ETBEce of condition (15 dogs) | Survival does not have and to lead normal performance, and it is less moving that wherein dog began few food on the 10th day | Only one the total hemocytes count rising occurs, SGPT slightly increases, and other are normal | No abnormality seen | Minority has slight degeneration of liver cells | No abnormality seen | No abnormality seen | No abnormality seen | Slight mucous membrane of gallbladder inflammatory reaction is arranged |
Claims (10)
1, prepares the method for known substance structural formula suc as formula compound shown in (I)
R, R ', R in the formula " be-CH
3,
It comprises makes the trimethyl carbinol shown in the formula (II) and ethanol under the katalysis of dilute sulphuric acid, in 60-90 ℃ of liquid temperature temperature range internal reactions, fractionation 8-10 hours, through washing, dry, remove alcohol after, rectifying obtains ethyl tert-butyl ether compound shown in the formula (I) under 72-73 ℃ of temperature again:
2, in accordance with the method for claim 1, wherein washing is time washing of volume moisture, and washing times is more than 15 times or 15 times.
3, in accordance with the method for claim 1, wherein desiccant siccative comprises Anhydrous potassium carbonate, Calcium Chloride Powder Anhydrous, sodium Metal 99.5.
4, utilize the ethyl tert-butyl ether compound of claim 1 preparation method preparation, wherein the molecular formula of compound is C
6H
14O, structural formula is represented suc as formula (I), purity 〉=99.5%, water white transparency, boiling point is 72-73 ℃.
5, pharmaceutical composition contains the pharmaceutical composition of (I) structural material that has formula, and preferred pharmaceutically acceptable molten stone solvent, emulsifying agent, complexing agent.
6, according to the described composition of claim 5, wherein said molten stone solvent is a hesperidene.
7, according to the described composition of claim 5, wherein emulsifying agent is a Yelkin TTS.
8, according to the described composition of claim 5, wherein complexing agent is 1,2-cyclohexanediaminetetraacetic acid (CDTA).
9, the application of treatment in the gall stone comprises cholelithiasis used the compound shown in the formula (I) or contained the pharmaceutical composition of this compound.
10,, contact, soak corrosion with Biliary Calculi or both alternately pour into corrosion several times comprising the combination solvent that makes this material solvent or contain this material according to the described application of claim 9.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 94118066 CN1123269A (en) | 1994-11-19 | 1994-11-19 | Method for preparation of ethyl tert-butyl ether and prdouct thereof and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 94118066 CN1123269A (en) | 1994-11-19 | 1994-11-19 | Method for preparation of ethyl tert-butyl ether and prdouct thereof and application thereof |
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|---|---|
| CN1123269A true CN1123269A (en) | 1996-05-29 |
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| CN 94118066 Pending CN1123269A (en) | 1994-11-19 | 1994-11-19 | Method for preparation of ethyl tert-butyl ether and prdouct thereof and application thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102614155A (en) * | 2012-01-13 | 2012-08-01 | 北京大学 | Mixed litholytic agent for dissolving cholesterol stone |
| CN102626402A (en) * | 2012-01-13 | 2012-08-08 | 北京大学 | Monolauryl phosphate-containing lithontriptic for litholysis of cholesterol gallstone |
| CN113509456A (en) * | 2020-04-09 | 2021-10-19 | 宁海德宝立新材料有限公司 | Diethylene glycol monobutyl ether litholytic agent |
| CN113521040A (en) * | 2020-04-22 | 2021-10-22 | 宁海德宝立新材料有限公司 | Litholytic agent for interventional dissolution of gallstone |
-
1994
- 1994-11-19 CN CN 94118066 patent/CN1123269A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102614155A (en) * | 2012-01-13 | 2012-08-01 | 北京大学 | Mixed litholytic agent for dissolving cholesterol stone |
| CN102626402A (en) * | 2012-01-13 | 2012-08-08 | 北京大学 | Monolauryl phosphate-containing lithontriptic for litholysis of cholesterol gallstone |
| CN102614155B (en) * | 2012-01-13 | 2013-10-16 | 北京大学 | Mixed litholytic agent for dissolving cholesterol stone |
| CN113509456A (en) * | 2020-04-09 | 2021-10-19 | 宁海德宝立新材料有限公司 | Diethylene glycol monobutyl ether litholytic agent |
| CN113509456B (en) * | 2020-04-09 | 2023-04-07 | 宁海德宝立新材料有限公司 | Diethylene glycol monobutyl ether litholytic agent |
| CN113521040A (en) * | 2020-04-22 | 2021-10-22 | 宁海德宝立新材料有限公司 | Litholytic agent for interventional dissolution of gallstone |
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