CN109928939A - A kind of preparation method of 2,2,6,6- tetramethyl morpholine - Google Patents
A kind of preparation method of 2,2,6,6- tetramethyl morpholine Download PDFInfo
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- CN109928939A CN109928939A CN201910147673.2A CN201910147673A CN109928939A CN 109928939 A CN109928939 A CN 109928939A CN 201910147673 A CN201910147673 A CN 201910147673A CN 109928939 A CN109928939 A CN 109928939A
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Abstract
The invention discloses one kind 2,2,6, the preparation method of 6- tetramethyl morpholine, belong to technical field of organic synthesis, Step 1: being warming up to 35-50 DEG C of reaction 25-40 minutes in the methanol solvate for the ammonia that the 2- methyloxetane of 2 equivalents is slowly added dropwise to 0.7-1 equivalent, methanol is removed, then vacuum distillation obtains intermediate；Step 2: the intermediate that step 1 is obtained is slowly added in the concentrated sulfuric acid, rise to 75-85 DEG C of reaction 2-4 hours, then sodium hydrate aqueous solution is added until reaction solution is in alkalescent, the fraction being evaporated under reduced pressure, which is adopted, to be extracted with dichloromethane, dry, decompression evaporates methylene chloride, then 2,2 are obtained after with water pump vacuum distillation under 30-60 DEG C, the vacuum condition of 0.8-0.1MPa, 6,6- tetramethyl morpholines.Not only operating procedure is safe by the present invention, and simple and convenient, production equipment is of less demanding, and on the basis of guaranteeing product quality and good yield, is suitble to amplification production.
Description
Technical field
The invention belongs to technical field of organic synthesis, more specifically, it relates to a kind of 2,2,6,6- tetramethyl morpholines
Preparation method.
Background technique
2,2,6,6- tetramethyl morpholines are one kind of morpholine derivative, chemical structural formula are as follows:Wherein
Quinoline is also known as morphine woods, molecular formula C4H9NO, or write as O (CH2CH2)2NH, its fusing point are -4.76 DEG C, boiling point 128.3
DEG C, density 1.0005g/cm3 (20 DEG C)；It is a kind of colourless oil liquid, chemical structural formula at normal temperature are as follows:
Morpholine can be by diethanol amineIt is prepared through sulfuric acid cyclodehydration.
It is reported that 2,2,6,6- tetramethyl morpholines are a kind of important medicine intermediates, document WO2006/66174 and
US2017/50973 reports its application on drug, document Journal of Medicinal Chemistry, and 1997,
Vol.40, # 11, p.1668-1681 report its research being used on anaesthetic.
This compound only has the synthetic route of document WO2006/66174 as follows at present:
Since above-mentioned reaction step is longer, total yield is low, is not suitable for amplification production, therefore we now provided with a kind of new preparation
The synthesis thinking of 2,2,6,6- tetramethyl morpholine.
Summary of the invention
In view of the deficiencies of the prior art, the present invention intends to provide a kind of system of 2,2,6,6- tetramethyl morpholines
Preparation Method, not only operating procedure safety, simple and convenient, production equipment is of less demanding, and is guaranteeing product quality and good
On the basis of yield, it is suitble to amplification production.
To achieve the above object, the present invention provides the following technical scheme that a kind of preparation of 2,2,6,6- tetramethyl morpholines
Method, including operating procedure:
Step 1: in the methanol solvate for the ammonia that the 2- methyloxetane of 2 equivalents is slowly added dropwise to 0.7-1 equivalent, heating
To 35-50 DEG C reaction 25-40 minutes, remove methanol, then vacuum distillation obtain intermediate；
Step 2: the intermediate that step 1 is obtained is slowly added in the concentrated sulfuric acid, 75-85 DEG C of reaction 2-4 hours is risen to, then
Sodium hydrate aqueous solution is added until reaction solution is in alkalescent, the fraction being evaporated under reduced pressure, which is adopted, to be extracted with dichloromethane, and is done
Dry, decompression evaporates methylene chloride, and then vacuum distillation obtains 2,2,6,6- tetramethyl morpholines.
Further, in step 1, the structural formula of the intermediate are as follows:
By using above-mentioned technical proposal, the molecular formula of above structure are as follows: C8H19NO2, English name is 1- (2-
Hydroxy-2-methyl-propylamino) -2-methyl-propan-2-ol, Chinese name are known as 1- (2- hydroxyl -2- first
Base-propyl amine) -2- methyI-oropvD -2- alcohol, hydroxyl, amino and methyl structural are contained in its molecular structure, it is opposite to meet it
The nucleus magnetic hydrogen spectrum diagram data answered.
Further, reaction equation involved in the step 1 are as follows:
Further, reaction equation involved in the step 2 are as follows:
By using above-mentioned technical proposal, first by the ammonia of the raw material 2- methyloxetane of 2 equivalents and 0.7-1 equivalent
Reaction, can obtain intermediate, the chemical name of intermediate after addition at this time are as follows: 1- (2- hydroxy-2-methyl-propyl amine) -2-
Methyl-propyl -2- alcohol, chemical structural formula are as follows:Then above-mentioned intermediate is added to dense
After carrying out dehydration contracting annulation in sulfuric acid, 2,2,6,6- tetramethyl of product is can be obtained after falling reaction dissolvent in vacuum distillation
Quinoline.
Further, in step 1, at 40-70 DEG C after reaction 25-40 minutes, vacuum degree is the condition of 0.08-0.1MPa
Lower decompression evaporates methanol, then increases temperature to 70-80 DEG C, vacuum degree 0.1-0.11MPa, vacuum distillation obtains after falling by-product
To intermediate.
By using above-mentioned technical proposal, in control reaction temperature and after the time, the raw material for still some are surplus
It is remaining, the addition reaction of 1:1 occurs between raw material 2- methyloxetane meeting a small amount of at this time and ammonia, so that by-product can be generated
Object；But since the boiling point of by-product is in 452.60K, the boiling point of raw material is 325.05K, and the boiling point of intermediate is
610.71K, the gap between by-product, raw material and intermediate is larger at this time, it is possible thereby to be gone by way of vacuum distillation
Except above-mentioned by-product and remaining raw material, it is hereby achieved that purer intermediate.
Further, the structural formula of the by-product are as follows:
By using above-mentioned technical proposal, when between raw material 2- methyloxetane and ammonia when reacting for 20 DEG C or less,
The 2- methyloxetane and ammonia for having part will carry out addition in the way of 1:1, when reaction temperature increases, by-product
Amount then can be reduced accordingly；Above-mentioned by-product can generate during step 1 simultaneously, and Chinese name is known as: 1- amino -2- first
Base-propyl -2- alcohol, English name 1-Amino-2-methyl-propan-2-ol, boiling point is in 452.60K.
Further, the chemical equation that the by-product generates are as follows:
By using above-mentioned technical proposal, as reactant 2- methyloxetane and NH3In such a way that molar ratio is 1:1
When being reacted, by-product can generatedThus will affect being normally carried out for second annulation,
Therefore the dosage and ratio of strict control reactant are needed.
Further, in step 2, the sodium hydrate aqueous solution tune pH to 10-12 of 3mol/L is added, then in 80-
120 DEG C, vacuum degree is evaporated under reduced pressure under conditions of being 0.08-0.1MPa, to vacuum distillation after 100- is added in obtained fraction
The methylene chloride of 150ml extracts 10-15 times, and the methylene chloride being obtained by extraction mutually is dried using anhydrous sodium sulfate, is filtered out
At 30-45 DEG C after anhydrous sodium sulfate, decompression evaporates methylene chloride under conditions of vacuum degree is 0.08-0.1MPa, obtains crude product, with
Afterwards at 45-60 DEG C, vacuum degree is evaporated under reduced pressure under conditions of being 0.1-0.11MPa with water pump, and 2,2,6,6- tetramethyls can be obtained
Morpholine.
By using above-mentioned technical proposal, in step 2, the addition of the concentrated sulfuric acid so that entire reaction solution is in highly acid,
Need to be added sodium hydrate aqueous solution at this time adjusts pH to alkalescent to it, furthermore reacts neutralization reaction through the concentrated sulfuric acid and sodium hydroxide
The mixing clear solution (i.e. sodium sulphate, sodium hydroxide are soluble easily in water) of sodium sulphate, water and sodium hydroxide is obtained, and reacts intermediate
Product, by-product and 2,2,6,6- tetramethyl morpholine of product belong to organic phase, and are soluble in this kind of organic of methylene chloride
Solution, therefore layering extracting operation can be carried out in such a way that methylene chloride extracts, so as to by extra sodium sulphate, hydrogen
Sodium oxide molybdena is got rid of, to facilitate the purity and quality of promotion product.
Further, in step 1, need the methanol that the ammonia of 1.8-2.2ml is added molten in the 2- methyloxetane of every 1g
Liquid, the molar ratio of ammonia and methanol is 1:(2-2.5 in the methanol solution of the ammonia).
During by using above-mentioned technical proposal, after Optimum Experiment, discovery is obtained when being reacted within the scope of said ratio
The yield of mesosome is higher.
Further, in step 2, the concentrated sulfuric acid that 3.5-5ml is added is needed in the intermediate of every 1g.
During by using above-mentioned technical proposal, after Optimum Experiment, discovery is obtained when being reacted within the scope of said ratio
The yield of mesosome is higher.
In conclusion the invention has the following advantages:
1, the present invention provides a kind of new 2,2,6,6- tetramethyl morpholine methods of synthesis, simple to operate, and can obtain
Purer product.
2, optimize, after the boiling point that liquid is reduced using distillation under pressure, not only reduce difficulty, the energy conservation and environmental protection of purification,
And the efficiency of purification is accelerated, it is very practical；
3, after the proportion by optimizing each substance, the consumption to raw material can be reduced on the basis of improving the yield of product,
Energy conservation and environmental protection.
Specific embodiment
Below in conjunction with each embodiment, invention is further described in detail.
Embodiment 1: a kind of preparation method of 2,2,6,6- tetramethyl morpholines, including operating procedure:
Step 1: the 2- methyloxetane of 50g to be slowly added dropwise to the methanol solvate containing 7% (V/V) liquefied ammonia of 90ml
In, it is warming up to 35 DEG C and reacts 40 minutes, then decompression evaporates methanol under 40 DEG C, the vacuum condition of 0.08MPa.It then proceedes to rise
For temperature to 70 DEG C, adjustment vacuum degree is 0.1MPa, and being evaporated under reduced pressure by-product, (structural formula of by-product is).It is finally evaporated under reduced pressure under conditions of 0.98MPa with oil pump at 70 DEG C, and obtains intermediate 48g, examined
The nucleus magnetic hydrogen spectrum diagram data of survey is NMR: δ H (CDC13；300MHz)2.32(3H,s,2OH+1NH),2.63(4 H,s,OCH2),
and 1.26(6H,s,CH3)；Therefore it is obtained after being analyzed jointly by the principle of above-mentioned nucleus magnetic hydrogen spectrum diagram data and reaction equation
The chemical structural formula for stating intermediate is
Reaction equation involved in step 1 are as follows:
Step 2: the 48g intermediate that step 1 obtains is slowly added in the concentrated sulfuric acid of 105ml, it is warming up to 75 DEG C instead
It answers 4 hours, is down to room temperature (15 DEG C)；Then the sodium hydrate aqueous solution tune pH to 10-10.5 of 3mol/L is added, then 120
DEG C, vacuum distillation processing is carried out with water pump under the vacuum condition of 0.08MPa, the dichloromethane of 100ml is then added into fraction again
Alkane extracts 10 times, and mutually merging anhydrous sodium sulfate is 5 hours dry for the methylene chloride being obtained by extraction, and filters out anhydrous sodium sulfate, and
Subtract upper pressure under 30 DEG C, the vacuum condition of 0.08MPa and falls methylene chloride；Then under 45 DEG C, the vacuum condition of 0.1MPa again
2,2,6,6- tetramethyl morpholine 37.5g is obtained after being evaporated under reduced pressure with water pump.Its nucleus magnetic hydrogen spectrum diagram data detected is NMR:1H
NMR(CDC13；300MHz)δ8.62(2H,br s),2.95(4H,s),1.29(12H,s)；Therefore by above-mentioned nucleus magnetic hydrogen spectrum figure
The principle of data and reaction equation obtains above-mentioned product 2,2,6,6- tetramethyl morpholine chemical structural formula after analyzing jointly is
Reaction equation involved in step 2 are as follows:
The yield of above-mentioned product 2,2,6,6- tetramethyl morpholine is 75.5%.
Embodiment 2: a kind of preparation method of 2,2,6,6- tetramethyl morpholines, including operating procedure:
Step 1: the methanol containing 7.2% (V/V) liquefied ammonia that the 2- methyloxetane of 50g is slowly added dropwise to 100ml is molten
In agent, it is warming up to 40 DEG C and reacts 35 minutes, then decompression evaporates methanol under 50 DEG C, the vacuum condition of 0.09MPa.It then proceedes to
It is warming up to 71 DEG C, adjustment vacuum degree is 0.103MPa, and being evaporated under reduced pressure by-product, (structural formula of by-product is).It is finally evaporated under reduced pressure under conditions of 0.103MPa with oil pump at 71 DEG C, and obtains intermediate 49.5g,
It is according to the chemical structural formula that the data of nucleus magnetic hydrogen spectrum figure obtain above-mentioned intermediate
Step 2: the 49.5g intermediate that step 1 obtains is slowly added in the concentrated sulfuric acid of 120ml, it is warming up to 80 DEG C
Reaction 3.5 hours, is down to room temperature (25 DEG C)；Then the sodium hydrate aqueous solution tune pH to 11-11.5 of 3mol/L is added, then exists
100 DEG C, vacuum distillation processing is carried out with water pump under the vacuum condition of 0.09MPa, is then added the two of 120ml into fraction again
Chloromethanes extracts 12 times, and mutually merging anhydrous sodium sulfate is 6 hours dry for the methylene chloride being obtained by extraction, and filters out anhydrous slufuric acid
Sodium, and methylene chloride is fallen in decompression under 40 DEG C, the vacuum condition of 0.09MPa；Then under 50 DEG C, the vacuum condition of 0.1MPa again
It is secondary be evaporated under reduced pressure with water pump after obtain 2,2,6,6- tetramethyl morpholine 40.2g, the production of above-mentioned 2,2,6,6- tetramethyl morpholine of product
Rate is 80.5%.
Embodiment 3: a kind of preparation method of 2,2,6,6- tetramethyl morpholines, including operating procedure:
Step 1: the methanol containing 7.6% (V/V) liquefied ammonia that the 2- methyloxetane of 50g is slowly added dropwise to 110ml is molten
In agent, it is warming up to 50 DEG C and reacts 25 minutes, then decompression evaporates methanol under 70 DEG C, the vacuum condition of 0.1MPa.It then proceedes to
It is warming up to 80 DEG C, adjustment vacuum degree is 0.1MPa, and being evaporated under reduced pressure by-product, (structural formula of by-product is).It is finally evaporated under reduced pressure under conditions of 0.11MPa with oil pump at 75 DEG C, and obtains intermediate 50g, according to
The chemical structural formula that the data of nucleus magnetic hydrogen spectrum figure obtain above-mentioned intermediate is
Step 2: the 50g intermediate that step 1 obtains is slowly added in the concentrated sulfuric acid of 150ml, it is warming up to 85 DEG C instead
It answers 2 hours, is down to room temperature (20 DEG C)；Then the sodium hydrate aqueous solution tune pH to 11.5-12 of 3mol/L is added, then 80
DEG C, vacuum distillation processing is carried out with water pump under the vacuum condition of 0.09MPa, the dichloromethane of 150ml is then added into fraction again
Alkane extracts 15 times, and mutually merging anhydrous sodium sulfate is 6.5 hours dry for the methylene chloride being obtained by extraction, and filters out anhydrous sodium sulfate,
And methylene chloride is fallen in decompression under 45 DEG C, the vacuum condition of 0.1MPa；Then used again under 60 DEG C, the vacuum condition of 0.1MPa
2,2,6,6- tetramethyl morpholine 42g are obtained after water pump vacuum distillation, the yield of above-mentioned 2,2,6,6- tetramethyl morpholine of product is
84.6%.
Specific embodiment is only explanation of the invention, is not limitation of the present invention, those skilled in the art
It can according to need the modification that not creative contribution is made to the present embodiment after reading this specification, but as long as in this hair
All by the protection of Patent Law in bright scope of the claims.
Claims (9)
1. the preparation method of 2,2,6,6- tetramethyl morpholine of one kind, which is characterized in that including operating procedure:
Step 1: in the methanol solvate for the ammonia that the 2- methyloxetane of 2 equivalents is slowly added dropwise to 0.7-1 equivalent, heating
To 35-50 DEG C reaction 25-40 minutes, remove methanol, then vacuum distillation obtain intermediate；
Step 2: the intermediate that step 1 is obtained is slowly added in the concentrated sulfuric acid, 75-85 DEG C of reaction 2-4 hours is risen to, then
Sodium hydrate aqueous solution is added until reaction solution is in alkalescent, the fraction being evaporated under reduced pressure, which is adopted, to be extracted with dichloromethane, and is done
Dry, decompression evaporates methylene chloride, obtains after being then evaporated under reduced pressure under 30-60 DEG C, the vacuum condition of 0.8-0.1MPa with water pump
2,2,6,6- tetramethyl morpholine.
2. according to claim 1 a kind of 2, the preparation method of 2,6,6- tetramethyl morpholines, which is characterized in that in step 1
In, the structural formula of the intermediate are as follows:
3. according to claim 2 a kind of 2, the preparation method of 2,6,6- tetramethyl morpholines, which is characterized in that step 1
In, at 40-70 DEG C after reaction 25-40 minutes, decompression evaporates methanol under conditions of vacuum degree is 0.08-0.1MPa, then increases
For temperature to 70-80 DEG C, vacuum degree 0.1-0.11MPa, vacuum distillation obtains intermediate after falling by-product.
4. according to claim 3 a kind of 2, the preparation method of 2,6,6- tetramethyl morpholines, which is characterized in that the by-product
The structural formula of object are as follows:
5. according to claim 1 a kind of 2, the preparation method of 2,6,6- tetramethyl morpholines, which is characterized in that the step
Reaction equation involved in one are as follows:
6. according to claim 5 a kind of 2, the preparation method of 2,6,6- tetramethyl morpholines, which is characterized in that in step 2
In, the sodium hydrate aqueous solution tune pH to 10-12 of 3mol/L is added, then at 80-120 DEG C, vacuum degree is 0.08-0.1MPa's
Under the conditions of be evaporated under reduced pressure, to vacuum distillation after the methylene chloride of 100-150ml be added in obtained fraction extract 10-15 time, extract
The methylene chloride obtained is mutually dried using anhydrous sodium sulfate, is filtered out after anhydrous sodium sulfate at 30-45 DEG C, vacuum degree is
Decompression evaporates methylene chloride under conditions of 0.08-0.1MPa, obtains crude product, then at 45-60 DEG C, vacuum degree 0.1-
It is evaporated under reduced pressure under conditions of 0.11MPa with water pump, 2,2,6,6- tetramethyl morpholines can be obtained.
7. according to claim 1 a kind of 2, the preparation method of 2,6,6- tetramethyl morpholines, which is characterized in that the step
Reaction equation involved in two are as follows:
8. according to claim 1 a kind of 2, the preparation method of 2,6,6- tetramethyl morpholines, which is characterized in that in step 1
In, the methanol solution that the ammonia of 1.8-2.2ml is added is needed in the 2- methyloxetane of every 1g, in the methanol solution of the ammonia ammonia with
The molar ratio of methanol is 1:(2-2.5).
9. according to claim 1 a kind of 2, the preparation method of 2,6,6- tetramethyl morpholines, which is characterized in that in step 2
In, the concentrated sulfuric acid that 3.5-5ml is added is needed in the intermediate of every 1g.
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| CN101080411A (en) * | 2004-12-17 | 2007-11-28 | 伊莱利利公司 | Thiazolopyridinone derivates as MCH receptor antagonists |
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| CN104428295A (en) * | 2012-05-09 | 2015-03-18 | 卡尔约药物治疗公司 | Nuclear transport modulators and uses thereof |
| CN106478549A (en) * | 2016-09-30 | 2017-03-08 | 王显权 | The preparation method of morpholine |
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2019
- 2019-02-27 CN CN201910147673.2A patent/CN109928939A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101080411A (en) * | 2004-12-17 | 2007-11-28 | 伊莱利利公司 | Thiazolopyridinone derivates as MCH receptor antagonists |
| CN104428295A (en) * | 2012-05-09 | 2015-03-18 | 卡尔约药物治疗公司 | Nuclear transport modulators and uses thereof |
| FR3008625A1 (en) * | 2013-07-18 | 2015-01-23 | IFP Energies Nouvelles | PROCESS FOR REMOVING ACIDIC COMPOUNDS FROM A GASEOUS EFFLUENT WITH AN ABSORBENT SOLUTION BASED ON DIHYDROXYALKYLAMINES |
| CN106478549A (en) * | 2016-09-30 | 2017-03-08 | 王显权 | The preparation method of morpholine |
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Application publication date: 20190625 |