CN110204517A - A kind of preparation method of (S)-(2- oxo-tetrahydrofuran -3- base) carbamate - Google Patents
A kind of preparation method of (S)-(2- oxo-tetrahydrofuran -3- base) carbamate Download PDFInfo
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- CN110204517A CN110204517A CN201910628124.7A CN201910628124A CN110204517A CN 110204517 A CN110204517 A CN 110204517A CN 201910628124 A CN201910628124 A CN 201910628124A CN 110204517 A CN110204517 A CN 110204517A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
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Abstract
The invention discloses a kind of preparation methods of (S)-(2- oxo-tetrahydrofuran -3- base) urethanes, using L- homoserine and ethyl chloroformate as raw material, reaction is prepared compound (I), and compound (I) cyclization reaction occurs in the presence of acid, target compound (S)-(2- oxo-tetrahydrofuran -3- base) urethanes is prepared.The present invention solves the problems such as complex for operation step tediously long, reaction yield is low in the prior art, is a completely new synthetic route.
Description
Technical field
The present invention relates to the technical fields of pesticide intermediate synthesis, more particularly, are related to a kind of (S)-(2- oxo tetrahydro
Furans -3- base) urethanes preparation method.
Background technique
Glufosinate-ammonium is a kind of wide spectrum, low toxicity, non-selective herbicide, has two kinds of enantiomters of L-type and D type, L-
Type glufosinate-ammonium activity of weeding is twice or more of DL- type glufosinate-ammonium, and (S)-(2- oxo-tetrahydrofuran -3- base) urethane
Ester is a kind of important intermediate for synthesizing L-glufosinate-ammonium.
CN 106083922A patent report, with L-Methionine and alpha-halogenated carboxylic acids or derivatives thereof in phase transfer catalyst
Lower elder generation's cyclization obtains L- homoserine lactone halogenation hydrogen salt, recycles amido protecting agent to protect amino, two step yields are
88.2%, the reaction yield of this approach is lower, and pilot process needs to isolate L- homoserine lactone halogenation hydrogen salt to carry out down again
Single step reaction, step are relatively cumbersome.
109232644 A patent report of CN is raw material by single bromine substitution, amination and amido protecting using gamma-butyrolacton
Glufosinate-ammonium intermediate (S)-(2- oxo-tetrahydrofuran -3- base) urethanes is obtained, also belongs to actually and first obtains cyclization production
Object carries out the approach of amido protecting again, from gamma-butyrolacton, obtains title intermediate by 3 steps, the 1st, 2,3 yield is most
Excellent difference 88.7%, 70.6% and 90%, whole yield are 56.4%, and relatively relatively low, at the same time, each step has separation
Process, complex steps.
It is, thus, sought for a kind of operating procedure is simple and efficient (S)-(the 2- oxo-tetrahydrofuran-for having both high reaction yield
3- yl) urethanes synthetic route.
Summary of the invention
In order to solve the problems such as complex for operation step tediously long, reaction yield is low in the prior art, of the invention provides one
(S)-(2- oxo-tetrahydrofuran -3- base) is prepared through two-step reaction using L- homoserine and ethyl chloroformate as raw material in kind
One completely new synthetic route of carbamate:
(a) using L- homoserine and ethyl chloroformate as raw material, compound (I) is prepared in reaction；
(b) (S)-(2- oxo-tetrahydrofuran -3- base) urethanes is prepared through cyclization reaction in compound (I).
Step (a) reaction is that amido protecting reaction generates compound (I), and ethyl chloroformate is participated in as amido protecting agent
Reaction.There is HCl generation in amido protecting reaction process, alkali therefore, in step (a) reaction process is added as acid binding agent, thus
Reaction forward is promoted to carry out.
Step (b) reaction is that the cyclization of compound (I) generates the reaction of lactone, is to carry out in the presence of acid, sour deposits
Acidic environment appropriate is being provided to cyclization reaction.There is water generation in cyclization reaction process, therefore, step (b) reaction process
In be preferably added to water azeotropic can be deviate to carry out the solvent of reflux water-dividing, to promote cyclization reaction forward to carry out.Also, it walks
Suddenly the cyclization reaction in (b) is synchronous carry out with reflux water-dividing.
To achieve the goals above, the preparation side of (S)-(2- oxo-tetrahydrofuran -3- base) urethanes of the invention
The technology path of method is shown below:
In acid binding agent presence, amido protecting reaction is carried out to L- homoserine using ethyl chloroformate, chemical combination is prepared
Object (I).Compound (I) carries out cyclization in the acidic environment that acid provides and reacts to obtain (S)-(2- oxo-tetrahydrofuran -3- base)
Urethanes.
The molar ratio of abovementioned steps (a) reaction ethyl chloroformate and L- homoserine used is 1~3:1, chloro-carbonic acid second
Ester is at least 1eq, and dosage is then not sufficient to ensure that L- homoserine fully reacting lower than 1eq.Meanwhile inventor also found, chloromethane
When acetoacetic ester dosage is excessively high, has more side reaction and occur.
Abovementioned steps (a) reaction can be using organic base or inorganic base as acid binding agent, and the effect of acid binding agent is to neutralize
The HCl generated in amido protecting reaction process, so that reaction forward be promoted to carry out.The preferred inorganic base of acid binding agent, inorganic base are selected from
Alkali metal hydroxide, alkali carbonate, alkali metal hydrogencarbonate, alkaline earth metal hydroxide, alkaline earth metal carbonate, alkali
Earth metal bicarbonate, ammonium hydrogen carbonate, ammonium hydroxide.Inventor has carried out a large amount of screening to the type of alkali, the results show that sodium carbonate
It is preferable with potassium carbonate effect.
The molar ratio of abovementioned steps (a) acid binding agent that uses of reaction and L- homoserine is 0.5~10:1, preferably 1~3:
1, more preferable 1~1.5:1.Acid binding agent dosage is very few, is not enough to the HCl generated in neutralization procedure (a) reaction process, and acid binding agent is used
It measures excessive, not only causes the waste of material, but also cause the increase of brine waste and the increase of rear end wastewater treatment difficulty.
The solvent one that uses of abovementioned steps (a) reaction is water, and the mass ratio of solvent one and L- homoserine is >=5:1, excellent
Select 5~8:1.The purpose that solvent one is added is to dissolve L- homoserine, keeps homogeneous reaction system, promote intermolecular contact
And reaction.One dosage of solvent is too small, is not enough to provide solvent environment；Dosage is excessive, can bring to the reflux water-dividing of step (b)
It is difficult.
Abovementioned steps (b) reaction is that the cyclization of compound (I) is reacted, and is carried out in the presence of acid, the acid is nothing
Machine acid, preferably hydrochloric acid or sulfuric acid, more preferable hydrochloric acid.
The acid that abovementioned steps (b) reaction uses and the molar ratio of L- homoserine are 1~10:1, preferably 1~3:1, more excellent
Select 1~1.25:1.The participation of acid provides acidic environment appropriate to reaction system, and sour dosage is too small, is not sufficient to ensure that acidity
Environment, cyclization reaction cannot carry out completely, and product yield is caused to reduce.Meanwhile inventor also found, when sour dosage is excessive,
It is unfavorable for the progress of reaction instead, product yield reduces.
The solvent that abovementioned steps (b) reaction process uses is any one of dichloroethanes, toluene, dimethylbenzene and trimethylbenzene
Or more than one, preferred dichloroethanes, more preferable 1,2- dichloroethanes.There is water generation in step (b) reaction process, water will cause
The reduction of acid concentration destroys the acidic environment of reaction system, be preferably added to it is a kind of can reflux water-dividing solvent, cyclization react into
Reflux water-dividing is carried out while row, to effectively keep the acidic environment of reaction system, promotes cyclization reaction.
Further, mass ratio >=5:1 of aforementioned solvents two and L- homoserine, preferably 5~10:1, more preferable 6:1.It is molten
Agent two is used as reflux water-dividing solvent, and dosage is too small, divides water low efficiency；Dosage is excessive, then causes unnecessary waste.
The temperature of abovementioned steps (b) cyclization reaction is 80~150 DEG C, preferably 90~120 DEG C, more preferable 100~110 DEG C.
Preferred temperature carry out cyclization reaction can synchronous with reflux water-dividing, if temperature is too low, water-separating time is longer, and divides water effect not
It is good, cyclization reaction forward cannot be promoted to carry out；Reaction temperature is excessively high, will cause some side reactions and increases.
Specific embodiment as one preferred, abovementioned steps (a) reaction and step (b) reaction can use one kettle way
It carries out, i.e. first step reaction is not post-treated, and two-step reaction successively carries out in same reaction unit.One kettle way does not produce centre
Compounds (I) are separated and are purified, and a large amount of cumbersome interminable processing steps are saved.Aforementioned one kettle way prepares (S)-(2-
Oxo-tetrahydrofuran -3- base) carbamate includes the following steps:
(1) L- homoserine and solvent one are added in mass ratio into reaction flask, stirs evenly, under the conditions of 25 DEG C, presses
Acid binding agent is added in proportion, stirs 20~50min；
(2) ethyl chloroformate is added dropwise according to the ratio, controls reacting liquid temperature at 25~30 DEG C, is added dropwise to complete subsequent continuation of insurance temperature and stirs
2~6h is mixed, the first solution is obtained；
(3) acid is added according to the ratio into the first solution, in mass ratio addition solvent two, obtains the second solution；
(4) if solvent two is 1,2- dichloroethanes, the second solution is warming up to 110 DEG C, reflux water-dividing promotes cyclization anti-
Answer, cyclization react with divide water process synchronize synchronize ends, subsequent filtering obtains (S)-(2- oxo-tetrahydrofuran -3- base) ammonia
Two solution of solvent of carbamate, decompression desolventizing two is up to target product.
In conclusion the present invention provides a kind of pesticide intermediate (S)-(2- oxo-tetrahydrofuran -3- base) carbamate
Preparation method, this method uses L- homoserine and ethyl chloroformate for raw material, carries out amido protecting in acid binding agent presence
Reaction；Cyclization reaction is carried out in the presence of acid, reflux water-dividing mode is used during cyclization, and cyclization forward direction is promoted to carry out.
The one kettle way that amido protecting reaction and cyclization reaction use carries out.
Compared with prior art, new technology route of the invention solves complex for operation step tediously long, anti-in the prior art
The problems such as answering yield low is a completely new synthetic route, and operating procedure is simple, and has high reaction yield.Also, this hair
Bright new technology route can also be carried out using one kettle way, the separation and purification to intermediate product be avoided, to effectively prevent
The use of all kinds of separating-purifying solvents, substantially saves time, material and energy consumption, which sufficiently combines two-step reaction
Own characteristic simplifies operating procedure, to improve efficiency.
Specific embodiment
Below with reference to embodiment, the present invention is further illustrated.
Embodiment 1
40g (0.336mol, 1eq) L- homoserine and 120g water are added into 500mL reaction flask, after mixing evenly in room
It is slowly added to 35.6g (0.336mol, 1eq) sodium carbonate under the conditions of temperature, continues to stir 30min, 47.4g is slowly added dropwise
(0.437mol, 1.3eq) ethyl chloroformate is added dropwise 25~30 DEG C of process temperature control, rear insulated and stirred 4h is added dropwise, reaction terminates
Afterwards, concentrated hydrochloric acid 34g (0.34mol, 1eq, concentration 36.5%) is added under room temperature, adds 250g 1,2- dichloroethanes rises
Temperature is down to room temperature to reflux water-dividing is carried out at 110 DEG C after dividing water, reaction solution filters to get (S)-(2- oxo tetrahydro furan
Mutter -3- base) urethanes/1,2- dichloroethane solution, detects in the solution (S)-(2- oxo four using HPLC external standard method
Hydrogen furans -3- base) urethanes absolute content, (S)-(2- oxo-tetrahydrofuran -3- is calculated according to the weight of filtrate
Base) urethanes absolute yield be 95%.
Embodiment 2
40g (0.336mol, 1eq) L- homoserine and 120g water are added into 500mL reaction flask, after mixing evenly in room
It is slowly added to 35.6g (0.336mol, 1eq) sodium carbonate under the conditions of temperature, continues to stir 30min, 47.4g is slowly added dropwise
(0.437mol, 1.3eq) ethyl chloroformate is added dropwise 25~30 DEG C of process temperature control, rear insulated and stirred 4h is added dropwise, reaction terminates
Afterwards, concentrated hydrochloric acid 42.5g (0.425mol, 1.25eq, concentration 36.5%) is added under room temperature, adds 250g 1,2- dichloro
Ethane is warming up at 110 DEG C and carries out reflux water-dividing, and room temperature is down to after dividing water, and reaction solution filters to get (S)-(2- oxo
Tetrahydrofuran -3- base) urethanes/1,2- dichloroethane solution, detects in the solution (S)-(2- using HPLC external standard method
Oxo-tetrahydrofuran -3- base) urethanes absolute content, (S)-(2- oxo tetrahydro is calculated according to the weight of filtrate
Furans -3- base) urethanes absolute yield be 94%.
Embodiment 3
40g (0.336mol, 1eq) L- homoserine and 120g water are added into 500mL reaction flask, after mixing evenly in room
It is slowly added to 35.6g (0.336mol, 1eq) sodium carbonate under the conditions of temperature, continues to stir 30min, 47.4g is slowly added dropwise
(0.437mol, 1.3eq) ethyl chloroformate is added dropwise 25~30 DEG C of process temperature control, rear insulated and stirred 4h is added dropwise, reaction terminates
Afterwards, concentrated hydrochloric acid 85g (0.85mol, 1eq, concentration 36.5%) is added under room temperature, adds 250g 1,2- dichloroethanes rises
Temperature is down to room temperature to reflux water-dividing is carried out at 110 DEG C after dividing water, reaction solution filters to get (S)-(2- oxo tetrahydro furan
Mutter -3- base) urethanes/1,2- dichloroethane solution, detects in the solution (S)-(2- oxo four using HPLC external standard method
Hydrogen furans -3- base) urethanes absolute content, (S)-(2- oxo-tetrahydrofuran -3- is calculated according to the weight of filtrate
Base) urethanes absolute yield be 90%.
The type and dosage of 4 acid binding agent of embodiment are screened
In four mouthfuls of reaction flasks of 500mL be added L- homoserine aqueous solution (homoserine containing L- 40g, 0.336mol,
1eq), be stirred at room temperature under state, be added acid binding agent after mixing evenly, under the conditions of room temperature water-bath be added dropwise ethyl chloroformate (48g,
0.44mol, 1.3eq), it is 20~30 DEG C that process control reaction temperature, which is added dropwise, and it is anti-to continue stirring after being added dropwise under room temperature
4h is answered, the HPLC content of L- homoserine in sample detection reaction solution.Result such as the following table 1 of type and the dosage screening of acid binding agent
It is shown.
Table 1
The invention is not limited to specific embodiments above-mentioned.The present invention, which expands to, any in the present specification to be disclosed
New feature or any new combination, and disclose any new method or process the step of or any new combination.
Claims (11)
1. a kind of preparation method of (S)-(2- oxo-tetrahydrofuran -3- base) urethanes, it is characterised in that:
(a) using L- homoserine and ethyl chloroformate as raw material, compound (I) is prepared in reaction；
(b) (S)-(2- oxo-tetrahydrofuran -3- base) urethanes is prepared through cyclization reaction in compound (I).
2. preparation method according to claim 1, which is characterized in that the step (a) carries out in the presence of acid binding agent,
The acid binding agent is selected from organic base or inorganic base, preferably inorganic base；The inorganic base preferred alkali metal hydroxide, alkali metal carbon
Hydrochlorate, alkali metal hydrogencarbonate, alkaline earth metal hydroxide, alkaline earth metal carbonate, alkali metal bicarbonates, ammonium hydrogen carbonate
Or ammonium hydroxide, more preferable sodium carbonate or potassium carbonate.
3. preparation method according to claim 2, which is characterized in that the molar ratio of the acid binding agent and L- homoserine is
0.5~10:1, preferably 1~3:1, more preferable 1~1.5:1.
4. preparation method according to claim 1-3, which is characterized in that the reaction dissolvent of the step (a) is
Water.
5. preparation method according to claim 1, which is characterized in that the reaction temperature of the step (a) is 0~100 DEG C,
It is preferred that 20~50 DEG C, more preferable 25~30 DEG C.
6. preparation method according to claim 1, which is characterized in that the step (b) carries out in the presence of acid；It is described
The preferred inorganic acid of acid, more preferable hydrochloric acid or sulfuric acid.
7. preparation method according to claim 6, which is characterized in that the acid and the molar ratio of L- homoserine be 1~
10:1, preferably 1~3:1, more preferable 1~1.25:1.
8. preparation method according to claim 1, which is characterized in that the reaction dissolvent of the step (b) be dichloroethanes,
Any one of toluene, dimethylbenzene and trimethylbenzene or more than one, preferred dichloroethanes, more preferable 1,2- dichloroethanes.
9. preparation method according to claim 1, which is characterized in that the step (b) further includes the steps that reflux water-dividing.
10. preparation method according to claim 1, which is characterized in that the temperature of the step (b) is 80~150 DEG C, excellent
Select 90~120 DEG C, more preferable 100~110 DEG C.
11. -10 described in any item preparation methods according to claim 1, which is characterized in that the step (a) and step (b) one
Pot is carried out continuously.
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