CN110041294A - The synthetic method and its application of the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide - Google Patents
The synthetic method and its application of the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide Download PDFInfo
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
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Abstract
The invention discloses one kind 2; the synthetic method and its application of the chloro- N- of 2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide; synthetic method therein is that acylation reaction occurs under alkaline condition with dichloroacetyl chloride and is made using α-(amino methyl) -2- furancarbinol as raw material.Synthetic method provided by the present invention is easy to operate, process is easily controllable, gained 2, and the yield of the chloro- N- of 2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide is 60~80%, it can be used as standard items, for detecting and monitoring the synthesis of furilazole.
Description
Technical field
The invention belongs to pharmaceutical fields, are related to the synthesis and application of a kind of pesticide impurities, specifically, being that 2,2- bis- is chloro-
A kind of N- [2- (2- furyl) -2- hydroxyethyl] synthetic method of acetamide and the application of corresponding synthetic product.
Background technique
In the production process of drug, it is often accompanied by the generation of impurity, the yield of product is not only will affect, also will affect medicine
The quality of product, and then influence the effect that drug uses.The generation of impurity during effective monitoring pharmaceutical synthesis produces guarantee
The influence of quality, yield and reduction impurity to drug effectiveness plays a key role.
Furilazole (Furilazole), chemical name are as follows: 3- dichloro-acetyl -5- (2- furans) -2,2- dimethyl oxazoline
Alkane, sterling are white crystal, molecular formula: C11H13Cl2NO3, molecular weight: 278.13.Structural formula is as follows:
Furilazole is a kind of novel herbicidal safener, it is used for gramineous crop in which can make many herbicide safeties, right
It reduces the phyto toxicity as caused by sulfonylurea herbicide and plays useful effect, most prominent feature is can be successfully as one
Serial sulfonylurea herbicide and imidazolinone herbicide use safener in the field of gramineous crop, without influencing to miscellaneous
The preventive effect of grass.
And furilazole can be synthesized using following synthetic route in industrial production at present:
During being synthesized with said synthesis route, discovery final step generation has impurity 2, the chloro- N- [2- of 2- bis-
(2- furyl) -2- hydroxyethyl] acetamide.The chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] second of above-mentioned generation
Amide will have a direct impact on the synthesis yield of furilazole, not avoid generation 2, chloro- N- [2- (the 2- furan of 2- bis- in the prior art
Mutter base) -2- hydroxyethyl] acetamide effective measures, also have no idea to detect this impurity in the product, therefore solve
Careless oxazole cannot be protected to the drug effect of weeds.
Summary of the invention
The technical problem to be solved in the present invention is to provide for the chloro- N- of 2,2- of one kind bis- [2- (2- furyl) -2- hydroxyl second
Base] acetamide synthetic method, be intended to using α-(amino methyl) -2- furancarbinol as raw material, under alkaline condition with dichloroacetyl
Chlorine occurs acylation reaction and is made.
Another object of the present invention is to provide the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide
A kind of application, it can be used as standard items, for detecting and monitoring the synthesis of furilazole.
In order to solve the above technical problems, the technical scheme adopted by the invention is that: 2,2- of one kind, bis- chloro- N- [2- (2- furans
Base) -2- hydroxyethyl] acetamide synthetic method, be by α-(amino methyl) -2- furancarbinol and dichloroacetyl chloride in alkalinity
Under the conditions of occur acylation reaction be made.
As limitation of the invention: the conjunction of the chloro- N- of the 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide
At route are as follows:
It is limited as to another kind of the invention, the acylation reaction sequentially carries out in accordance with the following steps:
1. α-(amino methyl) -2- furancarbinol is added in solvent A, dissolves, obtain solution B；
2. acid binding agent is mixed with solution B, solution C is obtained, dichloroacetyl chloride is added dropwise after stirring a period of time and solution C is anti-
It answers, obtains solution D after the reaction was completed；
3. solution D is quenched with water, it is extracted with ethyl acetate, continues to be washed with water organic phase to neutrality, concentration later is
Obtain the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide crude product.
As limitation of the invention further: 3. 4. the step is additionally provided with step afterwards, it may be assumed that
4. tied using solvent E to the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide crude product again
Crystalline substance dries after suction filtration, obtains the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide.
As the limiting 1. to step: the solvent A is in acetonitrile, ethyl acetate, benzene, toluene, methylene chloride, chloroform
It is a kind of.
As the restriction to step 2.:
The acid binding agent is any one in ammonium hydroxide, triethylamine, pyridine, potassium carbonate, sodium hydroxide or potassium hydroxide, institute
The equivalent proportion for stating acid binding agent and α-(amino methyl) -2- furancarbinol is 1~3:1；
Step 2. in, the equivalent proportion of the dichloroacetyl chloride and α-(amino methyl) -2- furancarbinol is 1~3:1；
Step 2. in, the acid binding agent is blended at a temperature of -15~25 DEG C with solution B and mixes.
As to further restriction of the invention: step 4. in, the solvent E be crystalline reagents methylene chloride, chlorine
One of the mixed liquor or the aqueous solution of methanol of imitative, benzene, toluene, ethyl acetate and petroleum ether.
The present invention also provides the application of the chloro- N- of 2,2- of one kind bis- [2- (2- furyl) -2- hydroxyethyl] acetamide, institutes
The chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide is stated as standard items, to detect and monitor furilazole
Synthesis.
By adopting the above-described technical solution, compared with prior art, the present invention acquired technological progress is: this hair
The synthetic method of bright offer is to be acylated under alkaline condition with α-(amino methyl) -2- furancarbinol with dichloroacetyl chloride
Reaction is prepared the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide, separation, side is not had in reaction process
Method is simple, and process is easily controllable, gained 2, and the yield of the chloro- N- of 2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide is 60
~80%；As a kind of application of the synthesized chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide, it can
It is used to detect and monitor the synthesis of furilazole as standard items.
The present invention is described in further detail below in conjunction with specific embodiment.
Detailed description of the invention
Fig. 1 is the chloro- N- of 2,2- bis- [2- (2- the furyl) -2- hydroxyethyl] acetyl synthesized in 1-7 of the embodiment of the present invention
The MS of amine schemes；
Fig. 2 is the chloro- N- of 2,2- bis- [2- (2- the furyl) -2- hydroxyethyl] acetamide synthesized in inventive embodiments 1-7
's1HNMR figure；
Fig. 3 is the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide in 1-7 of the embodiment of the present invention13CNMR figure；
Fig. 4 is the DSC of the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide in 1-7 of the embodiment of the present invention
Figure；
Fig. 5 is α-(nitromethyla) -2- furancarbinol in 1-7 of the embodiment of the present invention1HNMR figure；
Fig. 6 is α-(amino methyl) -2- furancarbinol in 1-7 of the embodiment of the present invention1HNMR figure；
Fig. 7 is the liquid phase figure of furilazole standard items in the embodiment of the present invention 8；
Fig. 8 is the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide standard items in the embodiment of the present invention 8
Liquid phase figure；
Fig. 9 is that the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyl second in furilazole is monitored in the embodiment of the present invention 8
Base] acetamide generate liquid phase figure；
Figure 10 is that the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyl in furilazole sterling Q is monitored in the embodiment of the present invention 8
Base ethyl] acetamide generate liquid phase figure；
Figure 11 is that the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyl in furilazole crude product P is monitored in the embodiment of the present invention 8
Base ethyl] acetamide generate liquid phase figure；
Figure 12 is bis- chloro- N- [2- (2- of 2,2- in the furilazole obtained under -15 DEG C of reaction conditions in the embodiment of the present invention 9
Furyl) -2- hydroxyethyl] acetamide generate liquid phase figure；
Figure 13 is chloro- N- [2- (the 2- furan of 2,2- bis- in the furilazole obtained under 0 DEG C of reaction condition in the embodiment of the present invention 9
Mutter base) -2- hydroxyethyl] the liquid phase figure that generates of acetamide；
Figure 14 is bis- chloro- N- [2- (2- of 2,2- in the furilazole obtained under 15 DEG C of reaction conditions in the embodiment of the present invention 9
Furyl) -2- hydroxyethyl] acetamide generate liquid phase figure.
Specific embodiment
The synthetic method of chloro- N- [2- (2- the furyl) -2- hydroxyethyl] acetamide of 1 2,2- of embodiment bis-
Synthetic method provided by the present embodiment, sequence carries out according to the following steps:
(1) preparation of raw material α-(amino methyl) -2- furancarbinol
Using 2 furan carboxyaldehyde as starting material, by condensation reaction, reduction reaction, α-(amino methyl) -2- furans is synthesized
Methanol, specific synthetic route are as follows:
Synthesis, α-(amino methyl) -2- furans of α-(nitromethyla) -2- furancarbinol are contained in said synthesis route
Synthesis to above two substance is illustrated by the synthesis of methanol, the present embodiment respectively.
The synthesis of α-(nitromethyla) -2- furancarbinol: 2 furan carboxyaldehyde 49.96g (i.e. 0.52mol), nitromethane are taken
158.70g (i.e. 2.6mol), barium hydroxide 8.57g (i.e. 0.05mol), water 500mL react 4h, after the reaction was completed, mistake at 25 DEG C
Barium hydroxide is filtered, ethyl acetate extracts reaction solution, is concentrated after dry organic phase, obtains α-(nitromethyla) -2- furancarbinol；Institute
Synthetic1HNMR figure is as shown in Figure 5.
The synthesis of α-(amino methyl) -2- furancarbinol: α-(nitromethyla) -2- furancarbinol is added in autoclave
81.37g (i.e. 0.64mol), isopropanol 500mL, 5%Pd/C 5g are (according to the 5% of α-(nitromethyla) -2- furancarbinol quality
It calculates), N is used by decompression water pump after sealing2Displacement three times, is passed through the hydrogen that purity is 99.999% and replaces three times, then plus
It is depressed into 10kg/cm3, 12h is reacted at 40 DEG C, and after the reaction was completed, Pd/C is filtered and recycled in slow pressure release, and filtrate is concentrated, uses acetic acid
Ethyl ester recrystallizes up to α-(amino methyl) -2- furancarbinol, yield 78.9%；Synthesized substance1HNMR schemes such as Fig. 6 institute
Show.
(2) acylation reaction
The reaction route of this step is as follows:
This step is successively carried out according to four substep (21)~(24):
(21) 10mL chloroform (solvent A 1) is taken, α-(the amino methyl) -2- furans of 9.90g (i.e. 0.078mol) is then added
Methanol is warming up to 30~35 DEG C of dissolutions and obtains solution B 1 under stirring；
(22) solution B 1 is cooled to 0 DEG C, the sodium hydrate aqueous solution that 2.09mL concentration is 33% is added, and (sodium hydroxide has
Effect ingredient is 6.90g, that is, 0.173mol), solution C 1 is obtained after stirring 10min, then by two chloroethene of 15.06g (i.e. 0.10mol)
Acyl chlorides is added drop-wise in solution C 1, continues to react at a temperature of 0 DEG C to complete, obtained solution D1 after being added dropwise；
(23) after the reaction was completed, solution D 1 is quenched with water, then successively carries out ethyl acetate extraction, washing, dense
Contracting is to get the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide solid crude product；
(24) above-mentioned crude product is recrystallized using methylene chloride, and dried after filtering to get the chloro- N- [2- of 2,2- bis-
(2- furyl) -2- hydroxyethyl] acetamide, the MS figure of synthetic,1HNMR、13CNMR figure, DSC figure see respectively as Fig. 1~
Fig. 4.
The synthetic method of the chloro- N- of embodiment 2-7 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide
Embodiment 2-7 is respectively the synthesis side of a kind of chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide
The synthetic method difference of method, they and embodiment 1 is essentially identical, the difference is that only in following table between listed procedure parameter not
Together, the amount of substance is in addition generated also different (being not shown in table).
Table 1
The application of chloro- N- [2- (2- the furyl) -2- hydroxyethyl] acetamide of 8 2,2- of embodiment bis-
(1) firstly, under -15~15 DEG C of temperature environment, furilazole is synthesized with following synthetic route:
The furilazole crude product of synthesis is denoted as P.P is purified by ethyl alcohol recrystallization, is obtained sterling furilazole, is denoted as Q.
(2) then, with the chloro- N- of 2,2- bis- prepared by embodiment 1-7 [2- (2- furyl) -2- hydroxyethyl] acetyl
Amine is disliked as standard reference material by the comparison chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide reconciliation grass
It whether there is 2,2- bis- during synthesis furilazole involved in the liquid phase figure detecting step (one) of azoles and in final product
Chloro- N- [2- (2- furyl) -2- hydroxyethyl] acetamide and contained amount are how many, realize to furilazole synthesis process
Monitoring.
The monitoring process of furilazole are as follows: precision weighs furilazole mark product 0.015g (being accurate to 0.001g), is dissolved in
In methanol, shake up；It is (accurate that precision weighs the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide mark product 0.015g
It to 0.001g), is dissolved in methanol, shakes up.Under the chromatographic condition set: mobile phase as methanol-water (volume ratio 75:
35), flow velocity 1.0mL/min, column temperature are set as 30 DEG C, sample volume 0.025mL, Detection wavelength 218nm.Respectively to solution grass
Oxazole mark product and 2, the chloro- N- of 2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide mark product are detected, furilazole mark product
Retention time be 4.730min, purity 99.850%；The chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide
The retention time of mark product is 3.030min, purity 99.755%.
Under identical chromatographic conditions, furilazole crude product P is detected, the peak that retention time is 4.730min is solution grass
Oxazole, content 89.463%；The peak that retention time is 3.030min is the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyl second
Base] acetamide, content 10.537% is shown in Fig. 9.
The application of chloro- N- [2- (2- the furyl) -2- hydroxyethyl] acetamide of 9 2,2- of example bis-
With under identical high-efficient liquid phase chromatogram condition in example 8, in example 8 recrystallize after furilazole sterling Q into
Row detection, the peak that retention time is 4.730min is furilazole, content 99.985%；Retention time is the peak of 3.030min
For the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide, content 0.015% is shown in Figure 10.
The application of chloro- N- [2- (2- the furyl) -2- hydroxyethyl] acetamide of 10 2,2- of example bis-
With under identical high-efficient liquid phase chromatogram condition in example 8, to the furilazole crude product P not recrystallized in example 8
It is detected, the peak that retention time is 4.730min is furilazole, content 79.865%；Retention time is 3.030min's
Peak is the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide, and content 20.135% is shown in Figure 11.
The application of chloro- N- [2- (2- the furyl) -2- hydroxyethyl] acetamide of 11 2,2- of example bis-
It, can be by the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetyl during synthesizing furilazole
Amine is used as the generation situation that standard items detected and monitored this impurity, this is significant to the improvement of reaction condition.
In the case where other conditions are constant, change reaction temperature, synthesizes solution under the conditions of -15 DEG C, 0 DEG C, 15 DEG C respectively
Careless oxazole crude product, specific operating method is identical as example 8, detects to obtained furilazole crude product P1, P2, P3.
Efficient liquid-phase chromatography method and example 8 are consistent.Testing result is as follows:
In the furilazole crude product P1 liquid phase figure reacted at -15 DEG C, the peak of retention time 4.730min is solution grass
Oxazole, content 94.038%；The peak of retention time 3.030min is the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyl second
Base] acetamide, content 5.962% is shown in Figure 12；
In the furilazole crude product P2 liquid phase figure reacted at 0 DEG C, the peak of retention time 4.730min is that solution grass is disliked
Azoles, content 85.457%；The peak of retention time 3.030min is the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl]
Acetamide, content 14.543%, is shown in Figure 13；
In the furilazole crude product P3 liquid phase figure reacted at 15 DEG C, the peak of retention time 4.730min is that solution grass is disliked
Azoles, content 69.998%；The peak of retention time 3.030min is the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl]
Acetamide, content 30.002%, is shown in Figure 14.
According to above-mentioned liquid phase result it is found that being reacted at -15 DEG C in resulting furilazole crude product P1, furilazole contains
Highest is measured, the content of 2,2- bis- chloro- N- [2- (2- furyl) -2- hydroxyethyl] acetamides is minimum, so in three temperature strips
Under part, -15 DEG C are optimal reaction temperature.
Therefore, by furilazole crude product P1, P2, the P3 obtained under different condition, in identical high performance liquid chromatography
Under the conditions of carry out furilazole and 2, the detection of the chloro- N- of 2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide can filter out
The content of optimal reaction condition, the i.e. chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide is lower, solves grass and dislikes
The yield of azoles is higher, then reaction condition is better.
Embodiment 1-11, is only presently preferred embodiments of the present invention, is not the restriction of other forms made for the present invention,
Any person skilled in the art cannot be changed or be modified as equivalent variations using above-mentioned technology contents as enlightenment
Equivalent embodiment, but all technical spirits without departing from the claims in the present invention simply repair to made by above embodiments
Change, equivalent variations and remodeling, still falls within the range of the claims in the present invention protection.
Claims (10)
1. one kind 2, the synthetic method of the chloro- N- of 2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide, it is characterised in that: be
Acylation reaction is occurred under alkaline condition for α-(amino methyl) -2- furancarbinol and dichloroacetyl chloride to be made.
The synthesis side of the chloro- N- of 2,2- bis- according to claim 1 2. [2- (2- furyl) -2- hydroxyethyl] acetamide
Method, it is characterised in that:
The synthetic line of the chloro- N- of the 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide are as follows:
The synthesis of the chloro- N- of 2,2- bis- according to claim 1 or 2 3. [2- (2- furyl) -2- hydroxyethyl] acetamide
Method, it is characterised in that: the acylation reaction sequentially carries out in accordance with the following steps:
1. α-(amino methyl) -2- furancarbinol is added in solvent A, dissolves, obtain solution B；
2. acid binding agent is mixed with solution B, solution C is obtained, is stirred, dichloroacetyl chloride is added dropwise, obtains solution D after the reaction was completed；
3. solution D is quenched with water, it is extracted with ethyl acetate, continues to be washed with water organic phase to neutrality, up to 2,2- after concentration
Two chloro- N- [2- (2- furyl) -2- hydroxyethyl] acetamide crude products.
The synthesis side of the chloro- N- of 2,2- bis- according to claim 3 4. [2- (2- furyl) -2- hydroxyethyl] acetamide
Method, it is characterised in that: the 3. 4. step is additionally provided with step afterwards, it may be assumed that
4. being recrystallized using solvent E to the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide crude product, take out
It is dried after filter, obtains the chloro- N- of 2,2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide.
The synthesis side of the chloro- N- of 2,2- bis- according to claim 3 5. [2- (2- furyl) -2- hydroxyethyl] acetamide
Method, it is characterised in that: step 1. in, the solvent A be acetonitrile, ethyl acetate, benzene, toluene, methylene chloride or chloroform in one
Kind.
The synthesis side of the chloro- N- of 2,2- bis- according to claim 3 6. [2- (2- furyl) -2- hydroxyethyl] acetamide
Method, it is characterised in that: step 2. in, the acid binding agent be ammonium hydroxide, triethylamine, pyridine, potassium carbonate, sodium hydroxide or potassium hydroxide
In any one, the equivalent proportion of the acid binding agent and α-(amino methyl) -2- furancarbinol is 1~3:1.
The synthesis side of the chloro- N- of 2,2- bis- according to claim 3 7. [2- (2- furyl) -2- hydroxyethyl] acetamide
Method, it is characterised in that: step 2. in, the equivalent proportion of the dichloroacetyl chloride and α-(amino methyl) -2- furancarbinol is 1~3:
1。
The synthesis side of the chloro- N- of 2,2- bis- according to claim 3 8. [2- (2- furyl) -2- hydroxyethyl] acetamide
Method, it is characterised in that: step 2. in, the acid binding agent and solution B -15~25 DEG C at a temperature of mix.
The synthesis side of the chloro- N- of 2,2- bis- according to claim 4 9. [2- (2- furyl) -2- hydroxyethyl] acetamide
Method, it is characterised in that: step 4. in, the solvent E be crystalline reagents methylene chloride, chloroform, benzene, toluene, ethyl acetate and stone
One of mixed liquor or the aqueous solution of methanol of oily ether.
A kind of application of 10.2,2- bis- chloro- N- [2- (2- furyl) -2- hydroxyethyl] acetamides, it is characterised in that: described 2,
The chloro- N- of 2- bis- [2- (2- furyl) -2- hydroxyethyl] acetamide is used as standard items, to detect and monitor the conjunction of furilazole
At.
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| CN114989115A (en) * | 2022-07-01 | 2022-09-02 | 河北科技大学 | Improved synthesis of alpha- (nitromethyl) -2-furancarbinols and method for maintaining catalyst activity in such a process |
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| CN114989115A (en) * | 2022-07-01 | 2022-09-02 | 河北科技大学 | Improved synthesis of alpha- (nitromethyl) -2-furancarbinols and method for maintaining catalyst activity in such a process |
| CN114989115B (en) * | 2022-07-01 | 2024-04-30 | 兰升生物科技集团股份有限公司 | Improved synthesis of alpha- (nitromethyl) -2-furanmethanol and method for maintaining catalyst activity in the process |
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