Process for preparation of uracil bromide derivatives
The uracil derivatives brominated by reaction of uracil derivatives with hydrobromic acid and hydrogen peroxide solve the problems of using bromine to humans and the environment and the generation of by-products in the existing methods, and achieve a safe, environmentally friendly and economical preparation process.
Patent Information
- Application Number
- CN202380065488.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2022-09-20
- Filing Date
- 2023-09-20
- Publication Date
- 2025-04-22
AI Technical Summary
Existing methods for the preparation of uracil brominated derivatives have problems with the use of bromine to pose a threat to humans and the environment, difficulty in handling and transporting bromine, and the generation of by-products caused by excessive bromination.
The preparation of the uracil derivative of formula II is achieved by reacting the uracil derivative with hydrobromic acid and then adding hydrogen peroxide to the reaction mixture, avoiding the direct use of bromine and reducing the generation of by-products.
This method is safe and environmentally friendly, reducing the generation of by-products, improving the safety and economic benefits of the process, and avoiding the difficulty of dealing with hazardous chemicals.
Smart Images
Figure CN119866331A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to a process for preparing a brominated uracil derivative having the formula I from a uracil derivative having the formula II, wherein R1, R2 and R3 are independently selected from H and a branched or unbranched alkyl group having C1-C7. Background Art
[0002] Bromouracil-based compounds such as bromacil are known to provide effective herbicidal activity as non-selective broad-spectrum herbicides, which are mainly used as bare ground herbicides or for industrial vegetation management. These compounds are well known for providing excellent selective weed control on many crops such as citrus fruits and pineapples and for controlling various types of perennial grasses.
[0003] Although many methods for preparing brominated uracil derivatives have been reported so far, conventional bromination reactions are plagued by many disadvantages, such as: (i) bromine is directly used as one of the reactants, which poses health hazards to humans and environmental problems; (ii) bromine is difficult to handle and transport on a commercial scale; and (iii) additional by-products, such as dibrominated products, are generated due to excessive bromination of brominated uracil derivatives. Conventional methods for preparing brominated uracil derivatives are schematically represented as follows:
[0004] Other known methods for preparing brominated uracil derivatives are also not completely satisfactory with respect to the above problems (and other problems). Therefore, there is a need for a new and improved method for preparing brominated uracil derivatives that can overcome one or more problems associated with conventional methods. The present invention meets existing needs as well as other needs and generally overcomes the deficiencies found in the prior art. Purpose
[0005] A primary object of the present invention is to provide a new and improved process that may overcome one or more limitations associated with conventional processes for preparing brominated uracil derivatives.
[0006] The object of the present disclosure is to provide an improved process for preparing brominated uracil derivatives which avoids the direct use of bromine.
[0007] It is also an object of the present disclosure to provide an improved process for preparing brominated uracil derivatives that reduces the amount of by-products produced during the reaction.
[0008] Another object of the present disclosure is to provide a safe and environmentally friendly method for preparing brominated uracil derivatives.
[0009] Another object of the present disclosure is to provide a process for the preparation of brominated uracil derivatives which is easy to follow, economical and industrially applicable. Summary of the invention
[0010] The present invention relates to a process for preparing brominated uracil derivatives of formula I from uracil derivatives of formula II.
[0011] The present disclosure is based on the unexpected discovery of the present inventors that the reaction of uracil derivatives with hydrobromic acid and hydrogen peroxide provides the production of the desired monobrominated uracil derivatives, thereby eliminating or at least substantially reducing the formation of additional byproducts (such as dibrominated uracil derivatives). Without wishing to be bound by theory, it is believed that the reaction of uracil derivatives with hydrobromic acid and hydrogen peroxide provides the in-situ generation of Br, which in turn affects the controlled bromination of uracil derivatives, and its seemingly reasonable reaction mechanism is schematically represented below:
[0012] Thus, one aspect of the present disclosure relates to a method for preparing a brominated uracil derivative having formula I, wherein R1, R2 and R3 are independently selected from H and branched or unbranched alkyl groups having C1-C7, The method comprises the following steps: (a) reacting a uracil derivative having the formula II with hydrobromic acid, wherein R1, R2 and R3 are as defined above; and (b) adding hydrogen peroxide to the reaction mixture from step (a) to obtain the brominated uracil derivative having formula I.
[0013] Other aspects, advantages, and salient features of the invention will become apparent to those skilled in the art from the following detailed description taken in conjunction with exemplary embodiments of the invention. DETAILED DESCRIPTION
[0014] The following are specific embodiments of embodiments of the present invention. These embodiments are so detailed that the present invention is clearly conveyed. However, the amount of detail provided is not intended to limit the expected changes of the embodiments; on the contrary, it is intended to cover all modifications, equivalents and alternatives that fall within the spirit and scope of the present invention as defined by the appended claims.
[0015] Each of the appended claims defines a separate invention, which for infringement purposes is deemed to include equivalents to the various elements or limitations specified in the claims. Depending on the context, all references to the "invention" below may in some cases refer to only certain specific embodiments. In other cases, it will be recognized that references to the "invention" will refer to the subject matter recited in one or more (but not necessarily all) of the claims.
[0016] The grouping of alternative elements or embodiments of the present invention disclosed herein should not be construed as limiting. Each group member can be mentioned and protected individually or with other members in the group or other elements found herein in any combination. For convenience and / or patentability reasons, one or more members in the group can be included in or deleted from the group.
[0017] Unless the context requires otherwise, throughout the following specification, the word "comprise" and variations such as "comprises" and "comprising" are to be interpreted in an open, inclusive sense, that is, as meaning "including but not limited to."
[0018] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the phrases "in one embodiment" or "in an embodiment" appearing in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[0019] As used subsequently in the specification herein and throughout the claims, the meaning of "a / an" and "the" includes plural referents unless the context clearly indicates otherwise. Furthermore, as used in the specification herein, the meaning of "in" includes "in" and "on", unless the context clearly indicates otherwise.
[0020] In certain embodiments, the numerals of the amount, characteristic (such as concentration) etc. of the expression composition for describing and claiming some embodiments of the present invention should be understood to be modified by the term "about" in some cases.Therefore, in certain embodiments, the numerical parameters set forth in the written description are approximate values, and these approximate values can change according to the desired characteristics sought to be obtained in specific embodiments.In certain embodiments, the numerical parameters should be explained according to the number of significant figures reported and by applying common rounding techniques.Although the numerical range and the parameters of the wide range of some embodiments of the present invention are approximate values, the numerical values set forth in the specific examples are reported as accurately as possible.
[0021] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each separate value is incorporated into the specification as if it were individually recited herein.
[0022] The titles and abstracts of the inventions provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0023] All methods described herein can be performed in any suitable order, unless otherwise indicated herein or otherwise clearly contradictory to the context. The use of any and all examples or exemplary language (e.g., "such as") provided with respect to certain embodiments herein is intended only to better illustrate the present invention and is not intended to limit the scope of the present invention as claimed by other claims. The language in the specification should not be interpreted as indicating any unclaimed element essential to the practice of the present invention.
[0024] The present invention relates to a process for preparing brominated uracil derivatives of formula I from uracil derivatives of formula II.
[0025] One aspect of the present disclosure relates to a method for preparing a brominated uracil derivative having formula I, wherein R1, R2 and R3 are independently selected from H and branched or unbranched alkyl groups having C1-C7, The method comprises the following steps: (a) reacting a uracil derivative having the formula II with hydrobromic acid, wherein R1, R2 and R3 are as defined above; and (b) adding hydrogen peroxide to the reaction mixture from step (a) to obtain the brominated uracil derivative having formula I.
[0026] In some embodiments, step (a) is performed in the presence of a solvent. The solvent may be selected from water, methanol, ethanol, isopropanol, DMSO, acetonitrile, monochlorobenzene and combinations thereof, but is not limited thereto.
[0027] In some embodiments, the reaction mixture obtained in step (a) is exposed to a temperature of about 10° C. to about 120° C., preferably about 50° C. to about 100° C., for example, about 50° C. to about 60° C., about 60° C. to about 70° C., about 70° C. to about 80° C., about 80° C. to about 90° C., or about 90° C. to about 100° C. In an embodiment, the reaction mixture obtained in step (a) is exposed to a temperature ranging from about 80° C. to about 90° C.
[0028] In embodiments, step (a) is performed in the presence of an aqueous medium and / or at a temperature ranging from about 50°C to about 100°C.
[0029] In embodiments, the molar ratio between hydrogen peroxide and the uracil derivative having Formula II is from about 1:1 to about 2:1.
[0030] In embodiments, the molar ratio between hydrobromic acid and the uracil derivative having Formula II is from about 1:1 to about 2:1.
[0031] In some embodiments, hydrogen peroxide is added dropwise to the reaction mixture obtained in step (a). In some embodiments, hydrogen peroxide is added to the reaction mixture obtained in step (a) over a period of time ranging from 45 minutes to 180 minutes.
[0032] In an embodiment, during the process for preparing a brominated uracil derivative having formula I, less than 2% w / w of a compound having formula Ia (i.e., a dibrominated uracil derivative) is obtained, wherein R1, R2 and R3 are as defined above.
[0033] In some embodiments, the uracil derivative having formula II is prepared from a compound having formula III, wherein R1 and R3 are as defined above, and R2 is Na.
[0034] In some embodiments, the uracil derivative of formula II is prepared by reacting a compound of formula III with an acid. The acid may be selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and combinations thereof, but is not limited thereto. In embodiments, the acid is hydrobromic acid. In some embodiments, the pH is about 0.5 to about 2.5.
[0035] In some embodiments, the brominated uracil derivatives having Formula I are prepared in situ from compounds having Formula III.
[0036] In some embodiments, the uracil derivative has formula III, wherein R1 is CH(CH3)CH2CH3, R2 is H, and R3 is CH3. In some embodiments, the uracil derivative of formula III is 3-sec-butyl-6-methylpyrimidine-2,4(1H,3H)-dione. In some embodiments, the brominated uracil derivative of formula I is 5-bromo-3-sec-butyl-6-methylpyrimidine-2,4(1H,3H)-dione (common name: herbicide).
[0037] In some embodiments, the method further comprises: neutralizing the crude product mixture comprising the brominated uracil derivative having Formula I from step (b) to a pH ranging from 6 to 8, maintaining the temperature between 60° C. and 90° C. In some embodiments, the step of neutralizing the crude product mixture comprises: adding a base to the crude product mixture to adjust the pH of the crude product mixture to about 7.5, maintaining the temperature of the crude product mixture between 70° C. and 90° C.
[0038] In some embodiments, the method further comprises: subjecting the neutralized crude product mixture to precipitation to obtain the brominated uracil derivative having Formula I.
[0039] The foregoing description of specific embodiments will so fully reveal the general nature of the embodiments herein that others can easily modify such specific embodiments and / or adapt them to various applications by applying current knowledge without violating the general concepts, and therefore such adaptations and modifications should and are intended to be included in the meaning and range of equivalents of the disclosed embodiments. It should be understood that the words or terms used herein are for illustrative and not limiting purposes. Therefore, although the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be modified in practice within the scope of the embodiments described herein. Examples
[0040] The disclosure will now be described with working examples, which are intended to illustrate the work of the disclosure and are not intended to restrictively imply any limitation to the scope of the disclosure. Unless otherwise defined, all technical terms and scientific terms used herein have the same meanings as those of ordinary skill in the art to which the disclosure belongs. Although methods and materials similar or equivalent to the methods and materials described herein can be used in the practice of the disclosed methods and compositions, exemplary methods, devices and materials are described herein. It should be understood that the disclosure is not limited to the described concrete method and experimental conditions, because such methods and conditions can change.
[0041] Preparation of Bromouracil Derivative-Herbamidobenzoic Acid (5-Bromo-3-Sec-butyl-6-Methylpyrimidine-2,4(1H,3H)-dione)
[0042] To a solution of uracil sodium salt (3-sec-butyl-6-methylpyrimidine-2,4 (1H, 3H) -dione sodium salt) in water (37.7 mol, about 20 w / w%, and pH of about 1) was added hydrobromic acid (48%, 9 Kg) and heated to about 85 ° C to obtain a reaction mixture. Hydrogen peroxide (35%, 4.8 Kg) was added dropwise to the reaction mixture over a period of about 120 minutes, and stirring was continued at about 85 ° C for another 60 minutes to obtain an acidic crude product mixture. The acidic crude product mixture was neutralized with NaOH solution (45%) until a pH of 7.5 at 80 ° C was reached. The neutralized mixture was precipitated while the reaction mixture was cooled to between 20 ° C and 30 ° C, and filtered to obtain herbicide. Herbicide was obtained with a yield of 90% and a purity of 95%. As determined by HPLC, the product did not contain dibrominated uracil derivatives as impurities / by-products.
[0043] It will be clear to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the invention may be embodied in other specific forms without departing from its essential attributes. It is therefore intended that the embodiments and examples of the invention be considered in all respects as illustrative and not restrictive, reference being made to the appended claims rather than to the foregoing description, and all changes coming within the meaning and range of equivalents of the claims are therefore intended to be embraced therein. Advantages
[0044] The present disclosure provides a new and improved method that may overcome one or more limitations associated with conventional methods for synthesizing brominated uracil derivatives.
[0045] The present disclosure provides an improved process for preparing brominated uracil derivatives that avoids the direct use of bromine.
[0046] The present disclosure provides an improved process for preparing brominated uracil derivatives that reduces the amount of by-products produced during the reaction.
[0047] The present disclosure provides a safe and environmentally friendly method for preparing brominated uracil derivatives.
[0048] The present disclosure provides an easy to follow, economical and industrially applicable process for preparing brominated uracil derivatives.
[0049] The present disclosure provides a method for preparing brominated uracil derivatives, which (i) allows bromine to be generated in situ during the preparation of the brominated uracil derivatives for bromination; (ii) does not require the handling of hazardous chemicals such as bromine; and (iii) prevents the generation of additional by-products such as dibrominated products (forming less than 2% w / w of compounds having formula Ia) due to excessive bromination of uracil derivatives compared to conventional methods, thereby greatly improving process safety while providing significant economic benefits.
Claims
1. A method for preparing a brominated uracil derivative having formula I, wherein R1, R2 and R3 are independently selected from H and branched or unbranched alkyl groups having C1-C7, The method comprises the following steps: (a) reacting a uracil derivative having the formula II with hydrobromic acid, wherein R1, R2 and R3 are as defined above; and (b) adding hydrogen peroxide to the reaction mixture from step (a) to obtain the brominated uracil derivative having formula I.
2. The method according to claim 1, wherein: The uracil derivative having formula II is prepared from a compound having formula III, wherein R1 and R3 are as defined above, and R2 is Na.
3. The method according to claim 2, wherein: The uracil derivative having the formula II is prepared by reacting the compound having the formula III with an acid.
4. The method according to claim 3, wherein: The acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and combinations thereof.
5. The method according to any one of claims 2 to 4, wherein: The pH is from about 0.5 to about 2.
5.
6. The method according to any one of claims 2 to 5, wherein: The brominated uracil derivatives of formula I are prepared in situ from compounds of formula III.
7. The method according to any one of claims 1 to 6, wherein: Step (a) is carried out in the presence of a solvent.
8. The method according to any one of claims 1 to 7, wherein: The solvent is selected from water, methanol, ethanol, isopropanol, DMSO, acetonitrile, monochlorobenzene and combinations thereof.
9. The method according to any one of claims 1 to 8, wherein: The reaction mixture obtained in step (a) is exposed to a temperature of about 10°C to about 120°C, preferably about 50°C to about 100°C.
10. The method according to any one of claims 1 to 4, wherein: Step (a) is carried out in an aqueous medium and / or at a temperature ranging from about 50°C to about 100°C.
11. The method according to any one of claims 1 to 10, wherein: The molar ratio between hydrogen peroxide and the uracil derivative having Formula II is from about 1:1 to about 2:
1.
12. The method according to any one of claims 1 to 11, wherein: The molar ratio between hydrobromic acid and the uracil derivative having Formula II is about 1:1 to about 2:
1.
13. The method according to any one of claims 1 to 12, wherein: The hydrogen peroxide is added dropwise to the reaction mixture obtained in step (a).
14. The method according to claim 13, wherein: The hydrogen peroxide is added to the reaction mixture obtained in step (a) over a period of time ranging from 45 minutes to 180 minutes.
15. The method according to any one of claims 1 to 14, wherein: less than 2% w / w of the compound of formula Ia is obtained, wherein R1, R2 and R3 are as defined above.
16. The method according to any one of claims 1 to 15, wherein: R1 is CH(CH3)CH2CH3, R2 is H, and R3 is CH3.