WO2024062479A1 - A process for preparing brominated uracil derivatives - Google Patents
A process for preparing brominated uracil derivatives Download PDFInfo
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- WO2024062479A1 WO2024062479A1 PCT/IL2023/051019 IL2023051019W WO2024062479A1 WO 2024062479 A1 WO2024062479 A1 WO 2024062479A1 IL 2023051019 W IL2023051019 W IL 2023051019W WO 2024062479 A1 WO2024062479 A1 WO 2024062479A1
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- formula
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- uracil derivative
- brominated
- uracil
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- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical class O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 title claims abstract description 63
- 238000004519 manufacturing process Methods 0.000 title description 6
- 238000000034 method Methods 0.000 claims abstract description 53
- 230000008569 process Effects 0.000 claims abstract description 44
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000002360 preparation method Methods 0.000 claims abstract description 21
- 239000011541 reaction mixture Substances 0.000 claims abstract description 14
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 238000011065 in-situ storage Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 239000012736 aqueous medium Substances 0.000 claims description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- 239000000203 mixture Substances 0.000 description 10
- 239000012043 crude product Substances 0.000 description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 6
- 238000005893 bromination reaction Methods 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- CTSLUCNDVMMDHG-UHFFFAOYSA-N 5-bromo-3-(butan-2-yl)-6-methylpyrimidine-2,4(1H,3H)-dione Chemical compound CCC(C)N1C(=O)NC(C)=C(Br)C1=O CTSLUCNDVMMDHG-UHFFFAOYSA-N 0.000 description 4
- 230000031709 bromination Effects 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000002363 herbicidal effect Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000004009 herbicide Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- WFTHAQQCTJGTLE-UHFFFAOYSA-N 1h-pyrimidine-2,4-dione;sodium Chemical compound [Na].O=C1C=CNC(=O)N1 WFTHAQQCTJGTLE-UHFFFAOYSA-N 0.000 description 1
- 235000007119 Ananas comosus Nutrition 0.000 description 1
- 244000099147 Ananas comosus Species 0.000 description 1
- 241000380130 Ehrharta erecta Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 231100000206 health hazard Toxicity 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
Definitions
- the present invention relates to a process for preparing brominated uracil derivative of Formula I from uracil derivative of Formula II,
- Ri, R2 and R3 are independently selected from H, and branched or unbranched alkyl group having C1-C7.
- Brominated uracil-based compounds such as bromacil are known to provide effective herbicidal activity as a non-selective broad-spectrum herbicide, used largely as a bare ground herbicide or for industrial vegetation management. They are well known for providing exceptional selective weed control on a number of crops such as citrus fruit and pineapple as well as controlling various types of perennial grasses.
- bromine being directly used as one of the reactants poses a health hazard to human while being problematic to the environment;
- bromine is difficult to handle and transport on a commercial scale;
- generation of additional by-products such as dibrominated products due to excessive bromination of brominated uracil derivative.
- a conventional process for the preparation of brominated uracil derivative is schematically represented below: ormu a
- Primary object of the present invention is to provide a new and improved process that may overcome one or more limitations associated with the conventional processes for preparation of brominated uracil derivatives.
- Another object of the present disclosure is to provide a process for preparation of brominated uracil derivatives that is safe and environment friendly.
- Further object of the present disclosure is to provide a process for preparation of brominated uracil derivatives that is easy to follow, economical and industrially applicable.
- the present invention relates to a process for preparing brominated uracil derivative of Formula I from uracil derivative of Formula II.
- the present disclosure is on the premise of a surprising discovery by inventors of the present disclosure that - reaction of a uracil derivative with hydrobromic acid and hydrogen peroxide affords production of desired mono-brominated uracil derivative, precluding, or at least substantially reducing, formation of additional by-products such as dibrominated uracil derivatives.
- reaction of uracil derivative with hydrobromic acid and hydrogen peroxide affords in-situ generation of Br2, which in turn effects controlled bromination of the uracil derivative, plausible reaction mechanism wherefor is schematically represented hereinbelow:
- an aspect of the present disclosure relates to a process for the preparation of a brominated uracil derivative of Formula I,
- Ri, R2 and R3 are independently selected from H, and branched or unbranched alkyl group having C1-C7, said process comprising the steps of:
- step (b) adding hydrogen peroxide to the reaction mixture from step (a) to obtain the brominated uracil derivative of Formula I.
- the numbers expressing quantities of ingredients, properties such as concentration, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.”
- the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment.
- the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
- the present invention relates to a process for preparing brominated uracil derivative of Formula I from uracil derivative of Formula II.
- An aspect of the present disclosure relates to a process for the preparation of a brominated uracil derivative of Formula I,
- Ri, R2 and R3 are independently selected from H, and branched or unbranched alkyl group having C1-C7, said process comprising the steps of:
- step (b) adding hydrogen peroxide to the reaction mixture from step (a) to obtain the brominated uracil derivative of Formula I.
- the step (a) is carried out in the presence of a solvent.
- the solvent can be selected from water, methanol, ethanol, isopropanol, DMSO, acetonitrile, monochlorobenzene and combinations thereof, but not limited thereto.
- the reaction mixture resulted in step (a) is exposed to a temperature from about 10°C to about 120°C, preferably from about 50°C to about 100°C, for example, from about 50°C to about 60°C, from about 60°C to about 70°C, from about 70°C to about 80°C, from about 80°C to about 90°C or from about 90°C to about 100°C.
- the reaction mixture resulted in step (a) is exposed to a temperature ranging from about 80°C to about 90°C.
- the step (a) is performed in presence of an aqueous medium and/or at a temperature ranging from about 50°C to about 100°C.
- the molar ratio between the hydrogen peroxide and the uracil derivative of Formula II is from about 1 : 1 to about 2: 1.
- the molar ratio between the hydrobromic acid and the uracil derivative of Formula II is from about 1 : 1 to about 2: 1.
- the hydrogen peroxide is added dropwise to the reaction mixture obtained in step (a). In some embodiments, the hydrogen peroxide is added to the reaction mixture obtained in step (a) over a time period ranging from 45 minutes to 180 minutes.
- the uracil derivative of Formula II is prepared from a compound of Formula III,
- the uracil derivative of Formula II is prepared by reacting the compound of Formula III with an acid.
- the acid can be selected from hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid and combinations thereof, but not limited thereto.
- the acid is hydrobromic acid.
- the pH is from about 0.5 to about 2.5.
- the brominated uracil derivative of Formula I is prepared in-situ from compound of Formula III.
- the uracil derivative has a Formula III, wherein Ri is CH(CH3)CH2CH3, R2 is H, and R3 is CH3.
- the uracil derivative of Formula III is 3- ec-Butyl-6-methylpyrimidine-2,4(lH, 3H)-dione.
- the brominated uracil derivative of Formula I is 5-Bromo-3-sec-butyl-6-methylpyrimidine- 2,4(lH,3H)-dione (Common name: Bromacil).
- the process further comprises: neutralizing crude product mixture from step (b) comprising the brominated uracil derivative of Formula I to a pH ranging from 6 to 8 maintaining temperature between 60°C to 90°C.
- the step of neutralizing the crude product mixture includes: effecting addition of an alkali to the crude product mixture to adjust the pH of the crude product mixture to about 7.5 maintaining temperature of the crude product mixture between 70°C to 90°C.
- the process further comprises: subjecting the neutralized crude product mixture to precipitation to obtain brominated uracil derivative of formula I.
- the neutralized mixture was precipitated while cooling the reaction mixture to between 20°C - 30°C and filtered to obtain Bromacil.
- the Bromacil was obtained with a yield of 90% and of 95% purity.
- the product did not contain the dibrominated uracil derivative as impurity /byproduct, as determined by HPLC.
- the present disclosure provides a new and improved process that may overcome one or more limitations associated with the conventional processes for synthesis of brominated uracil derivatives.
- the present disclosure provides an improved process for preparation of brominated uracil derivatives that avoids direct use of bromine.
- the present disclosure provides an improved process for preparation of brominated uracil derivative that reduces the amount of by-product(s) produced during the reaction.
- the present disclosure provides a process for preparation of brominated uracil derivative that is safe and environmental friendly. [00048] The present disclosure provides a process for preparation of brominated uracil derivative that is easy to follow, economical and industrially applicable.
- the present disclosure provides a process for preparation of brominated uracil derivative that (i) allow in-situ generation of bromine during preparation of brominated uracil derivative for bromination; (ii) does not require handling of hazardous chemical like bromine; and (iii) prevent generation of additional by-products such as dibrominated product (less than 2% w/w of a compound of Formula la is formed) due to excessive bromination of uracil derivatives in comparison to conventional methods, greatly improving the process safety while affording significant economic benefits.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present disclosure relates to a process for the preparation of a brominated uracil derivative of Formula I, wherein R1, R2 and R3 are independently selected from H, and branched or unbranched alkyl group having C1-C7, said process comprising the steps of: (a) reacting a uracil derivative of 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 of Formula I.
Description
A PROCESS FOR PREPARING BROMINATED URACIL DERIVATIVES
FIELD OF THE INVENTION
[0001] The present invention relates to a process for preparing brominated uracil derivative of Formula I from uracil derivative of Formula II,
Formula I wherein Ri, R2 and R3 are independently selected from H, and branched or unbranched alkyl group having C1-C7.
BACKGROUND
[0002] Brominated uracil-based compounds such as bromacil are known to provide effective herbicidal activity as a non-selective broad-spectrum herbicide, used largely as a bare ground herbicide or for industrial vegetation management. They are well known for providing exceptional selective weed control on a number of crops such as citrus fruit and pineapple as well as controlling various types of perennial grasses.
[0003] While numerous methods have been reported so far for the preparation of brominated uracil derivatives, the conventional bromination reactions suffer from several-fold shortcomings, such as: (i) bromine being directly used as one of the reactants, poses a health hazard to human while being problematic to the environment; (ii) bromine is difficult to handle and transport on a commercial scale; and (iii) generation of additional by-products such as dibrominated products due to excessive bromination of brominated uracil derivative. A conventional process for the preparation of brominated uracil derivative is schematically represented below:
ormu a
Formula I Formula la
[0004] Further known processes for preparation of brominated uracil derivatives are likewise not completely satisfactory with regard to the above-mentioned problems, inter-alia, others. Accordingly, need is felt of a new and improved process for preparation of brominated uracil derivatives that may overcome one or more problems associated with the conventional processes. The present invention satisfies the existing needs, as well as others, and generally overcomes the deficiencies found in the state of art.
OBJECTS
[0005] Primary object of the present invention is to provide a new and improved process that may overcome one or more limitations associated with the conventional processes for preparation of brominated uracil derivatives.
[0006] It is an object of the present disclosure to provide an improved process for preparation of brominated uracil derivatives that avoids direct use of bromine.
[0007] It is also an object of the present disclosure to provide an improved process for preparation of brominated uracil derivatives that reduces the amount of by-product(s) produced during the reaction.
[0008] Another object of the present disclosure is to provide a process for preparation of brominated uracil derivatives that is safe and environment friendly.
[0009] Further object of the present disclosure is to provide a process for preparation of brominated uracil derivatives that is easy to follow, economical and industrially applicable.
SUMMARY
[00010] The present invention relates to a process for preparing brominated uracil derivative of Formula I from uracil derivative of Formula II.
[00011] The present disclosure is on the premise of a surprising discovery by inventors of the present disclosure that - reaction of a uracil derivative with hydrobromic acid and hydrogen
peroxide affords production of desired mono-brominated uracil derivative, precluding, or at least substantially reducing, formation of additional by-products such as dibrominated uracil derivatives. Without wishing to be bound by the theory, it is believed that reaction of uracil derivative with hydrobromic acid and hydrogen peroxide affords in-situ generation of Br2, which in turn effects controlled bromination of the uracil derivative, plausible reaction mechanism wherefor is schematically represented hereinbelow:
[00012] Accordingly, an aspect of the present disclosure relates to a process for the preparation of a brominated uracil derivative of Formula I,
Formula I wherein Ri, R2 and R3 are independently selected from H, and branched or unbranched alkyl group having C1-C7, said process comprising the steps of:
Formula II
wherein Ri, 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 of Formula I.
[00013] Other aspects, advantages, and salient features of the invention will become apparent to those skilled in the art from the following detailed description, which, taken in conjunction with the exemplary embodiments of the invention.
DETAILED DESCRIPTION
[00014] The following is a detailed description of embodiments of the present invention. The embodiments are in such detail as to clearly communicate the invention. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present invention as defined by the appended claims.
[00015] Each of the appended claims defines a separate invention, which for infringement purposes is recognized as including equivalents to the various elements or limitations specified in the claims. Depending on the context, all references below to the “invention” may in some cases refer to certain specific embodiments only. In other cases it will be recognized that references to the “invention” will refer to subject matter recited in one or more, but not necessarily all, of the claims.
[00016] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability.
[00017] Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
[00018] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” 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.
[00019] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.
[00020] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.”Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
[00021] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.
[00022] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[00023] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[00024] The present invention relates to a process for preparing brominated uracil derivative of Formula I from uracil derivative of Formula II.
[00025] An aspect of the present disclosure relates to a process for the preparation of a brominated uracil derivative of Formula I,
Formula I wherein Ri, R2 and R3 are independently selected from H, and branched or unbranched alkyl group having C1-C7, said process comprising the steps of:
Formula II wherein Ri, 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 of Formula I.
[00026] In some embodiments, the step (a) is carried out in the presence of a solvent. The solvent can be selected from water, methanol, ethanol, isopropanol, DMSO, acetonitrile, monochlorobenzene and combinations thereof, but not limited thereto.
[00027] In some embodiments, the reaction mixture resulted in step (a) is exposed to a temperature from about 10°C to about 120°C, preferably from about 50°C to about 100°C, for example, from about 50°C to about 60°C, from about 60°C to about 70°C, from about 70°C to about 80°C, from about 80°C to about 90°C or from about 90°C to about 100°C. In an embodiment, the reaction mixture resulted in step (a) is exposed to a temperature ranging from about 80°C to about 90°C.
[00028] In an embodiment, the step (a) is performed in presence of an aqueous medium and/or at a temperature ranging from about 50°C to about 100°C.
[00029] In an embodiment, the molar ratio between the hydrogen peroxide and the uracil derivative of Formula II is from about 1 : 1 to about 2: 1.
[00030] In an embodiment, the molar ratio between the hydrobromic acid and the uracil derivative of Formula II is from about 1 : 1 to about 2: 1.
[00031] In some embodiments, the hydrogen peroxide is added dropwise to the reaction mixture obtained in step (a). In some embodiments, the hydrogen peroxide is added to the reaction mixture obtained in step (a) over a time period ranging from 45 minutes to 180 minutes.
[00032] In an embodiment, during the process for the preparation of the brominated uracil derivative of Formula I, less than 2% w/w of a compound of Formula la (i.e. dibrominated uracil derivative) is obtained,
Formula la wherein Ri, R2 and R3 are as defined above.
[00033] In some embodiments, the uracil derivative of Formula II is prepared from a compound of Formula III,
Formula III wherein Ri and R3 are as defined above, and R2 is Na.
[00034] In some embodiments, the uracil derivative of Formula II is prepared by reacting the compound of Formula III with an acid. The acid can be selected from hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid and combinations thereof, but not limited thereto. In an embodiment, the acid is hydrobromic acid. In some embodiments, the pH is from about 0.5 to about 2.5.
[00035] In some embodiments, the brominated uracil derivative of Formula I is prepared in-situ from compound of Formula III.
[00036] In some embodiments, the uracil derivative has a Formula III, wherein Ri is CH(CH3)CH2CH3, R2 is H, and R3 is CH3. In some embodiments, the uracil derivative of Formula III is 3- ec-Butyl-6-methylpyrimidine-2,4(lH, 3H)-dione. In some embodiments, the brominated uracil derivative of Formula I is 5-Bromo-3-sec-butyl-6-methylpyrimidine- 2,4(lH,3H)-dione (Common name: Bromacil).
[00037] In some embodiments, the process further comprises: neutralizing crude product mixture from step (b) comprising the brominated uracil derivative of Formula I to a pH ranging from 6 to 8 maintaining temperature between 60°C to 90°C. In some embodiments, the step of neutralizing the crude product mixture includes: effecting addition of an alkali to the crude product mixture to adjust the pH of the crude product mixture to about 7.5 maintaining temperature of the crude product mixture between 70°C to 90°C.
[00038] In some embodiments, the process further comprises: subjecting the neutralized crude product mixture to precipitation to obtain brominated uracil derivative of formula I.
[00039] The foregoing description of the specific embodiments will so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the scope of the embodiments as described herein.
EXAMPLES
[00040] The disclosure will now be illustrated with working examples, which is intended to illustrate the working of disclosure and not intended to take restrictively to imply any limitations on the scope of the present disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice of the disclosed methods and
compositions, the exemplary methods, devices and materials are described herein. It is to be understood that this disclosure is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary.
[00041] Preparation of brominated uracil derivative - Bromacil (5-Bromo-3-sec- butyl-6-methylpyrimidine-2,4(lH,3H)-dione)
[00042] To a solution of uracil sodium salt (3-sec-Butyl-6-methylpyrimidine-2,4(lH, 3H)- dione sodium salt) in water (37.7 mol, about 20 w/w% and pH ~1) hydrobromic acid (48%, 9 Kg) was added and heated for 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 was continued to stir for another 60 minutes at about 85°C 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 achieved. The neutralized mixture was precipitated while cooling the reaction mixture to between 20°C - 30°C and filtered to obtain Bromacil. The Bromacil was obtained with a yield of 90% and of 95% purity. The product did not contain the dibrominated uracil derivative as impurity /byproduct, as determined by HPLC.
[00043] It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the present embodiments and examples 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 the changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
ADVANTAGES
[00044] The present disclosure provides a new and improved process that may overcome one or more limitations associated with the conventional processes for synthesis of brominated uracil derivatives.
[00045] The present disclosure provides an improved process for preparation of brominated uracil derivatives that avoids direct use of bromine.
[00046] The present disclosure provides an improved process for preparation of brominated uracil derivative that reduces the amount of by-product(s) produced during the reaction.
[00047] The present disclosure provides a process for preparation of brominated uracil derivative that is safe and environmental friendly.
[00048] The present disclosure provides a process for preparation of brominated uracil derivative that is easy to follow, economical and industrially applicable.
[00049] The present disclosure provides a process for preparation of brominated uracil derivative that (i) allow in-situ generation of bromine during preparation of brominated uracil derivative for bromination; (ii) does not require handling of hazardous chemical like bromine; and (iii) prevent generation of additional by-products such as dibrominated product (less than 2% w/w of a compound of Formula la is formed) due to excessive bromination of uracil derivatives in comparison to conventional methods, greatly improving the process safety while affording significant economic benefits.
Claims
Formula I wherein Ri, R2 and R3 are independently selected from H, and branched or unbranched alkyl group having C1-C7, said process comprising the steps of:
Formula II wherein Ri, 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 of Formula I.
2. The process according to claim 1, wherein the uracil derivative of Formula II is prepared from a compound of Formula III
Formula III
wherein Ri and R3 are as defined above, and R2 is Na. The process according to claim 2, wherein the uracil derivative of Formula II is prepared by reacting the compound of Formula III with an acid. The process according to claim 3, wherein the acid is selected from hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid and combinations thereof. The process according to any one of claims 2-4, wherein pH is from about 0.5 to about 2.5. The process according to any one of claims 2-5, wherein the brominated uracil derivative of Formula I is prepared in-situ from compound of Formula III. The process according to any one of claims 1-6, wherein step (a) is carried out in the presence of a solvent. The process according to any one of claims 1-7, wherein the solvent is selected from water, methanol, ethanol, isopropanol, DMSO, acetonitrile, monochlorobenzene and combinations thereof. The process according to any one of claims 1-8, wherein the reaction mixture resulted in step (a) is exposed to a temperature from about 10°C to about 120°C, preferably from about 50°C to about 100°C. The process according to any one of claims 1-4, wherein step (a) is performed in aqueous medium and/or at a temperature ranging from about 50°C to about 100°C. The process according to any one of claims 1-10, wherein the molar ratio between hydrogen peroxide and the uracil derivative of Formula II is from about 1 : 1 to about 2: 1. The process according to any one of claims 1-11, wherein the molar ratio between hydrobromic acid and the uracil derivative of Formula II is from about 1 : 1 to about 2:1. The process according to any one of claims 1-12, wherein the hydrogen peroxide is added dropwise to the reaction mixture obtained in step (a).
The process according to claim 13, wherein the hydrogen peroxide is added to the reaction mixture obtained in step (a) over a time period ranging from 45 minutes to 180 minutes. The process according to any one of claims 1-14, wherein less than 2% w/w of a compound of Formula la is obtained,
Formula la wherein Ri, R2 and R3 are as defined above. The process according to any one of claims 1-15, wherein Ri is CH(CH3)CH2CH3, R2 is H, and R3 is CH3.
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