EA044105B1

EA044105B1 - 5-FLUORO-4-IMINO-3-(ALKYL/SUBSTITUTED Alkyl)-1-(arylsulfonyl)-3,4-DIHYDROPYRIMIDINE-2(1H)-ONE AND METHODS FOR THEIR PREPARATION

Info

Publication number: EA044105B1
Application number: EA201691353
Authority: EA
Inventors: Накиен ЧОЙ; мл. Росс Роналд
Original assignee: Адама Мактешим Лтд.
Priority date: 2013-12-31
Filing date: 2014-12-29
Publication date: 2023-07-24

Description

Cross reference to related applications

This application claims benefit from U.S. Provisional Patent Application Serial Nos. 61/922582 and 61/922572, each filed December 31, 2013, the disclosures of each being expressly incorporated herein by reference.

Field of technology to which the invention relates

Provided herein is 5-fluoro-4-imino-3-(alkyl/substituted alkyl)-1(arylsulfonyl)-3,4-dihydropyrimidin-2(1H)-one and methods for its preparation.

State of the art and essence of the invention

US Patent Application Serial No. 13/090616, US Patent Publication No. 2011/0263627, describes, among other things, certain N3-substituted-N1-sulfonyl-5-fluoropyrimidinone compounds and their use as fungicides. The application disclosure is expressly incorporated by reference herein. This patent describes various routes for the preparation of N3-substituted N1-sulfonyl-5-fluoropyrimidinone compounds.

Providing more direct and efficient methods for the preparation, isolation, and purification of N3-substituted-N-sulfonyl-5-fluoropyrimidinone fungicides and related compounds, for example, through the use of reagents and/or chemical intermediates and isolation and purification methods that provide improved durability and efficiency in terms of costs, may be advantageous.

Provided herein are 5-fluoro-4-imino-3-(alkyl/substituted alkyl)-1(arylsulfonyl)-3,4-dihydropyrimidin-2(1H)-one and methods for their preparation. In one embodiment, provided herein is a method for preparing compounds of formula III wherein R1 is selected from

SN _E °CH ₃ and R2 are selected from

CDs

_CHE which involves the reaction of compounds of formula II with a base such as an alkali metal carbonate, for example sodium, potassium, cesium and lithium carbonate (Na ₂ CO ₃ , K2CO3, Cs ₂ CO ₃ and Li ₂ CO ₃ respectively), or an alkoxide an alkali metal, for example, potassium tert-butoxide (KOtBu), and an alkylating agent, such as an alkyl halide of the formula R2-X, where R2 is the same as previously defined, and X is a halogen, for example, iodine, bromine and chlorine, in polar solvent such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), N-methylpyrrolidone (NMP), acetonitrile (CH3CN) and the like, at concentrations from about 0.1 M to about 3 M. In some embodiments, the molar ratio of compounds of Formula II to base is from about 3:1 to about 1:1, and the molar ratio of compounds of Formula II to alkylating agent is from about 1:1 to about 1:3. In other embodiments, molar ratios of compounds of Formula II to base and compounds of Formula II to alkylating agent are used that are approximately 2:1 and 1:3, respectively. In some embodiments, the reactions are carried out at temperatures from -78°C to 90°C, and in other embodiments, the reactions are carried out at temperatures from 22°C to 60°C.

One skilled in the art will appreciate that manipulation of the reaction parameters described above can result in the formation of product mixtures consisting of compounds of the formulas

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II, III, and IV, as shown in Scheme 1, wherein the ratios of the compounds of formulas II, III, and IV formed are from about 0:2:1 to about 1:2:0. In some embodiments, compositions containing mixtures of compounds of formulas II and III are preferred since isolation and purification can be achieved by precipitation and recrystallization, and the intermediate compounds of formula II can be recovered and reused in the process cycle. In contrast, compositions containing mixtures of compounds of formulas III and IV require chromatographic separation, which yields the compound of formula III along with the undesired dialkylated by-product of formula IV.

Scheme 1

O G J χΛ and

□foundation

Alkylating agent Solvent

Temperature

and [IJ IV

In another embodiment, the desired crude composition, that is, mixtures of compounds of formula II and compounds of formula III, wherein R1 is methoxy (OCH3) and R2 is methyl (CH3), is prepared by reacting the compound of formula II with Li2CO3 and methyl iodide (CH3I) in DMF (1.0 M) in a molar ratio of approximately 1:0.6:3 at 45°C. Upon completion, dilute the crude composition with a polar, aprotic solvent such as CH3CN, where the _ratio of _CH3CN : _DMF is from about 2:1 to about 1:2, followed by an aqueous solution of sodium thiosulfate ( _Na2S2O3 ) at pH from about 8 to about 10.5, where the ratio of 2.5% (by weight) aqueous Na ₂ S ₂ O ₃ :DMF solution is from about 1:2 to about 3:1, produces a precipitate that can be isolated by filtration . In one embodiment, the CH ₃ CN:DMF ratio is approximately 1:2, and the 2.5% aqueous Na ₂ S ₂ O ₃ :DMF ratio is approximately 1:1, and the resulting solid is further purified by crystallization /precipitation from a heated solution, at a temperature of approximately 30°C-40°C, of a solid in a solution of a polar, aprotic solvent such as CH3CN, by adding water (H ₂ O), where the ratio of H ₂ O:CH ₃ CN is from about 1:2 to about 3:1, which gives the purified compound of formula III, and in another embodiment, the ratio of H ₂ O:CH ₃ CN, which leads to the precipitation of pure compound III, is about 2:1.

In another embodiment, compounds of formula II can be prepared by reacting compounds of formula I with bis-N,O-trimethylsilylacetamide (BSA) at an elevated temperature, such as 70°C, for a period of approximately 1 hour, followed by cooling and reacting a solution containing the protected pyrimidinol with a substituted benzenesulfonyl chloride represented by the general formula R1-PhSO ₂ Cl, where R1 is the same as previously defined, at approximately 20°C-25°C. In some embodiments, the molar ratio of the compound of Formula I to BSA and sulfonyl chloride is about 1:3:1.1, respectively, and in another embodiment, adjusting the molar ratio of the reactants to about 1:1.1:1.1 provides improved yields.

[

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The term alkyl refers to a branched, straight-chain, or saturated cyclic carbon chain, including, but not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiary butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term alkenyl refers to a branched, straight-chain, or cyclic carbon chain containing one or more double bonds, including, but not limited to, ethenyl, propenyl, butenyl, isopropenyl, isobutenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.

The term aryl refers to any aromatic group, mono- or bi-cyclic, containing heteroatoms.

The term heterocycle refers to any aromatic or non-aromatic ring, mono or bi-cyclic, containing one or more heteroatoms.

The term alkoxo group refers to the -OR substituent.

The term halogen or halogeno refers to one or more halogen atoms, defined as F, Cl, Br and I.

The term haloalkyl refers to alkyl that is substituted with Cl, F, I, or Br or any combination thereof.

Throughout the disclosure, references to compounds of formulas I, II, III and IV should also be understood to include optical isomers and salts. Exemplary salts may include hydrochloride, hydrobromide, hydroiodide and the like. In addition, compounds of formulas I, II, III and IV may include tautomeric forms.

Some compounds disclosed herein may exist as one or more isomers. Those skilled in the art will appreciate that one isomer may be more active than other isomers. The structures disclosed in the present disclosure are drawn in only one geometric form for simplicity, but are intended to represent all geometric and tautomeric forms of the molecule.

In one exemplary embodiment, a method for preparing a compound of Formula III is provided. The method involves reacting a compound of formula II with an alkali metal carbonate and an alkylating agent; and preparing a compound of formula III

¹¹ 111 where R1 is selected from the group consisting of

and R2 is selected from the group consisting of

In a more specific embodiment, the reaction step is carried out at a temperature of from 22°C to 60°C.

In yet another more specific embodiment of any of the above-mentioned embodiments, the reaction step further includes a solvent selected from the group consisting of DMF, DMSO, DMA, NMP and CH3CN.

In yet another more specific embodiment of any of the above-mentioned embodiments, the alkali metal carbonate is selected from the group consisting of Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ and Li ₂ CO ₃ .

In yet another more specific embodiment of any of the above-mentioned embodiments, the alkylating agent is selected from the group consisting of alkyl halides and benzyl halides. In an even more specific embodiment, the alkyl halide and benzyl halide are selected from methyl iodide (CH ₃ I), ethyl iodide (C2H5I) and benzyl bromide (BnBr).

In yet another more specific embodiment of any of the above-mentioned embodiments, the alkali metal carbonate base is Cs ₂ CO ₃ and the solvent is DMF.

In another more specific embodiment of any of the above-mentioned embodiments, the molar ratio of Compound II to alkali metal carbonate base is from about 3:1 to about 1:1, and the molar ratio of Compound II to alkylating agent is from about 1:1 to approximately 1:3. In an even more specific embodiment, the molar ratio of Compound II to alkali metal carbonate base is approximately 2:1, and the molar ratio of Compound II to alkylating agent is 1:3.

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In yet another more specific embodiment of any of the above-mentioned embodiments, the method further includes the step of diluting the mixture obtained after completion of the reaction with CH3CN and a 2.5% aqueous solution of Na ₂ S ₂ O3. In an even more specific embodiment, the ratio of DMF to CH3CN is from about 1:1 to about 3:1, and the ratio of DMF to 2.5% aqueous Na ₂ S ₂ O ₃ solution is from about 1:2 to about 2 :1. In an even more specific embodiment, the ratio of DMF to CH3CN is approximately 2:1, and the ratio of DMF to 2.5% aqueous Na ₂ S ₂ O ₃ solution is approximately 1:1.

In another embodiment, a method for preparing a compound of Formula II is provided. The method involves reacting a compound of formula I with bis-N,O-trimethylsilylacetamide (BSA)

and the actual preparation of the compound of formula II

where the molar ratio of compound I to bis-N,O-trimethylsilylacetamide (BSA) is 1:1.1, and the reaction step is carried out at approximately 22°C to approximately 70°C.

In a more specific embodiment, the reaction step further includes reacting compound I with CH ₃ CN.

In another more specific embodiment of any of the above-mentioned embodiments, the method includes reacting the BSA-treated reaction mixture with arylsulfonyl chloride.

In another more specific embodiment of any of the above-mentioned embodiments, the molar ratio of Compound I to arylsulfonyl chloride is from about 1:2 to about 2:1. In an even more specific embodiment, the molar ratio of Compound I to arylsulfonyl chloride is 1:1.1.

The embodiments described above are intended to be provided by way of example only, and those skilled in the art will recognize, or will be able to identify, through routine experimentation alone, numerous equivalents of specific compounds, materials, and techniques. All such equivalents are intended to be within the scope of the invention and to be covered by the appended claims.

Detailed description

5-Fluoro-4-imino-3-(alkyl/substituted alkyl)-1-(arylsulfonyl)-3,4-dihydropyrimidin-2(1H)-one, as shown in examples 1-2.

Example 1. Preparation of 4-amino-5-fluoro-1-(phenylsulfonyl)pyrimidin-2(1H)-one (1)

To a dry 500 mL round bottom flask equipped with a mechanical stirrer, nitrogen inlet, dropping funnel, thermometer, and reflux condenser, add 5-fluorocytosine (20.0 grams (g), 155 millimol (mmol)) and CH ₃ CN ( 100 ml). BSA (34.7 g, 170 mmol) was added to the resulting mixture in one portion and the reaction mixture was heated to 70° C. and stirred for 30 minutes. The resulting homogeneous solution was cooled to 5°C using an ice bath and treated dropwise with benzenesulfonyl chloride. The reaction mixture was stirred at 0°C5°C for 1 hour and then overnight at room temperature. The resulting pale yellow suspension was poured into cold _H2O (1.5 L) and stirred vigorously for 1 hour. The resulting solid was collected by vacuum filtration, washed with H2O, and dried under vacuum in overnight at 40°C to give 4-amino-5-fluoro-1(phenylsulfonyl)pyrimidin-2(1H)-one (29.9 g, 72%) as a white powdery solid: Ή NMR (400 MHz , DMSO-d6) δ 8.56 (s, 1H), 8.35-8.26 (m, 2H), 8.07-7.98 (m, 2H), 7.84-7.74 (m ,

1H), 7.72-7.61 (m, 2H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -163.46; electrospray ionization mass spectrometry (ESIMS) m/z 270 ([M+H]+).

The following compounds 1-3 in table. 1a was prepared in accordance with the reaction shown in Scheme 1 and the procedures described in Example 1. Characteristic data for compounds 1-3 are shown in table. 1b.

Scheme 1

Table 1a

Connection Number Ri Appearance Exit (%) 1 n Powdery white solid 72 2 СНз Powdery white solid 61 3 OSN ₃ Powdery white solid 57

Table 1b

Connection Number Mass spectrometry P NMR (δΡ ¹³ C NMR or ¹⁹ F NMR (5)b,s 1 Electrospray ionization mass spectrometry (ESIMS) m/z 270 ( [M+Hp) P NMR (DMSO-X) δ 8.56 (s, 1H), 8.35-8.26 (m, 2H), 8.07-7.98 (m, 2H), 7.84-7.74 (m, 1H), 7.72-7.61 (m, 2H) ¹⁹ E NMR (DMSO-cU δ -163.46 2 ESIMS m/z 284 ([m+nr) ^2H NMR (DMSO-X) δ 8.54 (s, 1H), 8.40-8.16 (m, 2H), 8.05-7.76 (m, 2H), 7.66-7. 36 (m, 2N), 2.41 (s, ZN) ¹⁹ F NMR (DMSO-d ₆ ) δ -163.62 3 ESIMS m/z 300 ([m+nr) P NMR (CDC1 ₃ ) δ 8, 107.91 (m, 2H), 7.73 (d, D=5.4 Hz, 2H), 7.11-6.94 (m, 2H), 3.90 (s, ZN), 3.32 (d, D=0.6 Hz, ZN) ¹⁹ F NMR (CDC1 ₃ ) δ -158.58

^a All 1H NMR data measured at 400 MHz unless otherwise noted.

^b All ¹³ C NMR data measured at 101 MHz unless otherwise noted.

^c All ¹⁹ F NMR data measured at 376 MHz unless otherwise noted.

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Example 2. Preparation of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-dihydropyrimidin-2(1H)-one (5)

To a mixture of 4-amino-5-fluoro-1-tosylpyrimidin-2(1H)-one (5.66 g, 20 mmol) and Li ₂ CO ₃ (0.880 g, 12.0 mmol) in DMF (20 ml) was added CH ₃ I (8.52 g, 60.0 mmol), and the resulting mixture was heated to 40°C and stirred for 5 hours. The reaction mixture was cooled to room temperature, diluted with CH3CN (10 ml), and treated with 2 .5% aqueous solution of Na ₂ S ₂ O ₃ (20 ml). The resulting mixture was stirred at room temperature for 10 minutes, and the solids were collected by filtration. The filter cake was washed with an aqueous solution of CH3CN (10% solution of CH3CN in H ₂ O) and air dried for 2 hours. The filter cake was dissolved in CH ₃ CN (15 ml) at 40° C. and the solution was treated with H ₂ O (30 ml). The resulting suspension was cooled to room temperature, stirred for 2.5 hours, and filtered. The filter cake was again washed with 10% aqueous CH ₃ CN and then dried under vacuum at 50°C to obtain the title compound (2.70 g, 45%) as a white solid: melting point (mp) 156 -158°C; 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.54 (d, J=2.3 Hz, 1H), 7.99 (dd, J=6.0, 0.6 Hz, 1H), 7, 95-7.89 (m, 2H), 7.53-7.45 (m, 2H), 3.12 (d, J=0.7 Hz, 3H), 2.42 (s, 3H); 19F NMR (376 MHz, DMSO-d ₆ ) -157.86 (s); electrospray ionization mass spectrometry (ESIMS) m/z 298 ([M+H]+).

The following compounds 4-6 in the table. 2a was prepared in accordance with the reaction shown in Scheme 2 and the procedures described in Example 2. Characterization data for compounds 4-6 are shown in table. 2b.

Scheme 2

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Table 2a

Connection Number Ri r ₂ Appearance Exit (%) 4 N CH ₃ White solid 64 5 CH ₃ CH ₃ White solid 45 6 OSN ₃ CH ₃ White solid 62

Table 2b

Compound number Mass spectrometry Ή NMR (5) ^a ¹³ C NMR or ¹⁹ G NMR (5)b,c 4 Ionization mass spectrometry A NMR (CDC1 ₃ ) δ 8.14-8.02 (m, 2Η), ^19th NMR (CDC1 ₃ ) δ - electrospray (ESIMS) m/z 284 ([M+H] ⁺ ) 7.88-7.67 (μ, 3Η), 7.67-7.50 (μ, 2Η ) , 3.31 (d, J =0.7 Hz, 3H) 158.05 5 ESIMS m/z 298 ( [M+H] +) Ή NMR (DMSO-d ₆ ) δ 8.54 (d, J =2.3 Hz, 1H), 7.99 (dd, J =6, 0, 0.6 Hz, 1H), 7.95-7.89 (m, 2H), 7.53-7.45 ( μ, 2Η), 3.12 (d, J =0.7 Hz, 3Η), 2.42 (s, 3Η) ¹⁹ F NMR (DMSO-dp δ 157.86 (s) 6 ESIMS m/z 314 ( [M+H] ⁺ ) Ή NMR (CDC1 ₃ ) δ 8.10-7.91 (μ, 2Η), 7.73 (d, J =5.4 Hz, 2Η), 7.11-6.94 (μ, 2Η) , 3.90 (s, 3Η) , 3.32 (d, J =0.6 Hz, 3Η) ¹⁹ F nmr (CDC1 ₃ ) δ -

Claims

CLAIM

1. A method for preparing compounds of formula III, including the stages of reacting a compound of formula II with an alkali metal carbonate and an alkylating agent

where R1 is selected from the group consisting of

and R2 is selected from the group consisting of

where the molar ratio of the compound of formula II and the alkali metal carbonate is from 3:1 to 1:1.

2. The method according to claim 1, where the molar ratio of the compound of formula II and alkali metal carbonate is 2:1.

x-SNd ^ _CHD

3. The method according to claim 1 or 2, where R1 represents ' and R2 represents ' .

4. Method according to any one of claims 1-3, where:

a) the interaction stage is carried out at a temperature from 22 to 60°C,

b) the reaction step further comprises a solvent selected from the group consisting of DMF, DMSO, DMA, NMP and CH ₃ CN,

c) the alkali metal carbonate is selected from the group consisting of Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , and Li ₂ CO ₃ and/or

d) the alkylating agent is selected from the group consisting of alkyl halides and benzyl halides.

5. The method according to claim 4, wherein the alkyl halides and benzyl halides are selected from the group consisting of methyl iodide, ethyl iodide and benzyl bromide.

6. The method according to claim 4 or 5, wherein the alkali metal carbonate is Li ₂ CO ₃ and the solvent is DMF.

7. Method according to any one of claims 1 to 6, wherein the molar ratio of the compound of formula II to the alkylating agent is from 1:1 to 1:3.

8. Method according to any one of claims 1 to 7, wherein the molar ratio of the compound of formula II to the alkali metal carbonate is 2:1 and the molar ratio of the compound of formula II to the alkylating agent is 1:3.

9. The method according to any one of claims 1-8, additionally including the step of diluting the mixture formed after completion of the reaction with CH3CN and a 2.5% aqueous solution of Na ₂ S ₂ O ₃ .

10. The method according to claim 9, where the reaction step includes a DMF solvent.

11. Method according to claim 10, where:

a) the ratio of DMF to CH3CN is from 1:1 to 3:1 and the ratio of DMF to 2.5% aqueous Na ₂ S ₂ O ₃ solution is from 1:2 to 2:1 or

b) the ratio of DMF to CH3CN is 2:1 and the ratio of DMF to 2.5% Na ₂ S ₂ O ₃ aqueous solution is 1:1.

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12. A method for preparing a compound of formula II, including the stages of interaction between a compound of formula I

and bis-M,O-trimethylsilylacetamide and arylsulfonyl chloride to obtain the compound of formula II

II where Ri is selected from the group consisting of . СНз

and where the molar ratio of the compound of formula I to bis-M,O-trimethylsilylacetamide is 1:1.1, and the reaction step is carried out at a temperature of from 22 to 70°C.

13. The method of claim 12, wherein the reaction step further comprises reacting a compound of formula I with CH ₃ CN.

14. Method according to claim 12 or 13, wherein the molar ratio of the compound of formula I to arylsulfonyl chloride is from 1:2 to 2:1.

15. Compound of formula III

I

Ri

111 ^CH _a where Ri represents ' and ^CH _a

R ₂ represents ' or a salt thereof.

Eurasian Patent Organization, EAPO

Russia, 109012, Moscow, Maly Cherkassky lane, 2