RU2836442C2 - Pyrazole derivatives - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (X), which can be used in preparing a herbicide. In formula (X), ring A is A¹ or A², R^B2 is selected from a group consisting of methyl, ethyl, n-propyl, trifluoromethyl and difluoroethyl, R^B3SN is chlorine, fluorine, bromine, methyl, ethyl, difluoromethyl, trifluoromethyl, C₁-C₃haloalkoxy or C₁-C₃alkoxy, the broken line denotes a point of attachment to the rest of the compound of formula (X), each of R^Q1 and R^Q4 is hydrogen, R^Q2 and R^Q3 together with carbon atoms to which they are attached form a ring Q, where ring Q is Q1 or Q2, where R¹ is methyl, "a" denotes a point of attachment to ring A, and "c" denotes a point of attachment to a carboxylate fragment. Invention also relates to a method of producing a compound of formula (X), use thereof in the manufacture of a herbicide and a compound of formula (E), in which ring A is A¹ or A², R^B2 is C₁-C₃alkyl or C₁-C₃fluoroalkyl; R^B3SN is chlorine, fluorine, bromine, methyl, ethyl, difluoromethyl, trifluoromethyl, C₁-C₃haloalkoxy or C₁-C₃alkoxy; broken line denotes a point of attachment to the rest of the compound of formula (E) and R¹ is methyl.

EFFECT: compounds of the present invention can be used in the preparation of an herbicide.

5 cl, 8 tbl, 1 ex

Description

The present invention relates to pyrazole derivatives of formula (X) described herein, which are valuable intermediates in the production of agrochemicals and pharmaceuticals. The present invention extends to the production of such pyrazole derivatives and their subsequent use in the production of agrochemicals and/or pharmaceuticals.

In a first aspect, the present invention provides compounds of formula (X)

wherein ring A, given that it is a di- or trisubstituted pyrazole, is substituted with R ^B2 at one nitrogen atom in the ring and is substituted with R ^B3 at least at one carbon atom in the ring, wherein R ^B2 is C ₁ -C ₃ alkyl or C ₁ -C ₃ fluoroalkyl, n is an integer equal to 1 or 2, and each R ^B3 is independently halogen, C ₁ -C ₃ fluoroalkyl, C ₁ -C ₃ haloalkoxy, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ fluoroalkyl, C ₁ -C ₃ haloalkoxy, C ₁ -C ₃ alkoxy or C ₁ -C ₃ alkyl; each of R ^Q1 and R ^Q4 is hydrogen, and R ^Q2 and R ^Q3 together with the carbon atoms to which they are attached form a ring Q, which is an optionally substituted 5-membered thiolactam ring.

In a second aspect, there is provided a method for preparing a compound of formula (X) as defined above, wherein the ring Q is substituted with R ¹ , said method comprising:

(i) reacting a compound of formula (A) with ethyl acrylate under palladium catalysis conditions to obtain a compound of formula (B),

wherein ring A is a pyrazole ring substituted at a ring carbon atom with Hal, wherein Hal is iodine, bromine or chlorine, R ^B3 is a substituent on a ring nitrogen atom and is C ₁ -C ₃ alkyl or C ₁ -C ₃ fluoroalkyl, n is an integer equal to 1 or 2, R ^B3 is a substituent on a ring carbon atom, and each R ^B3 is independently halogen, C ₁ -C ₃ fluoroalkyl, C ₁ -C ₃ haloalkoxy, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ fluoroalkyl, C ₁ -C ₃ haloalkoxy, C ₁ -C ₃ alkoxy or C ₁ -C ₃ alkyl; (ii) reacting the compound of formula (B) of step (i) with a compound of formula (C),

wherein R ¹ is selected from the group consisting of C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, optionally substituted phenyl, optionally substituted C ₅ -C ₆ heteroaryl, -CR ¹² R ¹³ , -C(O)R ¹² ; R ¹² is hydrogen, OH, C ₁ -C ₃ alkoxy, or C ₁ -C ₄ alkyl; R ¹³ is -C(O)NH ₂ ;

by the mechanism of the cycloaddition reaction to obtain a mixture of compounds of formula (D) and (E);

(iii) reacting the compound of formula (E) with a base in the form

hydroxide in a mixed water/ether solvent system to obtain a compound of formula (X),

where A, R ^B2 , R ^B3 , n and R are defined in steps (i) and (ii) above.

Compounds of formula (B), (D) and (E) are also novel and form still further aspects of the present invention.

As used herein, the term "halogen" or "halo" refers to fluorine (fluorine), chlorine (chlorine), bromine (bromine) or iodine (iodine), preferably fluorine, chlorine or bromine, unless otherwise specified.

As used in this document, the term "cyano" refers to the -CN group.

As used herein, the term "hydroxy" means the -OH group.

As used in this document, the term "nitro" refers to the -NO ₂ group.

Each alkyl moiety, either by itself or as part of a larger group (such as alkoxy, alkylthio, haloalkyl, haloalkoxy, etc.) may be straight chain or branched, and as used herein the term specifically also includes cyclopropyl. Typically, alkyl is, for example, methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, neopentyl or n-hexyl. Alkyl groups are typically _C1 - _C6 alkyl groups (except where already more narrowly defined), but are preferably _C1 - _C4 alkyl or _C1 - _C3 alkyl groups, and more preferably _C1- or _C2 alkyl groups (i.e., methyl or ethyl).

As used herein, the term "C ₁ -C ₃ alkoxy" refers to a radical of the formula -OR _a , wherein R _a is a C ₁ -C ₃ alkyl radical as generally defined above. Examples of C ₁ -C ₃ alkoxy thus include methoxy, ethoxy, propoxy and isopropoxy.

As used herein, the term " _C1 - _C3 haloalkyl" refers to a _C1 - _C3 alkyl radical, as generally defined above, substituted by one or more identical or different halogen atoms. Examples of _C1 - _C3 haloalkyl thus include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1,1-difluoro-2,2,2-trichloroethyl, 2,2,3,3-tetrafluoroethyl and 2,2,2-trichloroethyl.

As used herein, the term " _C1 - _C3 haloalkoxy" refers to a _C1 - _C3 alkoxy group as defined above substituted by one or more identical or different halogen atoms. Examples of _C1 - _C3 haloalkoxy thus include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy and 2,2,2-trichloroethoxy.

The term "C ₁ -C ₆ alkylthio" refers to the group C ₁ -C ₆ alkyl-S- and is, for example, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio or tert-butylthio, preferably methylthio or ethylthio.

The term "C ₁ -C ₆ alkylsulfinyl" refers to the group C ₁ -C ₆ alkyl-S(O)- and is, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl or tert-butylsulfinyl, preferably methylsulfinyl or ethylsulfinyl.

The term "C ₁ -C ₆ alkylsulfonyl" refers to the group C ₁ -C ₆ alkyl-S(O) ₂ - and is, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl or tert-butylsulfonyl, preferably methylsulfonyl or ethylsulfonyl.

The compounds of formula (X) may exist as different geometric isomers or in different tautomeric forms. The present invention embraces the use of all such isomers and tautomers and mixtures thereof in all ratios, as well as isotopic forms such as deuterated compounds. They may contain one or more asymmetric centers, which may thus lead to the formation of optical isomers and diastereoisomers. Although the present invention is presented with respect to formula (X) without regard to stereochemistry, it embraces the use of all such optical isomers and diastereoisomers, as well as racemic and resolved, enantiomerically pure R- and S-stereoisomers and other mixtures of R- and S-stereoisomers and their agrochemically acceptable salts. It is believed that certain optical isomers or diastereoisomers may have more optimal properties than others. Thus, in the disclosure of the present invention and in the formulation of the claims, if a racemic mixture is disclosed, it is obviously intended that both optical isomers, including diastereoisomers containing substantially no other isomers, are also disclosed and claimed.

Similarly, the presence of one or more possible asymmetric carbon atoms in a compound of formula (D), (E), (H) and (I) means that these compounds may also occur in chiral isomeric forms, i.e. enantiomeric or diastereomeric forms. Also, atropisomers may arise as a result of limited rotation about a single bond. Formulae (D), (E), (H) and (I) are intended to include all of these possible isomeric forms and mixtures thereof. The present invention includes the use of all of these possible isomeric forms and mixtures thereof for compounds of formulae (D), (E), (H) and (I). Similarly, formulae (D), (E), (H) and (I) are intended to include all of the possible tautomers (including lactam-lactim tautomerism and keto-enol tautomerism), if present. The present invention thus includes the use of all possible tautomeric forms for the compounds of formula (D), (E), (H) and (I).

Suitable salts include those derived from alkali or alkaline earth metals and those derived from ammonia and amines. Preferred cations include sodium, potassium, magnesium and ammonium cations of the formula N ⁺ ( ^{R119R120R121R122} ), wherein ^R119 , ^{R120 , R121} and ^R122 are independently selected from hydrogen, _C1 - _C6 alkyl and _C1 - _C6 ^hydroxyalkyl . Salts of ^the compounds of formula (I) can be prepared by treating the compounds of formula (I) with a metal hydroxide such as sodium hydroxide or an amine such as ammonia, trimethylamine, diethanolamine, 2-methylthiopropylamine, bisallylamine, 2-butoxyethylamine, morpholine, cyclododecylamine or benzylamine. Amine salts are often preferred forms of the compounds of formula (I) because they are water soluble and are suitable for preparing the desired water-based herbicidal compositions.

Acceptable salts can be formed using organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic and the like known acceptable acids, if the compound of the present invention contains a basic functional group.

As used herein, the term "herbicide" means a compound that controls or modifies plant growth. The term "herbicidally effective amount" means the amount of such a compound or combination of such compounds that is capable of providing a controlling or modifying effect on plant growth. Controlling or modifying effects include all deviations from natural development, such as killing, inhibition of development, leaf scorching, albinism, dwarfing, etc.

The present invention is based on the following general reaction scheme, wherein ring A, R ^B2 , R ^B3 , n, R and R are as defined herein.

The desired halogenated pyrazole (A) is reacted with ethyl acrylate under palladium catalysis to give a substituted vinylpyrazole of formula (B). The substituted vinylpyrazole (B) is cycloadded with a dithiolan-isocyanate iminium salt methylide of formula (C) to give a mixture of pyrrolidine cycloadducts, i.e., compounds of formula (D) and compounds of formula (E), which can be separated by chromatography. The desired pyrrolidine cycloadduct (compound of formula (E) is illustrated in the reaction scheme above) is reacted with a base in the form of a hydroxide in a mixed water/ether solvent system to give a 3-carboxyl-substituted thiolactam of formula (X). Compounds of formula (C) can be prepared as described in Tempahedron Lett. 1995, 5(5:9409. Halogenated pyrazoles of formula (A) are either known or can be prepared according to methods widely known in the art.

Depending on the desired end product, the 3-carboxyl substituted thiolactam can be coupled with an aniline of formula (G) to provide the desired thiolactam carboxamide of formula (H) using standard amide bond forming conditions such as propanephosphonic anhydride in a suitable solvent such as dichloromethane and a suitable base as shown in Reaction Scheme 2 below. One skilled in the art will appreciate that the choice of R ² depends on the desired end product and can be any suitable substituent that can be attached via an amide bond.

The resulting thiolactam carboxamide of formula (H) can be sequentially subjected to oxidative hydrolysis using a solution of hydrogen peroxide and a suitable acid to form a lactam compound of formula (I) (reaction scheme 3).

Alternatively, a 3-carboxyl substituted thiolactam of formula (X) can be sequentially oxidatively hydrolyzed with hydrogen peroxide solution and a suitable acid to form a lactam compound of formula (L), as shown in Reaction Scheme 4. This compound can be sequentially coupled with an aniline of formula (G) to form the desired lactam compound of formula (H) using standard amide bond formation conditions as described above (see Reaction Scheme 5 below).

If desired, individual enantiomers may be obtained by chiral resolution. One skilled in the art will appreciate that compounds of formulae (D), (E), (X), (H), (I), and (J) may exist in different enantiomeric forms, such as:

In each case, in one group of embodiments, the following enantiomers are preferred (D1), (E1), (X1), (H1), (I1) and (J1).

In the compounds of formulae (A), (B), (D), (E), (X), (H) and (I) described herein, ring A is a pyrazole moiety containing at least two substituents, wherein one of said substituents (R ^B2 ) is related to a nitrogen atom in the ring and the second substituent (R ^B3 ) is related to a carbon atom in the ring. It is evident that in this configuration, A is a carbon atom attached to the remainder of the molecule.

If A is disubstituted and R ^B3 refers to a carbon atom in a ring adjacent to the substituted nitrogen atom in the ring, said R ^B3 substituent may be defined as R ^B3SN . For the avoidance of doubt, R ^B3SN is one of the additional definitions of R ^B3 applied solely to designate a location in the pyrazole moiety, and therefore R ^B3SN is also selected from the group consisting of halogen, C ₁ -C ₃ fluoroalkyl, C ₁ -C ₃ haloalkoxy, C ₁ -C ₃ alkoxy and C ₁ -C ₃ alkyl. Thus, if A is disubstituted, it may be represented by the groups A ¹ , A ² , A ³ , A ⁴ or A ⁵ , as shown below, where R ^B3 , R ^B3 and R ^B3SN are as defined above and the broken line denotes the point of attachment to the remainder of the corresponding molecule. In compounds of formula (A) it is the point of attachment to the corresponding halogen atom. In compounds of formula (B) it is the point of attachment to the moiety representing ethyl propenoate. In compounds of formulae (D) and (E) it is the point of attachment to the moiety representing 1,4-dithia-6-azaspiro[4.4]nonane-8-carboxylate. In compounds of formulae (X), (H) and (I) it passes through the carbon atom in position 4 of the (thio)lactam ring.

Groups ^A1 and ^A2 are particularly preferred, with ^A2 being the most preferred of the disubstituted pyrazoles.

In case the ring A is trisubstituted, it can be represented by groups ^A6 or ^A7 , where the third substituent (R ^B3 ) is also related to the carbon atom in the ring:

where R ^B2 , R ^B3 and R ^B3SN , as well as the broken line, are as defined above.

Preferably, R ^B2 is selected from the group consisting of methyl, ethyl, n-propyl, fluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and trifluoroethyl. More preferably, R ^B2 is selected from the group consisting of methyl, ethyl, n-propyl, trifluoromethyl and difluoroethyl. Even more preferably, R ^B2 is selected from the group consisting of methyl, ethyl and difluoroethyl.

Preferably, each of R ^B3 and/or R ^B3SN is independently selected from chloro, fluoro, bromine, methyl, ethyl, difluoromethyl, trifluoromethyl, C ₁ -C ₃ haloalkoxy, C ₁ -C ₃ alkoxy or C ₁ -C ₃ alkyl. One skilled in the art will understand that in case the ring A is trisubstituted, R ^B3 and R ^B3SN may be the same or different.

In compounds of formula (X) as defined herein, R ^Q1 and R ^Q4 are each hydrogen, and R ^Q2 and R ^Q3 , together with the carbon atoms to which they are attached, form a ring Q, which is an optionally substituted 5-membered thiolactam ring. In preferred embodiments, Q is characterized by the structure Q1 or Q2, wherein "a" denotes the point of attachment to ring A and "c" denotes the point of attachment to the carboxylate moiety.

In preferred embodiments, the Hal substituent in the compound of formula (A) is iodine or bromine.

Compounds of formula (X) can be used as intermediates in the preparation of pharmaceuticals and agrochemicals containing pyrazolopyrrolidone motifs. For example, US 2007/0123508 describes 2-oxo-1-pyrrolidone derivatives for use as PAR2 inhibitors, compounds of formula (X) can be used in the synthesis of such compounds, wherein R ¹ of the compound of US 2007/0123508 is a substituted pyrazole. US 2004/0242671 describes 2-oxo-1-pyrrolidine derivatives for use as therapeutic agents for the treatment of dyskinesia; compounds of formula (X) can be used to prepare such compounds, wherein R ³ of formula (II) of US 2004/0242671 is a di-/tri-substituted pyrazole and R ⁴ is amido.

US 4,874,422 describes 1-phenyl-3-carboxyamidopyrrolidones as herbicides, and the compounds of formula (X) can be used in the preparation of the compounds of formula (I) described therein, but wherein R ³ is a disubstituted pyrazole. The preparation of new herbicidal compounds using compounds of formula (X) is also described in this document.

Thus, in further aspects, the use of a compound of formula (X) in the production of an agrochemical, in particular in the production of a herbicide, as well as the use of a compound of formula (X) in the production of a pharmaceutical, in particular a pharmaceutical for the prevention and/or treatment of diseases and disorders associated with PAR2, and/or the treatment of dyskinesia is provided.

Depending on the desired end product, R ¹ is selected from the group consisting of C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, optionally substituted phenyl, optionally substituted C ₅ -C ₆ heteroaryl, CR ¹² R ¹³ or -C(O)R ¹² ; R ¹² is hydrogen, OH, C ₁ -C ₃ alkoxy or C ₁ -C ₄ alkyl. R ¹³ is -C(O)NH ₂ .

When substituted, said phenyl or _C5 - _C6 heteroaryl is preferably substituted with 1, 2 or 3 ^R11 substituents.

Each R ¹¹ is independently halogen, OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, nitro, cyano or amino.

In one embodiment, R ¹ is 3-CF ₃ -phenyl-.

More preferably R ¹ is C ₁ -C ₃ alkyl or -CR ¹² R ¹³ .

Preferably R ¹² is methyl or ethyl, more preferably ethyl. Most preferably R ¹ is methyl.

Examples of suitable ^R2 substituents include hydrogen, _C1-6alkyl , _-Cralkoxy - _Csalkyl , _C1 - _C6haloalkyl , _-Cralkoxy - _Cshaloalkyl , _C2 - _C6alkenyl ^, _{C2 - C6alkynyl} and -( ^CR21R22 ) _tR20 , wherein each ^R20 is independently -C(O) ^OR23 , -OC(O) ^R23 , _-C3 - _C6cycloalkyl , or an -aryl, -aryloxy-, -heteroaryl, -heteroaryloxy- or -heterocyclyl ring, wherein said ring is optionally substituted with ¹³ independent ^R25 ; r is an integer equal to 1, 2, 3, 4 or 5, s is an integer equal to 1, 2, 3, 4 or 5, and the sum of r+s is less than or equal to 6; t is an integer equal to 0, 1, 2, 3, 4, 5 or 6, each R ²¹ is independently hydrogen or C ₁ -C ₂ alkyl; each R ²² is independently hydrogen or C ₁ -C ₂ alkyl; R ²³ is hydrogen or C ₁ -C ₄ alkyl.

In some embodiments, when R ² is an aryl or heteroaryl ring optionally substituted with 1-3 R ²⁵ , and said aryl or heteroaryl ring is selected from the group consisting of a phenyl, pyridinyl and thienyl ring system, it can be represented by the following general structure, where ring B is a phenyl, pyridinyl, or thienyl ring, p is an integer or 0, 1, 2, or 3, and the broken line represents the point of attachment of the ring to the rest of the molecule, in this case via the amide nitrogen atom.

In some embodiments, R ² is selected from the group consisting of R ^2-1 , R ^2-2 , R ^2-3 , R ^2-4 , R ^2-5 , and R ^2-6 , wherein p and the broken line are as previously described, and each R ²⁵ is independently halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, cyano, nitro, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylsulfinyl, or C ₁ -C ₆ alkylsulfonyl.

More preferably, each R ²⁵ is independently halogen, C ₁ -C ₄ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy or C ₁ -C ₃ haloalkoxy; even more preferably chlorine, fluorine, bromine, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy or C ₁ -C ₂ alkoxy; even more preferably fluorine, ethyl, trifluoromethyl, difluoroethyl, methoxy, difluoromethoxy or trifluoromethoxy. As indicated herein, the value of p is 1, 2 or 3. Preferably, p is 0, 1 or 2, and each R ²⁵ is related to a carbon atom in a ring.

In one particular group of embodiments of compounds of formula (H) and formula (I), p is 2 and at least one R ²⁵ is fluoro.

Preferably, p is 0, 1, or 2, and each R ²⁵ is relative to a carbon atom in the ring.

As indicated above, the compounds of formulae (B), (D), (E), (X), (H) and (I) are novel, as are the compounds of formula (J), and all such compounds form still further aspects of the present invention. Specific examples of such compounds within the scope of the present invention are given in Tables 17 below.

Salt (I) can be prepared as described in Tempahedron Lett. 1995, 36, 9409.

Step 1 Ethyl (E)-3-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]prop-2-enoate

In a large microwave vial, 3-iodo-1-methyl-5-(trifluoromethyl)pyrazole (3.62 mmol, 1.00 g) was dissolved in acetonitrile (15.2 mL) and ethyl acrylate (1.19 mL, 10.9 mmol), triethylamine (0.507 mL, 3.64 mmol), tri-ortho-tolylphosphine (0.362 mmol, 0.110 g), and palladium(II) acetate (0.362 mmol, 0.0813 g) were added, the headspace above the stirred orange solution was purged with nitrogen, and the vial was capped and heated at 110 °C under microwave irradiation for 60 min. The reaction mixture was filtered (washing with small portions of EtOAc), and the combined filtrate and washings were concentrated to remove most of the solvent. The remaining orange-brown liquid was diluted with water (12 mL) and extracted with EtOAc (3 x 15 mL). The organic extracts were combined, washed with water (10 mL), passed through a phase separation cartridge, and then concentrated. Column chromatography (gradient elution with EtOAc/isohexane) gave ethyl (E)-3-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]prop-2-enoate as a yellow oil, 0.51 g (57%).

¹ H NMR: (400 MHz, CDCl ₃ ): δ=7.58 (d, J=16.1 Hz, 1H), 6.81 (s, 1H), 6.43 (d, J=16.1 Hz, 1H), 4.26 (q, J=1.1 Hz, 2H), 4.01 (d, J=0.6 Hz, 3H), 1.33 (t, J=7.1 Hz, 3H).

Step 2 Ethyl 6-methyl-8-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-1,4-dithia-6-azaspiro[4.4]nonane-9-carboxylate

To a suspension of finely ground cesium fluoride (12.7 mmol, 1.93 g) in tetrahydrofuran (9.51 ml) was added dropwise with stirring at -50 °C under nitrogen atmosphere a solution of ethyl (E)-3-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]prop-2-enoate (3.17 mmol, 0.787 g) and 1,3-dithiolan-2-ylidenemethyl-(trimethylsilylmethyl)ammonium trifluoromethanesulfonic acid (5.55 mmol, 2.06 g) in tetrahydrofuran (39.51 ml) over a period of about 15 min, maintaining the reaction temperature below -45 °C. The resulting very pale yellow suspension was allowed to warm slowly to room temperature and stirring was continued overnight. The reaction mixture was then diluted with DCM and filtered, washing with additional portions of DCM. The combined filtrate and washings were concentrated, and the crude material was purified by column chromatography (gradient elution with EtOAc/isohexane) to give ethyl 6-methyl-8-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-1,4-dithia-6-azaspiro[4.4]nonane-9-carboxylate as a pale yellow oil, 566 mg (45%).

¹ H NMR: (400 MHz, CDCl ₃ ): δ=6.45 (s, 1H), 4.31-4.17 (m, 2H), 3.90 (d, J=0.6 Hz, 3H), 3.89-3.79 (m, 2H), 3.35-3.06 (m, 5H), 2.97-2.91 (m, 1H), 2.47 (s, 3H), 1.31 (t, J=7.2 Hz, 3H).

Step 3 1-Methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxopyrrolidine-3-carboxylic acid

To a solution of ethyl 6-methyl-8-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-1,4-dithia-6-azaspiro[4.4]nonane-9-carboxylate (1.43 mmol, 0.566 g) in dioxane (34.3 mL) and water (11.4 mL) was added LiOH (14.3 mmol, 0.343 g), and the stirred mixture was heated to 60 °C under nitrogen for 1 h. The reaction mixture was then cooled to about 35 °C and concentrated to remove most of the dioxane. The residual mixture was diluted with water (10 mL) and partitioned between dilute HCl (5 mL, to pH 3) and DCM (20 mL). The two-phase mixture was filtered to remove fine solids, and the organic phase was separated. The aqueous phase was further extracted with DCM (2×15 mL) and all organic extracts were combined, dried over _MgSO4 , filtered and the filtrate was concentrated to give 1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxopyrrolidine-3-carboxylic acid as a light yellow solid, 399 mg (90%).

¹ H NMR: (400 MHz, CDCl ₃ ): δ=6.66 (s, 1H), 4.19-4.03 (m, 4H), 3.93 (d, J=0.5 Hz, 3H), 3.34 (s, 3H).

Step 4 N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxopyrrolidine-3-carboxamide

To a solution of 1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxopyrrolidine-3-carboxylic acid (0.340 g, 1.11 mmol) in DCM (8.0 mL) was added 2,3-difluoroaniline (0.112 mL, 1.11 mmol) to give a pale yellow solution. Propylphosphonic anhydride (50% by weight) in ethyl acetate (1.88 mmol, 1.12 mL) was added followed by N,N-diisopropylamine (3.32 mmol, 0.578 mL), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then quenched by adding water (2 mL) with stirring, transferred to a separation cartridge, and the organic phases were collected and concentrated. Column chromatography (gradient elution with EtOAc/isohexane) afforded N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxopyrrolidine-3-carboxamide as a colorless crystalline solid, 264 mg (57%).

^1H NMR: (400 MHz, CDCl ₃ ): δ=10.25 (brs, 1H), 8.01 (tdd, J=1.6, 6.6, 8.3 Hz, 1H), 7.04 (ddt, J=2.1, 5.9, 8.3 Hz, 1H), 6.94-6.86 (m, 1H), 6.58 (s, 1H), 4.40 (td, J=6.3, 8.6 Hz, 1H), 4.20 (d, J=6.4 Hz, 1H), 4.13 (dd, 1H), 4.00 (dd, 1H), 3.93 (d, 3H), 3.33 (s, 3H).

Step 5 N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxopyrrolidine-3-carboxamide

To a solution of N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxopyrrolidine-3-carboxamide (0.621 mmol, 0.260 g) in acetonitrile (6.21 mL) stirred and cooled to about 0 °C to -5 °C in an ice/salt bath, 50% hydrogen peroxide (0.746 mL) was added dropwise to give a white suspension. After 5 min, 45% aq. hydrobromic acid (0.0750 mL, 0.621 mmol) was added dropwise and after stirring for 10 min, the mixture was allowed to warm to room temperature. After 3 h, the reaction mixture was recooled to 5 °C and quenched with sodium thiosulfate solution (~10 mL). The mixture was diluted with EtOAc (15 mL) and water (10 mL) and the organic phase was separated. The aqueous phase was further extracted with EtOAc (2 x 10 mL) and the organic extracts were combined, passed through a phase separation cartridge, and concentrated to give a colorless gum. Column chromatography (gradient elution with EtOAc/isohexane) afforded N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxopyrrolidine-3-carboxamide as a white crystalline solid, 210 mg (84%).

^1H NMR: (400 MHz, CDCl ₃ ): δ=10.15 (br s, 1H), 8.04 (dd, J=6.6, 8.3 Hz, 1H), 7.06-6.99 (m, 1H), 6.89 (br dd, J=1.1, 8.6 Hz, 1H), 6.69 (s, 1H), 4.09 (q, 1H), 3.94 (s, 3H), 3.78 (d, J=9.5 Hz, 1H), 3.76-3.65 (m, 2H), 2.98 (d, 3H).

Racemic N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxopyrrolidine-3-carboxamide can be separated to give the enantiomers of (3S,4R)-H-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxopyrrolidine-3-carboxamide and (3R,4S)-N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxopyrrolidine-3-carboxamide using a Chiralpak IA column, 10 x 250 mm, 5 μm, and sc-CO ₂ (solvent A) B = isopropanol (solvent B) as solvents under isocratic conditions: 85% solvent A: 15% solvent B at a rate of 15 ml/min.

Examples of additional herbicidal compounds of formula (I) were prepared using the methods and compounds of the present invention described herein, directly by analogy with N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxopyrrolidine-3-carboxamide as described in Example 1 above. The structures and characteristic NMR data for such compounds are provided in Table 8 below.

Claims (40)

1. Compound of formula (X) where ring A is A ¹ or A ² ; R ^B2 is selected from the group consisting of methyl, ethyl, n-propyl, trifluoromethyl and difluoroethyl; R ^B3SN represents chlorine, fluorine, bromine, methyl, ethyl, difluoromethyl, trifluoromethyl, C ₁ -C ₃ haloalkoxy or C ₁ -C ₃ alkoxy; the broken line indicates the point of attachment to the rest of the compound of formula (X); each of R ^Q1 and R ^Q4 represents hydrogen; and R ^Q2 and R ^Q3 together with the carbon atoms to which they are attached form a Q ring, where the Q ring is Q1 or Q2 where R ¹ is methyl; and "a" denotes the point of attachment to the A ring, and "c" denotes the point of attachment to the carboxylate moiety. 2. A method for producing a compound of formula (X) according to claim 1, wherein said method comprises: (i) reacting a compound of formula (A) with ethyl acrylate under palladium catalysis conditions to obtain a compound of formula (B) , Where (a) the compound of formula (A) is selected from the group consisting of A ^1* and A ^2* , where R ^B2 independently represents methyl, ethyl, n-propyl, trifluoromethyl and difluoroethyl; R ^B3SN represents chloro, fluoro, bromine, methyl, ethyl, difluoromethyl, trifluoromethyl, C ₁ -C ₃ haloalkoxy or C ₁ -C ₃ alkoxy; Hal represents halogen; and (b) ring A in formula (B) is defined in paragraph 1; (ii) reacting the compound of formula (B) from step (i) with a compound of formula (C), wherein R ¹ is methyl, via a cycloaddition reaction mechanism to obtain a mixture of compounds of formula (D) and (E) ; (iii) reacting a compound of formula (E) with a base in the form of a hydroxide in a mixed water/ether solvent system to obtain a compound of formula (X) , where ring A and R ¹ are defined in steps (i) and (ii) above. 3. The method according to paragraph 2, additionally comprising: (iv) reacting the compound of formula (X) from step (iii) with an amine of formula (G) to obtain a thiolactam carboxamide of formula (H) using propanephosphonic anhydride in a suitable solvent and a suitable base , where R ² is selected from the group consisting of R ² -1, R ² -2, R ² -3, R ² -4, R ² -5 and R ² -6 , where p is an integer equal to 0, 1, 2, or 3, and the broken line represents the point of attachment of the ring to the amide nitrogen; and each R ²⁵ is independently halogen, C ₁ -C ₄ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, or C ₁ -C ₃ haloalkoxy. 4. Use of a compound of formula (X) according to claim 1 in the manufacture of a herbicide. 5. Compound of formula (E) , where ring A is A ¹ or A ² ; R ^B2 is C ₁ -C ₃ alkyl or C ₁ -C ₃ fluoroalkyl; R ^B3SN represents chlorine, fluorine, bromine, methyl, ethyl, difluoromethyl, trifluoromethyl, C ₁ -C ₃ haloalkoxy or C ₁ -C ₃ alkoxy; the broken line represents the point of attachment to the rest of the compound of formula (E); and R ¹ is methyl.