Chemical process

Abstract

The present invention provides, inter alia, a process for preparing a compound of formula (I) wherein the substituents are as defined in claim 1.

Description

[0001] CHEMICAL PROCESS

[0002] The present invention relates to a novel process for the synthesis of certain amide and carbamate compounds as well as novel processes to make benzovindiflupyr and isopyrazam. Such amide and carbamate compounds are useful intermediates in the synthesis of benzovindiflupyr and isopyrazam, which are known, for example from WO 2007 / 048556 and WO 2004 / 035589. Processes for making benzovindiflupyr are also known, for example from WO 2011 / 015416. Processes for making isopyrazam are also known, for example from WO 2010 / 072631 .

[0003] The present invention provides a process for the direct formation of acyl anilines from a cyclic 1 ,4-dione which (i) significantly reduces the number of chemical transformations required to make benzovindiflupyr or isopyrazam and (ii) reduces the need to use expensive transition metal catalysts and toxic chemicals. Surprisingly, we have now found that the formation of acyl anilines to deliver the desired amide or carbamate, a compound of formula (I), can be achieved via the process of the present invention which in turn can be further converted to benzovindiflupyr or isopyrazam as required. Such a process is not only more efficient and cost effective but also allows for telescoping with the subsequent hydrolysis of acyl aniline to the corresponding aniline, which is even more environmentally friendly and produces less waste products.

[0004] Thus, according to the present invention there is provided a process for the preparation of a compound of formula (I), wherein,

[0005] R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl, benzyl, phenoxy, benzoxy and 3-(difluoromethyl)-1-methyl-pyrazol-4-yl, wherein said phenyl, benzyl, phenoxy or benzoxy are optionally substituted by 1 , 2 or 3 R2substituents, which may be the same or different; each R2is independently selected from the group consisting of halogen, cyano, hydroxy, Ci-Cealkyl, Ci- Cealkoxy and Ci-Cehaloalkyl;

[0006] A is the group A-l or A-ll and wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I); comprising; reacting a compound of formula (II); wherein A is as defined above for a compound of formula (I), with a compound of formula (III); wherein R1is as defined above for a compound of formula (I) in the presence of a dehydrating agent and / or an acid, to give a compound of formula (I).

[0007] According to a second aspect of the invention, there is provided a compound of formula (l-la), wherein, R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl, benzyl, phenoxy and benzoxy, wherein said phenyl, benzyl, phenoxy or benzoxy are optionally substituted by 1 , 2 or 3 R2substituents, which may be the same or different; each R2is independently selected from the group consisting of halogen, cyano, hydroxy, Ci-Cealkyl, Ci- Cealkoxy and Ci-Cehaloalkyl;

[0008] A is the group A-l or A-ll and wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (l-la); and the compound of formula (l-la) is not N-[11-(dichloromethylene)-3-tricyclo[6.2.1.027]undeca-2,4,6- trienyl]acetamide, N-[11-(dichloromethylene)-3-tricyclo[6.2.1 .027]undeca-2,4,6-trienyl]-2,2-dimethyl- propanamide or N-[11-(dichloromethylene)-3-tricyclo[6.2.1 .027]undeca-2,4,6-trienyl]benzamide.

[0009] According to a third aspect of the invention, there is provided a compound of formula (lib),

[0010] According to a fourth aspect of the invention, there is provided the use of a compound of formula (III), as defined above, for preparing a compound of formula (I).

[0011] As used herein, the term "halogen" refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo).

[0012] As used herein, the term “hydroxyl" or “hydroxy” means an -OH group.

[0013] As used herein, the term "Ci-Cealkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond. Ci-C4alkyl and Ci- C2alkyl are to be construed accordingly. Examples of Ci-Cealkyl include, but are not limited to, methyl, ethyl, n-propyl, 1 -methylethyl (iso-propyl), n-butyl, and 1 -dimethylethyl (f-butyl).

[0014] As used herein, the term "Ci-Cealkoxy" refers to a radical of the formula -ORawhere Rais a Ci-Cealkyl radical as generally defined above. Ci-C4alkoxy is to be construed accordingly. Examples of Ci-4alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy and f-butoxy.

[0015] As used herein, the term "dehydrating reagent" refers to any chemical reagent capable of binding water irreversibly or practically irreversibly, including but not limited to, phosphorus pentoxide, phosphorus pentachloride and silicon tetrachloride.

[0016] As used herein, the term "reaction medium" refers to any solvent of suitable polarity and stability towards components of the reaction mixture or mixture of solvents thereof. The skilled person would appreciate that reactants and reagents used in the processes of the invention may also act as a solvent.

[0017] Where there are more than one process steps, the processes of the present invention can be carried out in separate process steps, wherein the intermediate compounds can be isolated at each stage. Alternatively, the process can be carried out in a one-step procedure wherein the intermediate compounds produced are not isolated. Thus, it is possible for the process of the present invention to be conducted in a batch wise or continuous fashion.

[0018] The following list provides definitions, including preferred definitions, for substituents R1, R2and A with reference to the process according to the invention. For any one of these substituents, any of the definitions given below may be combined with any definition of any other substituent given below or elsewhere in this document.

[0019] R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl, benzyl, phenoxy, benzoxy and 3-(difluoromethyl)-1-methyl-pyrazol-4-yl, wherein said phenyl, benzyl, phenoxy or benzoxy are optionally substituted by 1 , 2 or 3 R2substituents, which may be the same or different. Preferably, R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl, benzyl, phenoxy, benzoxy and 3- (difluoromethyl)-1-methyl-pyrazol-4-yl, wherein said phenyl, benzyl, phenoxy or benzoxy are optionally substituted by 1 or 2 R2substituents, which may be the same or different. More preferably, R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl, benzyl, phenoxy, benzoxy and 3- (difluoromethyl)-1-methyl-pyrazol-4-yl. Even more preferably, R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl, phenoxy and 3-(difluoromethyl)-1-methyl-pyrazol-4-yl. Yet even more preferably, R1is selected from the group consisting of methyl, methoxy, ethoxy, phenyl, phenoxy and 3-(difluoromethyl)-1-methyl-pyrazol-4-yl. Yet even more preferably still, R1is selected from the group consisting of methoxy, ethoxy and 3-(difluoromethyl)-1-methyl-pyrazol-4-yl. Most preferably, R1is methoxy or ethoxy. each R2is independently selected from the group consisting of halogen, cyano, hydroxy, Ci-Cealkyl, Ci- Cealkoxy and Ci-Cehaloalkyl. Preferably, each R2is independently selected from the group consisting of halogen, hydroxy, Ci-Cealkyl and Ci-Cealkoxy. More preferably, each R2is independently selected from the group consisting of halogen and Ci-Cealkyl. Even more preferably, each R2is independently selected from the group consisting of chloro, bromo, methyl and ethyl. Even more preferably still, each R2is independently selected from the group consisting of chloro and methyl.

[0020] A is the group A-l or A-ll and wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I).

[0021] In one embodiment A is the group A-l.

[0022] In another embodiment A is the group A-ll.

[0023] Scheme 1 below describes the reactions of the invention in more detail. The substituent definitions are as defined herein.

[0024] Scheme 1 :

[0025] Step (a) Acyl aniline formation:

[0026] Compounds of formula (I) can be prepared by reacting a compound of formula (II) wherein A is as defined herein, with a compound of formula (III); wherein R1is as defined herein, in the presence of a dehydrating agent and / or an acid, to give a compound of formula (I).

[0027] Typically the process described in step (a) is carried out in a suitable reaction medium. Preferably, the process described in step (a) is carried out in a suitable reaction medium selected from the group consisting of sulfolane, glycol diethers, chlorobenzene, anisol, N-methyl-2-pyrrolidone and methanesulfonic acid. More preferably, the process described in step (a) is carried out in a suitable reaction medium selected from the group consisting of sulfolane, diethylene glycol dimethyl ether (diglyme), chlorobenzene, anisol and methanesulfonic acid. Even more preferably, the process described in step (a) is carried out in a suitable reaction medium, wherein the suitable reaction medium is sulfolane.

[0028] The skilled person would understand that in the process described in step (a) the dehydrating agent and / or the acid may act as a suitable reaction medium, for example, but not limited to methane sulfonic acid.

[0029] Preferably, the dehydrating agent is selected from the group consisting of phosphorous chlorides, phosphorous oxychlorides, phosphorus pentoxide (known as P2O5 or P4O10), chlorosilanes, thionyl chloride, acid halides and acid anhydrides. More preferably, the dehydrating agent is selected from the group consisting of phosphorus pentachloride, phosphorus pentoxide, silicon tetrachloride, dimethyldichlorosilane, thionyl chloride, acetyl chloride and acetic anhydride. Even more preferably, the dehydrating agent is silicon tetrachloride or phosphorus pentoxide. The skilled person would understand that sub-stoichiometric amounts of the dehydrating reagent or acid can be used based on a compound of formula (II) (for example, but not limited to, from 0.5 to 0.9 equivalents). Preferably, from 1 to 2 equivalents of the dehydrating reagent or acid are used based on a compound of formula (II). More preferably, from 1 to 1 .5 equivalents of the dehydrating reagent or acid are used based on a compound of formula (II).

[0030] Typically, the dehydrating reagent may be added in any number of alternative ways, such as, but not limited to, a single charge, multiple charges over a period of time and / or continuously over a period of time. Preferably, the dehydrating reagent is added in multiple charges.

[0031] The skilled person would understand that the reaction can be performed batch-wise, wherein all the reactants and reagents are pre-charged and the reaction mixture is heated. Alternatively, the skilled person would also understand that the compound of formula (II) can also be added as a suspension or solution in a suitable reaction medium (for example, but not limited to sulfolane) to a compound of formula (III) and the dehydrating reagent or acid. Alternatively, the compound of formula (II) and the dehydrating reagent and / or acid can be added to a compound of formula (III). Likewise, the skilled person would also understand that the dehydrating reagent and / or acid could be added to a suspension or solution of a compound of formula (II) and a compound of formula (III).

[0032] The skilled person will appreciate that the period of time over which the dehydrating reagent is added will be dependent upon a number of different factors, such as, the scale of the reaction, the temperature of the reaction, the stirring speed, the wt% concentration of a compound of formula (II) and / or the wt% concentration of the compound of formula (III).

[0033] Preferably, the acid is a bronstead or lewis acid. More preferably, the bronstead or lewis acid is selected from the group consisting of sulfuric acid, methanesulfonic acid, aluminium trichloride, zinc chloride, magnesium chloride and zirconium (IV) chloride. Even more preferably, the acid is a bronstead acid selected from sulfuric acid or methanesulfonic acid.

[0034] Typically, the acid is present in a sub-stoichiometric amount (when used in combination with a dehydrating reagent). Preferably, the acid is present in an amount of from 0.5 mol% to 40 mol% based on a compound of formula (II). More preferably, the acid is present in an amount of from 1 mol% to 30 mol% based on a compound of formula (II). Even more preferably, the acid is present in an amount of from 2 mol% to 20 mol% based on a compound of formula (II).

[0035] The skilled person would also understand that the dehydrating reagents may also generate acids upon reaction with water, for example, wherein the dehydrating reagent is phosphorus pentoxide (P2O5), phosphoric acid (H3PO4) may be generated in the process of the invention.

[0036] In one embodiment, the compound of formula (II) is reacted with a compound of formula (III) in the presence of a dehydrating reagent and an acid. Typically, at least one (preferably, more than one) equivalent of a compound of formula (III) is used based on a compound of formula (II). Preferably, from 1 to 3 equivalents of a compound of formula (III) is used based on a compound of formula (II). More preferably, from 1.1 to 2 equivalents of a compound of formula (III) is used based on a compound of formula (II). Even more preferably, from 1.2 to 1.8 equivalents of a compound of formula (III) is used based on a compound of formula (II). Yet even more preferably, from 1.2 to 1.6 equivalents of a compound of formula (III) is used based on a compound of formula (II).

[0037] Typically, the compound of formula (I) may be isolated by crystallisation (after cooling the suitable reaction medium to room temperature) or also by distillation.

[0038] Typically this step can be carried out at a temperature of from 30 °C to 250 °C, preferably, from 60 °C to 200 °C, more preferably from 70 °C to 150 °C, even more preferably from 80 °C to 130 °C.

[0039] Scheme 2:

[0040] Step (b) hydrolysis:

[0041] Compounds of formula (IV) can be prepared by hydrolysis of a compound of formula (I).

[0042] The hydrolysis can be performed using methods known to a person skilled in the art. The hydrolysis is typically performed using suitable conditions, including, but not limited to basic conditions (such as aqueous sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate), or acidic conditions (such as aqueous sulfuric acid). Preferably, the process described in step (b) is carried out in basic conditions. More preferably, the process described in step (b) is carried out with an alkali metal hydroxide base or alkali metal carbonate base Even more preferably, the process described in step (b) is carried out with a base selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. Even more preferably, still the the process described in step (b) is carried out with sodium hydroxide. Typically the process described in step (b) is carried out in the absence of additional solvent, or in the presence of a solvent, or mixture of solvents, such as but not limited to, water, acetic acid, propionic acid, methanol, ethanol, propanol, isopropanol, tert-butanol, butanol, 3-methyl-1 -butanol or sulfolane.

[0043] The skilled person would appreciate that the choice of solvent for the process described in step (b) will depend upon whether basic or acidic coniditons are used.

[0044] In a preferred embodiment the process described in step (a) and the process described in step (b) are carried out in the same solvent or mixture of solvents.

[0045] In a preferred embodiment the compound of formula (IV) is isolated by distillation. Preferably, the compound of formula (IV) is isolated by distillation using a displacer (for example, but not limited to, bis(2-ethylhexyl) adipate, bis(2-ethylhexyl) phthalate or bis(2-propylheptyl) phthalate). The skilled person would understand that the displacer can be any substance with a boiling point higher than a compound of formula (IV) to isolate (IV) out of the distillation residue.

[0046] In another embodiment, the compound of formula (IV) is isolated by crystallisation either as a free aniline or as a salt thereof (for example, but not limited to, hydrochloride, sulfate, hydrosulfate or oxalate).

[0047] In another preferred embodiment, there is provided a process comprising steps (a) and (b) as described above, wherein the compound of formula (I) is not isolated.

[0048] Typically this step can be carried out at a temperature of from 30 °C to 200 °C, preferably, from 60 °C to 150 °C, more preferably from 80 °C to 130 °C, even more preferably from 80 °C to 120 °C.

[0049] Furthermore, the skilled person would understand that the process described in step (b) may be accelerated when operating under pressure in a closed vessel.

[0050] Scheme 3: Step (c) - Amide coupling:

[0051] Compounds of formula (la) can be prepared by reacting a compound of formula (IV) with a compound of formula (V) as shown in Scheme 3 above, wherein A is as defined herein and LG is a suitable leaving group (for example, but not limited to, chloro, bromo, acetate or benozoate.). In a preferred embodiment LG is bromo or chloro, preferably chloro.

[0052] This coupling, described in step (c) can be performed using methods known to the person skilled in the art, for example this process is disclosed in WO 2011 / 131544, see for example, page 19 step (f) and also in WO 2011 / 131545 page 21 step (g). For example, the process described in step (c) can be carried out in the presence of a base (for example but not limited to triethylamine) and in a suitable solvent (for example but not limited to xylene). Typically this step can be carried out at a temperature of from 30 °C to 200 °C, preferably, from 60 °C to 150 °C, more preferably from 60 °C to 130 °C, even more preferably from 80 °C to 120 °C.

[0053] The skilled person would appreciate that compounds of formula (la) may exist in two enantiomeric forms (lb) or (Ic) below,

[0054] (lb) (Ic) this invention covers processes to prepare all such isomers and mixtures thereof in all proportions from the compound (II).

[0055] The skilled person would appreciate that the temperature of the process according to the invention can vary in each of steps (a), (b) and (c). Furthermore, this variability in temperature may also reflect the choice of solvent used. Likewise, the skilled person would also appreciate that the pressure of the process according to the invention can vary in each of steps (a), (b) and (c) depending on the choice of solvent and temperature used.

[0056] Preferably, the process of the present invention is carried out under an inert atmosphere, such as nitrogen or argon. The skilled person would appreciate that process steps (a), (b) and (c) can be carried out in separate process steps, wherein the intermediate compounds can be isolated at each stage. Alternatively, the process steps (a), (b) and (c) can be carried out in a telescoped procedure wherein the intermediate compounds produced are not isolated. Thus, it is possible for the process of the present invention to be conducted in a batch wise, semi-batch wise or continuous fashion.

[0057] In a preferred embodiment of the invention there is provided a process forthe preparation of a compound of formula (I), wherein,

[0058] R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl, benzyl, phenoxy, benzoxy and 3-(difluoromethyl)-1-methyl-pyrazol-4-yl, wherein said phenyl, benzyl, phenoxy or benzoxy are optionally substituted by 1 , 2 or 3 R2substituents, which may be the same or different; each R2is independently selected from the group consisting of halogen, hydroxy, Ci-Cealkyl and Ci- Cealkoxy;

[0059] A is the group A-l or A-ll (preferably, A-l) and wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I); comprising; reacting a compound of formula (II); (II) wherein A is as defined above for a compound of formula (I), with a compound of formula (III); wherein R1is as defined above for a compound of formula (I) in the presence of a dehydrating agent and / or an acid, to give a compound of formula (I).

[0060] Preferably, there is provided a process for the preparation of a compound of formula (I), wherein,

[0061] R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl, benzyl, phenoxy, benzoxy and 3-(difluoromethyl)-1-methyl-pyrazol-4-yl, wherein said phenyl, benzyl, phenoxy or benzoxy are optionally substituted by 1 or 2 R2substituents, which may be the same or different; each R2is independently selected from the group consisting of halogen and Ci-Cealkyl;

[0062] A is the group A-l or A-ll (preferably, A-l) and wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I); comprising; reacting a compound of formula (II); wherein A is as defined above for a compound of formula (I), with a compound of formula (III); wherein R1is as defined above for a compound of formula (I) in the presence of a dehydrating agent and / or an acid, to give a compound of formula (I).

[0063] More preferably, there is provided a process for the preparation of a compound of formula (Id), wherein,

[0064] R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl, benzyl, phenoxy, benzoxy and 3-(difluoromethyl)-1 -methyl-pyrazol-4-yl; comprising; reacting a compound of formula (Ila); (Ila) with a compound of formula (III); wherein R1is as defined above for a compound of formula (Id) in the presence of a dehydrating agent and / or an acid, to give a compound of formula (Id).

[0065] Even more preferably, there is provided a process for the preparation of a compound of formula (Id), wherein,

[0066] R1is selected from the group consisting of Ci-Csalkyl, Ci-Csalkoxy, phenyl, phenoxy and 3- (difluoromethyl)-1-methyl-pyrazol-4-yl; comprising; reacting a compound of formula (Ila); with a compound of formula (III); wherein R1is as defined above for a compound of formula (Id) in the presence of a dehydrating agent and / or an acid, and wherein the dehydrating agent is selected from the group consisting of phosphorous chlorides, phosphorous oxychlorides, phosphorous oxides, chlorosilanes, thionyl chloride, acid halides and acid anhydrides, and the acid is a bronstead or lewis acid selected from the group consisting of sulfuric acid, methanesulfonic acid, aluminium trichloride, zinc chloride, magnesium chloride and zirconium (IV) chloride; to give a compound of formula (Id).

[0067] Even more preferably still, there is provided a process for the preparation of a compound of formula (Id), wherein,

[0068] R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl, phenoxy and 3- (difluoromethyl)-1-methyl-pyrazol-4-yl (preferably methyl, methoxy, ethoxy, phenyl, phenoxy and 3- (difluoromethyl)-1-methyl-pyrazol-4-yl); comprising; reacting a compound of formula (Ila); with a compound of formula (III); wherein R1is as defined above for a compound of formula (Id) in the presence of a dehydrating agent and / or an acid, wherein the dehydrating agent is selected from the group consisting of sulfuric acid, phosphorus pentachlonde, phosphorus pentoxide, silicon tetrachloride, dimethyldichlorosilane, thionyl chloride, acetyl chloride and acetic anhydride, and the acid is a bronstead or lewis acid selected from the group consisting of sulfuric acid, methanesulfonic acid, aluminium trichloride, zinc chloride, magnesium chloride and zirconium (IV) chloride, and wherein the process is carried out in a suitable reaction medium selected from the group consisting of sulfolane, glycol diethers, chlorobenzene, anisol, N-methyl-2-pyrrolidone and methanesulfonic acid (preferably, sulfolane) to give a compound of formula (Id).

[0069] In another preferred embodiment, there is provided a process for the preparation of a compound of formula (le), wherein,

[0070] R1is selected from the group consisting of Ci-Cealkyl, Ci-Csalkoxy, phenyl, benzyl, phenoxy, benzoxy and 3-(difluoromethyl)-1 -methyl-pyrazol-4-yl; comprising; reacting a compound of formula (lib); with a compound of formula (III); wherein R1is as defined above for a compound of formula (le) in the presence of a dehydrating agent and / or an acid, to give a compound of formula (le).

[0071] Even more preferably, there is provided a process for the preparation of a compound of formula (le), wherein,

[0072] R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl, phenoxy and 3- (difluoromethyl)-1-methyl-pyrazol-4-yl; comprising; reacting a compound of formula (lib); with a compound of formula (III);

[0073] O

[0074] H2N^^R1

[0075] (III) wherein R1is as defined above for a compound of formula (le) in the presence of a dehydrating agent and / or an acid, and wherein the dehydrating agent is selected from the group consisting of phosphorous chlorides, phosphorous oxychlorides, phosphorous oxides, chlorosilanes, thionyl chloride, acid halides and acid anhydrides, and the acid is a bronstead or lewis acid selected from the group consisting of sulfuric acid, methanesulfonic acid, aluminium trichloride, zinc chloride, magnesium chloride and zirconium (IV) chloride; to give a compound of formula (le).

[0076] Even more preferably still, there is provided a process for the preparation of a compound of formula (le), wherein,

[0077] R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl, phenoxy and 3- (difluoromethyl)-1-methyl-pyrazol-4-yl (preferably methyl, methoxy, ethoxy, phenyl, phenoxy and 3- (difluoromethyl)-1-methyl-pyrazol-4-yl); comprising; reacting a compound of formula (lib); with a compound of formula (III); wherein R1is as defined above for a compound of formula (le) in the presence of a dehydrating agent and / or an acid, wherein the dehydrating agent is selected from the group consisting of sulfuric acid, phosphorus pentachloride, phosphorus pentoxide, silicon tetrachloride, dimethyldichlorosilane, thionyl chloride, acetyl chloride and acetic anhydride, and the acid is a bronstead or lewis acid selected from the group consisting of sulfuric acid, methanesulfonic acid, aluminium trichloride, zinc chloride, magnesium chloride and zirconium (IV) chloride, and wherein the process is carried out in a suitable reaction medium selected from the group consisting of sulfolane, glycol diethers, chlorobenzene, amsol, N-methyl-2-pyrrohdone and methanesulfonic acid (preferably, sulfolane) to give a compound of formula (le).

[0078] In another preferred embodiment there is provided a process for the preparation of a compound of formula (IV), wherein,

[0079] A is the group A-l or A-ll

[0080] A-l A-ll and the jagged line defines the point of attachment to the remaining part of a compound of formula (I); comprising the steps of;

[0081] (a) reacting a compound of formula (II); wherein A is as defined above for a compound of formula (IV), with a compound of formula (III); wherein,

[0082] R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl, benzyl, phenoxy, benzoxy and 3-(difluoromethyl)-1 -methyl-pyrazol-4-yl; in the presence of a dehydrating agent and / or an acid, to give a compound of formula (I) wherein A is as defined above for a compound of formula (IV) and R1is as defined above for a compound of formula (III), and,

[0083] (b) hydrolysis (preferably, hydrolysis in basic conditions, more preferably, hydrolysis with an alkali metal hydroxide base or alkali metal carbonate base) to a compound of formula (IV).

[0084] In another preferred embodiment there is provided a process for the preparation of a compound of formula (la), wherein,

[0085] A is the group A-l or A-ll (preferably, A is the group A-l)

[0086] A-ll and the jagged line defines the point of attachment to the remaining part of a compound of formula (I); comprising the steps of;

[0087] (a) reacting a compound of formula (II); wherein A is as defined above for a compound of formula (la), with a compound of formula (III); wherein,

[0088] R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl and phenoxy (preferably, R1is selected from the group consisting of methyl, methoxy, ethoxy phenyl and phenoxy); in the presence of a dehydrating agent and / or an acid, to give a compound of formula (I) wherein A is as defined above for a compound of formula (la) and R1is as defined above for a compound of formula (III),

[0089] (b) hydrolysis to a compound of formula (IV), (IV) wherein A is as defined above for a compound of formula (la) and

[0090] (c) reacting a compound of formula (IV) with a compound of formula (V), wherein LG is a suitable leaving group (preferably, chloro or bromo, more preferably chloro) to give a compound of formula (la).

[0091] In another preferred embodiment there is provided a process for the preparation of a compound of formula (Ig), comprising the steps of;

[0092] (a) reacting a compound of formula (Ila); with a compound of formula (III); wherein,

[0093] R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl and phenoxy (preferably, R1is selected from the group consisting of methyl, methoxy, ethoxy phenyl and phenoxy); in the presence of a dehydrating agent and / or an acid, to give a compound of formula (Id) wherein R1is as defined above for a compound of formula (III), and (b) hydrolysis to a compound of formula (IVa), and

[0094] (c) reacting a compound of formula (IVa) with a compound of formula (V), wherein LG is a suitable leaving group (preferably, chloro or bromo, more preferably chloro) to give a compound of formula (Ig).

[0095] In another embodiment there is provided a compound of formula (l-la),

[0096] (l-la) wherein R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl, benzyl, phenoxy and benzoxy wherein said phenyl, benzyl, phenoxy or benzoxy are optionally substituted by 1 , 2 or 3 R2substituents (preferably optionally substituted by 1 or 2 R2substituents), which may be the same or different; each R2is independently selected from the group consisting of halogen, cyano, hydroxy, Ci-Cealkyl, Ci- Cealkoxy and Ci-Cehaloalkyl (preferably, each R2is independently selected from the group consisting of halogen and Ci-Cealkyl);

[0097] A is the group A-l or A-ll

[0098] A-l A-ll and wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (l-la), with the proviso that the compound of formula (l-la) is not

[0099] N-[11-(dichloromethylene)-3-tricyclo[6.2.1 ,02 7]undeca-2,4,6-trienyl]acetamide, N-[11-(dichloromethylene)-3-tricyclo[6.2.1 .02 7]undeca-2,4,6-trienyl]-2,2-dimethyl-propanamide or

[0100] N-[11-(dichloromethylene)-3-tricyclo[6.2.1 ,02 7]undeca-2,4,6-trienyl]benzamide.

[0101] Preferably, there is provided a compound of formula (l-la), wherein

[0102] R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl, benzyl, phenoxy and benzoxy;

[0103] A is the group A-l or A-ll (preferably A is the group A-l)

[0104] A-l A-ll and wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (l-la), with the proviso that the compound of formula (l-la) is not

[0105] N-[11-(dichloromethylene)-3-tricyclo[6.2.1.027]undeca-2,4,6-trienyl]acetamide,

[0106] N-[11-(dichloromethylene)-3-tricyclo[6.2.1.027]undeca-2,4,6-trienyl]-2,2-dimethyl-propanamide or

[0107] N-[11-(dichloromethylene)-3-tricyclo[6.2.1.027]undeca-2,4,6-trienyl]benzamide.

[0108] More preferably, there is provided a compound of formula (l-la), d-la) wherein

[0109] R1is selected from the group consisting of ethyl, methoxy, ethoxy and phenoxy (preferably R1is methoxy or ethoxy); A is the group A-l or A-ll (preferably A is the group A-l) and wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (l-la).

[0110] Even more preferably, the compound of formula (l-la) is selected from the group consisting of a compound of formula (l-l), (l-ll), (l-lll), (l-IV), (l-V) and (l-VI) below,

[0111] Even more preferably still, the compound of formula (l-la) is a compound of formula (l-l) or (l-ll) below,

[0112] (l-ll) Most preferably, the compound of formula (l-la) is a compound of formula (l-l), In another preferred embodiment, the compound of formula (l-la) is a compound of formula (l-IV),

[0113] (I-IV)

[0114] In another embodiment of the invention there is provided a compound of formula (lib),

[0115] In another embodiment of the invention there is provided the use of a compound of formula (III), wherein, R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl, benzyl, phenoxy, and benzoxy, wherein said phenyl, benzyl, phenoxy or benzoxy are optionally substituted by 1 , 2 or 3 R2substituents, which may be the same or different; and each R2is independently selected from the group consisting of halogen, cyano, hydroxy, Ci-Cealkyl, Ci- Cealkoxy and Ci-Cehaloalkyl, for preparing a compound of formula (I).

[0116] Preferably, there is provided the use of a compound of formula (III), wherein,

[0117] R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl, benzyl, phenoxy and benzoxy, wherein said phenyl, benzyl, phenoxy or benzoxy are optionally substituted by 1 or 2 R2substituents, which may be the same or different; and each R2is independently selected from the group consisting of halogen and Ci-Cealkyl, for preparing a compound of formula (I).

[0118] More preferably, there is provided the use of a compound of formula (III), wherein,

[0119] R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl, benzyl, phenoxy, and benzoxy, wherein said phenyl, benzyl, phenoxy or benzoxy are optionally substituted by 1 or 2 R2substituents, which may be the same or different; and each R2is independently selected from the group consisting of chloro and methyl, for preparing a compound of formula (I).

[0120] In another embodiment of the invention there is provided, a process for the preparation of the compound of formula (If)

[0121] which process comprises a) reacting the compound of formula (VI) with the compound of formula (VII) to the compound of formula (VIII)

[0122] (VIII), b) hydrogenating the compound of formula (VIII) to the compound of formula (lib) c) reacting the compound of formula (lib) with a compound of formula (III); wherein R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl and phenoxy (preferably, R1is selected from the group consisting of methyl, methoxy, ethoxy, phenyl and phenoxy, more preferably, R1is methoxy or ethoxy); in the presence of a dehydrating agent and / or an acid, to give a compound of formula (le-l)

[0123] (le-l) wherein R1is as defined above for a compound of formula (III), (d) hydrolysis to a compound of formula (IVb), and

[0124] (e) reacting a compound of formula (IVb) with a compound of formula (V), wherein LG is a suitable leaving group (preferably, chloro or bromo, more preferably chloro) to give a compound of formula (If). Preferably, there is provided, a process for the preparation of the compound of formula (If) which process comprises a) reacting the compound of formula (VI) in a suitable solvent (preferably a protic solvent, more preferably ethanol) with the compound of formula (VII) to the compound of formula (VIII)

[0125] (VIII), b) hydrogenating the compound of formula (VIII) in the presence of a metal catalyst (preferably, Pd / C) to the compound of formula (lib) c) reacting the compound of formula (lib) with a compound of formula (III); wherein R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl and phenoxy (preferably, R1is selected from the group consisting of methyl, methoxy, ethoxy, phenyl and phenoxy, more preferably, R1is methoxy or ethoxy); in the presence of a dehydrating agent and / or an acid, and wherein the dehydrating agent is selected from the group consisting of phosphorous chlorides, phosphorous oxychlorides, phosphorous oxides, chlorosilanes, thionyl chloride, acid halides and acid anhydrides, and the acid is a bronstead or lewis acid selected from the group consisting of sulfuric acid, methanesulfonic acid, aluminium trichloride, zinc chloride, magnesium chloride and zirconium (IV) chloride; to give a compound of formula (le-l) wherein R1is as defined above for a compound of formula (III),

[0126] (d) hydrolysis (preferably carried out with an alkali metal hydroxide base or alkali metal carbonate base) to a compound of formula (IVb), and

[0127] (e) reacting a compound of formula (IVb) with a compound of formula (V), wherein LG is a suitable leaving group (preferably, chloro or bromo, more preferably chloro) to give a compound of formula (If).

[0128] Examples:

[0129] The following examples further illustrate, but do not limit the invention. Those skilled in the art will promptly recognise appropriate variations from the procedures both as to the reactants and as to the reaction conditions and techniques.

[0130] The following abbreviations are used: s = singlet; br s = broad singlet; d = doublet; dd = double doublet; dt = double triplet; t = triplet, tt = triple triplet, q = quartet, quin = quintuplet, sept = septet; m = multiplet; GC = gas chromatography, RT = retention time, Ti = internal temperature, MH+= molecular mass of the molecular cation, M = molar, Q1HNMR = quantitative1H Nuclear Magnetic Resonance, RT = room temperature, UFLC = Ultra-fast liquid chromatography.1H NMR spectra are recorded at 400 MHz unless indicated otherwise and chemical shifts are recorded in ppm.

[0131] Some chemical yields have been calculated precisely using quantitative 1 H NMR and 1 ,3,5- trimethoxybenzene as an internal standard.

[0132] Example 1 - Preparation of 11-(dichloromethylene)tricyclo[6.2.1.02 71undeca-2,4,6-trien-3-amine (a compound of formula (IVa))

[0133] A double jacketed reactor equipped with a mechanical stirrer, thermometer and reflux condenser was warmed to 40° C and loaded with molten sulfolane (177.6 g), methyl carbamate (45.8 g, 0.599 mol), 11- (dichloromethylene)tricyclo[6.2.1.02 7]undecane-3, 6-dione (100.0 g, 0.374 mol, 97%) and methanesulfonic acid (7.3 g, 5.0 mL). The resulting mixture was heated to 100°C followed by the addition of phosphorous pentoxide (53.4 g, 0.374 mol) in 5 equal portions with an interval of 15 min while keeping the temperature at 100-105°C. The reaction mixture was stirred at 100°C for 4 h then cooled to 80°C. A solution of sodium hydroxide (49.9 g, 0.374 mol, 30%) was added in 20 min while keeping the temperature at 80-85°C. Water (5.2 g) was added. Then stirring was stopped and the aqueous (lower) phase was separated. The organic phase was discharged (302.7 g) and analysed by quantitative1H NMR in Methanol-cL? with tetrachloroethane as an internal standard. The concentration of methyl A / -[11 -

[0134] 2 7

[0135] (dichloromethylene)-3-tricyclo[6.2.1 .0 ]undeca-2,4,6-trienyl]carbamate was 31.5%and the yield was 86% .

[0136] 1H NMR (400 MHz, CD3OD) 6 ppm: 7.29 (broad d, J = 8.1 Hz, 1 H), 7.10 (m, 1 H), 6.99 (d, J = 7.3 Hz, 1 H), 4.12 (broad d, J = 2.8 Hz, 1 H), 3.92 (broad d, J = 2.8 Hz, 1 H), 3.74 (s, 3H), 2.02 - 2.10 (m, 2H), 1 .44 - 1 .50 (m, 1 H), 1 .29 - 1 .35 (m, 1 H), N-H is not visible due to exchange with deuterium.

[0137] 1H NMR (400 MHz, CDCb) 6 ppm: 7.46 (broad m, 1 H), 7.14 (m, 1 H), 6.99 (d, J = 7.3 Hz, 1 H), 6.47 (broad s, 1 H), 3.97 (broad d, J = 2.4 Hz, 1 H), 3.94 (broad d, J = 2.4 Hz, 1 H), 3.81 (s, 3H) 2.05 - 2.14 (m, 2H), 1.33 - 1.51 (m, 2H).

[0138] 13C NMR (100.6 MHz, CDCb) 6 ppm: 154.3, 151.1 , 145.9, 130.2, 127.4, 119.3, 116.7, 103.6, 52.5, 47.2, 43.9, 26.6, 25.9. One signal is missing either due to overlap with a different signal or due to its low intensity. (CDCb 6 = 77.00 ppm) The organic phase was placed back in the reactor and the jacket temperature was set to 80°C. Aqueous sodium hydroxide solution (173.2 g, 1.3 mol, 3.5 eq, 30%) was added in one portion and the mixture was heated at jacket temperature of 130°C for 5 h. Methanol was allowed to distil off from the mixture to attain the internal temperature of 106-107°C. A sample of the reaction mixture was taken and analysed by HPLC indicating >99% conversion to the title compound. The mixture was cooled to 80°C and water (29 g) was added. Then stirring was stopped and the aqueous (lower) phase was separated. The organic phase was discharged (288.5 g) and analysed by quantitative1H NMR in Methanol-cf? with tetrachloroethane as standard. The concentration of 11- (dichloromethylene)tricyclo[6.2.1.02 7]undeca-2,4,6-trien-3-amine was 26.9%. Quantitative yield.

[0139] 1H NMR (400 MHz, CD3OD) 6 ppm: 6.86 - 6.91 (m, 1 H), 6.53 - 6.59 (m, 2H), 4.09 (broad d, J = 2.8 Hz, 1 H), 3.82 (broad d, J = 2.8 Hz, 1 H), 1 .98 - 2.06 (m, 2H), 1 .25 - 1 .41 (m, 2H), NH2is not visible due to exchange with deuterium.

[0140] Distillation

[0141] The crude 11-(dichloromethylene)tricyclo[6.2.1.02 7]undeca-2,4,6-trien-3-amine solution (264.3 g) was freed of volatile components (water, residual amount of methanol) by rotary evaporation at 70°C and 1 mbar. The resulting solution (232.2 g, 26.9%) was mixed with bis(2-ethylhexyl) adipate (23.1 g; fluidizer and displacer) and the resulting mixture was fractioned in vacuum (2 — > 1 .5 mbar) via 20-cm distillation column packed with raschig rings to result in the title compound (61.2 g, b.p. 140-143°C).1H NMR in Methanol-c / 4 with tetrachloroethane as standard. The chemical purity was 94%.

[0142] 1H NMR (400 MHz, CD3OD) 6 ppm: 6.87 - 6.91 (m, 1 H), 6.53 - 6.59 (m, 2H), 4.09 (broad d, J = 2.8 Hz, 1 H), 3.82 (broad d, J = 2.8 Hz, 1 H), 1 .98 - 2.06 (m, 2H), 1 .24 - 1 .41 (m, 2H), NH2is not visible due to exchange with deuterium.

[0143] 1H NMR (400 MHz, DMSO-c / 6) 6 ppm: 6.78 - 6.82 (m, 1 H), 6.38 - 6.45 (m, 2H), 5.10 (s, 2H) 4.12 (broad d, J = 2.4 Hz, 1 H), 3.77 (broad d, J = 2.7 Hz, 1 H), 1.90 - 2.03 (m, 2H), 1.17 - 1.29 (m, 2H).

[0144] Example 2 - Preparation of methyl N-[11-(dichloromethylene)-3-tricyclo[6.2.1.02 71undeca-2,4,6- trienyllcarbamate (a compound of formula (l-D)

[0145] A screw cap septum vial was charged with molten sulfolane (1.87 g), 11-

[0146] (dichloromethylene)tricyclo[6.2.1.02 7]undecane-3, 6-dione (1.073 g, 4.00 mmol, 97%), methyl carbamate (0.497 g, 6.40 mol) and concentrated sulfuric acid (0.56 mL, 1 .03 g, 10.5 mmol). The resulting mixture was stirred at 100°C for 3 h.1H NMR analysis of the reaction mixture (400 MHz, Methanol-d6) indicated 43% chemical yield of the title compound (sulfolane was used as standard)

[0147] Example 2a - Preparation of methyl N-[11-(dichloromethylene)-3-tricyclo[6.2.1.02 71undeca-2,4,6- trienyllcarbamate

[0148] A screw cap septum vial was charged with molten sulfolane (4.02 g), 11-

[0149] (dichloromethylene)tricyclo[6.2.1.02 7]undecane-3, 6-dione (1.074 g, 4.00 mmol, 97%), methyl carbamate (0.493 g, 6.40 mol), methanesulfonic acid (0.053 mL, 0.8 mmol) and silicon tetrachloride (0.56 mL, 0.824 g, 4.8 mmol). The septum was pierced with a needle (to release HCI formed during the reaction) and heated at 100°C for 3 h.1H NMR analysis of the reaction mixture (400 MHz, Methanol-d6) indicated 73% chemical yield of the title compound (sulfolane was used as standard)

[0150] Example 2b - Preparation of methyl N-[11-(dichloromethylene)-3-tricyclo[6.2.1.02 71undeca-2,4,6- trienyllcarbamate

[0151] A screw cap septum vial was charged with chlorobenezene (2.0 mL), 11- (dichloromethylene)tricyclo[6.2.1.02 7]undecane-3, 6-dione (543 mg, 2.03 mmol, 97%), methyl carbamate (0.309 g, 4.03 mol), 1 ,2-dichlorobenzene (195.6 mg, internal standard), methanesulfonic acid (0.027 mL, 0.4 mmol) and silicon tetrachloride (0.276 mL, 0.409 g, 2.4 mmol). The septum was pierced with a needle (to release HCI formed during the reaction) and heated at 100°C for 1 h. HPLC analysis of the reaction mixture indicated 34% chemical yield of the title compound.

[0152] Example 2c - Preparation of methyl N-[11-(dichloromethylene)-3-tricyclo[6.2.1.02 71undeca-2,4,6- trienyllcarbamate

[0153] A screw cap septum vial was charged with anisole (2.0 mL), 11- (dichloromethylene)tricyclo[6.2.1.02 7]undecane-3, 6-dione (545 mg, 2.04 mmol, 97%), methyl carbamate (0.317 g, 4.14 mol), 1 ,2-dichlorobenzene (215.4 mg, internal standard), methanesulfonic acid (0.027 mL, 0.4 mmol) and silicon tetrachloride (0.276 mL, 0.409 g, 2.4 mmol). The septum was pierced with a needle (to release HCI formed during the reaction) and heated at 100°C for 1 h. HPLC analysis of the reaction mixture indicated 29% chemical yield of the title compound.

[0154] Example 2d - Preparation of methyl N-[11-(dichloromethylene)-3-tricyclo[6.2.1.02 71undeca-2,4,6- trienyllcarbamate

[0155] A screw cap septum vial was charged with molten sulfolane (1.90 g), 11-

[0156] (dichloromethylene)tricyclo[6.2.1.02 7]undecane-3, 6-dione (1.071 g, 4.00 mmol, 97%), methyl carbamate (0.499 g, 6.51 mol), phosphorus pentachloride (0.510 g, 2.40 mmol) and methanesulfonic acid (0.053 mL, 0.8 mmol). The septum was pierced with a needle (to release HCI formed during the reaction) and heated at 100°C for 3 h.1H NMR analysis of the reaction mixture (400 MHz, Methanol-d6) indicated 58% chemical yield of the title compound (sulfolane was used as standard).

[0157] Example 2e - Preparation of methyl N-[11-(dichloromethylene)-3-tricyclo[6.2.1.02 71undeca-2,4,6- trienyllcarbamate

[0158] A screw cap septum vial was charged with molten sulfolane (1.90 g), 11-

[0159] (dichloromethylene)tricyclo[6.2.1.02 7]undecane-3, 6-dione (1.082 g, 4.05 mmol, 97%), methyl carbamate (0.496 g, 6.48 mol), acetyl chloride (0.72 mL, 0.79 g, 9.6 mmol) and methanesulfonic acid (0.053 mL, 0.8 mmol). The septum was pierced with a needle (to release HCI formed during the reaction) and heated at 100°C for 3 h.1H NMR analysis of the reaction mixture (400 MHz, Methanol-d6) indicated 41 % chemical yield of the title compound (sulfolane was used as standard).

[0160] Example 2f - Preparation of methyl N-[11-(dichloromethylene)-3-tricyclo[6.2.1.02 71undeca-2,4,6- trienyllcarbamate

[0161] A screw cap septum vial was charged with molten sulfolane (1.89 g), 11-

[0162] (dichloromethylene)tricyclo[6.2.1.02 7]undecane-3, 6-dione (1.079 g, 4.04 mmol, 97%), methyl carbamate (0.500 g, 6.53 mol), acetic anhydride (0.92 mL, 1 .00 g, 9.6 mmol) and methanesulfonic acid (0.053 mL, 0.8 mmol). The septum was pierced with a needle (to release HCI formed during the reaction) and heated at 100°C for 3 h.1H NMR analysis of the reaction mixture (400 MHz, Methanol-d6) indicated 22% chemical yield of the title compound (sulfolane was used as standard).

[0163] Example 3 - Preparation of N-[11-(dichloromethylene)-3-tricyclo[6.2.1 .0271undeca-2,4,6-trienyl1-3- (difluoromethyl)-1-methyl-pyrazole-4-carboxamide, a compound of formula (Iq)

[0164] A screw cap septum vial was charged with molten sulfolane (7.10 g), 11-

[0165] (dichloromethylene)tricyclo[6.2.1.02 7]undecane-3, 6-dione (2.01 g, 7.50 mmol, 97%), 3-(difluoromethyl)- 1-methyl-pyrazole-4-carboxamide (1.44 g, 8.24 mmol), methanesulfonic acid (0.10 mL, 0.15g, 1.5 mmol) and phosphorous pentoxide (1.12 g, 7.8 mmol). The resulting mixture was stirred at 100°C for 3 h.1H NMR analysis of the reaction mixture (400 MHz, Methanol-d6) indicated 27% chemical yield of the title compound (sulfolane was used as internal standard).

[0166] After cooling the reaction mixture to below 80°C, a solution of sodium hydroxide (2.2 g, 16.5 mmol, 30%) and ethyl acetate (2 mL) were added. The phases were separated, and the organic phase was concentrated by rotary evaporation. The residue was chromatographed (CombiFlash) using hexane I EtOAc (gradient) as eluent. The combined fraction with the title compound were contaminated with sulfonate. For further purification, the fraction was concentrated by rotary evaporation then sulfolane was removed by Kugelrohr distillation in high vacuum (130°C, 0.1 mbar). The distillation residue was chromatographed again to result in the title compound as brown solid (680 mg).1H NMR in Methanol- d4 with tetrachloroethane as standard. The content of product was 86%. 20% yield.

[0167] 1H NMR (400 MHz, CD3OD) 6 ppm: 8.26 (s, 1 H), 7.07 - 7.34 (m, 4H), 4.04 (broad d, J = 3.3 Hz, 1 H), 3.99 (s, 3H), 3.96 (broad d, J = 3.3 Hz, 1 H), 2.16 (s, 3H), 2.02 - 2.13 (m, 2H), 1.57 - 1.64 (m, 1 H), 1.35 - 1 .40 (m, 1 H), N-H is not visible due to exchange with deuterium.

[0168] 1H NMR (400 MHz, CDCb) 6 ppm: 8.13 (broad s, 1 H), 8.05 (broad s, 1 H), 7.82 (d, J = 8.2 Hz, 1 H), 7.18 (m, 1 H), 7.04 (d, J = 7.3 Hz, 1 H), 6.91 (t, JH-F = 54.2 Hz, 1 H), 4.07 (broad d, J = 2.6 Hz, 1 H), 3.95 - 3.96 (m, 4H), 2.07 - 2.15 (m, 2H), 1.48 - 1.52 (m, 1 H), 1.37 - 1.41 (m, 1 H).

[0169] Example 4 - Preparation of N-[11-(dichloromethylene)-3-tricyclo[6.2.1.02 71undeca-2,4,6- trienyllacetamide

[0170] A screw cap septum vial was charged with molten sulfolane (10.03 g), 11- (dichloromethylene)tricyclo[6.2.1.02 7]undecane-3, 6-dione (2.01 g, 7.50 mmol, 97%), acetamide (0.906 g, 15.0 mmol), acetyl chloride (0.56 mL, 7.5 mmol) and silicon tetrachloride (1 .0 mL, 1.48 g, 8.7 mmol). The septum was pierced with a needle (to release HCI formed during the reaction) and the mixture was stirred at 100°C for 3 h.1H NMR analysis of the reaction mixture (400 MHz, Methanol-d6) indicated 24% chemical yield of N-[11-(dichloromethylene)-3-tricyclo[6.2.1 ,02 7]undeca-2,4,6-trienyl]acetamide (sulfolane is used as internal standard).

[0171] After cooling the reaction mixture to below 80°C, a solution of sodium hydroxide (2.2 g, 16.5 mmol, 30%), ethyl acetate (2-3 mL) and deionized water (1-2 mL) were added. The phases were separated, and the organic phase was concentrated by rotary evaporation. The remaining sulfolane was removed by Kugelrohr distillation in high vacuum (130°C, 0.1 mbar). The residue was chromatographed (CombiFlash) using hexane / EtOAc (gradient) as eluent to result in N-[11-(dichloromethylene)-3- tricyclo[6.2.1.02 7]undeca-2,4,6-trienyl]acetamide as brown solid (600 mg).1H NMR in Methanol-cL? with tetrachloroethane as standard. The content of product 84%. 24% yield.

[0172] 1H NMR (400 MHz, CD3OD) 6 ppm: 7.26 (d, J = 8.1 Hz, 1 H), 7.12 (m, 1 H), 7.05 (d, J = 7.2 Hz, 1 H), 4.08 (broad d, J = 3.2 Hz, 1 H), 3.94 (broad d, J = 3.1 Hz, 1 H), 2.16 (s, 3H), 2.00 - 2.11 (m, 2H), 1.49 - 1.56 (m, 1 H), 1 .30 - 1 .37 (m, 1 H), N-H is not visible due to exchange with deuterium.

[0173] 13C NMR (100.6 MHz, CD3OD) 6 ppm: 172.3, 153.5, 147.5, 139.0, 131.7, 128.3, 123.3, 118.9, 104.2, 46.3, 27.7, 26.9, 23.3. One aliphatic signal is not visible due to overlap with CD3OD.

[0174] (CD3OD 6 = 49.15 ppm)

[0175] Example 5 - Preparation of N-[11-(dichloromethylene)-3-tricyclo[6.2.1.02 71undeca-2,4,6- trienyllacetamide

[0176] A screw cap septum vial was charged with diethylene glycol dimethyl ether (2.0 mL), 11- (dichloromethylene)tricyclo[6.2.1.02 7]undecane-3, 6-dione (538 mg, 2.00 mmol, 97%), acetamide (251 mg, 4.2 mol), 1 ,2-dichlorobenzene (202.6 mg, internal standard), methanesulfonic acid (0.027 mL, 0.4 mmol) and silicon tetrachloride (0.276 mL, 0.409 g, 2.4 mmol). The septum was pierced with a needle (to release HCI formed during the reaction) and heated at 100°C for 2 h. HPLC analysis of the reaction mixture indicated 34% chemical yield of N-[11-(dichloromethylene)-3-tricyclo[6.2.1.02 7]undeca-2,4,6- trienyl]acetamide.

[0177] Example 6 - Preparation of ethyl N-[11-(dichloromethylene)-3-tricyclo[6.2.1.02 71undeca-2,4,6- trienyllcarbamate (a compound of formula (l-ID) A screw cap septum vial was charged with molten sulfolane (3.51 g), 11-

[0178] (dichloromethylene)tricyclo[6.2.1.02 7]undecane-3, 6-dione (2.01 g, 7.50 mmol, 97%), ethyl carbamate (1.10 g, 12.0 mmol), methanesulfonic acid (0.10 mL, 0.15 g, 1.5 mmol) and phosphorous pentoxide (1 .07 g, 7.49 mmol). The resulting mixture was stirred at 100°C for 3 h.1H NMR analysis of the reaction mixture (400 MHz, Methanol-d6) indicated 77% chemical yield of ethyl N-[11-(dichloromethylene)-3- tricyclo[6.2.1.02 7]undeca-2,4,6-trienyl]carbamate (sulfolane was used as internal standard).

[0179] After cooling the reaction mixture to below 80°C, a solution of sodium hydroxide (2.2 g, 16.5 mmol, 30%) and ethyl acetate (2-3 mL) were added. The phases were separated, and the organic phase was concentrated by rotary evaporation. The remaining sulfolane was removed by Kugelrohr distillation in high vacuum (130°C, 0.1 mbar). The residue was chromatographed (CombiFlash) using hexane / EtOAc (gradient) as eluent to result in ethyl N-[11-(dichloromethylene)-3-tricyclo[6.2.1.02 7]undeca-2,4,6- trienyl]carbamate as brown solid (960 mg).1H NMR in Methanol-cb with tetrachloroethane as standard. The content of product was 84%. 34% yield.

[0180] 1H NMR (400 MHz, CD3OD) 6 ppm: 7.34 (broad d, J = 8.2 Hz, 1 H), 7.13 (dd, J = 8.2 Hz, J = 7.3 Hz, 1 H), 7.02 (d, J = 7.3 Hz, 1 H), 4.23 (q, J = 7.1 Hz, 2H), 4.17 (broad d, J = 2.8 Hz, 1 H), 3.95 (broad d, J = 2.8 Hz, 1 H), 2.05 - 2.14 (m, 2H), 1.47 - 1.54 (m, 1 H), 1.33 - 1.39 (m, 4H), N-H is not visible due to exchange with deuterium.

[0181] 1H NMR (400 MHz, CDCb) 6 ppm: 7.50 (broad d, J = 8.1 Hz, 1 H), 7.13 (m, 1 H), 6.97 (d, J = 7.3 Hz, 1 H), 6.50 (broad s, 1 H), 4.26 (q, J = 7.1 Hz, 2H), 3.99 (broad d, J = 2.4 Hz, 1 H), 3.94 (broad d, J = 2.4 Hz, 1 H), 2.06 - 2.14 (m, 2H), 1.33 - 1.48 (m, 5H).

[0182] 13C NMR (100.6 MHz, CDCb) 6 ppm: 153.9, 151.2, 145.9, 130.4, 127.4, 119.0, 116.5, 103.5, 61.5, 47.2, 43.9, 26.6, 25.9, 14.5. One signal is missing either due to overlap with a different signal or due to its low intensity. (CDCb 6 = 77.00 ppm)

[0183] Example 7 - Preparation of N-[11-(dichloromethylene)-3-tricyclo[6.2.1.02 71undeca-2,4,6- trienyllbenzamide

[0184] A 25-mL flask was charged with molten sulfolane (7.0 mL, 8.8 g), benzamide (3.66 g, 29.9 mmol) and methanesulfonic acid (0.25 mL, 0.37 g). The flask content was heated to 95°C and 11- (dichloromethylene)tricyclo[6.2.1.02 7]undecane-3, 6-dione (5.00 g, 18.7 mmol, 97%) and phosphorous pentoxide (2.5 g, 17.5 mmol) were alternatingly added in 5 equal portions each (1 g 11- (dichloromethylene)tricyclo[6.2.1.02 7]undecane-3, 6-dione immediately followed by 0.5 g phosphorus pentoxide) with intervals of 15 min. The temperature was kept at 100 °C during the addition. The resulting mixture was stirred at 100°C for 3 h.

[0185] After cooling the reaction mixture to 80°C, a solution of sodium hydroxide (5.5 g, 41.2 mmol, 30% in water) was added and the mixture was stirred for 1 h. The phases were separated, and the organic phase was freed from water by rotary evaporation. The remining sulfolane was removed by Kugelrohr distillation in high vacuum (130°C, 0.1 mbar). The residue was chromatographed (CombiFlash) using hexane I EtOAc (gradient) as eluent to result in N-[11-(dichloromethylene)-3-tricyclo[6.2.1.02 7]undeca- 2,4,6-trienyl]benzamide (1 .3 g).

[0186] 1H NMR in DMSO-d6 with 1 ,3,5-trimethoxybenzene as standard. The content of product was 70%. 14% yield.

[0187] 1H NMR (400 MHz, DMSO-c / 6) 6 ppm: 10.17 (s, 1 H), 7.97 (m, 2H), 7.61 (m, 1 H), 7.54 (m, 2H), 7.24 (dd, J = 7.3 Hz, J = 2.0 Hz, 1 H), 7.13 - 7.19 (m, 2H), 3.98 (m, 2H), 1.97 - 2.09 (m, 2H), 1.59 - 1.64 (m, 1 H), 1.31 - 1.36 (m, 1 H).

[0188] 13C NMR (100.6 MHz, DMSO-c / 6) 6 ppm: 165.7, 152.5, 145.7, 138.1 , 134.4, 131.7, 131.0, 128.5, 127.9, 126.8, 122.8, 117.7, 101.6, 46.9, 45.1 , 26.4, 25.4.

[0189] Example 8 - Preparation of 11-(dichloromethylene)tricyclo[6.2.1.02 71undeca-2,4,6-trien-3-amine (a compound of formula (IVa))

[0190] A screw cap septum vial was charged with ethyl N-[11-(dichloromethylene)-3-tricyclo[6.2.1 ,02 7]undeca- 2,4,6-trienyl]carbamate (314 mg, 0.845 mmol, 84%), Ethanol (1 mL) and a solution of sodium hydroxide (381 mg, 2.85 mmol, 30% in water). The resulting mixture was heated at 80°C (external temperature) for 7 h to result in complete conversion to 11-(dichloromethylene)tricyclo[6.2.1 ,027]undeca-2,4,6-trien- 3-amine (HPLC).

[0191] After cooling to room temperature, water (2.5 mL) was added, and the mixture was extracted with a few milliliters of methyl tert-butyl ether (2x). The combined extract was dried over anhydrous sodium sulphate. The solvent was removed by rotary evaporation to result in 11- (dichloromethylene)tricyclo[6.2.1.02 7]undeca-2,4,6-trien-3-amine as a brown viscous liquid which solidified upon standing (220 mg).1H NMR in DMSO-d6 was identical to that of the authentic sample. Example 9 - Preparation of 11-(dichloromethylene)tricyclo[6.2.1.02 71undeca-2,4,6-trien-3-amine (a compound of formula (IVa))

[0192] A screw cap septum vial was charged with N-[11-(dichloromethylene)-3-tricyclo[6.2.1 ,02 7]undeca-2,4,6- trienyl]acetamide (207.2 mg, 0.616 mmol, 84%), 1-butanol (1 mL) and solid sodium hydroxide (93.1 mg, 2.26 mmol). The septum was pierced with a needle and the vial was heated at 135°C (external temperature) for 5.5 h to result in 97% conversion to the title compound (HPLC).

[0193] After cooling the reaction mixture to room temperature, water (1 mL) was added. The phases were separated, and the organic phase was concentrated by rotary evaporation. The residue was chromatographed (CombiFlash) using cyclohexane I EtOAc (gradient) as eluent to result in 11- (dichloromethylene)tricyclo[6.2.1.02 7]undeca-2,4,6-trien-3-amine as brown solid (160 mg).1H NMR in DMSO-d6 was identical to that of the authentic sample.

[0194] Example 10 - Preparation of 11-isopropylidenetricyclo[6.2.1.02 71undeca-4,9-diene-3, 6-dione exo endo

[0195] In a 50 mL round-bottom flask, 6,6-dimethylfulvene (11.5 mL, 10.1 g, 90.6 mmol, 95%) was added to a suspension of benzoquinone (recrystallized from boiling cyclohexane, 10.0 g, 90.7 mmol) in ethanol (13 mL) and the resulting reaction mixture was stirred vigorously. After 18 h the thick slurry was transferred onto a suction filter, where the solid was filtered, washed with cold ethanol (0 °C, 15 mL) and dried by sucking air through the filter cake for 30 min. An approximate 3.2:1 mixture of the endo- and the exo-Diels-Alder product (11-isopropylidenetricyclo[6.2.1.02 7]undeca-4,9-diene-3, 6-dione) was obtained as a yellowish powder (14.5 g, 67.7 mmol) corresponding to an overall yield of 75% for the Diels-Alder reaction. Based on the observed ratio, the content of the encto-isomer was estimated to be 76%.

[0196] Accurate determination of the ratio via qNMR is complex due to retro-Diels-Alder reaction in the NMR- tube. encto-isomer1H NMR (400 MHz, DMSO-d6) 6 ppm: 6.67 (s, 2H), 6.16-6.17 (m, 2H), 3.82-3.85 (m, 2H), 3.22-3.23 (m, 2H), 1.55 (s, 6H). exo-isomer1H NMR (400 MHz, DMSO-d6) 6 ppm: 6.74 (s, 2H), 6.44-6.45 (m, 2H), 3.56-3.58 (m, 2H), 2.54 (s, 2H), 1.35 (s, 6H).

[0197] Example 11 - Preparation of 11-isopropyltricyclo[6.2.1 .02 71undecane-3, 6-dione endo syn anti

[0198] To a 100 mL steel-autoclave were added 3.2:1 mixture of endo- and exo-Diels-Alder product from example 10 (11-isopropylidenetricyclo[6.2.1.02 7]undeca-4,9-diene-3, 6-dione, assumed 76% endo- product, 1.10 g, 3.90 mmol), Pd / C (5 mass%, 83.0 mg, 39.0 pmol) and tetrahydrofuran (9 mL). The autoclave was sealed, pressurized to 5 bar hydrogen pressure and the pressure was released. This cycle was repeated two additional times before the autoclave was pressurized to 4 bar hydrogen pressure and the reaction mixture was stirred under the hydrogen atmosphere. After 3 h, the pressure was released, and the reaction mixture was filtered. The remaining catalyst was washed with 5 mL of tetra hydrofuran and the filtrate was concentrated by rotary evaporation. The syn- and anf / -reduction products of 11-isopropyltricyclo[6.2.1.02 7]undecane-3, 6-dione were obtained in a ratio of 1.2:1 (1.15 g) together as a mixture with reduction products of the exo-Diels-Alder product and hydroquinone. The content of syn- and anf / -product was determined to be 66.2 mass% using qNMR(4,4’- bistrifluoromethylbiphenyl as internal standard), corresponding to a yield of 89%. syn-isomer1H NMR (400 MHz, DMSO-d6) 6 ppm: 3.03-3.05 (m, 2H), 2.85-2.71 (m, 2H)*, 2.33- 2.47 (m, 4H)*, 1.37-1.50 (m, 3H)*, 1.13-1.28 (m, 3H)*, 0.89 (d, J = 6.5 Hz, 6H). anf / -isomer1H NMR (400 MHz, DMSO-d6) 6 ppm: 2.97-3.00 (m, 2H), 2.85-2.71 (m, 2H)*, 2.33- 2.47 (m, 4H)*, 1.37-1.50 (m, 3H)*, 1.13-1.28 (m, 3H)*, 0.87 (d, J = 6.5 Hz, 6H). overlap between syn- and anf / -isomer for signals marked with * Example 12 - Preparation of methyl N-(11-isopropyl-3-tricyclo[6.2.1.02 71undeca-2,4,6-trienyl)carbamate syn anti synan^

[0199] A screw cap septum vial was charged with molten sulfolane (1.5 mL), syn- and anf / -diketone from example 11 (11-isopropylidenetricyclo[6.2.1.02 7]undeca-4,9-diene-3, 6-dione, 539 mg, 66.2 mass%, 1 .62 mmol, material was treated as pure diketone as also the reduced exo-diketone was present in the mixture obtained in the prior hydrogenation) and methyl carbamate (299 mg, 3.91 mmol). The reaction mixture was heated to 100 °C. After 10 min, the reaction mixture reached 100 °C and phosphorous pentoxide (120 mg, 0.829 mmol) was added. After 10 min, an additional portion of phosphorous pentoxide (234 mg, 1.62 mmol) was added. After 40 min NMR-analysis of the reaction mixture indicated formation of the desired product. NMR-analysis after an additional 40 minutes showed no additional product formation and the heating was stopped. After 30 min the reaction reached 65 °C and aqueous NaOH (50 mass%, 0.25 mL) was added. After two minutes, the reaction mixture was tranferrred into a separatory funnel and water (10 mL) and ethyl acetate (7 mL) were added. The phases were separated and the aqueous phase was extracted two time with ethyl acetate (7 mL each). The combined organic layers were dried over MgSO4, filtered and concentrated to give a solution of the product in sulfolane (1.709 g) The content of the desired product was determined via qNMR using 4,4’- bistrifluoromethylbiphenyl as internal standard and indicated a content of 17.12 mass%, corresponding to a yield of 70%. syn-isomer1H NMR (400 MHz, DMSO-d6) 6 ppm: 9.11 (br, 1 H), 7.23-7.31 (m, 1 H)*, 6.94-7.01 (m, 1 H)*, 6.86-6.93 (m, 1 H)*, 3.66 (S, 3H)*, 3.53 (br, 1 H), 3.14-3.16 (m, 1 H), 1.76-1.90 (m, 2H)*, 1.44- 1.48 (m, 1 H), 0.95-1.13 (m, 3H)*, 0.74-0.78 (m, 6H). anf / -isomer1H NMR (400 MHz, DMSO-d6) 6 ppm: : 9.07 (br, 1 H), 7.23-7.31 (m, 1 H)*, 6.94-7.01 (m, 1 H)*, 6.86-6.93 (m, 1 H)*, 3.66 (S, 3H)*, 3.48 (br, 1 H), 3.10-3.12 (m, 1 H), 1.76-1.90 (m, 2H)*, 1.25- 1.30 (m, 1 H), 0.95-1.13 (m, 3H)*, 0.85 (dd, J = 6.2, 3.6 Hz, 6H).

[0200] LRMS = 260 (M+H+)

Claims

CLAIMS:1 . A process for the preparation of a compound of formula (I),wherein,R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl, benzyl, phenoxy, benzoxy and 3-(difluoromethyl)-1-methyl-pyrazol-4-yl, wherein said phenyl, benzyl, phenoxy or benzoxy are optionally substituted by 1 , 2 or 3 R2substituents, which may be the same or different; each R2is independently selected from the group consisting of halogen, cyano, hydroxy, Ci- Cealkyl, Ci-Cealkoxy and Ci-Cehaloalkyl;A is the group A-l or A-lland wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I); comprising; reacting a compound of formula (II);wherein A is as defined above for a compound of formula (I), with a compound of formula (III);wherein R1is as defined above for a compound of formula (I) in the presence of a dehydrating agent and / or an acid, to give a compound of formula (I).

2. A process according to claim 1 , wherein R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl, benzyl, phenoxy, benzoxy and 3-(difluoromethyl)-1-methyl-pyrazol-4-yl.

3. A process according to any one of claims 1 to 2, wherein the dehydrating agent is selected from the group consisting of phosphorous chlorides, phosphorous oxychlorides, phosphorus pentoxide, chlorosilanes, thionyl chloride, acid halides and acid anhydrides.

4. A process according to any one of claims 1 to 3, wherein the dehydrating agent is selected from the group consisting of phosphorus pentachloride, phosphorus pentoxide, silicon tetrachloride, dimethyldichlorosilane, thionyl chloride, acetyl chloride and acetic anhydride.

5. A process according to any one of claims 1 to 4, wherein the dehydrating agent is silicon tetrachloride or phosphorus pentoxide.

6. A process according to any one of claims 1 to 5, wherein the acid is a bronstead or lewis acid selected from the group consisting of sulfuric acid, methanesulfonic acid, aluminium trichloride, zinc chloride, magnesium chloride and zirconium (IV) chloride.

7. A process according to any one of claims 1 to 6, wherein the process is carried out in a suitable reaction medium selected from the group consisting of sulfolane, glycol diethers, chlorobenzene, anisol, N-methyl-2-pyrrolidone and methanesulfonic acid.

8. A process according to claim 7, wherein the suitable reaction medium is sulfolane.

9. A process according to any one of claims 1 to 8, wherein the compound of formula (I) is hydrolysed to give a compound of formula (IV),(IV).

10. A process according to claim 9, wherein the process further comprises converting a compound of formula (IV) to a compound of formula (la),wherein,A is the group A-l or A-llA-l A-ll and the jagged line defines the point of attachment to the remaining part of a compound of formula (la).

11. A process according to any one of claims 1 to 10, wherein A is the group A-l below,A-l and the jagged line defines the point of attachment to the remaining part of a compound of formula (I).

12. A compound of formula (l-la),(l-la) wherein,R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl, benzyl, phenoxy and benzoxy, wherein said phenyl, benzyl, phenoxy or benzoxy are optionally substituted by 1 , 2 or 3 R2substituents, which may be the same or different; each R2is independently selected from the group consisting of halogen, cyano, hydroxy, Ci- Cealkyl, Ci-Cealkoxy and Ci-Cehaloalkyl;A is the group A-l or A-llA-l A-ll and wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (l-la); and the compound of formula (l-la) is not N-[11-(dichloromethylene)-3-tricyclo[6.2.1.02 7]undeca- 2,4,6-trienyl]acetamide, N-[11-(dichloromethylene)-3-tricyclo[6.2.1 ,02 7]undeca-2,4,6-trienyl]- 2,2-dimethyl-propanamide or N-[11-(dichloromethylene)-3-tricyclo[6.2.1 ,02 7]undeca-2,4,6- trienyl]benzamide.

13. A compound according to claim 12 wherein R1is methoxy or ethoxy.

14. A compound of formula (lib),15. The use of a compound of formula (III),wherein,R1is selected from the group consisting of Ci-Cealkyl, Ci-Cealkoxy, phenyl, benzyl, phenoxy and benzoxy, wherein said phenyl, benzyl, phenoxy or benzoxy are optionally substituted by 1 , 2 or 3 R2substituents, which may be the same or different; each R2is independently selected from the group consisting of halogen, cyano, hydroxy, Ci- Cealkyl, Ci-Cealkoxy and Ci-Cehaloalkyl, for preparing a compound of formula (I).

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