>2 or a salt thereof, or

ii. a compound of formula (R⁵)₂NCHO or a salt thereof and co-reagent (C-1), or

iii. a suitable amine of formula NH(R⁵)₂or salt thereof, a suitable ortho esters of formula CR⁷(OR⁵)₃or a salt thereof and co-reagent (C-2), or

iv. a suitable ortho esters of formula CR⁷(R⁶)₃or a salt thereof and co-reagent (C-3), or

v. a suitable formic acid/ester of formula HCOOR⁷or a salt thereof and co-reagent (C-4), or

vi. a suitable amine of formula N(R⁵)₃or a salt thereof and co-reagent (C-5), or

vii. a carbon monoxide and co-reagent (C-4),

wherein R⁵represents C₁-C₃-alkyl; R⁶represents OR⁵, N(R⁵)₂; R⁷represent hydrogen or C₁-C₃-alkyl;

In a preferred embodiment, the reagent-2 is selected from:

- i. a compound of formula (R⁵)₂NCH(OR⁵)₂or a salt thereof, or
- ii. a compound of formula (R⁵)₂NCHO or a salt thereof and co-reagent (C-1), or
- iii. a suitable amine of formula NH(R⁵)₂or salt thereof, a suitable ortho esters of formula CR⁷(OR⁵)₃or a salt thereof and co-reagent (C-2),

In a more preferred embodiment, the reagent-2 is a compound of formula (R⁵)₂NCH(OR⁵)₂or a salt thereof.

According to an embodiment, the co-reagent is defined as:

- (C-1) represents phosphorous oxyhalides (PO(X¹)₃); wherein is halogen;
- (C-2) and (C-3) represent acids such as p-toluenesulfonic acid (p-TSA), Lewis acids, (Ac)₂O, boron trifluoride (BF₃), tetrafluoroboric acid(HBF₄), zinc chloride (ZnCl₂), aluminium chloride (AlCl₃);
- (C-4) represents a base such as sodium hydride (NaH), metal alkoxides, piperidine, pyridine, triethyl amine, N,N-diisopropylethylamine; and
- (C-5) represents N,N-dimethylformamide dimethyl sulfate adduct (DMF-DMS);

In another embodiment, the multistep process as described above for preparing the compound of Formula (I) or a salt thereof, can also be performed in a continuous or semi-continuous flow process, involving either isolation or without isolation of intermediates produced during the flow process.

In a preferred embodiment, the present invention provides a process for the preparation of a compound of formula (I) or a salt thereof, wherein R¹and R²represent halogen, and is represented by the formula (I-a) or a salt thereof:

[Image Omitted]

wherein

- X represents halogen;
- R³is selected from the group consisting of hydrogen, halogen C₁-C₄alkyl, C₃-C₇cycloalkyl, C₁-C₃haloalkyl and C₁-C₄alkoxy;
- R⁴is selected from the group consisting of hydrogen, halogen, C₁-C₄alkyl, C₃-C₇cycloalkyl, C₁-C₃haloalkyl, heterocyclyl, O—R′, haloalkyl, O—C(0)R′ and CHO;
  - R′ is selected from the group consisting of C₁-C₆-alkyl and C₁-C₃haloalkyl; or
- R³and R⁴can form a 5-6 membered ring system, which is optionally substituted by halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy;
- R³and R⁴groups are optionally substituted with halogen, CN, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy;
- wherein

comprising the steps of:

- a) cyclizing a vinylogous nitrile of formula (II-a) or a salt thereof, by reacting it with a suitable acid (reagent-1) and optionally in the presence of a solvent, according to the reaction scheme-1a as depicted below:

[Image Omitted]

wherein X represents halogen; LG, R³and R⁴are as defined above;

- b) compound of formula (II-a) is obtained by reacting the α,β-unsaturated nitrile of formula (III-a) or a salt thereof,
  - with reagent-2 and optionally in the presence of a suitable solvent, according to the reaction scheme-2a as depicted below:

[Image Omitted]

wherein X, LG, co-reagents, R¹, R², R³, R³, R⁵, R⁶and R⁷are as defined above.

- c) obtaining the α,β-unsaturated nitrile of formula (III-a) or a salt thereof,
- from the substituted acrylonitrile of formula (III-b) or a salt thereof,
- by halogenation, in the presence of a halogenating reagent and optionally in the presence of a reagent-3 and a suitable solvent, according to the reaction scheme-3a as depicted below:

[Image Omitted]

- wherein X, R³and R⁴are as defined above.

In one embodiment, the multistep process as described above for preparing the compound of Formula (I-a) or a salt thereof, can also be performed in a continuous or semi-continuous flow process, involving either isolation or without isolation of intermediates produced during the flow process.

In one embodiment, the α,β-unsaturated nitrile of formula (III) or a salt thereof,

[Image Omitted]

wherein R²represents halogen; R³and R⁴are as defined above, is prepared by, halogenating a substituted acrylonitrile of formula (III) or a salt thereof,

[Image Omitted]

wherein R²represents hydrogen; R³and R⁴are as defined above; in the presence of a halogenating reagent and optionally in the presence of a reagent-3 and a solvent.

In a another embodiment, the present invention provides a process for the preparation of a compound of formula (I) or a salt thereof, wherein R¹and R²represent halogen and R⁴is H or CHO, and is represented as a compound of formula (I-b) or a salt thereof,

[Image Omitted]

wherein X¹represents Cl or Br; X represents F, Cl or Br. and R³is as defined above;

from the compound of formula (III-c) or salt thereof,

[Image Omitted]

wherein, X and R³are as defined above; by reacting it with a mixture of N,N-dimethylformamide and phosphorous oxyhalide (DMF-PO(X¹)₃), along with a compound of formula (I-a) according to the reaction scheme-4 as depicted below:

[Image Omitted]

Further, in another embodiment, the present invention provides a process for the preparation of a compound of formula (II) or salt thereof, wherein LG represents —N(R⁵)₂, and is represented as a compound of formula (II-b) or a salt thereof,

[Image Omitted]

- wherein R², R³, R⁴and R⁵are as defined above;
- comprising step of:
  
  by reacting a compound of formula (III) or a salt thereof,
  
  with reagent-2 and optionally in the presence of a solvent, according to the reaction scheme-2b as depicted below:

[Image Omitted]

- wherein R², R³and R⁴are as defined above.

In another embodiment, the process as described in scheme-2b for preparing the compound of formula (II-b) or a salt thereof, can also be performed in a continuous or semi-continuous flow process, involving either isolation or without isolation of intermediates produced during the flow process.

Further, yet another embodiment of the present invention provides a process for the preparation of a compound of formula (II) or a salt thereof wherein LG represents —OR⁵, and is represented as a compound of formula (II-c) or a salt thereof,

[Image Omitted]

- wherein R², R³, R⁴and R⁵have the same meaning as defined above;
  
  comprising the step of:
  
  by reacting a compound of formula (III) or a salt thereof,
  
  with reagent-2 selected from:
- iv. a suitable ortho esters of formula CR⁷(R⁶)₃or a salt thereof and co-reagent (C-3), or
- v. a suitable formic acid/ester of formula HCOOR⁷or a salt thereof and co-reagent (C₄),
  
  and optionally in the presence of a solvent, according to the reaction scheme-2c as depicted below:

[Image Omitted]

- wherein R², R³and R⁴are as defined above.

In one embodiment, the process as described in scheme-2c for preparing the compound of Formula (II-c) or salt thereof, can also be performed in a continuous or semi-continuous flow process, involving either isolation or without isolation of intermediates produced during the flow process.

In an embodiment, the compound of formula (III-d) or salt thereof, is reacted with N,N-Dimethylformamide dimethyl acetal (DMF-DMA) to obtain a compound of formula (II-d) or a salt thereof as per the reaction scheme provided below.

[Image Omitted]

In another embodiment, the compound of formula (III-d) or a salt thereof, is reacted with trimethyl orthoformate or a salt thereof to obtain a compound of formula (II-e) or a salt thereof, as per the reaction scheme provided below.

[Image Omitted]

In yet another embodiment, the compound of formula (III-d) or a salt thereof, is reacted with methyl formate or a salt thereof, to obtain a compound of formula (II-f) or a salt thereof, as per the reaction scheme provided below.

[Image Omitted]

In yet another embodiment, the compound of formula (III-e) or a salt thereof, is reacted with 1,1-dimethoxy-N,N-dimethylmethanmine (DMF-DMA) to obtain a compound of formula (II-g) or a salt thereof, as per the reaction scheme provided below.

[Image Omitted]

In yet another embodiment, the compound of formula (III-e) or a salt thereof, is reacted with trimethyl orthoformate or a salt thereof, to obtain a compound of formula (II-h) or a salt thereof, as per the reaction scheme provided below.

[Image Omitted]

In yet another embodiment, the compound of formula (III-e) or a salt thereof, is reacted with methyl formate or salt thereof, to obtain a compound of formula (II-i) as per the reaction scheme provided below.

[Image Omitted]

In yet another embodiment, the compound of formula (II-d) or a salt thereof, is reacted with hydrogen chloride gas to obtain a substituted pyridine of formula (I-c) or a salt thereof, as per the reaction scheme provided below.

[Image Omitted]

In yet another embodiment, the compound of formula (II-e) or a salt thereof, is reacted with hydrogen chloride gas to obtain a substituted pyridine of formula (I-c) or a salt thereof, as per the reaction scheme provided below.

[Image Omitted]

In yet another embodiment, the compound of formula (II-f) or a salt thereof, is reacted with hydrogen chloride gas to obtain a substituted pyridine of formula (I-c) or a salt thereof, as per the reaction scheme provided below.

[Image Omitted]

In yet another embodiment, the compound of formula (II-g) or a salt thereof, is reacted with hydrogen chloride gas to obtain a substituted pyridine of formula (I-d) or a salt thereof, as per the reaction scheme provided below.

[Image Omitted]

In yet another embodiment, the compound of formula (II-h) or a salt thereof, is reacted with hydrogen chloride gas to obtain a substituted pyridine of formula (I-d) or a salt thereof, as per the reaction scheme provided below.

[Image Omitted]

In yet another embodiment, the compound of formula (II-i) or a salt thereof, is reacted with hydrogen chloride gas to obtain a substituted pyridine of formula (I-d) or a salt thereof, as per the reaction scheme provided below.

[Image Omitted]

According to an embodiment, the compound of formula (I) or a salt thereof, represents compound of formula (I-a-a) or a salt thereof or compound of formula (I-b-a) or a salt thereof, wherein R²is chlorine, R¹is halogen and can be prepared from the compound of formula (III-d) or a salt thereof by halogenating with a halogenating agent and N,N-dimethylformanide, as per the reaction scheme provided below.

[Image Omitted]

In accordance with the embodiments of the present disclosure, the heating can be carried out at a temperature between 40° C. to 100° C.

Typically, the compound of formula (III-d) or a salt thereof, is reacted with phosphoryl chloride in N,N-dimethylformanide at 80° C. to obtain a substituted pyridine of formula (I-c) and a substituted compound of formula of (I-b-b), as per the reaction scheme provided below.

[Image Omitted]

Typically, the compound of formula (III-e) or a salt thereof, is reacted with phosphoryl chloride in dimethyl formamide at 80° C. to obtain a substituted pyridine of formula (I-d) or a salt thereof and a substituted pyridine of formula (I-b-c) or a salt thereof, as per the reaction scheme provided below.

[Image Omitted]

In yet another embodiment, the present invention provides a process for the preparation of a substituted 2-hydrazineyl pyridine of formula (VI) or a salt thereof,

[Image Omitted]

wherein,

- R²is selected from the group consisting of hydrogen, halogen, C₁-C₄alkyl, C₃-C₇cycloalkyl, C₁-C₃haloalkyl, heterocyclyl, O—R′, haloalkyl and O—C(O)R′;
- R³is selected from the group consisting of hydrogen, halogen C₁-C₄alkyl, C₃-C₇cycloalkyl, C₁-C₃haloalkyl and C_1-3alkoxy;
- R⁴is selected from the group consisting of hydrogen, halogen, C₁-C₄alkyl, C₃-C₇cycloalkyl, C₁-C₃haloalkyl, heterocyclyl, O—R′, haloalkyl, O—C(O)R′ and CHO;
  - R′ is selected from the group consisting of C₁-C₆-alkyl and C₁-C₃haloalkyl; or
- R²and R³or R³and R⁴can form a 5-6 membered carbocyclic or heterocyclic ring system, which is optionally substituted by halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy;
- R², R³and R⁴groups are optionally substituted with halogen, CN, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy;
- wherein, the said process comprises reaction of a substituted pyridine of formula (I) or a salt thereof prepared according to anyone of the process, as described in the aforementioned embodiments,

[Image Omitted]

wherein, R¹is halogen and R², R³, R⁴are as defined above, with hydrazine source and optionally in presence of base and a solvent as depicted in scheme below:

[Image Omitted]

The hydrazine source is selcted from hydrazine hydrate, hydrazine suphate or hydrazine chloride.

In further embodiment, the present invention provides an integrated, continuous or semicontinuous flow process for the preparation of a compound of formula (I) or salt thereof,

[Image Omitted]

wherein,

- R¹is selected from the group of halogen and C₁-C₄alkoxy;
- R²is selected from the group consisting of hydrogen, halogen, C₁-C₄alkyl, C₃-C₇cycloalkyl, C₁-C₃haloalkyl, heterocyclyl, O—R′, haloalkyl and O—C(O)R′;
- R³is selected from the group consisting of hydrogen, halogen C₁-C₄alkyl, C₃-C₇cycloalkyl, C₁-C₃haloalkyl and C₁-C₄alkoxy;
- R⁴is selected from the group consisting of hydrogen, halogen, C₁-C₄alkyl, C₃-C₇cycloalkyl, C₁-C₃haloalkyl, heterocyclyl, O—R′, haloalkyl, O—C(O)R′ and CHO;
  - R′ is selected from the group consisting of C₁-C₆-alkyl and C₁-C₃haloalkyl;
- wherein R³and R⁴can form a 5-6 membered ring system, which is optionally substituted by halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy;
- R³and R⁴groups are optionally substituted with halogen, CN, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy;
- comprising the steps of:
  - A. cyclizing a vinylogous nitrile of formula (II) or a salt thereof,
    - by reacting with a suitable acid (reagent-1) and optionally in the presence of a solvent, according to the reaction scheme-1 as depicted below:

[Image Omitted]

- wherein LG represents OR′ or N(R′)₂; R′, R¹, R², R³and R⁴are as defined above;
  - B. compound of formula (II) is obtained by reacting an α,β-unsaturated nitrile of formula (III) or a salt thereof,
    
    with reagent-2 selected from:
- i. with a compound of formula (R⁵)₂NCHO or a salt thereof and co-reagent (C-1) or
- ii. with a suitable amine compound of formula NH(R⁵)₂or a salt thereof, suitable ortho esters compound of formula CR⁷(OR⁵)₃or a salt thereof and co-reagent (C-2),
- and optionally in the presence of a suitable solvent, according to the reaction scheme-2 as depicted below:

[Image Omitted]

- wherein, LG, co-reagents, R¹, R², R³, R⁴, R⁵, R⁶and Ware as defined above;

In another embodiment, the present invention provides an integrated, continuous or semicontinuous flow process for the preparation of a compound of formula (I) or salt thereof,

[Image Omitted]

wherein,

- R¹and R²represents halogen; and R³and R⁴are same as defined above.
- comprising the steps of:
  - A. cyclizing a vinylogous nitrile of formula (II) or a salt thereof, by reacting with a suitable acid (reagent-1) and optionally in the presence of a solvent, according to the reaction scheme-1 as depicted below:

[Image Omitted]

- wherein LG represents OR′ or N(R′)₂; R′, R¹, R², R³and R⁴are as defined above;
  
  B. compound of formula (II) is obtained by reacting an α,β-unsaturated nitrile of formula (III) or a salt thereof,
  
  with reagent-2 selected from:
- i. with a compound of formula (R⁵)₂NCHO or a salt thereof and co-reagent (C-1) or
- ii. with a suitable amine of formula NH(R⁵)₂or a salt thereof, suitable ortho esters of formula CR⁷(OR⁵)₃or a salt thereof and co-reagent (C-2),
  
  and optionally in the presence of a suitable solvent, according to the reaction scheme-2 as depicted below:

[Image Omitted]

- wherein, LG, co-reagents, R¹, R², R³, R⁴, R⁵, R⁶and R⁷are as defined above;
  
  C. obtaining the α,β-unsaturated nitrile of formula (III) or a salt thereof,
- from a substituted acrylonitrile compounds of formula (III-b) or a salt thereof,
- by halogenation, in the presence of a halogenating reagent and optionally in the presence of a reagent-3 and a suitable solvent, according to the reaction scheme-3a as depicted below:

[Image Omitted]

- wherein R²is halogen; R³and R⁴are as defined above.

According to an embodiment, reagent-1 includes but is not limited to an acid such as inorganic acid selected from hydrogen fluoride, hydrogen chloride or hydrogen bromide; metal complex such as a Lewis acid selected from titanium tetrachloride, boron trifluoride etherate, copper chloride, aluminium trichloride and zinc chloride.

In one embodiment, the reaction of converting α,β-unsaturated nitrile of formula (III) or a salt thereof, to vinylogous nitriles of formula (II) is carried out optionally in the presence of a suitable solvent with a suitable compound of formula (R⁵)₂NCH(OR⁵)₂or a salt thereof or a suitable amine of formula NH(R⁵)₂or a salt thereof and suitable ortho esters of formula CR⁷(OR⁵)₃or salt thereof; optionally in the presence of co-reagent at a temperature within the range of 20° C. to 130° C.

The suitable solvents as used in any of the process steps of the present invention are selected from aliphatic, alicyclic or aromatic hydrocarbons such as, petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, toluene, xylene or decalin; aliphatic, alicyclic or aromatic halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane or trichloroethane; ethers such as diethylether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxy ethane, 1,2-diethoxyethane or anisole; nitriles such as acetonitrile, propionitrile, n- or iso-butyronitrile or benzonitrile; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide or sulfones such as sulfolane; alcohols such as methanol, ethanol, isopropanol, polyethylene glycols; water or mixtures thereof.

The suitable solvents for halogenation reaction (Step-c)) are aliphatic, alicyclic or aromatic halogenated hydrocarbons such chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane, trichloroethane; preferably dichloromethane, chloroform, dichloroethane, trichloroethane.

The suitable solvents for preparing vinylogus nitrile reaction (step-b) are aliphatic, alicyclic or aromatic hydrocarbons such as, heptane, cyclohexane, methylcyclohexane, toluene, xylene or decalin; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl formanilide, N-methylpyrrolidone; alcohols such as methanol, ethanol, isopropanol; ethers such as 1,2-dimethoxy ethane, 1,2-diethoxyethane dioxane; toluene, sulfoxides such as dimethyl sulfoxide or sulfones such as sulfolane;

The suitable solvents for cyclisation reaction (Step-a) aliphatic, alicyclic or aromatic halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane or trichloroethane; ethers such as diethylether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxy ethane, 1,2-diethoxyethane or anisole; alcohols such as methanol, ethanol, isopropanol, polyethylene glycols; acetic acid or mixtures thereof.

In one embodiment and in a non limiting way, the halogenating agent used in step-c is either chlorine gas, or hydrogen halogenides such as hydrogen fluoride, hydrogen chloride or hydrogen bromide, along with oxidizing reagents such as hydrogen peroxide

In one embodiment, the reagent-3 used in the halogenation/chlorination reaction (step-c) includes but is not limited to pyridine, lutidine, hydroquinone, piperidine and triethylamine, diisopropyl ethyl amine, pyridine, alkylated and dialkylated pyridines, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), or inorganic bases are preferably selected from the group comprising of alkali or alkaline earth metal hydroxide, carbonate, bicarbonate and the like, wherein the alkali and alkaline earth metals are selected from the group comprising of lithium, sodium, potassium, rubidium, caesium, calcium, magnesium, barium and the like or of mixtures thereof. Preferably, triethylamine, diisopropyl ethyl amine, pyridine, hydroquinone, sodium carbonate, potassium carbonate or of mixtures; more preferably triethylamine, hydroquinone, potassium carbonate or of mixtures;

In one embodiment, the catalyst used in the condensation reaction(step-b) includes but is not limited to acetic anhydride and p-toluene sulfonic acid.

In one embodiment, preferred reagent-1 used in the cyclisation reaction (step-a) includes but is not limited to an acid such hydrogen fluoride, hydrogen chloride or hydrogen bromide.

An embodiment of the present invention provides an integrated continuous flow process for step A, for the preparation of compound of formula (I) or a salt thereof, comprising, reacting a vinylogous nitrile of formula (II) or a salt thereof, with a suitable acid (reagent-1) and optionally in the presence of solvent (according to the reaction scheme-1), in a suitable reactor, wherein LG, R′, R¹, R², R³and R⁴are as defined above. The residence time of the mixture in the reactor typically ranges anywhere between 30 seconds and 30 minutes, preferably about 30 seconds to 10 minutes depending on the temperature. The temperature in the reactor is typically anywhere between 0° C. and 150° C., preferably between 10° C. and 100° C.

Optionally, all flow the reactors may be connected with batch equipment to get the right puritybefore introducing the flow in the following continuous reaction step.

Another embodiment of the present invention provides an integrated continuous flow process for step B, for the preparation of compound of formula (II) or a salt thereof, comprising, reactinig an α,β-unsaturated nitrile of formula (III-a) with any one of the reagents selected from group (i to vii) as described above (according to the reaction scheme-2) in a suitable reactor, wherein, LG, co-reagents, R¹, R², R³, R⁴, R⁵, R⁶and R⁷are as defined above. The residence time of the mixture in the reactor is typically anywhere between 30 seconds and 30 minutes, preferably about 30 seconds to 10 minutes, and more preferably 30 seconds to 5 minutes depending on the temperature. The temperature in the reactor is typically anywhere between 0° C. and 150° C., preferably between 0° C. and 100° C.

A further embodiment of the present invention provides an integrated continuous flow process for step C, for the preparation of compound of formula (III-a) or a salt thereof, comprising, halogenating a substituted acrylonitrile of formula (III-b) or a salt thereof, with a halogenating reagent and optionally in the presence of a catalyst and in a suitable solvent (according to the reaction scheme-3a) in a suitable reactor, wherein X, R³and R³are as defined above. The residence time of the mixture in the reactor is typically anywhere between seconds and 30 minutes, preferably about 30 seconds to 10 minutes, and more preferably 30 seconds to 5 minutes depending on the temperature. The temperature in the reactor is typically anywhere between 0° C. and 150° C., preferably between 10° C. and 120° C.

All the reactions steps A to C as described above are performed in flow reactors connected to each other in such a way as to provide an integrated system. There are many configurations of such connected reactor system, that a person skilled in the art is aware of.

Translating reactions into continuous-flow system is aiding more efficient, safer, and automated reactions. The ability of continuous-flow system to rapidly heat and cool reactions, micromix solutions, and improve reaction homogeneity affords opportunities to explore novel transformations while being environmentally conscious and creative.

The injected fluid flows into reactor coils where the specific transformation is subjected to a range of conditions. For example, the fluid entering the reactor coil can be rapidly heated or cooled to mediate an effective transformation.

The efficiency of the continuous or semi-continuous flow process depends upon several factors, some of which include temperature of the reactor, residence time, flow rate of the reactant mixture, pressure within the reactor. A persone skilled in the art can optimise the efficiency of the flow process by varying these factors.

In the context of the present invention, the term “without isolation” means that the product referred is not isolated, for example it is not isolated from the reaction mass and dried/concentrated to obtain a solid/sticky mass/liquid. Thus, “without isolation” may mean that the product remains insolution and is then used directly in the next synthetic step.

The residence time of the fluid within the system is determined by the internal diameter and length of the reactor coil.

Mixers and unions connect reactor coils together and allow the addition of new reagents to the continuous-flow stream. The solution can be flowed through packed bed reactors to ensure efficient mixing, or to provide exposure to immobilized reagents for synthetic transformations.

A continuous-flow system allows the possibility of in-line purification and reagent introduction at set points in the continuous-flow sequence.

Depending on the nature of the substituents, the intermediates as mentioned in the described schemes or compounds of formula such as (II) or (III) or a salt thereof, can also exist in one or more geometric isomer forms depending on the relative position (cis/trans) of the substituents. The invention thus relates equally to all cis/trans isomers and to all possible cis/trans mixtures, in all proportions. The cis/trans isomers can be separated according to general methods, which are known by a person having ordinary skilled in the art.

The compounds of the present disclosure may be present either in pure form or as mixtures of different possible isomeric forms such as geometric isomers. Any desired mixtures of these isomers fall within the scope of the claims of the present disclosure.

The processes as disclosed in the present invention can be run in the absence of a solvent or in the presence of one or more suitable solvents. The optional solvent should be resistant against oxidation (i.e. a solvent will be preferred whose rate of oxidation is substantially slower than that of the compounds of formula I to III) and suitable for suspending, or preferably dissolving the reactants.

Any person skilled in the art knows the best work-up of the reaction mixtures after the end of the respective reactions. In one embodiment, the work-up is usually carried out by isolation of the product by filtration, and optionally washing with solvent, further optionally drying of the product if required.

The process steps according to the invention are generally carried out under atmospheric pressure. Alternatively, however, it is also possible to carry out the reaction under pressure or reduced pressure.

Without further elaboration, it is believed that any person skilled in the art who is using the preceding description can utilize the present invention to its fullest extent. The following examples are therefore to be interpreted as merely illustrative and not limiting of the disclosure in any way whatever.

PREPARATION EXAMPLES
Example-1: Synthesis of 2,3-Dichloropyridine
Step-1: Synthesis of 2-chlorobut-2-enenitrile from but-2-enenitrile

[Image Omitted]

To a stirred solution of but-2-enenitrile (10 g, 149 mmol), pyridine (0.59 g, 7.45 mmol) and hydroquinone (0.41 g, 3.73 mmol) in dimethyl formamide (50 mL), chlorine gas was purged for 3-4 hours at 5-10° C. After completion of the reaction, nitrogen gas was purged into the reaction mixture until the pH reaches 5-7. Potassium carbonate (26.8 g, 194 mmol) was added portion wise into the reaction mixture over a period of 20 minutes at 0-5° C., and stirred further for 12 hours at 25-30° C. The reaction mass was quenched with water and extracted several times with dichloromethane (100 mL). The combined dichloromethane layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by vacuum distillation (30 mbar at 50° C.) to obtain 2-chlorobut-2-enenitrile (E/Z mixture).

GC-MS: MS: m/z=101.00

¹H-NMR: (400 MHz, CDCl₃-d₆) δ 6.71 (q, J=7.2 Hz, 1H), 1.92 (d, J=7.2 Hz, 3H) (major isomer). δ 6.21 (q, J=7.6 Hz, 1H), 2.01 (d, J=7.6 Hz, 3H) (minor isomer).