HK1170240A1 - Process for the preparation of 2-substituted-5-(1-alkylthio) alkylpyridines - Google Patents

Description

Process for preparing 2-substituted-5- ((1-alkylthio) alkyl) pyridines

The application is a divisional application of a patent application with Chinese application number 200780051093.9 entitled "method for preparing 2-substituted-5- ((1-alkylthio) alkyl) pyridine" and application date of 2007, 2, 9 days (PCT application number PCT/US 2007/003779).

Technical Field

The present invention relates to a process for the preparation of 2-substituted-5- ((1-alkylthio) alkyl) pyridines.

Background

2-substituted-5- (1-alkylthio) alkylpyridines are useful intermediates in the preparation of certain novel pesticides, see, for example, U.S. patent application publication 2005/0228027. It would be beneficial to obtain 2-substituted-5- ((1-alkylthio) alkyl) pyridines efficiently and in high yields.

Disclosure of Invention

One aspect of the present invention relates to a process for the preparation of 2-substituted-5- ((1-alkylthio) alkyl) pyridines (I),

wherein

R¹And R²Independent representation H, C₁-C₄Alkyl, or R¹Or R²Any of (1) and R³Taken together represent a 4-to 6-membered saturated ring, or R¹And R²Taken together represent a 3 to 6 membered saturated ring optionally containing an O or N atom;

R³is represented by C₁-C₄Alkyl, or R¹Or R²Any of (1) and R³Taken together represent a 4-to 6-membered saturated ring; and

R⁴is represented by C₁-C₄Alkyl or C₁-C₄A haloalkyl group;

the method comprises the following steps

a) Condensing the substituted ketene (II) with an enamine (III),

the structure of the substituted alkenone (II) is as follows,

wherein

R⁴As defined above; and

R⁵and R⁶Independently represent C₁-C₄An alkyl group;

the enamine (III) has the following structure,

wherein

R¹、R²And R³As defined above; and

R⁷and R⁸Independently represent C₁-C₄Alkyl, or R⁷And R⁸Taken together with N represents a 5-membered saturated or unsaturated ring;

b) cyclizing the reaction mixture from step a) in the presence of ammonia or a reagent capable of generating ammonia (reagent capableof generating ammonia) to give the 2, 3, 5-substituted pyridine (IV),

wherein

R¹、R²、R³、R⁴And R⁶As defined above; and

c) saponification and decarboxylation of the 2, 3, 5-substituted pyridine (IV) gives the 2-substituted-5- ((1-alkylthio) alkyl) pyridine (I). The process is particularly well suited for the preparation of R⁴Denotes CF₃The compound of (1).

Another aspect of the present invention relates to nicotinic acid derivative intermediates of formula (IV),

wherein

R¹And R²Independent representation H, C₁-C₄Alkyl, or R¹Or R²Any of (1) and R³Taken together represent a 4-to 6-membered saturated ring, or R¹And R²Taken together represent a 3 to 6 membered saturated ring optionally containing an O or N atom;

R³is represented by C₁-C₄Alkyl, or R¹Or R²Any of (1) and R³Taken together represent a 4-to 6-membered saturated ring;

R⁴is represented by C₁-C₄Alkyl or C₁-C₄A haloalkyl group; and

R⁶represents H or C₁-C₄An alkyl group.

Detailed Description

Unless otherwise limited, the term "alkyl" (including derivative terms such as "haloalkyl") as used herein includes straight chain, branched chain, and cyclic groups. Typical alkyl groups are thus methyl, ethyl, 1-methylethyl, propyl, 1-dimethylethyl and cyclopropyl. The term "halogen" includes fluorine, chlorine, bromine and iodine. The term "haloalkyl" includes alkyl groups substituted with one to the maximum possible number of halogen atoms.

One aspect of the present invention relates to a process for the preparation of 2-substituted-5- ((1-alkylthio) alkyl) pyridines (I),

wherein

R¹And R²Independent representation H, C₁-C₄Alkyl, or R¹Or R²Any of (1) and R³Taken together represent a 4-to 6-membered saturated ring, or R¹And R²Taken together represent a 3 to 6 membered saturated ring optionally containing an O or N atom;

R³is represented by C₁-C₄Alkyl, or R¹Or R²Any of (1) and R³Taken together represent a 4-to 6-membered saturated ring; and

R⁴is represented by C₁-C₄Alkyl or C₁-C₄A haloalkyl group;

the method comprises the following steps:

a) condensing the substituted ketene (II) with an enamine (III),

the structure of the substituted alkenone (II) is as follows,

wherein

R⁴As defined above; and

R⁵and R⁶Independently represent C₁-C₄An alkyl group;

the enamine (III) has the following structure,

wherein

R¹、R²And R³As defined above; and

R⁷and R⁸Independently represent C₁-C₄Alkyl, or R⁷And R⁸Taken together with N represents a 5-membered saturated or unsaturated ring;

b) cyclizing the reaction mixture from step a) in the presence of ammonia or a reagent capable of generating ammonia to give the 2, 3, 5-substituted pyridine (IV),

wherein

R¹、R²、R³、R⁴And R⁶As defined above; and

c) saponification and decarboxylation of the 2, 3, 5-substituted pyridine (IV) gives the 2-substituted-5- ((1-alkylthio) alkyl) pyridine (I).

Substituted enone (II) starting materials are commercially available or can be prepared from a ketoester substrate and an alkyl orthoformate. Typically, acetoacetate esters are condensed with trialkyl orthoformates to give compounds of type (II). The enamine (II) starting material may conveniently be prepared as follows: the addition of an appropriately substituted amine with an appropriately substituted aldehyde in the presence of a water-absorbing material in the presence or absence of a suitable solvent. Typically, the appropriately substituted propionaldehyde is reacted with the anhydrous disubstituted amine at-20 ℃ to 20 ℃ in the presence of a drying agent such as anhydrous potassium carbonate, and the product is isolated by distillation.

In steps a) and b), about equimolar amounts of substituted ketene (II) and enamine (III) and ammonia are required in the process, however a 2-4 fold excess of ammonia or ammonia precursor is generally preferred.

Typical reagents capable of generating ammonia include, for example, 1) ammonium salts of acids, preferably organic acids, 2) formamide, or 3) mixtures of formamide with acids or acid salts (acid salt). Any ammonium salt of an aliphatic or aromatic organic acid can be used, but for ease of handling, C₁-C₄Ammonium salts of alkanoic acids are preferred. Ammonium formate and ammonium acetate are preferred.

Step a) is illustratively carried out in a polar high boiling solvent that is miscible with water. Preferred solvents include: amides such as formamide, dimethylformamide, dimethylacetamide; alcohols such as methanol, ethanol, isopropanol, (2-methoxy) ethanol; and alkyl nitriles, including acetonitrile.

The reaction is carried out at a temperature of-20 ℃ to 150 ℃. Temperatures of 0 ℃ to 80 ℃ are preferred.

The product is isolated by conventional techniques such as silica gel chromatography or fractional distillation.

In a typical reaction, the substituted enone (II) and enamine (III) are dissolved in a polar solvent at-5 ℃ to 20 ℃ and then agitated until the substituted enone (II) and enamine (III) are depleted. In step b), the ammonium salt of the organic acid is then added and the mixture is heated at 50 ℃ to 150 ℃ until the reaction is complete. After dissolution in a non water miscible solvent and washing with water and optionally brine, the 2, 3.5-substituted pyridine (IV) is isolated by silica gel column chromatography or vacuum distillation.

In step c), the 2, 3, 5-substituted pyridine (IV) is saponified by known procedures with a base, preferably an alkali metal hydroxide such as lithium hydroxide, in a water-miscible polar solvent such as tetrahydrofuran at 0 ℃ to 50 ℃. The resulting pyridine carboxylate is neutralized and then decarboxylated by well known procedures, e.g., heating in a high boiling solvent such as Dow Therm A (available from The Dow Chemical Company), optionally with copper powder, at a temperature between 150 ℃ and 250 ℃ to yield 2-substituted-5- ((1-alkylthio) alkyl) pyridine (I), which can be isolated by conventional methods such as silica gel chromatography or vacuum distillation.

The present application also relates to the following aspects:

item 1. A process for producing 2-substituted-5- ((1-alkylthio) alkyl) pyridine (I),

wherein

R¹And R²Independent representation H, C₁-C₄Alkyl, or R¹Or R²Any of (1) and R³Taken together represent a 4-to 6-membered saturated ring, or R¹And R²Taken together represent a 3 to 6 membered saturated ring optionally containing an O or N atom;

R³is represented by C₁-C₄Alkyl, or R¹Or R²Any of (1) and R³Taken together to represent a 4-to 6-membered saturated ring(ii) a And

R⁴is represented by C₁-C₄Alkyl or C₁-C₄A haloalkyl group;

the method comprises the following steps:

a) condensing the substituted ketene (II) with an enamine (III),

the structure of the substituted ketene (II) is as follows

Wherein

R⁴As defined above; and

R⁵and R⁶Independently represent C₁-C₄An alkyl group;

the enamine (III) has the following structure

Wherein

R¹、R²And R³As defined above; and

R⁷and R⁸Independently represent C₁-C₄Alkyl, or R⁷And R⁸Taken together with N represents a 5-membered saturated or unsaturated ring;

b) cyclizing the reaction mixture from step a) in the presence of ammonia or a reagent capable of generating ammonia to give the 2, 3, 5-substituted pyridine (IV),

wherein

R¹、R²、R³、R⁴And R⁶As defined above; and

c) saponification and decarboxylation of the 2, 3, 5-substituted pyridine (IV) gives the 2-substituted-5- ((1-alkylthio) alkyl) pyridine (I).

Item 2 the method of item 1, wherein R⁴Denotes CF₃。

The method of item 3, item 2, wherein R¹Represents H, R²Represents CH₃And R³Represents CH₃。

Item 4. Compound of formula (IV)

Wherein

R¹And R²Independent representation H, C₁-C₄Alkyl, or R¹Or R²Any of (1) and R³Taken together represent a 4-to 6-membered saturated ring, or R¹And R²Taken together represent a 3 to 6 membered saturated ring optionally containing an O or N atom;

R³is represented by C₁-C₄Alkyl, or R¹Or R²Any of (1) and R³Taken together represent a 4-to 6-membered saturated ring;

R⁴is represented by C₁-C₄Alkyl or C₁-C₄A haloalkyl group; and

R⁶represents H or C₁-C₄An alkyl group.

The compound of item 5 or 4, wherein R⁴Denotes CF₃。

The following examples are set forth to illustrate the invention.

Examples

EXAMPLE 1 preparation of 5- (1-methylthioethyl) -2-trifluoromethylpyridine

Step 1.1 preparation of- (3-methylthiobut-1-enyl) pyrrolidine

A dry 5000 milliliter (mL) round bottom flask equipped with a mechanical stirrer, nitrogen inlet, addition funnel, and thermometer was charged with 591g (4.27mol) anhydrous granular potassium carbonate and 1428mL (17.1mol) anhydrous pyrrolidine. The mixture was stirred under nitrogen and then cooled to 4 ℃ with an ice bath before 1050ml (8.9mol) of 3-methylthio-butyraldehyde were added at a rate to maintain the temperature below 10 ℃. After the addition was complete, the cooling bath was removed and the reaction mixture was allowed to reach room temperature. The reaction contents were then filtered through a sintered glass filter funnel to remove the solids, which were washed with 200ml of anhydrous ether. The filtrate was concentrated in vacuo on a rotary evaporator until all pyrrolidine was removed to give 1,519g of 1- (3-methylthiobut-1-enyl) pyrrolidine as a red liquid. H NMR CDCl₃δ1.36(d，3H)，1.85(m，4H)，2.02(s，3H)，3.02(m，4H)，3.26(q，1H)，3.98(dd，1H)，6.25(d，1H)。

Step 2.5 preparation of ethyl 5- (1-methylthioethyl) -2-trifluoromethyl-nicotinate

A dry 50mL round bottom flask equipped with a mechanical stirrer, nitrogen inlet, addition funnel and thermometer was charged with 1- (3-methylthiobut-1-enyl) pyrrolidine (5.0g, 0.0291mol) and 100mL anhydrous acetonitrile. 2- [ 1-ethoxymethylene is added dropwise]-ethyl 4, 4, 4-trifluoro-3-oxo-butyrate (7.0g, 0.0291mol), and the reaction mixture was then stirred at room temperature for 1 hour. An aliquot was analyzed by Gas Chromatography (GC), which indicated that no starting material remained. Ammonium acetate (5.0g, 0.058mol) was added to the dark red solution and the reaction mixture was heated at reflux for 30 min. Cooled and concentrated in vacuo on a rotary evaporator and the crude product purified by silica gel column chromatography (gradient 5% ethyl acetate, 95% hexane to 50% ethyl acetate, 50% hexane over 20 minutes) to give 2.5g of the title compound as a pale yellow oil.¹H NMR(CDCl₃): δ 1.42(t, 3H), 1.62(d, 3H), 1.96(s, 3H), 3.94(q, 1H), 4.43(q, 2H), 8.08(s, 1H) and 8.71(s, 1H).

Step 3.5- (1-methylthioethyl) -2-trifluoromethyl-nicotinic acid preparation

A dry 50mL glass vial equipped with a mechanical stirrer, nitrogen inlet was charged with 0.5g (0.00170mol) of ethyl 5- (1-methylthioethyl) -2-trifluoromethylnicotinate and 10mL of Tetrahydrofuran (THF). The solution was cooled to 0 ℃ and then 5.1mL of 1N aqueous lithium hydroxide solution (0.00511mol) was added slowly via syringe. The reaction mixture was stirred at 0 ℃ for 1 hour, then at room temperature overnight. Aliquots were purified by Thin Layer Chromatography (TLC) and High Performance Liquid Chromatography (HPLC), which indicated that the reaction was substantially complete. The mixture was acidified to pH 2 with aqueous hydrochloric acid and extracted with 3 equal portions of 50mL ethyl acetate. The extract was purified over anhydrous magnesium sulfate (MgSO)₄) Drying, filtration and concentration in vacuo on a rotary evaporator gave 0.410g of the title compound, which wasAs a brown solid.¹H NMR(CDCl₃): δ 1.66(d, 3H), 1.96(s, 3H), 3.98(q, 1H), 8.01(bs, 1H), 8.30(s, 1H) and 8.80(s, 1H).

Step 4.5 preparation of- (1-methylthioethyl) -2-trifluoromethyl-pyridine

A dry 50mL round bottom flask equipped with a mechanical stirrer, nitrogen inlet, thermometer, and reflux condenser was charged with 0.35g (0.00132mol) of 5- (1-methylthioethyl) -2-trifluoromethylnicotinic acid, 0.17g (0.00264mol) of copper powder, and 10mL Dow Therm A. The reaction mixture was heated at 240 ℃ for 1 hour and then cooled to room temperature. The reaction mixture was extracted with 3 aliquots of 50mL ethyl acetate and then washed with 50mL water and 50mL saturated aqueous sodium chloride. The organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo on a rotary evaporator. The crude product thus obtained was purified by silica gel chromatography (gradient 100% hexane to 50% ethyl acetate, 50% hexane). The pure fractions were combined and then concentrated in vacuo on a rotary evaporator to give 0.13g of the title compound as a pale yellow oil.¹H NMR(CDCl₃): δ 1.62(d, 3H), 1.94(s, 3H), 3.93(q, 1H), 7.68(d, 1H), 7.90(d, 1H) and 8.66(s, 1H).

Claims (2)

1. A compound of formula (IV)

Wherein

R¹And R²Independently represent H or C₁-C₄An alkyl group;

R³is represented by C₁-C₄An alkyl group;

R⁴is represented by C₁-C₄A haloalkyl group; and

R⁶is represented by C₁-C₄An alkyl group.

2. The compound of claim 1, wherein R⁴Denotes CF₃。