HK1174028A - Process for the preparation of 2-substituted-5-(1-alkylthio)alkylpyridines - Google Patents

Description

process for the preparation of 2-substituted-5- ((1-alkylthio) alkyl) pyridines

The application is a divisional application of a patent application (PCT application number is PCT/US2007/003782) with Chinese application number of 200780044166.1, the name of the invention is 'preparation method of 2-substituted-5- ((1-alkylthio) alkyl) pyridine', and the application date is 2007, 2, 9 days.

This application claims benefit of U.S. provisional application 60/861,912 filed on 30/11/2006.

Technical Field

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

Background

For the preparation of some novel insecticides, 2-substituted-5- ((1-alkylthio) alkyl) pyridines are useful intermediates; see, for example, U.S. patent application publication 2005/0228027. It would be advantageous to be able to prepare 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 the content of the first and second substances,

R¹and R²Independently represent H or C₁-C₄Alkyl, or R¹And R²Together represent a 3-to 6-membered saturated ring optionally containing an O or N atom; and

R³is represented by C₁-C₄An alkyl group; 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),

alkenone (II) is:

wherein the content of the first and second substances,

R⁴as defined above; and

R⁵is represented by C₁-C₄An alkyl group;

enamines (III) are:

wherein the content of the first and second substances,

R¹and R²As defined above; and

R⁶and R⁷Independently represent C₁-C₄Alkyl, or R⁶、R⁷Together with N represents a 5-membered saturated or unsaturated ring;

and cyclisation in the presence of ammonia or of an agent capable of generating ammonia to give the 2, 5-disubstituted pyridine (IV),

wherein the content of the first and second substances,

R¹、R²and R⁴As defined above;

b) chlorinating or brominating the 2, 5-disubstituted pyridines (IV) to give haloalkylpyridines (V)

Wherein the content of the first and second substances,

R¹、R²and R⁴As defined above; and

x represents Cl or Br;

and

c) treating said haloalkylpyridine (V) with a thiolate (VI) to give a 2-substituted-5- ((1-alkylthio) alkyl) pyridine (I),

the mercaptides (VI) are:

R³S-M⁺(VI)

wherein the content of the first and second substances,

R³as defined above; and

m represents an alkali metal.

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

wherein R is¹And R²Independently represent H or C₁-C₄Alkyl, or R¹And R²Together represent a 3-to 6-membered saturated ring optionally containing an O or N atom; and

R³is represented by C₁-C₄An alkyl group; 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),

alkenone (II) is:

wherein the content of the first and second substances,

R⁴as defined above; and

R⁵is represented by C₁-C₄An alkyl group;

enamines (III) are:

wherein the content of the first and second substances,

R¹and R²As defined above; and R⁶And R⁷Independently represent C₁-C₄Alkyl, or R⁶、R⁷Together with N represents a 5-membered saturated or unsaturated ring;

and cyclisation in the presence of ammonia or of an agent capable of generating ammonia to give the 2, 5-disubstituted pyridine (IV),

wherein the content of the first and second substances,

R¹、R²and R⁴As defined above;

and

b) treating the 2, 5-disubstituted pyridine (IV) with a dialkyl disulfide (VII) and a strong base to give a 2-substituted-5- ((1-alkylthio) alkyl) pyridine (I),

the dialkyl disulfides (VII) are:

R³S SR³(VII)

wherein the content of the first and second substances,

R³as defined above.

Another aspect of the invention is a novel compound having formula (IV):

wherein the content of the first and second substances,

R¹and R²Independently represent H or C₁-C₄Alkyl, or R¹And R²Together represent a 3-to 6-membered saturated ring optionally containing an O or N atom; and

R⁴is represented by C₁-C₄A haloalkyl group.

Another aspect of the invention is a novel compound having formula (V):

wherein the content of the first and second substances,

R¹and R²Independently represent H or C₁-C₄Alkyl, or R¹And R²Together represent a 3-to 6-membered saturated ring optionally containing an O or N atom;

R⁴is represented by C₁-C₄A haloalkyl group; and

x represents Cl or Br.

Unless otherwise specifically limited, the term "alkyl" (including derivatives thereof such as "haloalkyl") as used herein includes straight chain, branched chain, and cyclic groups. Typical alkyl groups are therefore 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 from one halogen atom 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 the content of the first and second substances,

R¹and R²Independently represent H or C₁-C₄Alkyl, or R¹And R²Together represent a 3-to 6-membered saturated ring optionally containing an O or N atom; and

R³is represented by C₁-C₄An alkyl group; 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),

alkenone (II) is:

wherein the content of the first and second substances,

R⁴as defined above; and

R⁵is represented by C₁-C₄An alkyl group;

enamines (III) are:

wherein

R¹And R²As defined above; and

R⁶and R⁷Independently represent C₁-C₄Alkyl, or R⁶And R⁷Together with N represents a 5-membered saturated or unsaturated ring;

and cyclisation in the presence of ammonia or of an agent capable of generating ammonia to give the 2, 5-disubstituted pyridine (IV),

wherein the content of the first and second substances,

R¹、R²and R⁴As defined above;

b) chlorinating or brominating the 2, 5-disubstituted pyridine (IV) to obtain haloalkylpyridine (V),

wherein the content of the first and second substances,

R¹、R²and R⁴As defined above; and the number of the first and second groups,

x represents Cl or Br;

and

c) treating said haloalkylpyridine (V) with a thiolate (VI) to give a 2-substituted-5- ((1-alkylthio) alkyl) pyridine (I),

the mercaptides (VI) are:

R³S-M⁺(VI)

wherein the content of the first and second substances,

R³as defined above; and

m represents an alkali metal.

The starting material α, β -unsaturated ketone (II) is commercially available or can be prepared from the corresponding vinylogous compound(s) and acylating agent(s). In general, alkyl vinyl ethers (alkylvinyl ethers) can be acylated with haloalkylacetic anhydride (haloalkylacetic anhydride) to give compounds of type (II). The starting enamine (III) may conveniently be prepared by: the suitably substituted amine is added to the suitably substituted aldehyde in the presence of a water absorbing material, with or without a suitable solvent. Typically, the appropriately substituted propionaldehyde is reacted with the anhydrous disubstituted amine at-20 ℃ to 20 ℃ and in the presence of a drying agent (e.g., anhydrous potassium carbonate), and the product is isolated by distillation.

In step a), the process requires approximately equimolar amounts of the α, β -unsaturated ketone (II) and the enamine (III) and ammonia, but it is often preferred to use a 2-to 4-fold excess of ammonia or ammonia precursor.

Typical agents capable of producing 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 organic acid or an aromatic organic acid may be used, but for convenience of handling, C is preferred₁-C₄An ammonium salt of an alkanoic acid. Ammonium formate and ammonium acetate are most preferred.

Preferably, step a) is carried out in a polar high boiling solvent miscible with water. Preferred solvents include amides such as formamide, dimethylformamide, dimethylacetamide, alcohols such as methanol, ethanol, isopropanol, (2-methoxy) ethanol and alkyl nitriles, with acetonitrile being particularly preferred.

The reaction is carried out at a temperature of-20 ℃ to 150 ℃. It is generally preferred to have a temperature of from 0 ℃ to 80 ℃.

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

In a typical reaction, the α, β -unsaturated ketone (II) and enamine (IH) are dissolved in a polar solvent at-5 ℃ to 20 ℃ and stirred until the α, β -unsaturated ketone (II) and enamine (III) are depleted. The ammonium salt of the organic acid is then added and the mixture is heated until the reaction is complete. After dissolution in a water-immiscible solvent and washing with water and optionally with brine, the 2, 5-disubstituted pyridine (IV) is isolated by column chromatography on silica gel or, preferably, by vacuum distillation.

In step b), the 2, 5-disubstituted pyridine (IV) is selectively halogenated with N-chlorosuccinimide or preferably N-bromosuccinimide, the halogenation reaction being carried out in a suitable solvent (e.g. dichloromethane) and at from-78 ℃ to 100 ℃ and optionally with catalytic amounts of a Lewis acid (e.g. zirconium tetrachloride) or a free radical initiator (e.g. benzoyl peroxide). The resulting 2-substituted-5-monohaloalkylpyridine (V) is then further reacted in step c) in a suitable solvent (e.g. ethanol or tetrahydrofuran) and at a temperature of from 0 ℃ to 60 ℃ with a thiolate (VI)) to give the 2-substituted-5- ((1-alkylthio) alkyl) pyridine (I).

Alternatively, the 2, 5-disubstituted pyridine (IV) from step a) is reacted with a dialkyl disulfide (VII) and a strong base (e.g. lithium diisopropylamide) in a suitable solvent (e.g. tetrahydrofuran or diethyl ether) to give the 2-substituted-5- (1-alkylthio) pyridine (I).

Typically, treatment of the 2, 5-disubstituted pyridine (IV) with a strong base, such as lithium diisopropylamide, at-100 ℃ to 0 ℃ in a suitable solvent, such as tetrahydrofuran, and subsequent treatment with a dialkyl disulfide (VII) affords a 2-substituted-5- ((1-alkylthio) alkyl) pyridine (I), which 2-substituted-5- ((1-alkylthio) alkyl) pyridine (I) can be isolated by conventional methods, such as silica gel chromatography or vacuum distillation.

The following examples are provided to illustrate the invention.

The present application also provides the following aspects:

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

wherein R is¹And R²Independently represent H or C₁-C₄Alkyl, or R¹And R²Together represent a 3-to 6-membered saturated ring optionally containing an O or N atom; and

R³is represented by C₁-C₄An alkyl group; 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),

alkenone (II) is:

wherein R is⁴As defined above; and

R⁵is represented by C₁-C₄An alkyl group;

enamines (III) are:

wherein R is¹And R²As defined above; and

R⁶and R⁷Independently represent C₁-C₄Alkyl, or R⁶And R⁷Together with N represents a 5-membered saturated or unsaturated ring;

and cyclisation in the presence of ammonia or of an agent capable of generating ammonia to give the 2, 5-disubstituted pyridine (IV),

wherein R is¹、R²And R⁴As defined above;

b) chlorinating or brominating the 2, 5-disubstituted pyridine (IV) to obtain haloalkylpyridine (V),

wherein R is¹、R²And R⁴As defined above; and

x represents Cl or Br;

and

c) treating said haloalkylpyridine (V) with a thiolate (VI) to give a 2-substituted-5- ((1-alkylthio) alkyl) pyridine (I),

the mercaptides (VI) are:

R³S-M⁺(VI)

wherein R is³As defined above; and

m represents an alkali metal.

The method of item 2, item 1, wherein R⁴Denotes CF₃。

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

Item 4. A method for producing a 2-substituted-5- ((1-alkylthio) alkyl) pyridine (I),

wherein R is¹And R²Independently represent H or C₁-C₄Alkyl, or R¹And R²Together represent a 3-to 6-membered saturated ring optionally containing an O or N atom; and

R³is represented by C₁-C₄An alkyl group; 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),

alkenone (II) is:

wherein R is⁴As defined above; and

R⁵is represented by C₁-C₄An alkyl group;

enamines (III) are:

wherein R is¹And R²As defined above; and

R⁶and R⁷Independently represent C₁-C₄Alkyl, or R⁶And R⁷Together with N represents a 5-membered saturated or unsaturated ring;

and the number of the first and second groups,

cyclisation in the presence of ammonia or of an agent capable of generating ammonia to give the 2, 5-disubstituted pyridine (IV),

wherein R is¹、R²And R⁴As defined above;

and

b) treating the 2, 5-disubstituted pyridine (IV) with a dialkyl disulfide (VII) and a strong base to give a 2-substituted-5- ((1-alkylthio) alkyl) pyridine (I),

the dialkyl disulfides (VII) are:

R³S SR³(VII)

wherein R is³As defined above.

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

The method of item 6 or 5, wherein R¹Represents H, R²Represents CH₃And R³Represents CH₃。

Item 7. the compound of the formula (IV),

wherein the content of the first and second substances,

R¹and R²Independently represent H or C₁-C₄Alkyl, or R¹And R²Together represent a 3-to 6-membered saturated ring optionally containing an O or N atom; and

R⁴is represented by C₁-C₄A haloalkyl group.

The compound of item 8 or 7, wherein R⁴Denotes CF₃。

The compound of item 9 or 8, wherein R¹Represents H, and R²Represents CH₃。

Item 10. Compounds of formula (V),

wherein R is¹And R²Independently represent H or C₁-C₄Alkyl, or R¹And R²Together represent a 3-to 6-membered saturated ring optionally containing an O or N atom; and

R⁴is represented by C₁-C₄A haloalkyl group; and

x represents Cl or Br.

The compound of item 11 or 10, wherein R⁴Denotes CF₃。

The compound of item 12 or 11, wherein R¹Represents H, and R²Represents CH₃。

Detailed description of the preferred embodiments

Examples

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

Step 1.1 preparation of- (but-1-enyl) pyrrolidine

To a dry 500 milliliter (mL) three neck round bottom flask equipped with a magnetic stirrer, nitrogen inlet, addition funnel, and thermometer was added pyrrolidine (83.45mL,1.0mmol) and potassium carbonate (34.55g,0.25 mol). The mixture was cooled to 0 ℃ and butyraldehyde (30.05 grams (g),0.42mol) was added dropwise with stirring and under a nitrogen atmosphere, at a rate such that the temperature remained below 15 ℃. After the addition was complete (about 10 minutes), the cooling bath was removed and the reaction mixture was allowed to warm to room temperature over 3 hours. The reaction mixture was filtered through a sintered glass filter to remove solids. The solid was washed thoroughly with diethyl ether (ether), the washings combined with the filtrate and concentrated on a rotary evaporator to give crude 1- (but-l-enyl) pyrrolidine, which was purified by vacuum distillation (at 15mmHg and 65-78 ℃);¹H NMR(CDCl₃):δ6.20(d,1H),4.18(q,1H),2.95(m,4H),1.80,(m,4H),0.97(d,3H)。

step 2.5 preparation of ethyl-2-trifluoromethylpyridine

To a dry 500mL round bottom flask equipped with a magnetic stirrer, nitrogen inlet, addition funnel, thermometer, and reflux condenser was added 1- (but-1-enyl) pyrrolidine (15.0mL,0.12mol, freshly distilled at 15mmHg and 65-78 ℃) and anhydrous acetonitrile (150 mL). 4-ethoxy-1, 1, 1-trifluorobut-3-en-2-one (24mL,0.12mol) was added dropwise and stirred at room temperature for 2 hours. Ammonium acetate (18.5g,0.389mol) was then added in one portion and the mixture was heated to reflux for 1 hour and then held at ambient temperature overnight. The reaction mixture was poured into water (200mL) and the aqueous mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water, brine and dried (MgSO)₄) Filtered and concentrated on a rotary evaporator under reduced pressure. The residue was purified by silica gel column chromatography (using a gradient of 100% hexane to 50% ethyl acetate: 50% hexane (15 min)). The pure fractions were combined and concentrated in vacuo to give 12.6g of 5-ethyl-2-trifluoromethylpyridine as a red liquid;¹H NMR(CDCl₃)δ8.58(s,1H),7.68(d,1H),7.61(d,1H),2.73(q,1H),1.28(d,3H)。

step 3.5 preparation of- (1-bromoethyl) -2-trifluoromethylpyridine

N-bromosuccinimide (1.78g,0.01mol) was added to dry fresh dichloromethane (60mL) at room temperature under a nitrogen atmosphere. Once dissolved, the solution was cooled to 0 ℃. 5-Ethyl-2-trifluoromethyl-pyridine (1.75g,0.01mol) was dissolved in a small amount of anhydrous dichloromethane and added to the above solution by syringe, followed by zirconium tetrachloride (117mg,0.5 mmol). The ice bath was removed and the mixture was allowed to stir at room temperature overnight. TLC (9:1, hexane: ethyl acetate) indicated the end of the reaction. The reaction was quenched with saturated sodium bicarbonate solution (25mL)The mixture was quenched. The organic layer was separated, washed with brine and dried (MgSO)₄). The residue was purified by column chromatography (1:20, ethyl acetate: hexane) to give the product: 2.04g (80%) as a pale yellow liquid;¹H NMR(CDCl₃)δ8.77(s,IH),7.97(d,IH),7.69(d,IH),5.21(q,IH),2.08(d,3H)。

step 4.5 preparation of- (1-methylthioethyl) -2-trifluoromethylpyridine

A solution of 5- (1-bromoethyl) -2-trifluoromethylpyridine (1.02g,4.0mmol) in ethanol (30mL) was cooled to 0 ℃ under a nitrogen atmosphere. Sodium methyl mercaptide (364mg,5.2mmol) was added portionwise. Once addition was complete, the ice bath was removed and the reaction mixture was allowed to stir at room temperature under a nitrogen atmosphere overnight. TLC (9:1, hexane: ethyl acetate) indicated the end of the reaction. The cloudy solution was quenched with water and extracted with ether. The organic layer was then washed with brine and dried (MgSO)₄). The solvent was removed in vacuo to give the crude product as a pale yellow liquid, 0.83g (93%);¹H NMR(CDCl₃)δ8.65(s,1H),7.89(d,1H),7.67(d,1H),3.93(q,1H),1.94(s,3H),1.62(d,3H)。

Claims (6)

1. A compound of the formula (IV),

wherein the content of the first and second substances,

R¹and R²Independently represent H or C₁-C₄Alkyl, or R¹And R²Together represent a 3-to 6-membered saturated ring optionally containing an O or N atom; and

R⁴to representC₁-C₄A haloalkyl group.

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

3. The compound of claim 2, wherein R¹Represents H, and R²Represents CH₃。

4. A compound of the formula (V),

wherein R is¹And R²Independently represent H or C₁-C₄Alkyl, or R¹And R²Together represent a 3-to 6-membered saturated ring optionally containing an O or N atom; and

R⁴is represented by C₁-C₄A haloalkyl group; and

x represents Cl or Br.

5. The compound of claim 4, wherein R⁴Denotes CF₃。

6. The compound of claim 5, wherein R¹Represents H, and R²Represents CH₃。