Method for producing 2-chloro-5-chloromethyl-1,3-thiazol

Details Method for producing 2-chloro-5-chloromethyl-1,3-thiazol Method for producing 2-chloro-5-chloromethyl-1,3-thiazol

2002-04-19

2004-11-02

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06812348

ABSTRACT:

The invention relates to a process for the preparation of 2-chloro-5-chloromethyl-1,3-thiazole (CCT), and also intermediates used therein.
2-Chloro-5-chloromethyl-1,3-thiazole is a useful intermediate in the preparation of pesticides or of pharmaceutical products.
The literature discloses a multiplicity of highly varied processes for the preparation of CCT. For example, EP 0 260 560 and EP 0 446 913 describe the preparation of CCT by reaction of allyl isothiocyanate or an allyl isothiocyanate substituted with a leaving group with a chlorinating agent, and EP 0 763 531 describes the reaction of 2-chloroallyl isothiocyanate with a chlorinating agent. These processes have disadvantages in that, for example, several by-products occur in the first variant, which cause CCT prepared in this way to have a low purity, and the starting material in the second variant can only be obtained at high cost. Further, a considerable excess of chlorinating agents must be used and the process must be operated at high dilution. Also, exact control of the reaction temperature is necessary and the stable intermediates formed in the course of the reaction have to be converted exothermically to the desired final product in an additional reaction step. EP 0 794 180 describes the preparation of CCT from 1,3-dichloropropene and a thiocyanate salt via 3-chloro-1-isothiocyanate-1-propene as an improvement.
Other variants, such as the process according to EP 0 775 700, in which the CCT is prepared via 2-amino-5-methylthiazole by means of diazotization and subsequent chlorination, also have the disadvantage that CCT is contaminated by a multiplicity of by-products, which are very difficult or impossible to remove and lead to high yield losses.
It is an object of the invention to provide novel processes which facilitate the preparation of the CCT in high purity and yield.
The invention accordingly provides a process for the preparation of 2-chloro-5-chloromethyl-1,3-thiazole, which comprises reacting a compound of the formula
in which X is Cl, —OR, —SR or —NR
2
, where R is H or a suitable protecting group; Y is H or Cl; and Z is Cl or O,
the compounds of the formula (I) having a maximum of one double bond between C* and C″ or between C″ and Z, with the proviso that the bond between C″ and Z is a double bond when Z is O and is a single bond when Z is Cl,
a) where X and Y are Cl and Z is O either
a
1
) first with thiocyanate to give a compound of the formula
and then with an acid/R′OH or acid/orthoester mixture, where R′ is C
1
to C
6
-alkyl, to give the compound of the formula
or first converting the compound of the formula (I) to the acetal and then reacting with thiocyanate to give the compound of the formula (III), then converting it to 2-chloro-5-chloromethyl-1,3-thiazole,
or
a
2
) with thiourea to give; a mixture of compounds of the formulae
and, after basic cleavage to give the corresponding thiol or amine, converting to 2-chloro-5-chloromethyl-1,3-thiazole by Sandmeyer diazotization and optional reaction with a chlorinating agent
or
b) where X is OR, SR or NR
2
, and R is H or a suitable protecting group, Y is Cl and Z is O, with thiourea to give a compound of the formula
and then substituting the amino group by a chlorine atom by Sandmeyer reaction, and obtaining 2-chloro-5-chloromethyl-1,3-thiazole by chlorination and optional ether cleavage or
c) where X is OR, SR or NR
2
, and R is H or a suitable protecting group, Y is Cl and Z is O, with ammonium dithiocarbamate or ammonium thiocarbamate to give the compound
and, if necessary, converting the radical X into the corresponding radical OH, SH or NH
2
by removal of the protecting group, and then obtaining 2-chloro-5-chloromethyl-1,3-thiazole by reaction with suitable chlorinating agents, or
d) where X, Y and Z are all Cl, and the compound contains no double bonds,
with thiourea to give a thiazolidine of the formula
and then dehydrogenating and diazotizing to give 2-chloro-5-chloromethyl-1,3-thiazole or
e) where X and Z are both Cl and Y is H, and the compound contains a double bond between C* and C″, with an oxidizing agent to convert it to the corresponding epoxide, which
e
1
) is converted directly to 2-amino-5-chloromethyl-1,3-thiazole using thiourea in a suitable solvent and/or is converted to the compound of the formula (V), where X is OR′, and R′ is H or C
1
-C
6
-alkyl, and is then converted to 2-chloro-5-chloromethyl-1,3-thiazole by diazotization and, if necessary, ether cleavage and/or chlorination, or
e
2
) similarly to c), is converted to 2-chloro-5-chloromethyl-1,3-thiazole by reaction with ammonium dithiocarbamate or ammonium thiocarbamate.
According to the invention, CCT is prepared by starting from a compound of the formula (I) in which X is Cl, —OR, —SR or —NR
2
, where R is H or a protecting group; Y is H or Cl and Z is Cl or O, the compounds of the formula (I) having a maximum of one double bond between C* and C″ or between C″ and Z, with the proviso that the bond between C″ and Z is a double bond when Z is O and is a single bond when Z is Cl.
In the formula (I), the radical R is H or a protecting group. Useful protecting groups include all groups suitable for protection of the oxygen, sulfur or nitrogen radical. These include C
1
-C
6
-alkyl groups, such as methyl, ethyl, propyl, i-butyl, t-butyl, hexyl, or the phthalimide group.
Variant a):
In variant a), X and Y are both chlorine and Z is oxygen, so that 2,3-dichloropropanal is used as starting compound of the formula (I).
2,3-Dichloropropanal is easily accessible, for example by chlorination of acrolein in dichloromethane. According to the invention, the conversion of the aldehyde to CCT can be carried out by the variants a
1
) or a
2
).
Variant a
1
):
Variant a
1
) involves aldehyde first being reacted with sodium or ammonium thiocyanate to give the compound of the formula (II). The thiocyanate can be used in an equimolar quantity, or in excess or deficiency based on the aldehyde. Thiocyanate is preferably used in deficiency. The reaction takes place in a suitable solvent. Suitable solvents include all customary organic solvents, for example carboxylic acids having from 1 to 6 carbon atoms, such as formic acid, acetic acid, propionic acid, etc.; halogenated aliphatic and aromatic hydrocarbons, such as methylene chloride, trichloromethane, trichloroethylene, carbon tetrachloride, chlorobenzene, dichlorobenzene etc.; alcohols, such as methanol, ethanol, propanol, t-butanol, etc.; ethers, such as diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, t-butyl methyl ether, ethylene glycol monomethyl ether, tetrahydrofuran, dioxane etc; ketones, such as acetone, methyl ethyl ketone, methyl i-butyl ketone, cyclohexanone etc.; amides, such as N,N-dimethylformamide, N,N-diethylformamide, N-methylpyrrolidone, etc.; sulfoxides, such as dimethyl sulfoxide, etc. and nitriles, such as acetonitrile, propionitrile, etc.
Further useful solvents include water or solvent/water mixtures.
It can also be advantageous to add a phase transfer catalyst to the solvent. The preferred quantity of added phase transfer catalyst is in the range from 0.1 to 15 mol %. Useful phase transfer catalysts include crown ethers, quaternary ammonium salts, such as tetramethylammonium chloride, tetraethylammonium chloride, tetrabutylammonium chloride, benzyltrimethylammonium chloride, and also quaternary phosphonium salts.
Preferred solvents in the variant a
1
) are C
1
-C
3
-carboxylic acids, nitriles, chlorinated aliphatic hydrocarbons and amides. Most preferred are acetic acid, acetonitrile, dimethylformamide and a methylene chloride/crown ether mixture.
The temperature is in the range from 10 to 150° C., more preferably from 15 to 130° C., most preferably from 20 to 80° C.
The compound of the formula (II) is novel and therefore likewise forms part of the subject matter of the invention.
The compound of the formula (II) is then converted to the acetal of the formula (III) by addition of an acid/R′OH or acid/orthoester mixture a

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