CA1116609A - Process for preparing thiazole derivatives - Google Patents
Process for preparing thiazole derivativesInfo
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- CA1116609A CA1116609A CA000320315A CA320315A CA1116609A CA 1116609 A CA1116609 A CA 1116609A CA 000320315 A CA000320315 A CA 000320315A CA 320315 A CA320315 A CA 320315A CA 1116609 A CA1116609 A CA 1116609A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/14—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/16—Sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/34—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/36—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
NOVEL PROCESS FOR PREPARING THIAZOLE DERIVATIVES
ABSTRACT OF THE DISCLOSURE
A novel process for preparing thiazole derivatives of the formula I:
I
wherein A is oxygen, sulfur, imino, alkylimino or alkenyl-imino; and R' is alkyl, phenyl, or substituted phenyl which consists of (1) a reaction of 1-alkoxy-2-halogenoethyl isothicyanate with a compound of the formula III: R'AH where-in A and R' each has the same meaning as defined above and (2) an alcohol-elimination reaction of the thiazoline derivative yielded in the above step (1).
ABSTRACT OF THE DISCLOSURE
A novel process for preparing thiazole derivatives of the formula I:
I
wherein A is oxygen, sulfur, imino, alkylimino or alkenyl-imino; and R' is alkyl, phenyl, or substituted phenyl which consists of (1) a reaction of 1-alkoxy-2-halogenoethyl isothicyanate with a compound of the formula III: R'AH where-in A and R' each has the same meaning as defined above and (2) an alcohol-elimination reaction of the thiazoline derivative yielded in the above step (1).
Description
i6~)9 1 This invention relates to a novel process for preparing thiazole derivatives and the pharmaceutically acceptable salts thereof. More precisely, this invention provides a novel synthetic process for preparing thiazole derivatives having a substituent at 2 position.
According to this invention there is provided a compound of the formula I :
l N
wherein A is oxygen, sulfur, lmino, alkylimino or alkenyl-imino; and R' is alkyl, phenyl or substituted phenyl; and pharmaceutically acceptable salts thereof.
The following definitions are given for various terms as used throughout this specification. The term "alkyl"
refers to both straight- andbranched-chain aliphatic radicals having from one to five carbon atoms including, for example, methyl, ethyl, propyl, isoprophyl, butyl, isobutyl, pentyl, and the like. "Alkenyl" refers to both straight- and branched-chain aliphatic radicals having two to five carbon atomsincluding, for example, vinyl, allyl, methallyl, l-pentenyl,
According to this invention there is provided a compound of the formula I :
l N
wherein A is oxygen, sulfur, lmino, alkylimino or alkenyl-imino; and R' is alkyl, phenyl or substituted phenyl; and pharmaceutically acceptable salts thereof.
The following definitions are given for various terms as used throughout this specification. The term "alkyl"
refers to both straight- andbranched-chain aliphatic radicals having from one to five carbon atoms including, for example, methyl, ethyl, propyl, isoprophyl, butyl, isobutyl, pentyl, and the like. "Alkenyl" refers to both straight- and branched-chain aliphatic radicals having two to five carbon atomsincluding, for example, vinyl, allyl, methallyl, l-pentenyl,
2-isopentenyl and the like. The term "substituted phenyl"
refers to phenyl having one to three substituents. Any group can be placed on the phenyl group as long as it gives no adverse effect to the process of this invention. They are exemplified alkyl, alkenyl, aralkyl, alkynyl, halogen, cyano, hydroxy, alkoxy, nitro, and the like. Furthermore, a group represented by the formula ~H R2 (wherein R is hydrogen, alkyl, cycloalkyl-alkyl, alkenyl, alkynyl or aralkyl; and R is carboxy, protected carboxy, or cyano) can substitute - ~166Q9 1 the phenyl group. The protected carboxy means a carboxy group esterified with alkoxy, aralkoxy, aryloxy and the like.
The above exemplified groups may be present on the alkyl when the group R' is alkyl.
Furthermore, the term "alkynyl" is a radical having two to five carbon atoms including l-propynyl, 2-propynyl, l-butynyl, 2-pentynyl and the like. "Halogen" includes fluorine, iodine, chlorine and bromine. "Alkoxy" is a radical having 1 to 5 carbon atoms including methoxy, ethoxy, propoxy, i-propoxy, butoxy, t-butoxy, pentoxy and the like.
"Cycloalkyl-alkyl" means alkyl substituted with cycloalkyl of 1 to 6 carbon atoms including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. "Aralkyl" means alkyl substituted with aryl of 6 to 10 carbon atoms including phenyl and naphthyl.
"Aralkoxy" includes ether radicals having aralkyl. "Aryloxy"
is a radical having 6 to 10 carbon atoms including phenoxy and naphthoxy.
The present inventor has been studying synthetic methods to prepare thiazole derivatives having a substituent such as alkoxy, alkylthio, alkylamino, dialkylamino, phenoxy, phenylthio, anilino and the like at 2 position. It is known certain thiazole derivatives having a substituent at 2 position are useful medicament exhibiting anti-inflammatory, analgesic, anti-rheumatic and anti-pyretic activities, for example, those described in Japanese Patent Publication (Unexamined) No.
1975/69075. The initial purpose has finally attained with the process including a reaction of l-alkoxy-2-halogenoethyl isothiocyanate with a compound of the formula R'AH (wherein R' and A are the same as defined above) followed by an alcohol-elimination reaction of a resultant thiazoline derivative.
i~6~i~9 1 Many methods have been developed to prepare thiazole derivatives substituted at 2 position with alkoxy or hydroxy such as that shown by Elderfield on "Heterocyclic Compounds"
5, 548. They are, however, defective in some respects, for example, poor yield, expensive or hardly obtainable starting materials, air-pollution with adverse reagents and the like.
On the other hand, the process of this invention excels in good yield, low-costed and easily obtainable starting materials and simple operation.
There are some known methods for preparing thiazoline derivatives from isothicyanate; e.g. Synthetic Communications, 5, 143 (1975) and Heterocycles, 7, 109 (1977). These references show none of preparation of thiazole derivatives from the yielded thiazolines.
Meanwhile, Japanese Patent Publication No. 1975/31346 discloses a method for preparing thiazole derivatives from thiazoline. The method, however, can be practised only with thiazolines substituted at both 4 and 5 positions. Therefore, the process of this invention is novel and excellenk in providing thiazole derivatives having a substituent at 2 position economically and in good yield.
The process of this invention may be represented by the scheme set out below:
R'AH RO +
<OR (III) ~ N H ~ N
NCS Step 1 S - R' Step 2 ~S A- R' IV II
wherein X is halogen; R is alkyl; and A and R' are the same as defined above.
The process of this invention includes two steps as shown in the above scheme; i.e., (1) reaction of 1-alkoxy-2-i6Q9 1 halogenoethyl isothiocyanate (IV) with a compound of the formula III (wherein A and R' are the same as defined above) in the presence of acid-receptor and (2) alcohol-elimination reaction of the yielded thiazoline derivative (II).
The starting compound of the first step (Step 1), l-alkoxy-2-halogenoethyl isothiocyanate is novel and the preparation will be mentioned later. The more preferable compound IV is l-isobutoxy-2-halogenoethyl isothiocyanate because it is less volatile and easily obtainable.
The compound of the formula III used in Step 1 includes lower alcohols (e.g. methanol, ethanol, isopropanol, butanol, isobutanol, and pentanol), alkanethiols (e.g. methanethiol, ethanethiol, and propanethiol), phenol, substituted phenol, thiophenol, substituted thiophenols, alkylamines (e.g.
ethylamine, propylamine, and isobutylamine), dialkylamines (e.g. diethylamine, and dipropylamine), alkyl alkenylamines (e.g. ethyl allylamine), aniline, substituted anilines, N-alkylanilines (e.g. N-methyl aniline, N-ethylaniline, and N-propylaniline), N-alkenylanilines (e.g. N-allylaniline and N-methallylaniline), N-alkyl substituted-anilines, and N-alkenyl-substituted anilines. The substituents on the benzene ring of the substituted phenol, thiophenol, aniline, N-alkylan-iline and N-alkenylaniline are any group as long as it gives no adverse effect to the process and have been already mentioned in the definition of R'.
The reaction of Step 1 is effected in the presence of an acid receptor. The acid receptors to be used are, for example, alkali metal alkoxide (e.g. sodium ethoxide, or potassium -t-butoxide), alkali metal carbonate (e.g. potassium carbonate, sodium carbonate, or sodium bicarbonate), sodium ;6Q~
1 hydride, alkyl amine (e.g. triethylamine), magnesium, molecular sieve and the like. The reaction proceeds more smooth in the presence of sodium hydride or potassium carbonate.
Illustrative of reaction solvent are alcohols (e.g. ethanol), ketones (e.g. acetone and methyl ethyl kenone), nitriles (e.g.
acetonitrile), ethers (e.g. dioxane, monoglyme, and diglyme), esters (e.g. ethyl acetate), halogenohydrocarbons (e.g. dichloroe-thane and carbon tetrachloride), dimethyloformamide and the like. They are used combined or in single. Acetone and acetonitrile are favourable to high yield when potassium carbonate is used as acid-receptor. The reaction proceeds smooth even at room temperature r although reaction temperature should be control~ed depending on other-reaction conditions.
The alcohol-elimination reaction of the second step (Step 2) is effected in the presence of a catalytic amount of an acid. Lewis acids other than both organic and inorganic acids are applicable. They are, for example, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, hydrochloric acid, sulfuric acid, potassium hydrogensulfate, phosphoric acid, potassium dihydrogenphosphate, aluminum chloride, zinc chloride and the like. Additionally, salts of strong acid such as pyridine hydrochloride are also applicable.
Compound I~ happens to decompose in an extreme small portion during the reaction of Step 1 to give isothiocyanic acid or a hydrohalogenic acid. It is unnecessary to add any acid during the reaction of Step 2 under the condition that Compound III produces a catalytic amount of acid and steps 1 and 2 are effected successively.
The alcohol-elimination reaction may be practised at 1~1L166'~9 1 ordinary temperature or under heating. The temperature, therefore, ranges from about 20C to about 200C. Solvent is not requisite though the solvents exemplified in Step 1 ean be used, if necessary.
Steps 1 and 2 can be effected successively without isolating Compound II. Addition of an acid for Step 2 can be omitted in the case mentioned above. Compound I can be obtained only by the operation of Step 1 when the reaetant Compound III
is an amine or an aniline, i.e. the compound of which A is imino, alkylimino, or alkenylimino in the formula R'AH.
The starting compound IV is a novel compound and can be prepared by a process as shown by the following scheme:
~R OR
XCH2CH<y > XCH2CHGCS
V IV
wherein Y is halogen, alkoxy, or acyloxy and X and R are the same as defined above. The acyloxy of Compound V refers to both straight and branched-chain aliphatic radicals having two to six carbon atoms including, for example, aeetoxy, propionyloxy and the like.
As shown above, introduction of an isothiocyano group to Compound V gives Compound IV. The isothioeyanation ean be effeeted with a salt of thioeyanie aeid (e.g. ammonium thioeyanate or potassium thioeyanate) with a Lewis aeid (e.g. silieon tetraehloride, aluminium ehloride, zine ehloride, titanium tetraehloride, or euprie ehloride), or a salt of isothioeyanie aeid (e.g. silieon tetraisothioeyanate) option-ally in an inert organie solvent sueh as aeetone, aeetonitrile, benzene, diehloroethane, carbon tetraehloride and the like L66~9 1 when 1,1-dialkoxy-2-halogenoethane and 1-acyloxy-1-alkoxy-2-halogenoethane are subjected to the reaction. The reaction may be effected at room temperature or under heating, if necessary.
The reaction with a salt of thiocyanic acid or that with a salt of isothiocyanic acid in an alcohol introduces a isothiocyano group to l-alkoxy-1,2-dihalogenoethane. The alcohols to be used are, for example, methanol, ethanol, propanol, i-butanol and the like. The reaction may be effected at room temperature or under heating.
~dditionally, l-alkoxy-1,2-dihalogenoethane which is prepared by halogenation an alkoxyethene is fragile and volatile. Therefore, the compound may be subjected to isothiocyanation without isolating after prepared from alkoxyethene by halogenation. Alternatively, an isothio-cyanation reagent is added to a solution of alkoxyethene followed by addition of a halogenation reagent. Ordinary halogenation reagents are applicable to the above preparation of Compound IV. Chlorine and bromine are useful reagent in this process.
The product of the reaction of Step 2 may be hydrolyzed, if necessary. Such hydrolysis may be effected in any way usually used to hydrolyze carboxy acit esters, e.g. with an acid (e.g. hydrochloric acid, sulfuric acid, hydrobromic acid, or acetic acid) or a base (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate) in water or in a suitable solvent containing water.
When the product of Step 2 is a malonate, it is further subjected to decarboxylation, if desired,although decarboxylation ~166~C~
l is occassionally completed during the hydrolysis. The decarboxylation is easily effected by a conventional method such as heating the product. Heating with a catalytic amount of acetic acid is very effective for decarboxylation.
Besides, propionic acid residue can be delivered from di-ester of 2-methyl malonic acid by refluxing with an alkali metal carbonate or an alkali metal bicarbonate in a water miscible solvent. The alkali metal carbonates and bicarbonates to be used are exemplified sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. The applicable solvents are, for example methanol, ethanol, propanol, butanol, dioxane, ethylene-glycol, acetone, methylethylketone and the like.
Further, the thus-obtained compound I can be converted into its pharmaceutically acceptable non-toxic salts in conventional methods. They include, for example, alkali metal salts (e.g. sodium, potassium, and lithium salts), alkaline earth metals (e.g. calcium, magnesium and barium salts) and aluminum salt.
As noted above, the process of this invention is very useful for preparing thiazole derivatives substituted at 2 ; position, especially the thiazole derivatives havina excellent therapeutic activities.
Thus, this invention provides a novel and excellent process for preparing 2-substituted thiazole derivatives including useful medicament.
The invention will now be further illustrated and described by way of the following specific examples.
6~i~9 Example l l-Ethoxy-2-bromoethyl isothiocyanate A mixture of 2-bromoacetoaldehyde diethylacetal (4.0g), absolute benzene (40 ml) and silicon tetraiso-thiocyanate (1.8g) is refluxed for 7.S hours with stirring.The solution is evaporated to remove benzene. Ether and some ice pieces are added thereto. The ether layer is separated, washed with cold water and an aqueous solution of sodium bicarbonate, dried over magnesium sulfate, and evaporated to remove the solvent. The residue is distilled under reduced pressure to remove the first distillate yielding the title compound as an oil, (2.55 g), bp20100-108C. Yield: 61~
IR: ~CC14 2100 (~/2 140) NMR: CDC13 5-0t(6Hz), 6.5d(6Hz) C*13NMR: 140ppm Example 2 l-Ethoxy-2-chloroethyl isothiocyanate (a) To a solution of 1,2-dichloro-1-ethoxy-ethane (4 g) in absolute acetonitrile (12 ml) is added ammonium thiacyanate powder (2.55) with stirring under ice-cooling. The mixture is allowed to react at the same temperature for 2.5 hours and then evaporated to remove acetonitrile. Benzene is added thereto. The benzene solution is washed with cold water and a dilute aqueous solution of sodium bicarbonate, dried over magnesium sulfate and evaporated to remove the solvent.
The residue is distilled under reduced pressure to give the title compound (4.3g), bp29 103 - 105~C Yield: 93~.
IR: ~CC14 cm 2000 (~/2 130cm NMR: CDCL3 5.0t (6Hz), 6.4d(6Hz) g 66~9 .
1 (b) Chlorine gas (4.8g) is bubbled into a solution of ethoxyethene (4.85g) in carbon tetrachloride (25 ml) at -20 - -15 C with stirring under shielding the light for 1.5 hours. Ammonium thiocyanate powder (6.15 g) is added thereto. The mixture is stirred at room tempera~ure for 4 hours and then ice-cold water is added thereto. The carbon tetrachloride layer is separated. The aqueous layer is extracted with carbon tetrachloride. The carbon tetrach-loride layer, combined with the extract, is washed wlth cold water and a dilute aqueous solution of sodium bicarbonate, dried over magnesium sulfate and evaporated to remove the solvent. The residue is distilled under reduced pressure to remove the distillate of bp2870 - 99 C, yielding the title compound (7.65 g) as an oil, bp28102 - 108 C. Yield: 69%.
(c) To a mixture of 2-chloroacetoaldehyde diethylacetal (5.0 g), ammonium thiocyanate powder (3.0 g) and dichloroe-thane (25 ml) is added dropwise a solution of silicon tetrach-loride (2.94 g) in dichloroethane (7 ml). The mixture is allowed to react at 75 C for 7 hours. Ice-cold water is added thereto. The mixture is neutralized with an aqueous solution of sodium bicarbonate and extracted with methylene chloride. The dichloroethane-methylene chloride layer is separated, washed with an aqueous solution of sodium bicar-bonate, dried over magnesium sulfate and evaporated to remove the solvent. The residue is distilled under reduced pressure to give the title compound (2.75 g), bp29103 - 106C.
Yield: 50.5%.
Example 3 l-Methoxy-2-chloroethyl isothiocyanate (a) The mlxture of 2-chloroacetoaldehyde dimethylacetal 11~66~!9 (4.0 g) and silicon tetraisothiocyanate (4.4 g) is stirred at 80 - 85C for 6 hours and then benzene and ice-cold water are added thereto. The mixture is made alkaline with an aqueous solution of sodium bicarbonate and stirred further for 20 minutes. The precipitated silicon compound is filtered off.
The separated benzene layer is washed with a dilute aqueous solution of sodium bicarbonate, dried over magnesium sulfate and evaporated to remove the solvent. The residue is distilled under reduced pressure to give the title compound, bp37 99 - 100 C. Yield: 90.5%.
IR: ~CC14 m 2000 (~/2 125 cm NMR: vCDC13 5.01qlH, 6.3d2H, 6.4s3H
(b) A mixture of l-methoxy-2-chloroethyl acetate (4.9 g) and silicon tetraisothiocyanate (4.4 g) is stirred at room temperature for 2 days and further at 40 C for 6 hours and then some pieces of ice are added thereto. The mixture is neutralized with a dilute aqueous solution of sodium bicarbonate and methylene chloride is added thereto. The mixture is stirred for 20 minutes. The precipit-ate is filtered off. The filtrate is washed with a diluteaqueous solution of sodium bicarbonate and water, dried over magnesium sulfate and evaporated to remove the solvent. The residue is distilled under reduced pressure to give the title compound (4.34 g), bp25 91 - 92 C. Yield: 89.5%.
Example 4 l-Isobutoxy-2-chloroethyl isothiocyanate (a) Chlorine gas (7.55 g) is bubbled into a solution of isobutoxyethene (10.6 g) in carbon tetrachloride (50 ml) at - 20 - - 15C with stirring during 1.5 hours and then ammonium thiocyanate powder (9.7 g) is added thereto.
66~
1 The mixture ls allowed to react at room temperature for 2 hours. The same procedure as in Example 2 (b) is proceeded to give the title compound (16.4 g), bp5 85 - 90 C. Yield: 80%.
IR: CC14 cm 1995 ( /2 140 cm MNR: CDC13 5.0tlH, 6.4d2H, - 6.6m2H, - 8.2mlH, 9.08d6H
(b) Chlorine gas is bubbled into a mixture of isobutoxyethene (10.0 g) and ammonium thiocyanate (8.4 g) in carbon tetrachloride (50 ml) at - 7 - - 2 C with stirring durlng 2 hours. The mixture is allowed to rea~ at - 5 C for 0.5 hour and at room temperature for another 0.5 hour and then treated in the same manner as in Example 2 (b) to give the title compound (12.4 g), bp890 - 94C. Yield: 70%.
Example 5 2-Ethoxythiazole An ethanol solution of sodium ethozide, prepared from metallic sodium (126 mg) and absolute ethanole (6 ml), is added dropwise to a solution of l-ethoxy-2-bromoethyl isothiocyanate (1.05 g) in absolute ethanol (3 ml) with stirring under ice-cooling. The mixture is stirred at room temperature for 30 minutes, then neutralized with acetic acid and evaporated to remove ethanol. The residue is dissolved in ether. The ethereal solution is washed with water and an aqueous solution of sodium bicarbonate, dried over magnesium sulfate and evaporated to remove ether. The residue is subjected to chromatography on silica gel to give oily 2, 4-diethoxy-2-thiazoline (550 mg). Yield: 68%.
IR: ~CC14 cm 1625 NMR: ~CDC13 4.5 lH, - 6.5 2H.
A mixture of the product (100 mg), absolute p-toluene-sulfonic acid prepared from the corresponding monohydrate ~66~
1 (130 mg), and absolute benzene (5 ml) is stirred at room temperature for 1 hour and then at 50 - 55 C for 5 minutes.
The reaction mixture is diluted with ether, washed with an aqueous solution of sodium bicarbonate, and extracted with 10% hydrochloric acid~ The extract is neutralized with sodium bicarbonate and extracted with ether. The ethereal extract is dried over potassium carbonate and evaporated to remove the solvent yielding 2-ethoxythiazole (50 mg) as a volatile oil. Yield: 626.
NMR: CDC13 2.7d(4Hz) lH, 3.4d(4Hz) lH, 5.55q(7Hz)2H, 8.6t(7Hz)3E.
Example 6 . . _ 2-Phenoxythiazole A mixture of phenol (2.00 g), 1-ethoxy-2-chloroethyl isothiocyanate (4.05g), anhydrous potassium carbonate powder (4.40 g) and acetonitrile (10 ml) is stirred at room temperature for 5 hours and evaporated to remove the solvent.
The residue is dissolved in benzene. Insoluable materials are filtered off. The filtrate is washed with 2N sodium hydroxide and water, dried over magnesium sulfate and evaporated to remove the solvent yielding 4-ethoxy-2-ph~enoxy-2-thiazoline (5.0 g)-IR: CCl cm 1625v 4 A mixture of the product (4.8 g), p-tolunenesulfonic acid monohydrate (40 mg) and dimethyl formamide (24 ml) is stirred at 130 - 133 C for 5 minutes and then evaporated to remove the solvent. The residue is dissolved in benzene.
The benzene solution is washed with a 10-6 aqueous solution of sodium hydroxide, lN hydrochloric acid, and a dilute 0 aqueous solution of sodium bicarbonate and dried over 1~16609 1 magnesium sulfate. The solution is purified by chromatography on silica gel and on alumina successively to give 2-phenoxy-thiazole (3.07 g). Yield: 81.6%.
NMR: ~CDC13 2.7m6H, 3.2d (4Hz) lH
Example 7 2-(4-Chlorophenylthio) thiazole A mixture of p-chlorothiophenol (1.00 g), l-ethoxy-2-chloroethyl isothiocyanate (1.26 g), anhydrous potassium carbonate powder (1.43 g) and acetonitrile (5 ml) is stirred at room temperature for 2 hours. The mineral materials are filtered off. The filtrate is condensed. The residue is dissolved in benzene. The benzene solution is washed with a dilute aqueous solution of sodium bicarbonate and water, dried over magnesium sulfate and evaporated to remove the solvent yielding 4-ethoxy-2-(4-chlorophenylthio)-2-thiazoline (1.97 g). Yield: 94.2%
IR: ~CC14 cm 1565 The product is treated in the same manner as in Example 6 to give the title compound (1.48 g).
2G NMR: ~CDC13 2.37 - 2.88m Example 8 2-(4-Acetylphenoxy)thiazole In the same manner as in Example 5, 4-acetylphenol is converted to the sodium salt and~allowed to react with 1-ethoxy-2-chloroethyl isothiocyanate in a mixture of dioxane and dimethylformamide at room temperature. The yielded 4-ethoxy-2-(4-acetylphenoxy)-2-thiazoline of mp 67 - 69 C is allowed to react with p-toluenenesulfonic acid at 130 - 135 C for 10 minutes to give the title compound, mp 82 - 83 C.
Yield: 40.2 %.
~66~9 1 Example 9 2-(N-Methylanilino)thiazole A mixture of N-methylaniline (2.00 g), 1-ethoxy-2-chloroethyl isothiocyanate (3.40 g), anhydrous potassium carbonate powder (3.87 g) and acetonitrile (10 ml) is stirred at room temperature for 1 hour. The mineral materials are filtered off. The filtrate is evaporated to remove the solvent. The residue is extracted with benzene.
The benzene extract is washed with a dilute aqueous solution of sodium bicarbonate and water, dried over magnesium sulfate and evaporated to remove the solvent. The residue is subjected to column chromatography on alumina. From the hexane eluate, 2-(N-methylanilino)thiazole (3.35 g) is obtained.
Yield: 94.3%.
NMR: CDC13 2.6 - 2.8m5H, 2.9dlH, 2.67dlH, 6.5s3H.
In the same manner, 2-anilinothiazole is obtained by the reaction of aniline with l-ethoxy-2-chloroethyl iso-thiocyanate for 4.5 hours under ice-cooling in the presence of potassium carbonate. Mp 129 - 130 C. Yield: 58%.
Similarly, 2-diethylaminothiazole is obtained by the reaction of l-ethoxy-2-chloroethyl isothiocyanate with diethylamine at room temperature. Yield: 100%.
~ NMR: CDC13 2.8d(4Hz)lH, 3.5d(4Hz), 6.5q(7Hz)4H, 8.75t ; (7Hz)6H.
Example 10 Ethyl 2-[4-(2-thiazolyloxy)phenyl]propionate (a) To a mixture of ethyl 2-(4-hydroxyphenyl)-propion-ate (1.63 g), anhydrous potassium carbonate powder (1.74 g) and absolute acetone (16 ml) is added 1-ethoxy-2-chloroethyl isothiocyanate (1.46 g) with stirring. The mixture is allowed ~1166Q9 1 to react at room temperature for 8 hours and then evaporated under reduced pressure to remove acetone. The residue is extracted with benzene. The benzene extract is washed with water, dried over magnesium sulfate and evaporated to remove the solvent yielding ethyl 2-[4-(4-ethoxy-2-thiazoline-2-yloxy)-phenyl]propionate (2.71 g).
IR: CC14 cm 1735, 1630.
NMR: CDC13 2.7aromatic 4H, 5.8q2H, 8.5d3H, 8.8t6H, 4.4mlH, 6.0-6.7.5H
The product (1.37 g) is mixed with potassium hydrogen-sulfate (12 mg) and diemethylformamide (6 ml). The mixture is stirred at 130 - 135 C for 5 minutes and evaporated under reduced pressure to remove dimethylformamide. The residue is extracted with benzene. The benzene extract is washed with a 10% aqueous solution of sodium hydroxide, 10~ hydrochloric acid and an aqueous solution of sodium bicarbonate successively, dried over magnesium sulfate and evaporated o remove the solvent yielding the title compound (1.13 g). Yield: 97.5%.
(a) The same procedure as in the above (a) using 1-methoxy-2-chloroethyl isothiocyanate (1.36 g) instead of l-ethoxy-2-chloroethyl isothiocyanate gives ethyl 2-[4-(4-methoxy-2-thiazolin-2-yloxy)phenyl] propionate (2.67 g).
The product (1.33 g) is dissolved in dimethylformamide (6 ml).
The solution is stirred at 130 - 135 C for 9 minutes in the presence of p-tolunenesulfonic acid monohydrate (4 mg). The reaction mixture is treated in the same manner as in the above (a) to give the title compound. Yield: 96%.
Furthermore, the above thiazole compound (2.26 g) is allowed to react with potassium hydroxide (2.26 g), water (9 ml) and ethanol (11 ml) at room temperature for 1 hour.
6~ 9 1 The mixture is evaporated to remove ethanol. The residue is adjusted to pH 4 with dilute hydrochloric acid to give the free carboxylic acid (1.95 g) of the above title compound.
Recrystallization from ethyl acetate gives the crystals melting at 121 - 122 C.
Example 11 Ethyl 2-[4-(2-thiazolyloxy)phenyl]-2-methylmalonate (a) To ethyl 2-(4-hydroxyphenyl)-2-methylmal-monate (1.12 g) is added sodium isopropoxide prepared from metallic sodium (97 mg) and isopropanol. The mixture is evaporated to remove isopropanol, and dimethylformamide (5 ml) and 1-ethoxy-2-chloroethyl isothiocyanate (700 mg) are added thereto under ice-cooling. The mixture is stirred at room temperature for 2 hours and further at 150 - 155C for 15 minutes and evaporated under reduced pressure to remove the solvent.
The residue is extracted with benzene. The extract is washed with water, a 10~ aqueous solution of sodium hydroxide, 10%
hydrochloric acid, and an aqueous solution of sodium bicar-bonate successively, dried and evaporated to remove the solvent yielding ethyl 2-[4-(2-thiazolyloxy)phenyl]-2-methylmalonate (1.25 g). Yield: 85~.
(b) A mixture of ethyl 2-(4-hydroxyphenyl)-2-methyl-malonate (7.0 g), anhydrous potassium carbonate powder (5.45 g), l-isobutoxy-2-chloroethyl isothiocyanate (5.82 g) and absolute acetonitrile 935 ml) is stirred at room temperature for 8.5 hours. The same procedure as in Example 6 is proceeded to give ethyl 2-[4-(2-thiazolyloxy)phenyl]-2-methylmalonate (8.4 g). Yield: 915%.
Furthermore, to the product (7.8 g) are added a 20~
aqueous solution of potassium hydroxide (40 ml) and ethanol (40 ml). The mixture is heated at 55C for 3 hours, adjusted 6~9 1 to pH 8 with hydrochloric acid after cooling, and evaporated to remove ethanol. The residue is adjusted to pH 2 to give crystals. The product is recrystallized from acetone to give 2~[4-(2-thiazolyloxy)-phenyl]-2-methylmalonic acid (3.5 g), mp 148 - 150 C (decomp.). Yield: 50%.
The product is heated at 135 - 140 C for lO minutes in the presence of a catalytic amount of acetic acid to give 2-[4-(2-thiazolyloxy)phenyl]propionic acid quantitatively.
Example 12 Methyl 2-[4-(2-thiazolyloxy)phenyl]-2-methylmalonate (a) To a mixture of methyl 2-(4-hydroxyphenyl)-2-methylmalmona~e (80.0 g), potassium carbonate powder (92.5 g) and absolute acetone (280 ml) is added dropwise a solution of l-isobutoxy-2-chloroethyl isothiocyanate (75.0 g) in absolute acetone during 5 to 8 minutes at the temperature below 25 C with stirring. The mixture is allowed to react at 28 - 30 C for 8 hours and at room temperature overnight.
Mineral materials are filtered off under reduced pressure.
The residue is washed with acetone and toluene. The acetone filtrate and the washings are combined and evaporated. The residue is dissolved in toluene. The solution is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give methyl 2-[4-(4-isobutoxy-2-thiazoline-2-yloxy)phenyl]-2-methylmalonate as an oil.
IR: ~CC14 cm 1740, 1635, 1605, 1240 NMR: ~CDC13 2.7m4H, 4.4mlH, 6.2s, 6.15 - 6.9mlO H, 8.ls+m4H, 9.ld6H
The product is allowed to react with p-toluene-sulfonic acid in the same manner as in Example 6 to give the title compound (92.45 g), mp 73 - 74 C. Yield: 86%.
1~66~'9 1 The above product (92.45 g) is mixed with potassium carbonate (41.7 g) and 50% methanol (462 ml). The mixture is refluxed for 8 hours and evaporated to remove methanol under reduced pressure. The residue is dissolved in the original amount of water. The solution is washed with dichlor-omethane, and decoloring carbon is added thereto. The mixture is filtered and the residue is washed with hot water. The filtrate and washings are combined and toluene (144 ml) is added thereto. Under vigorous stirring, 20% hydrochloric acid (108 g) is added dropwise to make the solution pH 3.
The solution is stirred for 30 minutes to give crystals of 2-[4-(2-thiazolyloxy)phenyl]propionic acid, mp 120 - 121 C.
The crystals are obtained by filtration. The total amount is 65.1 g. The total yield is 78.2%.
Example 13 Methyl 2-[4-2-thiazolyloxy)phenyl]propionate The same procedure as in Example 12 using methyl 2-(4-hydroxyphenyl)propionate (63.05 g) instead of methyl 2-[4-(4-hydroxyphenyl)-2-methylmalonate to give methyl 2-[4-(4-isobutoxy-2-thiazoline-2-yloxy)phenyl]-propionate as an oil.
The product is allowed to react with p-to_uene-sulfonic acid in the same manner as in Example 6 to give the title compound (86.55 g) as an oil. Crystallization from hexane gives the title compound melting at 32 - 35 C. Yield: 94%
IR: CC14 cm 1740, 1500, 1460, 1310, 1230, 1160 NMR: CDC13 2.7m5H, 3.2d(5Hz)lH, 6.03s+q4H, 8.5d(7.5Hz) Example 14 The following compounds are yielded in the same procedure as in Example 9 or 10.
66Qg \ R
A l X R R ~p (C
1 O 3-OCH3 CH3 COOH Ca.H2O 175 (d) 103 O HCH2CH=CH2COOH Ca.H2O 134 (d) NH H H ~ COOH 195 - 196 6 N-CH3 H H ~ COOH 202 - 204 7 N-CH3 HCH3 ! COOH ~123 - 124 158~-CH2CH=CH2 H H COOH 139 - 140 9-CH2CH=CH2 HCH3 COOH 118 - 119 11 O HCH2Ph COOH 121 - 122 12 O HCH2C=CH~ COOH I99 - 100 2013 O H CH2C(=CH2)CH3j COOH111 - 112 14 O H ¦ CH2-C I COOH I85 - 86 O 3-CH3 ¦ 3j COOH !93 ~ 94 16 O 2-CH3 CH3I COOH ¦ 120 - 121 17 O 3-Cl CH3~ COOH ~ 115 - 116 2518 O 2-Cl CH3~ COOH 86 - 87 19 N-CH3 3-Cl ¦ CH3~ COOH Ca 4H2 175-_ _ ~ ~ _ 178 '~
S H ~ CH3 COOH 85 ~ 87 21 O 2-Cl j CH3 COOH 147 - 148 1022 O 3-F ¦ CH3 COOH 107 - 108 23 O 5-ClH3 CH3 COOH 130 - 131 24 NH 3-CL ~ CH3 COOH 144 - 145 ~25 NH 2-F CH3 COOH 190 - 191.5 ¦26 N-CH3 2-F CH3 COOH ¦111 - 112.5 28 NH 3-F CH3 ¦COOH 160 - 161 29 N-CH3 2-CH3 j CH3 ICOOH 165 - 166 N-CH3 3-F ! CH3 ¦COOH 98 - 100 31 INH 2-Cl ~ CH3 ICOOH 174 - 175 20 ~ ¦ NH 2-CH3 ~CH3 ~COOH i 160 - 161.5 33 ¦N-CH3 2-Cl ~ CH3 !COOH ¦141 - 142 34 ¦O ~ CH3 ,CN ¦50 - 51 Notes: *l The thiazolyloxy group of this compound substitutes the benzene ring at 3 position.
*2 "Ca.H2O" stands for calcium salt monohydrate.
refers to phenyl having one to three substituents. Any group can be placed on the phenyl group as long as it gives no adverse effect to the process of this invention. They are exemplified alkyl, alkenyl, aralkyl, alkynyl, halogen, cyano, hydroxy, alkoxy, nitro, and the like. Furthermore, a group represented by the formula ~H R2 (wherein R is hydrogen, alkyl, cycloalkyl-alkyl, alkenyl, alkynyl or aralkyl; and R is carboxy, protected carboxy, or cyano) can substitute - ~166Q9 1 the phenyl group. The protected carboxy means a carboxy group esterified with alkoxy, aralkoxy, aryloxy and the like.
The above exemplified groups may be present on the alkyl when the group R' is alkyl.
Furthermore, the term "alkynyl" is a radical having two to five carbon atoms including l-propynyl, 2-propynyl, l-butynyl, 2-pentynyl and the like. "Halogen" includes fluorine, iodine, chlorine and bromine. "Alkoxy" is a radical having 1 to 5 carbon atoms including methoxy, ethoxy, propoxy, i-propoxy, butoxy, t-butoxy, pentoxy and the like.
"Cycloalkyl-alkyl" means alkyl substituted with cycloalkyl of 1 to 6 carbon atoms including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. "Aralkyl" means alkyl substituted with aryl of 6 to 10 carbon atoms including phenyl and naphthyl.
"Aralkoxy" includes ether radicals having aralkyl. "Aryloxy"
is a radical having 6 to 10 carbon atoms including phenoxy and naphthoxy.
The present inventor has been studying synthetic methods to prepare thiazole derivatives having a substituent such as alkoxy, alkylthio, alkylamino, dialkylamino, phenoxy, phenylthio, anilino and the like at 2 position. It is known certain thiazole derivatives having a substituent at 2 position are useful medicament exhibiting anti-inflammatory, analgesic, anti-rheumatic and anti-pyretic activities, for example, those described in Japanese Patent Publication (Unexamined) No.
1975/69075. The initial purpose has finally attained with the process including a reaction of l-alkoxy-2-halogenoethyl isothiocyanate with a compound of the formula R'AH (wherein R' and A are the same as defined above) followed by an alcohol-elimination reaction of a resultant thiazoline derivative.
i~6~i~9 1 Many methods have been developed to prepare thiazole derivatives substituted at 2 position with alkoxy or hydroxy such as that shown by Elderfield on "Heterocyclic Compounds"
5, 548. They are, however, defective in some respects, for example, poor yield, expensive or hardly obtainable starting materials, air-pollution with adverse reagents and the like.
On the other hand, the process of this invention excels in good yield, low-costed and easily obtainable starting materials and simple operation.
There are some known methods for preparing thiazoline derivatives from isothicyanate; e.g. Synthetic Communications, 5, 143 (1975) and Heterocycles, 7, 109 (1977). These references show none of preparation of thiazole derivatives from the yielded thiazolines.
Meanwhile, Japanese Patent Publication No. 1975/31346 discloses a method for preparing thiazole derivatives from thiazoline. The method, however, can be practised only with thiazolines substituted at both 4 and 5 positions. Therefore, the process of this invention is novel and excellenk in providing thiazole derivatives having a substituent at 2 position economically and in good yield.
The process of this invention may be represented by the scheme set out below:
R'AH RO +
<OR (III) ~ N H ~ N
NCS Step 1 S - R' Step 2 ~S A- R' IV II
wherein X is halogen; R is alkyl; and A and R' are the same as defined above.
The process of this invention includes two steps as shown in the above scheme; i.e., (1) reaction of 1-alkoxy-2-i6Q9 1 halogenoethyl isothiocyanate (IV) with a compound of the formula III (wherein A and R' are the same as defined above) in the presence of acid-receptor and (2) alcohol-elimination reaction of the yielded thiazoline derivative (II).
The starting compound of the first step (Step 1), l-alkoxy-2-halogenoethyl isothiocyanate is novel and the preparation will be mentioned later. The more preferable compound IV is l-isobutoxy-2-halogenoethyl isothiocyanate because it is less volatile and easily obtainable.
The compound of the formula III used in Step 1 includes lower alcohols (e.g. methanol, ethanol, isopropanol, butanol, isobutanol, and pentanol), alkanethiols (e.g. methanethiol, ethanethiol, and propanethiol), phenol, substituted phenol, thiophenol, substituted thiophenols, alkylamines (e.g.
ethylamine, propylamine, and isobutylamine), dialkylamines (e.g. diethylamine, and dipropylamine), alkyl alkenylamines (e.g. ethyl allylamine), aniline, substituted anilines, N-alkylanilines (e.g. N-methyl aniline, N-ethylaniline, and N-propylaniline), N-alkenylanilines (e.g. N-allylaniline and N-methallylaniline), N-alkyl substituted-anilines, and N-alkenyl-substituted anilines. The substituents on the benzene ring of the substituted phenol, thiophenol, aniline, N-alkylan-iline and N-alkenylaniline are any group as long as it gives no adverse effect to the process and have been already mentioned in the definition of R'.
The reaction of Step 1 is effected in the presence of an acid receptor. The acid receptors to be used are, for example, alkali metal alkoxide (e.g. sodium ethoxide, or potassium -t-butoxide), alkali metal carbonate (e.g. potassium carbonate, sodium carbonate, or sodium bicarbonate), sodium ;6Q~
1 hydride, alkyl amine (e.g. triethylamine), magnesium, molecular sieve and the like. The reaction proceeds more smooth in the presence of sodium hydride or potassium carbonate.
Illustrative of reaction solvent are alcohols (e.g. ethanol), ketones (e.g. acetone and methyl ethyl kenone), nitriles (e.g.
acetonitrile), ethers (e.g. dioxane, monoglyme, and diglyme), esters (e.g. ethyl acetate), halogenohydrocarbons (e.g. dichloroe-thane and carbon tetrachloride), dimethyloformamide and the like. They are used combined or in single. Acetone and acetonitrile are favourable to high yield when potassium carbonate is used as acid-receptor. The reaction proceeds smooth even at room temperature r although reaction temperature should be control~ed depending on other-reaction conditions.
The alcohol-elimination reaction of the second step (Step 2) is effected in the presence of a catalytic amount of an acid. Lewis acids other than both organic and inorganic acids are applicable. They are, for example, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, hydrochloric acid, sulfuric acid, potassium hydrogensulfate, phosphoric acid, potassium dihydrogenphosphate, aluminum chloride, zinc chloride and the like. Additionally, salts of strong acid such as pyridine hydrochloride are also applicable.
Compound I~ happens to decompose in an extreme small portion during the reaction of Step 1 to give isothiocyanic acid or a hydrohalogenic acid. It is unnecessary to add any acid during the reaction of Step 2 under the condition that Compound III produces a catalytic amount of acid and steps 1 and 2 are effected successively.
The alcohol-elimination reaction may be practised at 1~1L166'~9 1 ordinary temperature or under heating. The temperature, therefore, ranges from about 20C to about 200C. Solvent is not requisite though the solvents exemplified in Step 1 ean be used, if necessary.
Steps 1 and 2 can be effected successively without isolating Compound II. Addition of an acid for Step 2 can be omitted in the case mentioned above. Compound I can be obtained only by the operation of Step 1 when the reaetant Compound III
is an amine or an aniline, i.e. the compound of which A is imino, alkylimino, or alkenylimino in the formula R'AH.
The starting compound IV is a novel compound and can be prepared by a process as shown by the following scheme:
~R OR
XCH2CH<y > XCH2CHGCS
V IV
wherein Y is halogen, alkoxy, or acyloxy and X and R are the same as defined above. The acyloxy of Compound V refers to both straight and branched-chain aliphatic radicals having two to six carbon atoms including, for example, aeetoxy, propionyloxy and the like.
As shown above, introduction of an isothiocyano group to Compound V gives Compound IV. The isothioeyanation ean be effeeted with a salt of thioeyanie aeid (e.g. ammonium thioeyanate or potassium thioeyanate) with a Lewis aeid (e.g. silieon tetraehloride, aluminium ehloride, zine ehloride, titanium tetraehloride, or euprie ehloride), or a salt of isothioeyanie aeid (e.g. silieon tetraisothioeyanate) option-ally in an inert organie solvent sueh as aeetone, aeetonitrile, benzene, diehloroethane, carbon tetraehloride and the like L66~9 1 when 1,1-dialkoxy-2-halogenoethane and 1-acyloxy-1-alkoxy-2-halogenoethane are subjected to the reaction. The reaction may be effected at room temperature or under heating, if necessary.
The reaction with a salt of thiocyanic acid or that with a salt of isothiocyanic acid in an alcohol introduces a isothiocyano group to l-alkoxy-1,2-dihalogenoethane. The alcohols to be used are, for example, methanol, ethanol, propanol, i-butanol and the like. The reaction may be effected at room temperature or under heating.
~dditionally, l-alkoxy-1,2-dihalogenoethane which is prepared by halogenation an alkoxyethene is fragile and volatile. Therefore, the compound may be subjected to isothiocyanation without isolating after prepared from alkoxyethene by halogenation. Alternatively, an isothio-cyanation reagent is added to a solution of alkoxyethene followed by addition of a halogenation reagent. Ordinary halogenation reagents are applicable to the above preparation of Compound IV. Chlorine and bromine are useful reagent in this process.
The product of the reaction of Step 2 may be hydrolyzed, if necessary. Such hydrolysis may be effected in any way usually used to hydrolyze carboxy acit esters, e.g. with an acid (e.g. hydrochloric acid, sulfuric acid, hydrobromic acid, or acetic acid) or a base (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate) in water or in a suitable solvent containing water.
When the product of Step 2 is a malonate, it is further subjected to decarboxylation, if desired,although decarboxylation ~166~C~
l is occassionally completed during the hydrolysis. The decarboxylation is easily effected by a conventional method such as heating the product. Heating with a catalytic amount of acetic acid is very effective for decarboxylation.
Besides, propionic acid residue can be delivered from di-ester of 2-methyl malonic acid by refluxing with an alkali metal carbonate or an alkali metal bicarbonate in a water miscible solvent. The alkali metal carbonates and bicarbonates to be used are exemplified sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. The applicable solvents are, for example methanol, ethanol, propanol, butanol, dioxane, ethylene-glycol, acetone, methylethylketone and the like.
Further, the thus-obtained compound I can be converted into its pharmaceutically acceptable non-toxic salts in conventional methods. They include, for example, alkali metal salts (e.g. sodium, potassium, and lithium salts), alkaline earth metals (e.g. calcium, magnesium and barium salts) and aluminum salt.
As noted above, the process of this invention is very useful for preparing thiazole derivatives substituted at 2 ; position, especially the thiazole derivatives havina excellent therapeutic activities.
Thus, this invention provides a novel and excellent process for preparing 2-substituted thiazole derivatives including useful medicament.
The invention will now be further illustrated and described by way of the following specific examples.
6~i~9 Example l l-Ethoxy-2-bromoethyl isothiocyanate A mixture of 2-bromoacetoaldehyde diethylacetal (4.0g), absolute benzene (40 ml) and silicon tetraiso-thiocyanate (1.8g) is refluxed for 7.S hours with stirring.The solution is evaporated to remove benzene. Ether and some ice pieces are added thereto. The ether layer is separated, washed with cold water and an aqueous solution of sodium bicarbonate, dried over magnesium sulfate, and evaporated to remove the solvent. The residue is distilled under reduced pressure to remove the first distillate yielding the title compound as an oil, (2.55 g), bp20100-108C. Yield: 61~
IR: ~CC14 2100 (~/2 140) NMR: CDC13 5-0t(6Hz), 6.5d(6Hz) C*13NMR: 140ppm Example 2 l-Ethoxy-2-chloroethyl isothiocyanate (a) To a solution of 1,2-dichloro-1-ethoxy-ethane (4 g) in absolute acetonitrile (12 ml) is added ammonium thiacyanate powder (2.55) with stirring under ice-cooling. The mixture is allowed to react at the same temperature for 2.5 hours and then evaporated to remove acetonitrile. Benzene is added thereto. The benzene solution is washed with cold water and a dilute aqueous solution of sodium bicarbonate, dried over magnesium sulfate and evaporated to remove the solvent.
The residue is distilled under reduced pressure to give the title compound (4.3g), bp29 103 - 105~C Yield: 93~.
IR: ~CC14 cm 2000 (~/2 130cm NMR: CDCL3 5.0t (6Hz), 6.4d(6Hz) g 66~9 .
1 (b) Chlorine gas (4.8g) is bubbled into a solution of ethoxyethene (4.85g) in carbon tetrachloride (25 ml) at -20 - -15 C with stirring under shielding the light for 1.5 hours. Ammonium thiocyanate powder (6.15 g) is added thereto. The mixture is stirred at room tempera~ure for 4 hours and then ice-cold water is added thereto. The carbon tetrachloride layer is separated. The aqueous layer is extracted with carbon tetrachloride. The carbon tetrach-loride layer, combined with the extract, is washed wlth cold water and a dilute aqueous solution of sodium bicarbonate, dried over magnesium sulfate and evaporated to remove the solvent. The residue is distilled under reduced pressure to remove the distillate of bp2870 - 99 C, yielding the title compound (7.65 g) as an oil, bp28102 - 108 C. Yield: 69%.
(c) To a mixture of 2-chloroacetoaldehyde diethylacetal (5.0 g), ammonium thiocyanate powder (3.0 g) and dichloroe-thane (25 ml) is added dropwise a solution of silicon tetrach-loride (2.94 g) in dichloroethane (7 ml). The mixture is allowed to react at 75 C for 7 hours. Ice-cold water is added thereto. The mixture is neutralized with an aqueous solution of sodium bicarbonate and extracted with methylene chloride. The dichloroethane-methylene chloride layer is separated, washed with an aqueous solution of sodium bicar-bonate, dried over magnesium sulfate and evaporated to remove the solvent. The residue is distilled under reduced pressure to give the title compound (2.75 g), bp29103 - 106C.
Yield: 50.5%.
Example 3 l-Methoxy-2-chloroethyl isothiocyanate (a) The mlxture of 2-chloroacetoaldehyde dimethylacetal 11~66~!9 (4.0 g) and silicon tetraisothiocyanate (4.4 g) is stirred at 80 - 85C for 6 hours and then benzene and ice-cold water are added thereto. The mixture is made alkaline with an aqueous solution of sodium bicarbonate and stirred further for 20 minutes. The precipitated silicon compound is filtered off.
The separated benzene layer is washed with a dilute aqueous solution of sodium bicarbonate, dried over magnesium sulfate and evaporated to remove the solvent. The residue is distilled under reduced pressure to give the title compound, bp37 99 - 100 C. Yield: 90.5%.
IR: ~CC14 m 2000 (~/2 125 cm NMR: vCDC13 5.01qlH, 6.3d2H, 6.4s3H
(b) A mixture of l-methoxy-2-chloroethyl acetate (4.9 g) and silicon tetraisothiocyanate (4.4 g) is stirred at room temperature for 2 days and further at 40 C for 6 hours and then some pieces of ice are added thereto. The mixture is neutralized with a dilute aqueous solution of sodium bicarbonate and methylene chloride is added thereto. The mixture is stirred for 20 minutes. The precipit-ate is filtered off. The filtrate is washed with a diluteaqueous solution of sodium bicarbonate and water, dried over magnesium sulfate and evaporated to remove the solvent. The residue is distilled under reduced pressure to give the title compound (4.34 g), bp25 91 - 92 C. Yield: 89.5%.
Example 4 l-Isobutoxy-2-chloroethyl isothiocyanate (a) Chlorine gas (7.55 g) is bubbled into a solution of isobutoxyethene (10.6 g) in carbon tetrachloride (50 ml) at - 20 - - 15C with stirring during 1.5 hours and then ammonium thiocyanate powder (9.7 g) is added thereto.
66~
1 The mixture ls allowed to react at room temperature for 2 hours. The same procedure as in Example 2 (b) is proceeded to give the title compound (16.4 g), bp5 85 - 90 C. Yield: 80%.
IR: CC14 cm 1995 ( /2 140 cm MNR: CDC13 5.0tlH, 6.4d2H, - 6.6m2H, - 8.2mlH, 9.08d6H
(b) Chlorine gas is bubbled into a mixture of isobutoxyethene (10.0 g) and ammonium thiocyanate (8.4 g) in carbon tetrachloride (50 ml) at - 7 - - 2 C with stirring durlng 2 hours. The mixture is allowed to rea~ at - 5 C for 0.5 hour and at room temperature for another 0.5 hour and then treated in the same manner as in Example 2 (b) to give the title compound (12.4 g), bp890 - 94C. Yield: 70%.
Example 5 2-Ethoxythiazole An ethanol solution of sodium ethozide, prepared from metallic sodium (126 mg) and absolute ethanole (6 ml), is added dropwise to a solution of l-ethoxy-2-bromoethyl isothiocyanate (1.05 g) in absolute ethanol (3 ml) with stirring under ice-cooling. The mixture is stirred at room temperature for 30 minutes, then neutralized with acetic acid and evaporated to remove ethanol. The residue is dissolved in ether. The ethereal solution is washed with water and an aqueous solution of sodium bicarbonate, dried over magnesium sulfate and evaporated to remove ether. The residue is subjected to chromatography on silica gel to give oily 2, 4-diethoxy-2-thiazoline (550 mg). Yield: 68%.
IR: ~CC14 cm 1625 NMR: ~CDC13 4.5 lH, - 6.5 2H.
A mixture of the product (100 mg), absolute p-toluene-sulfonic acid prepared from the corresponding monohydrate ~66~
1 (130 mg), and absolute benzene (5 ml) is stirred at room temperature for 1 hour and then at 50 - 55 C for 5 minutes.
The reaction mixture is diluted with ether, washed with an aqueous solution of sodium bicarbonate, and extracted with 10% hydrochloric acid~ The extract is neutralized with sodium bicarbonate and extracted with ether. The ethereal extract is dried over potassium carbonate and evaporated to remove the solvent yielding 2-ethoxythiazole (50 mg) as a volatile oil. Yield: 626.
NMR: CDC13 2.7d(4Hz) lH, 3.4d(4Hz) lH, 5.55q(7Hz)2H, 8.6t(7Hz)3E.
Example 6 . . _ 2-Phenoxythiazole A mixture of phenol (2.00 g), 1-ethoxy-2-chloroethyl isothiocyanate (4.05g), anhydrous potassium carbonate powder (4.40 g) and acetonitrile (10 ml) is stirred at room temperature for 5 hours and evaporated to remove the solvent.
The residue is dissolved in benzene. Insoluable materials are filtered off. The filtrate is washed with 2N sodium hydroxide and water, dried over magnesium sulfate and evaporated to remove the solvent yielding 4-ethoxy-2-ph~enoxy-2-thiazoline (5.0 g)-IR: CCl cm 1625v 4 A mixture of the product (4.8 g), p-tolunenesulfonic acid monohydrate (40 mg) and dimethyl formamide (24 ml) is stirred at 130 - 133 C for 5 minutes and then evaporated to remove the solvent. The residue is dissolved in benzene.
The benzene solution is washed with a 10-6 aqueous solution of sodium hydroxide, lN hydrochloric acid, and a dilute 0 aqueous solution of sodium bicarbonate and dried over 1~16609 1 magnesium sulfate. The solution is purified by chromatography on silica gel and on alumina successively to give 2-phenoxy-thiazole (3.07 g). Yield: 81.6%.
NMR: ~CDC13 2.7m6H, 3.2d (4Hz) lH
Example 7 2-(4-Chlorophenylthio) thiazole A mixture of p-chlorothiophenol (1.00 g), l-ethoxy-2-chloroethyl isothiocyanate (1.26 g), anhydrous potassium carbonate powder (1.43 g) and acetonitrile (5 ml) is stirred at room temperature for 2 hours. The mineral materials are filtered off. The filtrate is condensed. The residue is dissolved in benzene. The benzene solution is washed with a dilute aqueous solution of sodium bicarbonate and water, dried over magnesium sulfate and evaporated to remove the solvent yielding 4-ethoxy-2-(4-chlorophenylthio)-2-thiazoline (1.97 g). Yield: 94.2%
IR: ~CC14 cm 1565 The product is treated in the same manner as in Example 6 to give the title compound (1.48 g).
2G NMR: ~CDC13 2.37 - 2.88m Example 8 2-(4-Acetylphenoxy)thiazole In the same manner as in Example 5, 4-acetylphenol is converted to the sodium salt and~allowed to react with 1-ethoxy-2-chloroethyl isothiocyanate in a mixture of dioxane and dimethylformamide at room temperature. The yielded 4-ethoxy-2-(4-acetylphenoxy)-2-thiazoline of mp 67 - 69 C is allowed to react with p-toluenenesulfonic acid at 130 - 135 C for 10 minutes to give the title compound, mp 82 - 83 C.
Yield: 40.2 %.
~66~9 1 Example 9 2-(N-Methylanilino)thiazole A mixture of N-methylaniline (2.00 g), 1-ethoxy-2-chloroethyl isothiocyanate (3.40 g), anhydrous potassium carbonate powder (3.87 g) and acetonitrile (10 ml) is stirred at room temperature for 1 hour. The mineral materials are filtered off. The filtrate is evaporated to remove the solvent. The residue is extracted with benzene.
The benzene extract is washed with a dilute aqueous solution of sodium bicarbonate and water, dried over magnesium sulfate and evaporated to remove the solvent. The residue is subjected to column chromatography on alumina. From the hexane eluate, 2-(N-methylanilino)thiazole (3.35 g) is obtained.
Yield: 94.3%.
NMR: CDC13 2.6 - 2.8m5H, 2.9dlH, 2.67dlH, 6.5s3H.
In the same manner, 2-anilinothiazole is obtained by the reaction of aniline with l-ethoxy-2-chloroethyl iso-thiocyanate for 4.5 hours under ice-cooling in the presence of potassium carbonate. Mp 129 - 130 C. Yield: 58%.
Similarly, 2-diethylaminothiazole is obtained by the reaction of l-ethoxy-2-chloroethyl isothiocyanate with diethylamine at room temperature. Yield: 100%.
~ NMR: CDC13 2.8d(4Hz)lH, 3.5d(4Hz), 6.5q(7Hz)4H, 8.75t ; (7Hz)6H.
Example 10 Ethyl 2-[4-(2-thiazolyloxy)phenyl]propionate (a) To a mixture of ethyl 2-(4-hydroxyphenyl)-propion-ate (1.63 g), anhydrous potassium carbonate powder (1.74 g) and absolute acetone (16 ml) is added 1-ethoxy-2-chloroethyl isothiocyanate (1.46 g) with stirring. The mixture is allowed ~1166Q9 1 to react at room temperature for 8 hours and then evaporated under reduced pressure to remove acetone. The residue is extracted with benzene. The benzene extract is washed with water, dried over magnesium sulfate and evaporated to remove the solvent yielding ethyl 2-[4-(4-ethoxy-2-thiazoline-2-yloxy)-phenyl]propionate (2.71 g).
IR: CC14 cm 1735, 1630.
NMR: CDC13 2.7aromatic 4H, 5.8q2H, 8.5d3H, 8.8t6H, 4.4mlH, 6.0-6.7.5H
The product (1.37 g) is mixed with potassium hydrogen-sulfate (12 mg) and diemethylformamide (6 ml). The mixture is stirred at 130 - 135 C for 5 minutes and evaporated under reduced pressure to remove dimethylformamide. The residue is extracted with benzene. The benzene extract is washed with a 10% aqueous solution of sodium hydroxide, 10~ hydrochloric acid and an aqueous solution of sodium bicarbonate successively, dried over magnesium sulfate and evaporated o remove the solvent yielding the title compound (1.13 g). Yield: 97.5%.
(a) The same procedure as in the above (a) using 1-methoxy-2-chloroethyl isothiocyanate (1.36 g) instead of l-ethoxy-2-chloroethyl isothiocyanate gives ethyl 2-[4-(4-methoxy-2-thiazolin-2-yloxy)phenyl] propionate (2.67 g).
The product (1.33 g) is dissolved in dimethylformamide (6 ml).
The solution is stirred at 130 - 135 C for 9 minutes in the presence of p-tolunenesulfonic acid monohydrate (4 mg). The reaction mixture is treated in the same manner as in the above (a) to give the title compound. Yield: 96%.
Furthermore, the above thiazole compound (2.26 g) is allowed to react with potassium hydroxide (2.26 g), water (9 ml) and ethanol (11 ml) at room temperature for 1 hour.
6~ 9 1 The mixture is evaporated to remove ethanol. The residue is adjusted to pH 4 with dilute hydrochloric acid to give the free carboxylic acid (1.95 g) of the above title compound.
Recrystallization from ethyl acetate gives the crystals melting at 121 - 122 C.
Example 11 Ethyl 2-[4-(2-thiazolyloxy)phenyl]-2-methylmalonate (a) To ethyl 2-(4-hydroxyphenyl)-2-methylmal-monate (1.12 g) is added sodium isopropoxide prepared from metallic sodium (97 mg) and isopropanol. The mixture is evaporated to remove isopropanol, and dimethylformamide (5 ml) and 1-ethoxy-2-chloroethyl isothiocyanate (700 mg) are added thereto under ice-cooling. The mixture is stirred at room temperature for 2 hours and further at 150 - 155C for 15 minutes and evaporated under reduced pressure to remove the solvent.
The residue is extracted with benzene. The extract is washed with water, a 10~ aqueous solution of sodium hydroxide, 10%
hydrochloric acid, and an aqueous solution of sodium bicar-bonate successively, dried and evaporated to remove the solvent yielding ethyl 2-[4-(2-thiazolyloxy)phenyl]-2-methylmalonate (1.25 g). Yield: 85~.
(b) A mixture of ethyl 2-(4-hydroxyphenyl)-2-methyl-malonate (7.0 g), anhydrous potassium carbonate powder (5.45 g), l-isobutoxy-2-chloroethyl isothiocyanate (5.82 g) and absolute acetonitrile 935 ml) is stirred at room temperature for 8.5 hours. The same procedure as in Example 6 is proceeded to give ethyl 2-[4-(2-thiazolyloxy)phenyl]-2-methylmalonate (8.4 g). Yield: 915%.
Furthermore, to the product (7.8 g) are added a 20~
aqueous solution of potassium hydroxide (40 ml) and ethanol (40 ml). The mixture is heated at 55C for 3 hours, adjusted 6~9 1 to pH 8 with hydrochloric acid after cooling, and evaporated to remove ethanol. The residue is adjusted to pH 2 to give crystals. The product is recrystallized from acetone to give 2~[4-(2-thiazolyloxy)-phenyl]-2-methylmalonic acid (3.5 g), mp 148 - 150 C (decomp.). Yield: 50%.
The product is heated at 135 - 140 C for lO minutes in the presence of a catalytic amount of acetic acid to give 2-[4-(2-thiazolyloxy)phenyl]propionic acid quantitatively.
Example 12 Methyl 2-[4-(2-thiazolyloxy)phenyl]-2-methylmalonate (a) To a mixture of methyl 2-(4-hydroxyphenyl)-2-methylmalmona~e (80.0 g), potassium carbonate powder (92.5 g) and absolute acetone (280 ml) is added dropwise a solution of l-isobutoxy-2-chloroethyl isothiocyanate (75.0 g) in absolute acetone during 5 to 8 minutes at the temperature below 25 C with stirring. The mixture is allowed to react at 28 - 30 C for 8 hours and at room temperature overnight.
Mineral materials are filtered off under reduced pressure.
The residue is washed with acetone and toluene. The acetone filtrate and the washings are combined and evaporated. The residue is dissolved in toluene. The solution is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give methyl 2-[4-(4-isobutoxy-2-thiazoline-2-yloxy)phenyl]-2-methylmalonate as an oil.
IR: ~CC14 cm 1740, 1635, 1605, 1240 NMR: ~CDC13 2.7m4H, 4.4mlH, 6.2s, 6.15 - 6.9mlO H, 8.ls+m4H, 9.ld6H
The product is allowed to react with p-toluene-sulfonic acid in the same manner as in Example 6 to give the title compound (92.45 g), mp 73 - 74 C. Yield: 86%.
1~66~'9 1 The above product (92.45 g) is mixed with potassium carbonate (41.7 g) and 50% methanol (462 ml). The mixture is refluxed for 8 hours and evaporated to remove methanol under reduced pressure. The residue is dissolved in the original amount of water. The solution is washed with dichlor-omethane, and decoloring carbon is added thereto. The mixture is filtered and the residue is washed with hot water. The filtrate and washings are combined and toluene (144 ml) is added thereto. Under vigorous stirring, 20% hydrochloric acid (108 g) is added dropwise to make the solution pH 3.
The solution is stirred for 30 minutes to give crystals of 2-[4-(2-thiazolyloxy)phenyl]propionic acid, mp 120 - 121 C.
The crystals are obtained by filtration. The total amount is 65.1 g. The total yield is 78.2%.
Example 13 Methyl 2-[4-2-thiazolyloxy)phenyl]propionate The same procedure as in Example 12 using methyl 2-(4-hydroxyphenyl)propionate (63.05 g) instead of methyl 2-[4-(4-hydroxyphenyl)-2-methylmalonate to give methyl 2-[4-(4-isobutoxy-2-thiazoline-2-yloxy)phenyl]-propionate as an oil.
The product is allowed to react with p-to_uene-sulfonic acid in the same manner as in Example 6 to give the title compound (86.55 g) as an oil. Crystallization from hexane gives the title compound melting at 32 - 35 C. Yield: 94%
IR: CC14 cm 1740, 1500, 1460, 1310, 1230, 1160 NMR: CDC13 2.7m5H, 3.2d(5Hz)lH, 6.03s+q4H, 8.5d(7.5Hz) Example 14 The following compounds are yielded in the same procedure as in Example 9 or 10.
66Qg \ R
A l X R R ~p (C
1 O 3-OCH3 CH3 COOH Ca.H2O 175 (d) 103 O HCH2CH=CH2COOH Ca.H2O 134 (d) NH H H ~ COOH 195 - 196 6 N-CH3 H H ~ COOH 202 - 204 7 N-CH3 HCH3 ! COOH ~123 - 124 158~-CH2CH=CH2 H H COOH 139 - 140 9-CH2CH=CH2 HCH3 COOH 118 - 119 11 O HCH2Ph COOH 121 - 122 12 O HCH2C=CH~ COOH I99 - 100 2013 O H CH2C(=CH2)CH3j COOH111 - 112 14 O H ¦ CH2-C I COOH I85 - 86 O 3-CH3 ¦ 3j COOH !93 ~ 94 16 O 2-CH3 CH3I COOH ¦ 120 - 121 17 O 3-Cl CH3~ COOH ~ 115 - 116 2518 O 2-Cl CH3~ COOH 86 - 87 19 N-CH3 3-Cl ¦ CH3~ COOH Ca 4H2 175-_ _ ~ ~ _ 178 '~
S H ~ CH3 COOH 85 ~ 87 21 O 2-Cl j CH3 COOH 147 - 148 1022 O 3-F ¦ CH3 COOH 107 - 108 23 O 5-ClH3 CH3 COOH 130 - 131 24 NH 3-CL ~ CH3 COOH 144 - 145 ~25 NH 2-F CH3 COOH 190 - 191.5 ¦26 N-CH3 2-F CH3 COOH ¦111 - 112.5 28 NH 3-F CH3 ¦COOH 160 - 161 29 N-CH3 2-CH3 j CH3 ICOOH 165 - 166 N-CH3 3-F ! CH3 ¦COOH 98 - 100 31 INH 2-Cl ~ CH3 ICOOH 174 - 175 20 ~ ¦ NH 2-CH3 ~CH3 ~COOH i 160 - 161.5 33 ¦N-CH3 2-Cl ~ CH3 !COOH ¦141 - 142 34 ¦O ~ CH3 ,CN ¦50 - 51 Notes: *l The thiazolyloxy group of this compound substitutes the benzene ring at 3 position.
*2 "Ca.H2O" stands for calcium salt monohydrate.
Claims (3)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing thiazole derivatives of the formula I:
(I) wherein A is oxygen, sulfur, imino, alkylimino or alkenylimino and R' is alkyl, phenyl or phenyl substituted with one to three groups selected from a group consisting of alkyl, alkenyl, aralkyl, alkynyl, halogen, cyano, hydroxy, alkoxy, nitro and a group represented by the formula:
wherein R1 is hydrogen, alkyl, cycloalkyl-alkyl, alkenyl, alkynyl or aralkyl and R2 is carboxy, protected carboxy or cyano, which comprises one of the following steps:
(1) subjecting 1-alkoxy-2-halogenoethyl isothiocyanate to reaction with a compound of the formula III
R'AH (III) wherein A and R' are the same as defined above in the presence of an acid-receptor selected from a group consisting of alkali metal alkoxide, alkali metal carbonate, sodium hydride, alkyl amine, magnesium and molecular sieve, or (2) subjecting the resultant thiazoline derivative of the formula II:
(II) wherein R is alkyl and A and R' are the same as defined above to an alcohol-elimination reaction.
(I) wherein A is oxygen, sulfur, imino, alkylimino or alkenylimino and R' is alkyl, phenyl or phenyl substituted with one to three groups selected from a group consisting of alkyl, alkenyl, aralkyl, alkynyl, halogen, cyano, hydroxy, alkoxy, nitro and a group represented by the formula:
wherein R1 is hydrogen, alkyl, cycloalkyl-alkyl, alkenyl, alkynyl or aralkyl and R2 is carboxy, protected carboxy or cyano, which comprises one of the following steps:
(1) subjecting 1-alkoxy-2-halogenoethyl isothiocyanate to reaction with a compound of the formula III
R'AH (III) wherein A and R' are the same as defined above in the presence of an acid-receptor selected from a group consisting of alkali metal alkoxide, alkali metal carbonate, sodium hydride, alkyl amine, magnesium and molecular sieve, or (2) subjecting the resultant thiazoline derivative of the formula II:
(II) wherein R is alkyl and A and R' are the same as defined above to an alcohol-elimination reaction.
2. The process according to claim 1, wherein the acid-receptor is sodium hydride or potassium carbonate.
3. The process according to claim 1, wherein the reaction is effected in acetone or acetonitrile.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1612778A JPS54109969A (en) | 1978-02-14 | 1978-02-14 | Novel method of preparing thiazole derivative |
| JP16127/1978 | 1978-02-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1116609A true CA1116609A (en) | 1982-01-19 |
Family
ID=11907826
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000320315A Expired CA1116609A (en) | 1978-02-14 | 1979-01-26 | Process for preparing thiazole derivatives |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS54109969A (en) |
| AR (1) | AR221715A1 (en) |
| CA (1) | CA1116609A (en) |
| CH (1) | CH639963A5 (en) |
| DK (1) | DK60979A (en) |
| ES (1) | ES477646A1 (en) |
| IT (1) | IT1113001B (en) |
| SE (1) | SE437987B (en) |
| ZA (1) | ZA79673B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3708201A1 (en) * | 1987-03-13 | 1988-09-22 | Bayer Ag | NEW THIAZOLYL ETHER AND THIOETHER DERIVATIVES |
| DE19548417A1 (en) * | 1995-12-22 | 1997-06-26 | Bayer Ag | Process for the preparation of 2-chloro-5-chloromethylthiazole |
-
1978
- 1978-02-14 JP JP1612778A patent/JPS54109969A/en active Granted
-
1979
- 1979-01-26 CA CA000320315A patent/CA1116609A/en not_active Expired
- 1979-02-13 SE SE7901250A patent/SE437987B/en not_active IP Right Cessation
- 1979-02-13 DK DK60979A patent/DK60979A/en not_active Application Discontinuation
- 1979-02-13 IT IT20146/79A patent/IT1113001B/en active
- 1979-02-13 ES ES477646A patent/ES477646A1/en not_active Expired
- 1979-02-14 ZA ZA79673A patent/ZA79673B/en unknown
- 1979-02-14 AR AR275509A patent/AR221715A1/en active
- 1979-02-14 CH CH142679A patent/CH639963A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6229432B2 (en) | 1987-06-25 |
| ZA79673B (en) | 1980-05-28 |
| SE437987B (en) | 1985-03-25 |
| SE7901250L (en) | 1979-08-15 |
| DK60979A (en) | 1979-08-15 |
| JPS54109969A (en) | 1979-08-29 |
| ES477646A1 (en) | 1979-10-16 |
| IT7920146A0 (en) | 1979-02-13 |
| AR221715A1 (en) | 1981-03-13 |
| CH639963A5 (en) | 1983-12-15 |
| IT1113001B (en) | 1986-01-20 |
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