KR810000758B1 - Process for preparing phenyl piperazine derivatives - Google Patents

Abstract

Title compds. (I; R = substd. furyl, thienyl, oxazolyl, thiazolyl; R1 = H, CF3, Cl, MeO, etc.; Z = (CH2)n;CHMeCH2; n = 1-4) were prepd. for use in treatment of asthma. Thus, AcOCH2CN reacted with H2S to give 87 % 2-(hydroxymethyl)-4-phenylthiazole(II). Reaction of II with SOCL2 gave 94.5 % of chloromethyl compd., which reacted with 1-phenylpiperazine to give 75 % I(R = 4-phenyl-2-thiazolyl; R' = H; Z = CH2).

Description

Method for preparing phenyl piperazine derivative

The present invention relates to a process for the preparation of phenyl piperazine derivatives having useful pharmacological activity. A pharmacologically active compound of the present invention and a pharmaceutical composition containing the same are useful for the treatment of an animal, including a human, by administering a chemotherapeutic effective amount.

According to the present invention, the phenyl piperazine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof is as follows:

Wherein R ¹ is benzyl, C _1-6 alkyl or optionally substituted phenyl, R ² is optionally substituted phenyl, R ³ is hydrogen or C _1-4 alkyl, Q is furan, thiophene, oxazole Or thiazole, m is 1-3 and n is 0 or 1)

When R ² and R ¹ are phenyl, halogen, C _1-4 alkyl, C _1-4 haloalkyl, amino, C _2-4 alkanoylamino, hydroxy, C _1-4 alkoxy, nitro and C _1-4 alkyl Preference is given to phenyl optionally substituted with one or two groups of sulfonic acid amido.

The term “C _1-4 alkyl” as used herein refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms, for example methyl, ethyl, iso-propyl, n -butyl, s -butyl, iso- Butyl and t -butyl. “C _1-4 haloalkyl” refers to the aforementioned C _1-4 alkyl group substituted by one or more fluorine, chlorine, cancelled or oxo, and includes airway such as trifluoromethyl or penta chloroethyl.

In addition, the term “C _1-4 alkoxy” refers to the aforementioned C _1-4 alkyl group bonded to a phenyl group via oxygen.

The compound represented by the general formula (I) is preferably a compound having one or more of the following characteristics.

A) m is 1 and n is 0;

B) Q is thiazole;

C) Q is oxazole;

D) Q is thiophene;

E) Q is furan;

F) R ¹ is C _1-3 alkyl such as methyl or i-propyl;

G) R ¹ is phenyl;

A) R ¹ is benzyl;

I) R ² is phenyl substituted by one or two methyl groups.

In particular, the phenyl piperazine derivatives represented by the general formula (I) which are actives include furan represented by the following general formula (II);

Wherein R ¹ is phenyl optionally substituted by one or two groups of halogen, C _1-4 alkyl, C _1-4 alkoxy, and R ² is C _1-4 alkyl, amino, C _1-4 alkylsulfonami and the help by C _1-4 alkoxy optionally substituted phenyl, R ¹ is unsubstituted phenyl, m is 1 and R ² except for the compound of unsubstituted phenyl and m is 1 or 3, or R ¹ is methyl or when, m is 1 and R ² is disubstituted by phenyl optionally substituted by a single group of halogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl or two C _1-4 alkyl groups)

Thiophene represented by the following general formula (III):

(Wherein R ¹ is phenyl, R ² is monosubstituted by phenyl, C _1-4 alkyl or C _1-4 haloalkyl or by a group in a group which is halogen, C _1-4 haloalkyl and C _1-4 alkyl) Di-substituted phenyl, m is 1 or 2 and n = 0 or m is 1, n is 1, R ³ is ethyl)

Oxazole (IV) represented by the following general formula (IV):

Wherein R ¹ is phenyl optionally substituted by C _1-4 alkoxy or halogen and R ² is substituted by C _1-4 alkyl C _1-4 haloalkyl, halogen, amino or C _2-4 alkanoylamino Phenyl, m is 1 or 2)

Thiazole represented by the following general formula (V):

Wherein R ¹ is benzyl and R ² is phenyl or p-halophenyl

Or thiazoles of the general formula:

Wherein R ¹ is C _1-4 alkyl or C _1-4 alkyl, C _1-4 alkoxy, phenyl optionally substituted by nitro and C _1-4 haloalkyl, and R ² is selected from C _1-4 haloalkyl Phenyl optionally substituted) and their pharmaceutically acceptable salts.

It is suitable that m is 1 in the derivative. Particularly preferred compounds represented by the general formula (I) are as follows:

1- [2- (5-phenylthioben-2-yl) ethyl] -4-phenylpiperazine; 1- (5-methylfuran-2-ylmethyl) -4- (3-chlorophenyl) piperazine; 1- [5- (4-methoxyphenyl) -furan-2-ylmethyl] -4-phenylpiperazine; 1- [5- (3,4-dimethylphenyl) -furan-2-ylmethyl] -4-phenylpiperazine; 1-3- [5- (3,4-dichlorophenyl) -furan-2-yl] prop-1-yl-4- (4-methylphenyl) piperazine; 1- [2- (5-phenylthiophen-2-yl) but-1-yl] -4-phenylpiperazine; 1- (5-phenylthiophen-2-ylmethyl) -4- (3,4-dimethylphenyl) piperazine; 1- [3- (5-phenylfuran-2-yl) prop-1-yl] -4- (4-methylphenyl) piperazine; 1- [5- (4-methoxyphenyl) -furan-2-ylmethyl] -4- (4-methylphenyl) piperazine; 1- (5-phenyloxazol-4-ylmethyl) -4- (4-methylphenyl) -piperazine; 1- (2-benzylthiazol-4-ylmethyl) -4-phenylpiperazine and their pharmaceutically acceptable acid addition salts.

Other examples of the new hop of the present invention are as follows; 1- (5-phenylthiophen-2-ylmethyl) -4- (3-chlorophenyl) piperazine; 1- (5-phenylthiophen-2-ylmethyl) -4- (4-methoxyphenyl) piperazine; 1- [5- (3-trifluoromethyl-4-chlorophenyl) -furan-2-ylmethyl-4- (4-chlorophenyl) piperazine; 1- [3- (5-phenylfuran-2-yl) prop-1-yl] -4- (3-trifluoro methylphenyl) piperazine; 1- (2-methylthiazol-4-ylmethyl) -4- (3-chlorophenyl) piperazine; 1- [2- (4-phenylthiazol-2-yl) -4- (4-aminoylfe) piperazine; 1- [2- (4-phenylthiazol-2-yl) ethyl] -4- (4-nitrophenyl) piperazine; 1- (5-phenyloxazol-2-ylmethyl) -4-phenylpiperazine; 1- [4- (3-trifluoromethylphenyl) -thiazol-2- ylmethyl] -4-phenylpiperazine; 1- (4-phenylthiazol-2-ylmethyl) -4-phenylpiperazine; 1- {2- [5- (4-chlorophenyl) oxazol-2-yl] ethyl} -4-phenylpiperazine; 1- [2- (5-phenyloxazol-2-yl) ethyl] -4- (4-chlorophenyl) -piperazine; 1- [2- (5-phenyloxazol-2-yl) ethyl] -4- (4-methoxyphenyl) -piperazine; 1- [1- (5-phenyloxazol-2-yl) prop-2-yl] -4- (4-methylphenyl) -piperazine; 1- [1- (5-phenyloxazol-2-yl) ethyl] -4- (4-methylphenyl) -piperazine; 1- (5-phenyloxazol-2-ylmethyl) -3-methyl-4- (4-methylphenyl) -piperazine; 1- (5-phenyloxazol-2-ylmethyl) -2,3-dimethyl-4- (4-methylphenyl) -piperazine; 1- {2- [4- (chlorophenyl) -thiazol-2-yl] ethyl} -4-phenylpiperazine; 1- [2- (4-phenylthiazol-2-yl) ethyl] -4- (4-chlorophenyl) piperazine; 1- [1- (4-phenylthiazol-2-yl) ethyl] -4- (4-methoxyphenyl) piperazine; 1- [1- (4-phenylthiazol-2-yl) prop-2-yl] -4- (4-methylphenyl) piperazine; 1- [1- (4-phenylthiazol-2-yl) ethyl] -4- (4-methylphenyl) piperazine; 1- (4-phenylthiazol-2-ylmethyl] -4- (4-methanesulfonamidophenyl) piperazine; 1- {2- [5- (4-chlorophenyl) -furan-2-yl] Ethyl} -4-phenylpiperazine; 1- [2- (5-phenylfuran-2-yl) ethyl] -4- (4-chlorophenyl) piperazine; 1- [2- (5-phenylfuran-2 -Yl) ethyl] -4- (4-methoxyphenyl) -piperazine; 1- [1- (5-phenylfuran-2-yl) prop-2-yl] -4- (4-methylphenyl)- Piperazine; 1- [1- (5-phenylfuran-2-yl) ethyl] -4- (4-methylphenyl) -piperazine; 1- (5-phenylfuran-2-yl methyl) -4- (4 -Methylphenyl) -piperazine; 1- (5-phenylfuran-2-yl methyl) -4- (4-methanesulfonamidophenyl) -piperazine; 1- [4- (4-phenylthiazole-2- 1) [but-1-yl] -4-phenylpiperazine 1- [5-phenylthiophen-2-yl methyl) -4- (4-methylphenyl) piperazine; 1- [5-phenylthiophen-2-yl methyl) -4-phenylpiperazine; 1- [5-methyloxazol-2-yl methyl) -4-phenylpiperazine; 1- (4-methyloxazol-2-ylmethyl) -4- (4-methylphenyl) -piperazine; 1- [2- (5-methyloxazol-2-yl) ethyl] -4- (4-chlorophenyl) -piperazine; 1- [2- (4-methyloxazol-2-yl) ethyl] -4- (3-methylphenyl) -piperazine; 1- [3- (5-methyloxazol-2-yl) prop-1-yl] -4- (2-chlorophenyl) piperazine; 1- (5-benzyloxazol-2-ylmethyl] -4- (4-nitrophenyl) piperazine; 1- (4-benzyloxazol-2-ylmethyl] -4- (3-acetylaminophenyl) Piperazine; 1- [2- (5-benzyloxazol-2-yl) ethyl] -4- (4-ethylphenyl) piperazin; 1- [3- (5-benzyloxazol-2-yl) prop Ph-1-yl] -4- (4-methoxyphenyl) piperazine; 1- (5-methylthiazol-2-ylmethyl) -4-phenylpiperazine; 1- (4-methylthiazole-2 -Ylmethyl) -4- (4-methylphenyl) piperazine; 1- [2- (5-methylthiazol-2-yl) ethyl] -4- (4-chlorophenyl piperazine; 1- [2- ( 4-methylthiazol-2-yl) ethyl] -4- (3-methylphenyl) piperazine; 1- [3- (5-methylthiazol-2-yl] prop-1-yl] -4- ( 2-chlorophenyl) piperazine; 1- (5-benzylthiazol-2-ylmethyl) -4- (4-nitrophenyl) -piperazine; 1- (4-benzylthiazol-4- (3-yl Methylacetylaminophenyl) piperazine; 1- [2- (5-benzylthiazol-2-yl) ethyl] -4- (4-aminophenyl) piperazine; 1- [2- (5-benzylthiazole- 2-yl) ethyl] -4- (4-ethylphenyl) piperazine; 1- [3- (5-benzylthiazol-2-yl) prop-1-yl] -4- (4-ethoxyfe Piperazine; 1- (5-methylfuran-2-ylmethyl) -4-phenylpiperazine; 1- (4-methylfuran-2-ylmethyl) -4- (4-methylphenyl) piperazine1- [ 2- (5-methylfuran-2-yl) ethyl] -4- (4-chlorophenyl) -piperazine; 1 [2- (4-methylfuran-2-yl) ethyl-4- (3-methylphenyl) ] -Piperazine; 1- [3- (5-methylfuran-2-yl) prop-2-yl] -4- (2-chlorophenyl) piperazine; 1- (5-benzylfuran-2-yl Methyl) -4- (4-nitrophenyl) piperazine; 1- (4-benzylfuran-2-ylmethyl) -4- (3-acetylaminophenyl) piperazine; 1- [2- (5-benzylfuran -2-yl) ethyl] -4- (4-ethylphenyl) piperazine; 1- [3- (5-benzylfuran-2-yl) prop-1-yl] -4- (4-ethoxyphenyl Piperazine 1- (5-methylofen-2-ylmethyl) -4-phenylpiperazine 1- (4-methylthiophen-2-ylmethyl) -4- (4-methylphenyl) -piperazine; 1- [2- (5-methylthiophen-2-yl) ethyl] -4- (4-chlorophenyl) piperazine; 1- [2- (4-methylthiophen-2-yl) ethyl] -4 -(3-methylphenyl) piperazine; 1- [2- (4-methylthiophen-2-yl) ethyl] -4- (3-methylphenyl) piperazine; 1- [3- (5-methylthiophen-2-yl) prop-1-yl] -4- (2-chlorophenyl) piperazine; 1- (5-benzylthiophen-2-ylmethyl) -4- (4-nitrophenyl) piperazine; 1- (4-benzylthiophen-2-ylmethyl) -4- (3-acetylaminophenyl) piperazine; 1- [2- (5-benzylthiophen-2-yl) ethyl] -4- (4-nitrophenyl) piperazine; 1- [2- (5-benzylthiophen-2-yl) ethyl] -4- (4-ethylphenyl) piperazine; 1- [3- (5-benzylthiophen-2-yl) prop-1-4- (4-ylethoxyphenyl) piperazine; And their pharmaceutically acceptable acid addition salts.

In the production method of the present invention, the compound represented by the following general formula (VI) is condensed with the compound of the following general formula (VII), and the piperazine derivative represented by the general formula (I) and a pharmaceutically acceptable salt thereof To manufacture:

R ¹ -Q- (CH ₂ ) m- (CHR ³ ) nL (VI)

(Where L represents a leaving group)

The condensation is preferably carried out in the presence of a base such as proton acceptor such as sodium carbonate, and a polar solvent such as alkane, for example ethanol, is a suitable solvent to advantageously achieve the reaction under heating reflux. The leaving group L is any known group for effecting such condensation reactions, and halogen atoms such as chlorine or methylsulfonyl or substituted benzene sulfonyl groups give good results in this reaction. The temperature range of the reaction is preferably carried out at 20-150 ° C., and the compound of formula (VI) is known (see JACS 56 470-1 1934 and 53 1470-3 1931), or prepared by known techniques. Can be.

Compounds of formula (I) prepared by the above-mentioned methods can be isolated in their own or in acid addition salt form. Acid addition salts are organic or organic acids such as hydrochloric acid, briquettes, sulfuric acid or phosphoric acid, for example glycolic acid, maleic acid, hydroxymaleic acid, nitric acid, tartaric acid, citric acid, salicylic acid, 0-acetoxybenzoic acid, nicotinic acid or isonicotinic acid. Pharmaceutically acceptable non-toxic acid addition salts with an organic sulfonic acid such as acid or methane sulfonic acid, ethane sulfonic acid, 2-hydroxyethane sulfonic acid, toluene- P -sulfonic acid or naphthalene-2-sulfonic acid desirable.

In addition to pharmaceutically acceptable acid addition salts, other salts are included within this range, for example, picric acid or acid addition salts with aquatic acid; They are used as intermediates in the preparation of compound tablets or other pharmaceutically acceptable acid addition salts and are also useful for purification, characterization or identification of bases.

The resulting acid addition salts can be converted into free compounds by known methods, for example alkali metals such as metal hydroxides or alkoxides, for example lithium hydroxide, sodium hydroxide, calcium hydroxide, alkali earth metal hydroxides, alkali metals or alkaline earth metals. Bases of metal carbonates such as carbonates or hydrogen carbonates, or hydroxyl ion exchange agents, or any other suitable reagent can be converted under treatment. The acid addition salts produced can also be converted to other acid addition salts by known methods, for example the salts of inorganic acids can be subjected to treatment with metal salts such as sodium, barium or silver salts of the acid in a suitable diluent, wherein the resulting inorganic The salt is insoluble and therefore removed from the reaction medium.

Acid addition salts can be converted to other acid addition salts by treatment with an anion exchange agent.

A pharmaceutical composition prepared by mixing a compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable agent is prepared.

The compounds of formula (I) and their pharmaceutically acceptable salts are useful for the prevention and treatment of acute hypersensitivity diseases, including asthma in mammals, and the compounds have low toxicity.

The compounds or compositions of the present invention can be administered in a variety of ways and can be made in many forms for this purpose.

Thus, the compound or composition may contain 1-10% by weight of the active ingredient in tablets, dragees, sublingual tablets, lumen, sachets, periodicals, suspensions, suppositories, aerosols, ointments (e.g. by weight in a suitable base). ), Transdermal gelatin capsules, suspensions in injection and physiologically acceptable media, sterile packaged powder adsorbed on adjuvant to prepare injections orally and rectally or parenterally (e.g. by injection or By injection into a continuous or discontinuous artery).

Furthermore, the composition is in the form of a dosage unit, preferably 5-500 mg of the compound of formula (I) (5.0-500 mg for parenteral administration, 5.0-500 mg for inhalation, 25 for oral or rectal administration) For each dosage unit containing -500 mg). The active ingredient is administered daily at a dose of 0.5-300 mg / kg, preferably 0.5-20 mg / kg. In practice, however, the amount of the compound or compound of formula (I) to be administered is determined by the physician in accordance with all appropriate circumstances, including the condition being treated, the choice of the compound to be administered, the choice of the method of administration and the like.

Compositions of the present invention are usually sealed in a capsule, a sabhet, a cachet, a paper or other container, into a product that can be ingested in the stomach or sealed in a container that can be treated as an ampule or diluted by the product. Or at least one mixture represented by the general formula (I), or mixed with a preparation. The formulation or diluent may be a solid, semisolid or base, excipient. Diluents or preparations that may be used in the pharmaceutical compositions of the invention include, for example, lactose, glucose, sucrose, sorbitan, mannitol, propylene glycol, weak paraffin white soft paraffin, kaolin, calcined silicic acid dioxide, microcrystalline cellulose Rose, Calcium Silicate, Silica, Polyvinyl Phyloridine, Cerrostearyl Alcohol, Starch, Mixed Starch, Arabian Rubber, Calcium Phosphate, Cocoa, Butter Ethoxy and Ester, Gagao Oil, Peanut Oil, Alginate, Francanth , Gelatin, syrup rain. P., Methylcellulose, polyoxyethylene, sorbitan monolaurate, lactic acid, ethyl, methyl and propyl hydroxybenzoate, sorbitan trioleate, sorbitan sesquioleate and oleyl alcohol and trichloromonruo There are fossa drugs such as romethane, dichlorodifluolmethane and dichlorotetra fluoroethane. In the case of tablets, lubricants may be used to prevent powder components from entering or adhering to the dies or punches of the purifier, and aluminum stearate, magnesium or calcium talc or mineral oil may be used for this purpose.

An embodiment of the present invention will be described as follows.

Example 1

(A) 2-acetoxythioacetamide

The steam of dry H ₂ S gas is passed rapidly with vigorous stirring with a solution of triethanolamine and 2-acetoxy acetonitrile (150 g, 1.52 mol) dissolved in anhydrous ethanol (500 ml) and the internal temperature is raised to about 55 ° C. The gas flow was maintained for 3 hours to terminate the reaction when GLC appeared. Excess H ₂ S is blown off with nitrogen vapor and the solvent ethyl alcohol is evaporated to dryness. The remaining rod crystals are extracted with boiling ether and a small amount of insoluble residue is discarded. The mixed extract is treated with decolored charcoal, filtered and evaporated to about 400 ml. Cooling to 0 ° C. yields about 170 g of rod-like 2-acetoxy thioacetamide. Use this for the next step.

(B) 2-hydroxymethyl-4-phenylthiazole

2-bromoacetophenone (39.9 g, 0.2 mol) and 2-acetoxy thioacetamide (30 g, 0.225 mol) are dissolved in dioxane (150 ml), the mixture is stirred and heated on a steam bath for 15 minutes to determine Water is produced. Aqueous 5NHCl (40 ml) is added and heating is continued for 30 minutes, dioxane is evaporated in vacuo and the residue is neutralized with aqueous Na ₂ CO ₃ solution. The solid was washed with water, dried and recrystallized with benzene to give a product having a weight of 33.5 g (87%) and a melting point of 88-9 ° C.

(C) 2-chloromethyl-4-phenylthiazole

Anhydrous pyridine (4.0 g, 0.0512 mole) and 2-hydroxymethyl-4-phenylthiazole (9.55 g, 0.05 mole) dissolved in thionyl chloride (6.25 g, 0.052 mole) in anhydrous benzene (60 ml) kept at room temperature ) Is added dropwise to the stirred solution, and the mixture is stirred and heated to boil for 1 hour. The cooled reaction mixture was shaken with 2 × 70 mlH ₂ O and dried over anhydrous MgSO ₄ .

The solvent is removed in vacuo and the remaining red oil is extracted with 40-60 ° C. petroleum ether (100 ml) and a small amount of tar residue is removed. The extract is treated with bleached charcoal, evaporated and cooled leaving crystallized sulfur-red oil.

Yield 9.9 g, 94.5%

The material is used directly in the next step without further purification.

(D) 1- (4-phenyl-2-thiazolylmethyl) -4-phenylpiperazine

A mixture of 2-chloromethyl-4-phenylthiazole (4.19 g, 0.02 mol), N-phenyl piperazine (3.24 g, 0.02 mol) and powder anhydrous sodium carbonate powder in anhydrous ethanol (60 ml) was stirred for 8 hours , Boil under reflux. The solvent is evaporated to dryness and the solid residue is suspended in water (100 ml) and then extracted with 2 × 100 ml CH ₂ Cl ₂ . The extract is washed with water and dried over anhydrous MgSO ₄ . The solvent is evaporated and the winsa recrystallized with a benzene / 60 | 80 ° C. petroleum ether mixture (treated with charcoal) to give the desired product (5.03 g, 75%) with a melting point of 142-3 ° C.

Example 2-19

In a similar manner, the following compounds are prepared:

(2) 1- (4-phenyl-2-thiazolylmethyl) -4- (3-bromophenyl) -piperazine, melting point 127.5-128.5 ° C

(3) 1- (4-phenyl-2-thiazolylmethyl) -4- (3,4-dichlorophenyl) -piperazine, melting point 144-6 deg.

(4) 1- (4-phenyl-2-thiazolylmethyl) -4- (3-trifluoromethylphenyl) -piperazine, melting point 112-3 占 폚

(5) 1- (4-phenyl-2-thiazolylmethyl) -4- (4-chloro-2-trifluoromethyl) -phenylpiperazine, melting point 117: 9 ° C

(6) 1- (4-phenyl-2-thiazolylmethyl) -4- (4-methylphenyl) -piperazine, melting point 141-3 ° C

(7) 1- (4-phenyl-2-thiazolylmethyl) -4- (4-methoxyphenyl) -piperazine, melting point 148-9 ° C.

(8) 1- [4- (4-chlorophenyl) -2-thiazolylmethyl] -4-phenylpiperazine, melting point 164-5 deg.

(9) 1- [4- (4-chlorophenyl) -2-thiazolylmethyl] -4- (3-bromophenyl) -piperazine, melting point 100-101 ° C

(10) 1- [4- (4-bromophenyl) -2-thiazolylmethyl] -4-phenylpiperazine, melting point 166 deg.

(11) 1- [4- (4-chlorophenyl) -2-thiazolylmethyl] -4-phenylpiperazine, melting point 129-131 ° C

(12) 1- [4- (4-chlorophenyl) -2-thiazolylmethyl] -4-phenylpiperazine, melting point 100-101 ° C

(13) 1- [4- (3,4-dichlorophenyl) -2-thiazolylmethyl] -4-phenylpiperazine, melting point 138-139 ° C

(14) 1- [4- (3-trifluoromethyl) -2-thiazolylmethyl] -4-phenylpiperazine, melting point 110-111 占 폚

(15) 1- [4- (4-methoxyphenyl) -2-thiazolylmethyl] -4-phenylpiperazine, melting point 201 占 폚

(16) 1- [4- (4-methylphenyl) -2-thiazolylmethyl] -4-phenylpiperazine, melting point 175-180 ° C

(17) 1- [4- (3-methylphenyl) -2-thiazolylmethyl] -4-phenylpiperazine, melting point 113-113.5 ° C

(18) 1- [4- (4-hydroxyphenyl) -2-thiazolylmethyl] -4-phenyl piperazine, melting point 228-230 ° C.

(19) 1- [4- (4-nitrophenyl) -2-thiazolylmethyl] -4-phenylpiperazine, melting point 195-8 deg.

Example 20

(A) N-phenacylchloroacetamide

Chloroacetin chloride (25 g, 0.226 mol) is slowly added to an agitated solution of phenacylamine hydrogen chloride (25.9 g, 0.151 mol) at room temperature with anhydrous thiamethylformamide (DMF), raising the internal temperature to about 40 ° C. . The mixture is stirred for 4 hours after addition and most of the DMF is evaporated in vacuo. The residue is treated with water (200 ml) and the crystalline precipitates are collected, washed and dried. Yield 24.75 (77%), melting point 118-119 ° C

(B) 2-chloromethyl-5-phenyloxazole

N-phenacyl chloroacetamide (22.6 g 0.107 mol) is mixed with polyphosphoric acid (200 g) and heated with stirring at 150 ° C. for 30 minutes, then the hot liquid is poured into water (800 ml) with strong and stirring. The resulting mixture is extracted with 3 × 300 ml of chloroform, the extract is washed with water and dried over magnesium sulfate.

CHCl ₃ is evaporated off and the remaining oil is extracted with 400 ml of boiling point 60-80 ° C. petroleum ether, and the resulting solution is treated with decolored charcoal to remove tar, evaporate and quickly determined to give a pale yellow oil. Yield 18.8 g (19%) Melting Point 70-1 ° C

(C) 1- (5-phenyl-oxazol-2-ylmethyl) -4-phenylpiperazine

A solution of N-phenylpiperazine and 2-chloromethyl-5-phenyloxazole (3.87 g 0,02 mol) in anhydrous ethanol (60 ml) is boiled and stirred with finely ground anhydrous sodium carbonate (5 g) for 6 hours. . The solution is dried under evaporation and treated with water (60 ml). The suspension thus obtained is extracted with 2 x 70 ml dichloromethane and the extract is dried over magnesium sulfate and evaporated to dryness. The solid residue is recrystallized with decolored charcoal with 80-100 ° C. petroleum ether. Yield 4.67 g, melting point 96 ° C

Example 21-35

In a similar manner, the following compounds are prepared:

(21) 1- (5-phenyl-oxazol-2-ylmethyl-4-methylphenyl) -piperazine, melting point 113-114 ° C

(22) 1- (5-phenyl-oxazol-2-ylmethyl) -4- (3-chlorophenyl) -piperazine, melting point 73 ° C

(23) 1- (5-phenyl-oxazol-2-ylmethyl) -4- (4-chlorophenyl) -piperazine, melting point 125-6 ° C

(24) 1- (5-phenyl-oxazol-2-ylmethyl) -4- (3-trifluoromethylphenyl) -piperazine, melting point 19-70 deg.

(25) 1- (5-phenyl-oxazol-2-ylmethyl) -4- (3,4-dichlorophenyl) -piperazine, melting point 134-5 deg.

(26) 1- (5-phenyl-oxazol-2-ylmethyl) -4- (4-methoxyphenyl) -piperazine, melting point 121-2 ° C

(27) 1- (5-phenyl-oxazol-2-ylmethyl) -4- (3-methoxyphenyl) -piperazine, melting point 100 ° C

(28) 1- (5-phenyl-oxazol-2-ylmethyl) -4- (2,4-dimethoxyphenyl) -piperazine, melting point 89-91 deg.

(29) 1- (5-phenyl-oxazol-2-ylmethyl) -4- (3,4-dimethoxyphenyl) -piperazine, melting point 93-5 ° C

(30) 1- (5-phenyl-oxazol-2-ylmethyl) -4- (4-methoxyphenyl) -piperazine, melting point 98 占 폚

(31) 1- [5- (4-fluorophenyl) -oxazol-2-ylmethyl) -4-phenylpiperazine, melting point 114-116 ° C

(32) 1- [5- (4-fluorophenyl) -oxazol-2-ylmethyl] -4- (4-methoxyphenyl) -piperazine, melting point 112 ° C

(33) 1- [5- (4-methoxyphenyl) -oxazol-2-ylmethyl] -4-phenylpiperazine, melting point 112-115 deg.

(34) 1- [5- (4-methoxyphenyl) -oxazol-2-ylmethyl) -4- (4-methoxyphenyl) -piperazine, melting point 148-50 ° C.

(35) 1- (5-phenyloxazol-2-ylmethyl) -4- (4-nitrophenyl) -piperazine, melting point 170-2 ° C

Example 36

1- (5-phenyloxazol-2-yl-ylmethyl) -4- (4-aminophenyl) -piperazine.

To a solution of 1- (5-phenyloxazol-2-ylmethyl) -4- (4-nitrophenyl) -riperazine (7.28 g, 0.02 mol) dissolved in glacial acetic acid (50 ml) The hydrogenation is done with% palladium catalyst until the capture of hydrogen is complete. The solvent is evaporated off in vacuo and the residue is treated with sodium bicarbonate solution to give a white crystalline solid. Weight after drying 6.54g (98%) Melting point 130 ℃

Example 37

1- (5-phenyloxazol-2-ylmethyl) -4- (4-acetamidophenyl) -piperazine

The 4-aminophenyl-compound of Example 36 was heated in a steam bath with glacial acetic acid (5 ml) and acetic anhydride (10 ml) for 1 hour, the mixture was poured into water (200 ml), stirred well and the collected precipitate washed with water. To dry. After recrystallization with ethanol the product weighs 2.45 g and has a melting point of 196-7 ° C.

Example 38

1- (5-phenyloxazol-2-ylmethyl) -4- (4-hydroxyphenyl) -piperazine

Propane-1-thiol (5.02 g, 0.066 mol) is added to a stirred suspension of 50% sodium hydride / mineral mixture (3.17 g, 0.006 mol) suspended in anhydrous dimethylformamide (140 ml). 1- (5-phenyloxazol-2-ylmethyl) -4- (4-methoxyphenyl) -piperazine (7.7 g, 0.022 mol) was added to the sodium propane-1-thiolate solution formed here, and the solution was Heat under reflux on an oil bath under nitrogen atmosphere for 10 hours. The mixture is poured into water (600 ml) and extracted with 3 × 200 ml ethyl acetate, the extract is shaken several times with water, dried and evaporated to give a white solid. Recrystallization from dioxane / 60-80 ° C. petroleum ether gives the product a weight of 5.5 g (74.5%) and a melting point of 189-190 ° C.

Example 39

1- [5- (3-trifluoromethyphenyl) -furan-2-ylmethyl] -4-phenyl piperazine

(A) 2-hydroxymethyl-5- (3-trifluoromethylphenyl) -furan

2- (3-trifluoromethylphenyl) -furan (J. Chem. Soc (C) 1968, 2737 and Acta Chem. Scand. 24, 2379 (1970 (21.2 g, 0.1 mol)) in tetrahydrofuran (100 ml) Stir, cool to −40 ° C. and add n -butyl lithium (0.1 mole, hexane solution) dropwise, stir at −40 ° C. for 1 hour, then gradually add paraformaldehyde (3.3 g, 0.11 mole). The mixture is stirred for 30 minutes at -40 ° C. and then the temperature is raised The exothermic reaction at 10 ° C. causes the temperature to gradually rise to 40 ° C. (more than 10 minutes) and then gradually falls to 20 ° C. Stir for 1 hour After that, the clear brown solution is poured into ice water, adjusted to pH4 with diluted hydrochloric acid, and extracted with ethyl acetate.

Evaporation of the dried acetic acid extract (MgSO ₄ ) yields a brownish yellow viscous oil, which is distilled under vacuum to give a colorless liquid, 2-hydroxymethyl-5- (boiling point at 125 ° C / 0.5mm (16.2g). 30 trifluoromethylphenyl) -furan is obtained, which when left is obtained crystals. Melting point 45 ℃

(B) 2-bromomethyl-5- (3-trifluoromethylphenyl) furan

The hydroxymethyl compound (4.84 g, 0.02 mol) prepared in (a) above was dissolved in dimethylformamide cooled to 0-5 ° C, and embrittled thionyl (1.7 g 0.02 mol) was added dropwise with stirring. The greenish yellow solution is poured into ice water for 2 hours and extracted with diethyl ether. The ether extract was washed with NaCl (saturated solution), dried over molecular sieve 3A and evaporated to give a slowly crystallized pale brown oil (4.6 g).

(C) 1- [5- (3-trifluoromethylphenyl) -furan-2-ylmethyl] -4-phenylpiperazine

The (B) bromomethyl (0.015 mol) was stirred in N-phenylpiperazine (2.75 g, 0.017 mol) and dioxane (50 ml) in the presence of anhydrous sodium carbonate (1.5 g), and the mixture was refluxed for 7 hours. Under heating, poured into ice water, extracted with chloroform, washed with chloroform extract, saturated salt solution and then evaporated to an end to give an oil which is treated with ether hydrochloric acid to give a creamy colored crystalline solid (2.2 g). This hydrogen chloride (2 g) is dissolved in chloroform (15 ml), stirred with water (15 ml), and the saturated sodium carbonate solution is added dropwise until alkaline. The phases were separated and the chloroform layer was evaporated to give a pale yellow oil (1.7 g), which was slowly crystallized and recrystallized from 60/80 ° C. petroleum ether to 1.2 g, melting point 94 ° C. of the compound 1- [5- (3-tree Fluoromethylphenyl) -furan-2-ylmethyl] -4-phenylpiperazine is obtained. The following compound is prepared in the same manner except for converting the intermediate hydroxymethyl compound to chloromethyl compound through thionyl chloride.

Example 40

1- [5- (4-chlorophenyl) -furan-2-ylmethyl] -4-phenylpiperazine

Melting point 140 ℃

Example 41

1- [5- (4-Chlorophenyl) -furan-2-ylmethyl] -4- (3-trifluoromethylphenyl) -piperazine monohydrochloride

Free bases are obtained as viscous oils that are difficult to handle and are converted to monohydrochloride. Melting point 220 ℃

Example 42

1- [5- (4-Chlorophenyl) -furan-2-ylmethyl] -4-chlorophenyl) -piperazine monohydrochloride

Melting point 215 ℃

Example 43

(A) 5-phenyl-2- (2-hydroxyethyl) thiophene

2-phenylthiophene (16.0 g 0.1 mol) was reacted in a similar manner to Example 40 except that ethyl oxide (10 ml, 0.2 mol) was used instead of paraformaldehyde, and the compound was pale yellow crystalline having a melting point of 74 ° C. Obtained as a solid.

(B) 1- [2- (5-phenylthiophen-2-yl) ethyl] -4-phenylpiperazine

The hydroxyethyl compound (6.13 g, 0.03 mole) was reacted as in Example 40 (b) except that thionyl chloride was used instead of the embrittled thionyl from (a). A chloroethyl compound is obtained, which is a pale yellow oil (6.2 g) having a melting point of 40 DEG C, which crystallizes when left unattended.

The product is stirred in N -phenyl piperazine (4.8 g, 0.03 mol) and dioxane (50 ml) in the presence of anhydrous sodium carbonate (3.0 g) and the mixture is heated at reflux for 24 h. The mixture was filtered from sodium carbonate and the filtrate was evaporated to give a pale yellow oil which was captured by hot 40/60 ° C. petroleum ether and extracted through a column of silica gel using ethyl benzene 4: 1V / V as the developing solvent. The first rapid shift contains unreacted chloroethyl (3.5 g) and the later shift contains the present compound which, when recrystallized from ethyl acetate, has a melting point of 124 ° C.

The following compound is prepared in a similar manner.

Example 44

1- (2-methylthiazol-4-ylmethyl) -4- (3-bromophenyl) piperazine

4-chloromethyl-2-methylthiazole (17.4 g, 0.05 mole), 1- (3-bromophenyl) piperazine (12.05 ml, 0.05 mole) and anhydrous sodium carbonate (10 ml) are suspended in anhydrous ethanol (150 ml). Let's do it. The mixture is stirred under reflux for 8 hours and boiled.

The solvent is evaporated to dryness and then water is added (100 ml). The emulsion thus formed is extracted with dichloromethane and the organic extract is dried over magnesium sulfate and evaporated to oil. It is dissolved in hot benzene, treated with bleached charcoal and filtered. Evaporation of the filtrate affords the present compound as a fully crystallized oil having a melting point of 82 ° C. (ether).

In a similar manner, the following compounds are prepared.

Example 45

1- (2-methylthiazol-4-ylmethyl-4- (3-trifluoromethylphenyl) piperazine, dihydrochloride melting point 176-80 ° C

Example 46

1- (2-methylthiazol-4-ylmethyl) -4- (3-chlorophenyl) piperazine melting point 71-2 ° C

Example 47

1- (2-methylthiazol-4-ylmethyl) -4- (3-methoxyphenyl) -piperazine melting point 71.5-72.5 ° C.

Example 48

1- (2-methylthiazol-4-ylmethyl) -4- (4-bromophenyl) piperazine melting point 114-115 ° C

Example 49

1- (2-methylthiazol-4-ylmethyl) -4- (2-bromophenyl) piperazine melting point 85-86.5 ° C

Example 50

1- (2-methylthiazol-4-ylmethyl) -4- (3,4-dichlorophenyl) piperazine dihydrochloride, melting point 175-176 ° C

Example 51

1- (2-methylthiazol-4-ylmethyl) -4- (3-nitrophenyl) piperazine hydrochloride, melting point 218-222 ° C.

Example 52

1- (2-methylthiazol-4-ylmethyl) -4- (4-methylphenyl) piperazine hydrochloride, melting point 190-2 ° C

Example 53

1- (2-methylthiazol-4-ylmethyl) -4- (3-methylphenyl) piperazine hydrochloride, melting point 158-160 ° C

Example 54

1- (2-methylthiazol-4-ylmethyl) -4- (4-chloromethyl) piperazine melting point 98 ° C

Example 55

1- (2-methylthiazol-4-ylmethyl) -4- (4-chloro-3-trifluoromethylphenyl) piperazine hydrochloride 185-7 ° C

Example 56

1- (2-methylthiazol-4-ylmethyl) -4- (4-methoxyphenyl) piperazine hydrochloride, melting point 134-5 ° C

Example 57

(A) 2- n -propyl-4-chloromethylthiazole

To a solution of thiabutanamide (30.96 g, 0.3 mol) in anhydrous ethanol (200 ml) was slowly added a solution of 1,3-dichloroacetone (38.1 g, 0.3 mol) in ethanol (100 ml), the mixture was boiled under reflux for 1 hour and the solvent Evaporate. The residue is treated with excess saturated sodium bicarbonate solution and extracted with ether. The extract is evaporated to dryness to give a brown oil, which is distilled under vacuum to give a pale yellow oil having a boiling point of 50 ° C./0.06 mmHg. This is converted to the present compound using ether hydrogen chloride. Melting point 60 ℃

In a similar manner, the following compounds are prepared:

(B) 2-benzyl-4-chloromethylthiazole boiling point 116-118 ° C / 0.09mmHg

(C) 2-isopropyl-4-chloromethylthiazole hydrochloride, melting point 58 DEG C (decomposition)

Example 58

1- (2- n -propylthiazol-4-ylmethyl) -4-phenylpiperazine

A mixture of 2- n -propyl-4-chloromethylthiazole hydrochloride (3.18 g, 0.015 mol), 1 phenylpiperazine (2.43 g, 0.015 mol) and sodium carbonate (anhydride, 10 g) in anhydrous ethanol (60 ml) Stir at reflux for 6 hours and boil. The suspension is filtered and the filtrate is evaporated to yield a yellow oil. It is dissolved in boiling benzene and treated with bleached charcoal. Removing benzene after filtration gives 4.27 g of yellow oil which crystallizes. Recrystallization of this solid with petroleum ether at 0 ° C. yields a white-yellow crystalline solid (melting point 38-39 ° C.).

In a similar manner, the following compounds are prepared:

Example 59

1- (2- n -propylthiazol-4-ylmethyl) -4- (4-chloropepe) piperazine, melting point 51-54 ° C

Example 60

1- (2- n -propylthiazol-4-ylmethyl) -4- (4-methylphenyl) piperazine, melting point 41-44 ° C

Example 61

1- (2- n -propylthiazol-4-ylmethyl) -4- (4-methoxyphenyl) piperazine, melting point 46-47 ° C

Example 62

1- (2- n -propylthiazol-4-ylmethyl) -4- (3-trifluoromethylphenyl) piperazine hydrochloride, melting point 162-6 ° C.

Example 63

1- (2- n -propylthiazol-4-ylmethyl) -4- (3,4-dichlorophenyl) piperazine dihydrochloride, melting point 158-160 ° C.

Example 64

1- (2- n -propylthiazol-4-ylmethyl) -4- (4-chloro-3-trifluoromethylphenyl) piperazine dihydrochloride melting point 174-8 ° C

Example 65

1- (2-benzylthiazol-4-ylmethyl) -4-phenylpiperazine melting point 60-62 ° C

Example 66

1- (2-benzylthiazol-4-ylmethyl) -4- (4-chlorophenyl) piperazine melting point 74 ° C

Example 67

1- (2-benzylthiazol-4-ylmethyl) -4- (4-methoxyphenyl) piperazine melting point 65 ° C

Example 68

1- (2-benzylthiazol-4-ylmethyl) -4- (3-bromophenyl) piperazine melting point 69 ° C

Example 69

1- (2-benzylthiazol-4-ylmethyl) -4- (4-chloro-3-trifluoromethylphenyl) piperazine, colorless oil

Example 70

1- [2- (4-chlorobenzyl) -thiazol-4-ylmethyl] -4-phenylpiperazine dihydrochloride melting point 150 DEG C (decomposition)

Example 71

1- (2-isopropylthiazol-4-ylmethyl) -4- (4-chlorophenyl) piperazine, melting point 54 ° C

Example 72

1- (2-isopropylthiazol-4-ylmethyl-4-3-methoxyphenyl) piperazine, melting point 65 ° C

Example 73

1- (2-isopropylthiazol-4-ylmethyl-4- (3-bromophenyl) piperazine, colorless

Example 74

1- (2-isopropylthiazol-4-ylmethyl) -4- (4-chloro-3-trifluoromethylphenyl) piperazine, colorless

Claims (1)

A process for preparing a phenylpiperazine derivative or salt thereof represented by the following general formula (I), which is prepared by condensing a compound represented by the following general formula (IV) with a compound represented by the following general formula (VII):

In which R ¹ is benzyl, C _1-6 alkyl or optionally substituted phenyl; R ² is optionally substituted phenyl; R ³ is hydrogen or C _1-4 alkyl; Q is furan, thiophene, oxazole or thiazole; m is 1-3 and n is 0 or 1; L represents a leaving group; Where m is 2, n is 0 and Q is a thiazol-5-yl group then R ¹ cannot be methyl)