HU213097B - Process for producing phenylpiperazines - Google Patents

Abstract

Pharmaceutical intermediate, N-phenyl-piperazines of formula (I) (R = H, halogen, tri:fluoro-methyl-, low carbon-alkyl- or alkoxy-gp.; n = 1 or 2), are prepd. via cyclo-condensation of aniline -hydrochloride (II) and di:ethanolamine (III). The reaction proceeds in the presence of di:phosphorus -pentoxide condensing agent and of a phlegmatising agent.

Description

The present invention relates to a novel process for the preparation of N-phenylpiperazines optionally substituted with one or two halogen atoms, trifluoromethyl, lower alkoxy or lower alkyl.

The compounds of the present invention are valuable intermediates for the preparation of other biologically active compounds.

The intermediates of the present invention are particularly useful in the preparation of the drug Trazodon.

U.S. Patent Nos. 2,927,924 and 2,833,770, Japanese Patent Nos. 8,242,679 and 6,041,670, and J. Am. Chem. Soc. and J. Am. Chem. Soc., 76, 1853-1855 (1954).

In U.S. Patent No. 2,833,770 and in J. Am. Chem. Soc., 76, 1853-55 (1954), substituted phenylpiperazines are prepared by equimolar mixtures of aniline derivative and diethanolamine with concentrated aqueous hydrochloric acid. then slowly warm to 220 ° C and keep at this temperature for a further 3-5 hours.

U.S. Pat. No. 2,927,924 discloses the hydrochloric acid salt formation described above by introducing hydrochloric acid gas (also described in J. Am. Chem. Soc., 56, 2199-2200 (1934)).

According to the process described in Japanese Patent No. 6,041,670, an aniline is prepared by reaction of bis (bromomethylamine) hydrochloride with 30% aqueous potassium hydroxide; the desired product is obtained in 76% yield.

According to Japanese Patent Publication No. 8,242,679, an aniline hydrochloride salt is cyclocondensed with diethanolamine in the presence of polyphosphoric acid or diphosphorus pentoxide. The application merely describes condensation with polyphosphoric acid.

The literature cited does not describe the quality of the product obtained, and the reported yields are generally moderate.

According to Japanese Patent Publication No. 8,242,679, attempts have been made to cyclocondensate N-phenylpiperazine derivatives in the presence of aniline hydrochloride and diethanolamine in the presence of diphosphorus pentoxide. It has been found that the reaction is highly exothermic and thus difficult to control and not suitable for industrial scale. It is also unsuitable because of the high yields of tar under the reaction conditions, which greatly degrade product quality and production.

On the basis of the literature reviewed, the known methods have the following disadvantages:

- polyphosphoric acid used for cyclocondensation must be freshly prepared in a separate reaction step;

- the use of a large excess of polyphosphoric acid condensing agent, which adversely affects the economics of the process and is a significant environmental contributor to the reaction mixture;

- the quality of the final product is uncertain;

- use of aqueous hydrochloric acid and / or hydrochloric acid causes significant corrosion problems in industrial conditions;

- long reaction time.

In the course of our work, we aimed to develop an economical procedure without the above disadvantages. Unexpectedly, it has been found that cyclocondensation can be carried out in the presence of diphosphorus pentoxide and a phlegmatizer when a mineral oil is used as the phlegmatizer. The most suitable mineral oils are those having a viscosity of 9-16.5 mm ² / sec., With a pour point lower than -8 'C and a flash point above 150' C.

The present invention relates to a process for the preparation of N-phenylpiperazines optionally substituted with one or two halogen atoms, trifluoromethyl or C 1-6 or alkyl or alkoxy groups in the presence of diphosphorus pentoxide starting from diethanolamine and optionally substituted aniline hydrochloride. such that the cyclocondensation is carried out in the presence of a phlegmatizer.

According to our process, a substituted aniline hydrochloride is reacted with diethanolamine in the presence of a diphosphorus pentoxide condensing agent, wherein the oil is a phlegmatizer. The reaction is preferably carried out at 200-240 'Con at 220-230' C for a reaction time of not more than two hours. Of course, at lower temperatures the reaction is slower, but higher temperatures are not advisable because of the increase in side reactions.

The process according to the invention has several advantages over the known processes. The product obtained is a high purity resin-tar product and does not contaminate

- the specific utilization of the device is very good,

- the reaction is safe to carry out,

- the secondary by-product of the reaction (eg in the manufacture of fertilizers),

- the phlegmatizer is suitable for reuse,

the reaction yield is higher than any process known in the literature.

The process of the present invention is illustrated by the following examples (Op and Fp data in the examples are uncorrected).

Example I (General Production Method)

Diethanolamine (1.0-1.1 mol) and a substituted aniline hydrochloride (1.0 mol) are reacted with stirring to maintain a temperature of 60-70 ° C. After fifteen minutes, 150 cm ^{3 of} spindle oil and diphosphorus pentoxide (0.3-0.35 mol) were added to the resulting melt.

The temperature of the reaction mixture was raised to 200230C for 1-2 hours. Then 100 cm ³ of water is added to the cooling system, and after separation the aqueous layer was extracted with 50 ^cm3 of dichloroethane, basified with 175 cm ³ concentrated ammonium hydroxide,

And then extracted with ³ x 50 cm ^{3 of} chloroform. The chloroform solution was evaporated. If desired, it is purified by fractional vacuum distillation or desalted.

Following the procedure of Example 1, the following compounds were prepared:

Example 2

N- (3-Chloro-phenyl) -piperazine Yield: 173 g (88%)

MP: 100-120 * 013.3 Pa (Literature: 90120 * C / O, 1 mm Hg)

Analysis calculated for C ₁₀ H ₁₃ ClN ₂ (196.69): N, 14.24;

Found: N, 14.11%.

Content (titrated to perchloric acid): 99.1%

Content (GK): 99.4% ng = 1.5981

Example 3

N- (4-Chloro-phenyl) -piperazine Yield: 155.39 g (79%)

MP: 150-160 * C / 66.5 Pa (Literature: 155.6157.2 * C / 0.5 mm Hg)

Mp 72-74 'C (Literature: 71.5-73.5' C)

Analysis calculated for C ₁₀ H ₁₃ ClN ₂ (196.69): C, 18.03; N, 14.24;

Found: Cl, 17.95% N, 14.18%

Content (by perchloric acid titration): 98.5%

Content (GK): 98.2%

Example 4

N- (2-Fluorophenyl (piperazine) Yield: 146.01 g (81%)

M.p. 90-95 ° C / 66.5 Pa (liter: 93 ° C / 0.5 mm Hg) Hydrochloric acid salt m.p. 186-187 ° C Analysis based on C ₁₀ H ₁₃ FN ₂ (180.23) Calculated: F 10.54% N 15.54%;

Found: F 10.42% N 15.45%

Content (by perchloric acid titration): 98.9%

Content (GK): 97.0%

Example 5

N- (3-Trifluoromethylphenyl (piperazine) Yield: 183.04 g (79.5%)

Mp 110-115 ° C / 53.2 Pa (liter: -) Hydrogen bromide salt m.p. 250-253 'C (liter:

250-253 'C)

Calcd for C _n H ₁₃ F ₃ N ₂ (230.24) calculated: N 12.17% F 24.75%;

Found: F 24.32% N 12.05%

Content (by perchloric acid titration): 97.9%

Content (GK): 98.9%

Example 6

N- (3,4-dichlorophenyl) piperazine Yield: 176.44 g (75.9%)

MP: 150-153 ° C / 39.9 Pa (Literature: 202 ° C / 15 mm Hg) Analysis calculated for C ₁₀ H ₁₂ Cl ₂ N ₂ (231.14): Calculated: Cl 30.68% N 12 , 12%;

Found: Cl 30.20% N 12.07%

Content (by perchloric acid titration): 98.2%

Content (GK): 99.0%

Example 7

N- (2-ethylphenyl) piperazine

Yield: 146.5 g (77%)

MP: 90-110 'C / 39.9 Pa

Hydrochloric acid salt, m.p.

Analysis calculated for C ₁₂ H ₈ N ₂ (190.29): N, 14.72;

Found: N, 14.67%

Content (by perchloric acid titration): 97.7%

Content (GK): 98.2%

Example 8

N - [(2-Ethyl-6-methyl) phenyl] piperazine

Yield: 165.48 g (81.0%)

Mp .: 102-108 'C / 93.1 Pa

Analysis calculated for C [ ₃ H ₂₀ N ₂ (204.32): N, 13.71%;

Found: N, 13.52%

Content (by perchloric acid titration): 98.2%

Content (GK): 98.0%

Example 9

N- (2-methoxyphenyl) piperazine

Yield: 166.3 g (86.5%)

Mp .: 98-102 'C / 53.2 Pa

Hydrogen bromide salt m.p. 245.0'C ng = 1.5755

Analysis for C ₁₁ H ₁₆ N ₂ O (192.27): Calculated: N, 14.57;

Found: N, 14.41%

Content (by titration with perchloric acid): 96.9%

Content (GK): 97.1%

Claims (7)

PATENT CLAIMS A process for the preparation of N-phenylpiperazines of formula II wherein R is hydrogen, halogen, trifluoromethyl, C 1-6 alkyl or C 1-6 alkoxy and n is 1 or 2 By cyclocondensation of the aniline hydrochloride (II) and diethanolamine (III) in the presence of diphosphorus pentoxide, characterized in that the reaction is carried out in the presence of a phlegmatizer. 2. A process according to claim 1 wherein 0.1-0.5 mole of diphosphorus pentoxide is used per mole of the compound of formula (Π). 3. A process according to claim 2 wherein 0.3 to 0.35 moles of diphosphorus pentoxide are used. 4. A process according to claim 1 wherein the phlegmatizer is mineral oil. 5. Process according to any one of claims 1 to 4, characterized in that the mineral oil used as a phlegmatizer has a viscosity of 9-16.5 mm ² / sec, a pour point lower than -8 ° C and a flash point above 150 ° C. HU 213 097 Β 6. A process according to any one of claims 1 to 4, wherein the phlegmatizer is spindle oil. 7. A process according to claim 1 wherein the compound of formula II is m-chloroaniline hydrochloride.