SU440838A1 - Method of producing derivatives of 4-benzyl phthalazone - Google Patents

Method of producing derivatives of 4-benzyl phthalazone

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Publication number
SU440838A1
SU440838A1 SU1739937A SU1739937A SU440838A1 SU 440838 A1 SU440838 A1 SU 440838A1 SU 1739937 A SU1739937 A SU 1739937A SU 1739937 A SU1739937 A SU 1739937A SU 440838 A1 SU440838 A1 SU 440838A1
Authority
SU
USSR - Soviet Union
Prior art keywords
2h
phthalazinone
benzyl
solution
chlorobenzyl
Prior art date
Application number
SU1739937A
Other languages
Russian (ru)
Other versions
SU440838A3 (en
Inventor
Дитрих Фогельзанг
Герхард Шеффлер
Норберт Брок
Дитер Ленке
Original Assignee
Аста Верке АГ, Хемише Фабрик ФРГ
Publication date
Priority to CH101271A priority Critical patent/CH572914A5/xx
Application filed by Аста Верке АГ, Хемише Фабрик ФРГ filed Critical Аста Верке АГ, Хемише Фабрик ФРГ
Application granted granted Critical
Publication of SU440838A3 publication Critical patent/SU440838A3/ru
Publication of SU440838A1 publication Critical patent/SU440838A1/en

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Description

The invention relates to a process for the preparation of new compounds — derivatives of 4-benzylphthalazone of formula 1 (—J where RI and Ra are the same or different, are a hydrogen or halogen atom, lower alkyl, OXI—, lower alkoxy, nitro or indispensable; enia or substituted amino or trifluoromethyl; X is non-opeptide, enna or monosubstituted by the methyl group of the methylene or ethylene group; w and n is an integer from 1 to 3; 0 or 1; the residue —CHY means Y-alkyl-substituted, enylene pyrrolidinyl or piperidyl, esamesh, or N-alkyl-substituted perhydroazepinyl, quinuclidyl, tropanil or a salt thereof with acids. These compounds have valuable physiologically active properties. The method is based on the reaction of phthalazones known in organic synthesis for the reaction of o-acyl benzoic acids with hydrazines. The proposed method is that the compound of formula 2 where RI,: R2 , the type has the indicated meanings, is reacted with a compound of the formula 3 H, N — NH — R 3, (3) where R s is a hydrogen atom or a group

- (X) p -CHY, where X, / j and -CHY have the indicated meanings,

and the resulting 4-benzylphthalazone derivatives, in the event that Ks is a hydrogen atom, are reacted with an alcohol of formula 4

HE- (X) „- SC Y

where X, p and -CHY have the indicated meanings,

or with a reactive ester of formula 4, and the target product is isolated as a free base or unreacted into an acid salt, separating the racemates into optically active anti-iodides using conventional techniques.

The structure of the obtained products was confirmed by elemental analysis, IR and NMR spectra.

Example 1. 4-bezyl-2- (N-methylpyrrolidinyl-3) -methyl -1 - (2H) -phthalazinon.

10.3 g of feiylacetophenone-o-carboxylic acid and 6.1 g of hydrazinsulfate are dissolved in a solution of 3.6 g of sodium hydroxide in 100 ml of water and heated to boiling for 2 hours. The precipitated solid is filtered off with suction, washed with water and dried. The resulting 9.2 g of 4-benzyl-1 (2H) -phthalazinone is added to a solution of 1.4 g of potassium in 250 ml of absolute alcohol and boiled for 30 minutes. After distilling off the alcohol, 10.6 g of potassium salt, 12.4 g of 3-hydroxymethyl-N-methylpyrrolidine tosyl ester and 10.6 g of potassium salt of 4-benzyl-1- (2H) -phthalazinone are obtained, heated in 100 ml of dimethylformamide 1 hour at 100 ° C. The solvent is removed on a rotary centrifuge and the residue is triturated with water. The insoluble material is taken up in ether and the ether solution is extracted with dilute hydrochloric acid. The acidic extract is made alkaline with potassium hydroxide solution, the separated oil is again taken up in ether and dried over sodium sulfate. After evaporation of the ether, 11 g of base are obtained. Fumarate is crystallized as a monohydrate; m.p. 129-132 ° C.

Example 2. 4-benzyl-2- 2- (L - methylpiperidyl-2) -ethyl -1 - (2H) -phthalazinon.

13.3 g of phenylacetophenone-o-carboxylic acid and 7.9 g of hydrazine sulfate are heated with 4.7 g of sodium hydroxide in 150 ml of water. Obtained analogously to example 1 of 11.9 g of 4-benzyl- (2H) -phthalazinone in a solution of 1.9 g of potassium in 300 ml of absolute alcohol is converted into 13.7 g of potassium salt.

A solution of 8.9 g of 2- (2 chloroethyl) -N-methylpiperidine in 25 ml of dimethylformamide is added dropwise to a solution of 13.7 g of the potassium salt of 4-benzyl-1 (2H) -phthalazinone in 150 ml of dimethylformamide at 100 ° C and continued for 2 hours stir The solvent is distilled off and the residue is treated with water. Undissolved

the product is taken up in ether, extracted with dilute hydrochloric acid, the acidic extract is alkalinized with a solution of potassium hydroxide when cooled, and the oil that is separated out is dissolved in ether. 14 g of hydrochloride are precipitated from a solution of sodium hydroxide solution dried over sodium sulfate by adding dropwise an ethereal solution of hydrochloric acid. After recrystallization, it melts at 201-203 ° C.

Analogously to Examples 1 and 2, the following compounds were obtained:

2 - (p - chlorobenzyl) - 2- (L-methylpyrrolidinyl-2) - methyl - 1 - (2H) -phthalazinone hydrochloride; m.p. 206-207 ° C;

4 - (ha - chlorobenzyl) - 2 - (N - methylpiperidyl - 2) - methyl - 1 - (2H) - phthalazine non sulfate - hydrate; m.p. from 90 ° C (decomposition); 4 - benzyl - 2- (N - methylpiperidyl-3) -methyl -1- (2H) - phthalazinone - hydrochloride hydrate; m.p. from 77 ° C (decomposition);

4 - (ft - methylbenzyl) - 2- (N - methylpyrrolidinyl-2) - methyl - 1 - (2H) -phthalazine hydrochloride hydrate; m.p. 126-128 ° C; 4 - (p - methoxybenzyl) -2- (N-methylpyrrolidinyl-2) - methyl - 1- (2H) - phthalazinone; m.p. 111-114 ° C;

4 - (- chlorobenzyl) - (L-methylpiperidyl-2) ethyl - 1- (2H) - phthalazinone - citrate; m.p. 103-105 ° C.

Example 3. 4-benzyl-2-L-methylperhydroazepinyl- (4) -1 - (2H) -phthalazinon.

To the highly stirred suspension of 13.7 g of the potassium salt of 4-benzyl-1- (2H) -phthalazinone in 250 ml of dry toluene at 40 ° C is added dropwise

a solution of 8 g of 4-chloro-L-methylperhydroazepine in 20 ml of toluene and, after slowly heating to the boiling point, is boiled for another 5 hours in the presence of reflux. The solvent is removed on a rotary evaporator and the residue is washed with water. The undissolved, oily substance is taken up in ether and extracted with dilute hydrochloric acid. After alkalizing the acidic extract with a solution of potassium hydroxide, the liberated oil is redissolved in ether and dried over sodium sulfate. After concentrating the solution, 32 g of crude product remain. By conversion to fumarate and after recrystallization, 4-benzyl-2- (iN-methylperhydroazepinyl 4) -1- (2H) -phthalazinone is isolated as fumarate hydrate; m.p. 156-160 ° C.

Another 4-benzyl-2-2-N-methyl pyrupo-dinyl-2) ethyl -1 - (2H) -phthalazinone can be obtained from the mother liquor.

Example 4. 4 - (p-chlorobenzyl) -2-N-methylpergndroazepinyl- (4) -1 - (2H) -phthalazinone.

30.6 g p-chlorobenzylYetsetophenop-o-carboxylic

acids and 16 g of hydrazinsulfate are heated

with 9.4 g of sodium hydroxide in 250 ml of water. After

washing and drying IP get 27 g of 4- (lhlorbenzyl) -1- (2H) -phthalazinone.

20 g of 2- (2-chloroethyl) - N-methylnirrolidine hydrochloride are added to a solution of 4.4 g of caustic

soda in 20 ml of water and heated to 70 ° C. This

the solution is added dropwise to a mixture of 27 g of 4 - (/ g-chlorobenzyl) -1- (2H) -phthalazione and heated to 70 ° C and 40 ml of a 50% aqueous solution of sodium hydroxide and stirred for another 1 hour at the same temperature. After cooling and diluting with water, the insoluble material is taken up in methylene chloride and extracted with dilute hydrochloric acid. The acidic extract is alkalinized with potassium hydroxide solution, the separated oil is again dissolved in methylene chloride, dried and concentrated. The crude product obtained with a yield of over 90% of the theory is converted into salt and clear, ayr by recrystal, ;;;: isation. Hydrochloride 4- (pkhlsrbepzil) - 2 - (M-methylpergidroazepinil4) -1- (2H) - {Talazunjun melts at 25-229 ° C.

From the filtrate after recrystallized, 4 - (/ g-chlorobenzyl) (M-ketnylpyrrnodnyl-2) -ethyl -1 - (2H) -phthalazinone can be isolated.

Analogously to Examples 3 and 4, the following compounds were prepared:

4 - (p - methylbenznl) -2- (N-methyl pergndrszazepinil-4) - 1 - (2H) - phthalazinop sulfate, so pl. 199-203 ° C;

4 - (ha - methoxybenzyl) -2- (M-methylnergidroazepinil-4) - 1 - (2H) - phthalazinone-sulb:) at, so pl. 203-205 ° C;

4 - (3,4 - dimethoxybenzene) -2- (M-methyl perhydroazepinyl-4) - 1 - (2H) -phthalazico: -sulfate, so nl. 118-120 ° C (decomposition);

4 - (2 - chlorobenzyl) -2 - (N-methylperhydroazepinyl-4) - 1 - (2H) -phthalazinone hydrochloride, m.p. 198-200 ° C;

4 - (3 - chlorobenzyl) -2- (M-metnlperhydroazepinil-4) - 1 - (2H) -phthalazinon, t. Nl. 77-78 ° C;

4 - (p - chlorobenzyl) -6,7-dimethoxy-2- (L-methyl perhydroazepinil-4) - 1 - (2H) -phthalazinone sulfate, so pl. 286-290 ° C;

4 - (2,4 - dichlorobenzyl) -2- (L-methylpergndroazepinil-4) - 1 - (2H) -phthalazine-fumarate, so nl. 207-21 HS;

4 - (l - dimethylaminobenzyl) -2- (L-methylnergidroazepinil-4) - 1 - (2H) - phthalazine fumarate, t. Pl. 177-182 ° C (decomposition).

4 - ("-fluorobenzyl) - 2 - (N-methyl perhydroazepnnnl-4) - 1 - (2H) - phthalazinone sulfate, t. Ch. 211-220 ° C.

4 - (p - bromobenznl) -2- (N - metlpergi; foazepinil-4) - 1 - (2H) - phthalaznon-sulfate, so pl. 215-220 ° C;

4 - (p - acetaminobenznl) -2- (M - methyl perhydroazepinil-4) - 1 - (2H) -phthalazinone-hydrochloride-hydrate, so nl. 275-278 ° C;

4 - (p - amyiobenzyl) -2- (N-metnlpergidrolzepinil-4) - 1- (2H) - phthalaznon-dihydrochloride-hydrate, so pl. 270-277 ° C;

4 - (p - hydroxybenzyl) -2- (L-methylperhydroazepnnl-4) - 1- (2H) -phthalazinone-hydrochloride hydrate, t. Nl. 260-266 ° C.

Example 5. 4 - (p-chlorobenzyl) -2- (quinuclidyl-3) -1- (2H) -phthalazinon.

5.5 g / g-chlorophenylacetophenone-o-carboxylic acid is dissolved in 30 ml of 2N. a solution of caustic soda in 30 ml of water, displaced from 4.3 g of 3-hinuklidnlgndrazin-hydrochloride and heated for 3 hours in nitrogen atmosphere until boiling. After cooling, a viscous redder oil is released, which crystallizes upon grinding. The solid is filtered off with suction, washed with water and re-installed. 4.4 g of product are obtained which melts at 181.

At capacity 6, 4- (p-chlorobenzyl-2- (N-methylpiperidnl-4) -1- (2H) -phthalaznon.

11 g of d-chlorophenne acetophenone-o-carboxylic acid is dissolved in 120 ml of alcohol, mixed with a solution of 8 g of (N-methylpiperidyl-4) hydrazine dihydrochloride and refluxed for 8 hours under nitrogen. The alcohol is distilled off and the residue is triturated with a dilute sodium hydroxide solution. The insoluble ointment is taken up in chloroform, washed and dried. After concentration, 8.4 g of base remain. Fumarate melts at 191 ° -193 ° C.

Similarly, the 5n 6 printers do not follow the connection, not the connections:

4 - benzyl -2- (L-methylpneridyl-4) -1- (2H) phthalazinone hydrate, m.p. 106-110 ° C;

4 - (p - chlorobenzyl) -2- (1,3-dnmethylpiperidyl-4) -1- (2P) - phthalazinone-fumarate, t. Pl. 219-221 ° C;

4 - (p - chlorobenzyl) -2- (tropanil-3) -1- (2H) phthalazinone-hydrochloride hydrate, so pl. 270-274 ° C;

4 - benzyl - (-methylnirrolidinyl-2) ethyl -1- (2H) -phthalazinone - fumarate - hydrate, so pl. 95-99 ° C;

4 - benzyl - 2 (quinuclidyl-3) -1- (2H) -phthalazinone-fumarate hydrate, so pl. 233-235 ° C; 4 - (p - chlorobenzyl) (M-methylnirrolidnil-2) -ethyl - 1 - (2H) -phthalazinone-hydrochloride, so pl. 220-224 ° C;

4 - (p - chlorobenzyl) -2- (M-methylpyrrolidinyl-3) -1- (2P) -phthalazinone, so pl. 117-120 ° C;

4 - (p - methoxybenzyl) -2- (quinuclidyl-3) -1 (2H) -phthalazinone hydrochloride, so pl. 236-

237 ° C;

4 - (p - fluorobenzyl) -2- (K-methyl pyrrolidinyl-3) -1- (2H) -phthalazinon, t. Nl. 90-93 ° C; 4 - (p - methylbenzyl) -2- (N-methylpyrrolidinyl-3) -1- (2H) -phthalazinon, t. Nl. 96-98 C;

4 - (p - chlorobenznl) -2 - (nortropanil-3) -1 (2H) -phthalazinone-hydrochloride, so pl. 320 ° C;

4 - (p - chlorobenzyl) -2- (nerhydroazenin4) -1- (2H) -phthalazinon-fumarate (decomposition).

7. The subject invention

The method of obtaining derivatives of 4-benzylfatalone formula 1

. {)

N-a) p-CHjf

where RI and C3, identical or different, are a hydrogen or halogen atom, lower alkyl, OXI-, lower alkoxy, nitro or indispensable, enna or mixed, enna amino group or trifluoromethyl;

X is indispensable; enna or mono-mixed with methyl group of methylene or ethylene group; .

m and n is an integer from 1 to 3; / O or 1;

the residue —CHY means N-alkylzamesh, enene pyrrolidinyl or piperidyl, indispensable or H-alkylzamesh, enolen perhydroazepinyl, quinuclidyl, tropanil or cistil, or their salts with acids, distinguished by the fact that the compound of formula 2

(one}

soon

where Ri, R2, and l have the indicated values,

subjected to interaction with the compound of the formula 3

HaN-fNH-tRa,

(3)

where Rs is a hydrogen atom or a group - (X) p-CHY.

where X, p and -CHY have the indicated meanings,

and the resulting 4-benzylphthalazone derivatives, in the event that Rs is a hydrogen atom, is reacted with an alcohol of formula 4

"N- (x)

()

where X, p and CHY have the indicated meanings.

or with a reactive ester of an alcohol of formula 4 and the desired product is isolated as a free base or converted into an acid salt with the separation of the racemates into optically active antipodes by conventional methods.

SU1739937A 1971-01-22 1972-01-20 SU440838A3 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
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DE (1) DE2164058C3 (en)
DK (1) DK136981C (en)
ES (1) ES398949A1 (en)
FI (1) FI53704C (en)
FR (1) FR2122517B1 (en)
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Families Citing this family (16)

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Publication number Priority date Publication date Assignee Title
AT49205T (en) * 1984-09-14 1990-01-15 Asta Pharma Ag Substituted benzylphthalazinon derivatives.
PT88984B (en) * 1987-11-13 1993-01-29 Asta Medica Ag Method for the preparation of azelastine embonate and earmaceutical compositions containing as active ingredient
EP0316639B1 (en) * 1987-11-13 1994-06-08 ASTA Medica Aktiengesellschaft Azelastin embonate, process for its preparation and pharmaceutical compositions containing azelastin embonate as the active ingredient
DE3836579A1 (en) * 1987-11-13 1989-05-24 Asta Pharma Ag Azelastine-containing pharmaceutical compositions for use in the nose and/or on the eye
ES2053678T3 (en) * 1987-11-13 1994-08-01 Asta Medica Ag Process for preparing a medicine containing azelastine for nasal and / or ocular application.
DE3912292A1 (en) * 1988-04-20 1989-11-09 Asta Pharma Ag Azelastine-containing pharmaceuticals with controlled release of active substance
US5110814A (en) * 1989-01-11 1992-05-05 Asta Pharma Ag Azelastine and its salts used to combat psoriasis
EP0396069B1 (en) * 1989-05-05 1994-06-22 ASTA Medica Aktiengesellschaft Salts of azelastine having advanced solubility
DE4207234A1 (en) * 1992-03-07 1993-09-09 Asta Medica Ag New amino carboxylic acid derivatives having antiallergic / anti-asthmatic effect and process for their preparation
DE4345224C2 (en) * 1993-12-18 1999-07-01 Asta Medica Ag A process for the preparation of acid addition salts of the azelastine and Flezelastins
DE4343409C2 (en) * 1993-12-18 1997-03-20 Asta Medica Ag An improved process for the preparation of Hexahydroazepinonen and Hexahydroazepinolen
GB2389530B (en) 2002-06-14 2007-01-10 Cipla Ltd Pharmaceutical compositions
US8758816B2 (en) 2004-11-24 2014-06-24 Meda Pharmaceuticals Inc. Compositions comprising azelastine and methods of use thereof
US20070020330A1 (en) 2004-11-24 2007-01-25 Medpointe Healthcare Inc. Compositions comprising azelastine and methods of use thereof
HUE030388T2 (en) 2004-11-24 2017-05-29 Meda Pharmaceuticals Inc Compositions comprising azelastine and methods of use thereof
JP4489143B2 (en) * 2006-04-20 2010-06-23 グラクソ グループ リミテッドGlaxo Group Limited 2-Substituted 4-benzylphthalazinone derivatives as histamine H1 and H3 antagonists

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Publication number Priority date Publication date Assignee Title
DE1046625B (en) * 1957-08-15 1958-12-18 Hydrierwerk Rodleben Veb A process for preparing basic substituents Phthalazone
GB1100911A (en) * 1963-08-20 1968-01-24 Benger Lab Ltd Phthalazine derivatives
FR1512879A (en) * 1966-10-28 1968-02-09 Hydrierwerk Rodleben Veb A method for manufacturing phtalazones with basic substituents

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