DE2252378A1 - PROCESS FOR THE PREPARATION OF BENZODIAZEPINE DERIVATIVES - Google Patents

Description

Dr. Ing.A. van der Werth Dr. Franz Lederer

PATENT LAWYERS

2IMT. 1972

RAN 4008/234

F. HoiFmann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland

Process for the preparation of benzodiazepine iteratives

The present invention relates to a method of manufacture of behzodiazepine derivatives of the general formula

where IL is hydrogen, halogen or ITitro, Rp is hydrogen or methyl and B phenyl, o-fluorophenyl, o-chlorophenyl. or 2-fyridyl,

which known sedatives, muscle relaxants and anticonvulsants represent,

ι It is known benzodiazepine Dorivate the above E'ormel prepare by condensation of a 2-Aminophenylketons or a salt thereof with glycine, a functional derivative or a salt I thereof. It has now surprisingly been found that the condensation of a compound of the general formula

30 9 8 21/119 5 bad original

II

where Rj is hydrogen or halogen and R _? and B have the meaning given above «

with glycine gives significantly better yields if you use the Reaction in a dipolar, aprotic solvent which is inert under the reaction conditions in the presence of phosphorus oxychloride or a Qemisoh Fhosphoroxychlorld / Phosphorpentoxyd as a condensation agent, »pulls a · connection of the formula I, in which R, denotes nitro, is desired, a compound of the formula I obtained in which R is hydrogen means to be nitrated.

The term "halogen" used in this description includes the four halogens fluorine, chlorine, bromine and iodine.

In a preferred embodiment of the present invention, R _{1 is} hydrogen or chlorine. The preferred meaning of B is phenyl. In a very particularly preferred embodiment, R 1 denotes hydrogen or chlorine, R 1 denotes hydrogen and B denotes phenyl. ·

The condensation of a compound of the formula II with glycine takes place - as already stated above - in a dipolar, aprotic solvent which is inert under the reaction conditions. Solvents suitable for this purpose are, above all, those; which have an E _T value ofWlO Kcal / mol and a DK value of ^ 9 (the E _T value of a "solvent means that from the position of the charge transfer band of a standard

30 9 8 2 1/119 5 bad original

the calculated transition energy of the dye in a solvent; see also Chr. Reichardt, "Solvent Effects in Organic Chemistry", pp. 14l ff., Verlag Chemie, 19-69). Representative examples of such solvents are methylene chloride, 1,2-dichloroethane. Nitrobenzene, nitromethari and the like. or mixtures thereof. The use of nitrobenzene is particularly preferred.

As the condensing agent is used a mixture of phosphorus oxychloride or phosphorus oxychloride / Phosphorpentoxyd.Vorzugsweise "is intended in this mixture, the content of P ₀ O ₁ - about 25 $ does not exceed

2 5

rise. The condensing agent is in equxmolar amount or used up to a fourfold excess; about 1.1-1.5 mole equivalents are preferred. used.

The reaction temperature should preferably not exceed 45 ö, since by-products are formed at higher temperatures, the difficulties in crystallizing the desired end product can cause. The preferred temperature range is therefore 40 ~ 45 ° O, very particularly preferably 41-43 ° C. The pressure is not critical, but for reasons of expediency one works at normal pressure. . . ·. . '

The optionally subsequent nitration of a compound of the formula I in which R is hydrogen can be carried out in a known manner Way. So this reaction becomes for example carried out with nitric acid or an alkali metal nitrate in sulfuric acid at a temperature between about 0 ° and room temperature.

The following examples illustrate the process according to the invention. All temperatures are in ⁰ C.

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example 1

200g (0.863 mol) of 2-amino-5-chlorobenzophenone and 143g (1.906 mol) of glycine are placed in 1000ml of nitrobenzene and mixed with 90ml (0.983 mol) of phosphorus oxychloride added so that the temperature rises to 43 within about 30 minutes. After finished The reaction mixture is added for a further Iy to 2 hours at 40 ° stirred and then with about 500ml 305 ^ sodium hydroxide solution and 1000ml water of 2 added so that the temperature does not ■ exceed 15 °. When the neutralization is complete, the pH should be 7.0-0.2. The nitrobenzene is then distilled off with steam until crystals precipitate, the reaction mixture is treated with 200 ml of ethyl acetate without cooling, and stirring is continued until the temperature drops to 20. Then the crystals are filtered off, washed 3 times with 50ml ethyl acetate each time and washed under dried under reduced pressure overnight at 60, giving 7-chloro-1,3-dihydrO "5-phenyl-2H-1,4-benzodiazepin-2-one, M.p. 217 °.

Example 2

300g (1.521 mol) 2-aminobenzophenone and 450g (5.994 mol) glycine are in 3000ml abs. Nitrobenzene presented and with 201ml (2.185 mol) phosphorus oxychloride added so that the temperature rises to 41-45 within about 45 minutes. After the addition the reaction mixture is stirred for a further 3 hours, then cooled to 0-3 and treated with a mixture of 1000 ml of 30% sodium hydroxide solution and 1000ml water of 2-5 added, whereby the temperature should not exceed 15. When the addition is complete, the The reaction mixture is stirred for a further 15 minutes and then approx. 150 ml of 30% sodium hydroxide solution are added again so that the pH value is reached 7.0 ^ 0.1. The nitrobenzene is then distilled with steam, the reaction cools down to 30,

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check the pH again and, if necessary, adjust the pH to 8.0 with 30% sodium hydroxide solution «; The reaction mixture is then slowly cooled further to 20. The crystallized crude product is filtered off, washed 3 times with 200 ml of low-ion water and dried under reduced pressure at 70. The product obtained in this way is dissolved in 2200 ml of toluene at 100 °, 6 g of Uorit XXX are added to the solution and the hot solution is filtered. The piltrate is then concentrated under reduced pressure to about 900 ml and slowly cooled to room temperature with stirring. After stirring for 4-5 hours, the axis-crystallized product is filtered off, washed twice with 80 ml of toluene at 10 ° each time and increased over fold under reduced pressure at about 90 ° dried to give l, 3-dihydro-5-phenyl »2H-l, 4 _- receives on 2-benzodiazepin-, mp 182-184..

Example 3

200g (1.014 mol) of 2-aminobenzophenone and 167g (2.225 mol) of glycine are placed in 1000ml of nitrobenzene and 100ml (1.092 mol) of phosphorus oxychloride are added so that the temperature rises to 45 within 20 to 30 minutes. The reaction mixture is cooled to 40-43 °, stirred for 3 hours and then with about 550ml 30 ^ sodium hydroxide solution and 1000ml water of -2 ° added, the temperature should not exceed 15 °. After the end of the neutralization, the pH should be 7.0 * 0.2. Thereafter The nitrobenzene is distilled off with steam until crystals precipitate and the reaction mixture is treated with 2000 ml of hot Toluene, so that the precipitated crystals go back into solution »Then the organic phase is separated and the aqueous phase washed twice with 500 ml of hot toluene each time. the combined toluene extracts are washed with 1000ml hot water, the water is distilled off azeotropically and the remaining solution is concentrated to about 250 ml. Let stand after 2 to 3 hours the product crystallizes at room temperature. From-

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Crystals that have fallen are filtered off, 3 times with 25 ml of toluene each time Washed from 5 and dried at 80-90 under reduced pressure overnight, 1,3-Dihydro-5-phenyl-2H-1,4-benS: odiazepln-2-one obtained, m.p. 183-185 °.

Example 4

In a manner analogous to Example 3, 1,3-dihydro-5-phenyl- 2H-l, 4-benzodiazepin-2-one using dimethyl carbonate instead of toluene as a solvent in the work-up produced by steam distillation, m.p. 187 °.

Example 5

100 g (0.416 mol) of 2-methylamino-5-chlorobenzophenone and 125 g (0.16 mol) of glycine are placed in 1500 ml of nitrobenzene, stirred for 10-15 minutes and mixed with 60 ml (0.655 mol) of phosphorus oxychloride. After the addition has ended, the reaction mixture is stirred for 15-20 minutes, then heated to 42 for 20 minutes and then stirred for another 3-4 hours. Thereafter, about 320 ml of 30% sodium hydroxide solution and 500 ml of water at 2 ° are added to the reaction mixture in such a way that the temperature does not exceed 10. When the neutralization is complete, the pH should be 7.0 * 0.1. The nitrobenzene is then distilled off with steam until crystals precipitate, 700 ml of hot isopropyl acetate are added to the reaction mixture without cooling and the reaction mixture is stirred for 15 minutes so that the precipitated crystals dissolve again. The organic phase is then separated off and the aqueous phase extracted with 100 ml of hot isopropyl acetate. The combined organic phases are concentrated to about 350-4000 degrees, filtered hot and crystallized at -10 °. The precipitated crystals are filtered off and dried at 60 °, 7-chloro-1,3-dihydro-1-methyl-5-pheriyl-i ^> Hl, ¹ i-benz.odiazepin-2-one, mp 131 being obtained -134.

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Example 6

In a manner analogous to Example 5, 7-chloro-1,3-dihydro ~ 1-ynethyl ~ 5-phenyl-2H ~ 1,4 ~ benzodiazepine-2 "On using of methyl ethyl ketone instead of isopropyl acetate as the solvent produced during work-up after steam distillation, melting point 131-134 °.

Example 7

50g (0.180 mol) 2- (2-amino-5-bromobenzoyl) pyridine and 55g (0.733 mol) glycine are placed in 250ml nitrobenzene, Stirred for 10 minutes and mixed with 25ml (0.275 mol) of phosphorus oxychloride and 5g (0.035 mol) of phosphorus pentoxide, the temperature rises to about 30. When the addition is complete, the reaction mixture becomes Stirred for 3-4 hours, then about 150ml of 3076 strength sodium hydroxide solution and 200ml of water of 2 are added so that the temperature does not exceed 10. After the end of neutralization the pH should be 7.0 ^ 0.2. The nitrobenzene is then distilled off with steam. The precipitated crystals are filtered off, washed with hot water, dried and recrystallized from methylene chloride / n-butanol, with 7-bromo-1,3-dihydro-5- (2-pyridyl) -2H-1,4-benzodiazepin-2-one obtained, m.p. 245 °.

Example 8

A solution of 0.1 mol of 1,3-dihydro-5-phenyl-2H-1,4-benzo-di.azepin-2-one in 50ml of conc. Sulfuric acid is concentrated dropwise at -5 to 0 ° with a solution of 0.12 mol of potassium nitrate in 25ml. Sulfuric acid added. When the addition is complete, the reaction mixture is subsequently stirred for about 8 hours at a temperature between -5 and 0. Thereafter, the reaction mixture '. rrrjt ammonia neutralized, the precipitate is filtered off, with

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Washed water and dissolved in methylene chloride. The methylene chloride solution is dried over anhydrous sodium sulfate and evaporated to an oil. Crystallization of the residue from ethanol gives 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzo-

diazepin-2-one, m.p. 224-226 °.

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Claims (13)

Claims 1. The method for the preparation of benzodiazepine derivatives of the general formula where R _{1 is} hydrogen, halogen or nitro, Rp is hydrogen or methyl and B is phenyl, ο-fluorophenyl, o-chlorophenyl or 2-pyridyl, characterized in that one connects the general. formula II where R 'is hydrogen or halogen and R ₂ and B have the meaning given above, in an inert, dipolar, aprotic solvent under the reaction conditions in the presence of phosphorus oxychloride or a mixture of phosphorus oxychloride / phosphorus pentoxide as a condensing agent and, if necessary, a compound obtained of the formula I, in which R _{1 is} hydrogen, nitrated, 309821/1195 . ίο · ■ 2. The method according to claim 1, characterized in that that the condensation is carried out in a solvent which has an E ^ value of ^ 40 Kcal / mol and a DK value of - has 9. 3. The method according to claim 2, characterized in that y & Fs solvent uses methylene chloride, 1,2-dichloroethane, nitrobenzene, nitromethane or mixtures thereof. 4. The method according to claim 3 »characterized in that that the solvent used is nitrobenzene. 5. The method according to any one of claims 1-4 »characterized in that that phosphorus oxychloride is used as the condensing agent. 6. The method according to any one of claims 1-4, characterized in that that a mixture of phosphorus oxychloride / phosphorus pentoxide is used as the condensing agent. 7. The method according to claim 6, characterized in that the content of phosphorus pentoxide does not exceed $ 25. 8. The method according to any one of claims 1-7 »characterized in that that you can get the condensation in a temperature range ο ' between 40 and 45 performs. 9. The method according to any one of claims 1-8, characterized in that that 2-aminobenzophenone is used as the starting material. 10. The method according to claim 9 »characterized in that that the l, 3-dihydro-5-phenyl-2H-l, 4-benzodiazepin-2-one obtained nitrided. 309821/1195 - li - 11. The method according to any one of claims 1-8, characterized in that that you have 2-amino ~ 5 ~ chloro "benzophenone as the starting material used. 12 »Method according to one of claims 1-8, characterized in that that you can get 2-Methyla.mino-5-chlorldenzophenone used as starting material. 13. The method according to any one of .Ansprüche 1-8, characterized in that that he. 2- (2-Amino ~ 5-bromo'benzoyl) pyridine used as starting material. 309821/1195 BATH ORIGINAL