DE2005292A1 - Process for the preparation of benzodiazepines and their salts - Google Patents

Description

"Process for the preparation of benzodiazepines and their salts "- ■" "■■■ · ■ - ■ _ ■} - ..

Priority: February 8, 1969, Japan, Ir. 9396/69

The invention relates to a new method for the production of Benzodiazepines of the general formula I. j

(D

in which R _{1 is} an alkyl radical with 1 to 4 carbon atoms, a Bönzyl or phenyl group or a halogen-substituted phenyl group or a phenyl group substituted by a lower alkyl radical, Ej _{2 is} a hydrogen or halogen atom or an alkyl radical with 1! to 4

ι ■■ "■ -.-- - I

- '■■ .- ■. "." ■■. . i

C atoms and R, a hydrogen or halogen atom, a nitro or trifluoromethyl group, and their acid addition salts. ■. -

00983 ^ / 2031

20D5292

The halogen atoms include fluorine, chlorine and iodine atoms. The expression "lower alkyl radical ¹¹ means one or branched alkyl radical with 1" to 4 carbon atoms.

a.

unbranched

The benzodiazepines of the above general formula I which can be prepared according to the invention are valuable medicaments which can be used as tranquilizers, sedatives, muscle relaxants, antispasmodics, analgesics and hypnotics. - [

Some processes for the preparation of the benzodiazepines of the general formula I are known. In one of these known methods is first unsubstituted in the 1-position; 1,3-dihydro-2H-1,4-benzodiazepin-2-one produced, which is then made to react with an isocyanate; compare, Laid-open application 6713963.

Incidentally, various methods of manufacturing are various Benzodiazepines known. In this way, benzodiazepines which are not substituted in the! Position are obtained by reaction

Low-

one

2-aminobenzophenones with glyein hydrochloride or glycine ethyl ester; See Sternbach et al., J. med. Chem. 1962, page 815, Belgian patent specification 692621, German patent specification; 1145626 and L.H. Sternbach et al., J. Org. Chem., Volume 26, Page 4936 (I96I). A wider variety of benzodiazepines can be prepared by reacting o-haloacetamidobenzopftenones with ammonia; compare L, H. Sternbach et al., J. Org. Chem. Volume 27, page 3788 (1962) and German Patent II36709 and J. med. Chem., Volume 6, page 261. ί

The methods described above have several disadvantages. As a result of steric influences, the yield is about

009833/2031]

ORIGINAL INSPECTED

Ring fault reaction very different. _: Under certain conditions, ammond lysis of the o-haloaceteamidobenzophenones formed the corresponding 3-amino-4-phenyl-2 (iH) -quinolones. '-'. . , ι

The object of the invention was to create a new and economic liberty. Process for the preparation of the benzodiazepines of the above general formula I to make available. :

- -. ^; ■ '■■■ ■:!' ■ '

The subject of the invention is thus a process for the production the benzodiazepines of the general formula I, which is characterized is that you have a 2-aminomethylindole of the general formula II. i

(II)

in which R- ,, -H ₂ and R have the above meaning, or the salt thereof is treated with an oxidizing agent in at least a stoichiometric amount and, if appropriate, the free base obtained by reaction with an inorganic or organic acid

Converted into the acid addition salt. 'j

■ ■■ ... ■ ".'- ■." ί

The 2-aminomethylindoles used in the process of the invention of the general formula II are new compounds which can be obtained in a simple manner by reducing the corresponding indole-2-carbonyltriles can be produced.

0 09 833/2031

For the preparation of the benzodiazepines of the general formula 1, the 2-aminemethylindoles of the general formula II 'or their salts, for example the hydrochlorides, hydrobromides, sulfates or phosphates, are reacted with a suitable oxidizing agent. Examples of suitable oxidizing agents are ozone, hydrogen peroxide, peracids such as performic acid, peracetic acid and perbenzoic acid, chromic acid and potassium permanganate. The reaction proceeds smoothly at room temperature, but the reaction temperature can also be higher or lower, for example from

ο
fe 0 to about 100 C. You can do the implementation in one

Carry out solvents with a boiling point of preferably 10 to 6O ⁰ C in order to control the reaction. The reaction temperature depends on the type of oxidizing agent used. The preferred oxidizing agent is chromic acid or ozone. The reaction is preferably carried out in the presence of a solvent. The type of solvent depends on the type of oxidizing agent. Examples of solvents that can be used are water, acetone, carbon tetrachloride, formic acid, acetic acid and sulfuric acid. The oxidant is in at least

·

^ψ stoichiometric amount used. If the oxidation is carried out with chromic acid in the presence of acetic acid, the chromic acid is preferably used in 2 to 3 times the equimolar amount and the reaction is carried out at room temperature. The 2-aminomethylindole is dissolved or suspended in the solvent, and the oxidizing agent is added to the solution or suspension with stirring.

When using ozone as the oxidizing agent, the reaction is also preferred at. Carried out at room temperature. That

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ORIGINAL INSPECTS »

2-AminömethylirKipl is in a solvent such as formic acid, Acetic acid or carbon tetrachloride, dissolved or ouspenjäiert, and oxygen containing ozone is introduced into the solution or suspension with stirring. 'ί

The benzodiazepine formed can be neutralized from the if necessary Reaction mixture can be isolated by extraction or by evaporation to dryness. The product can go through Recrystallization from a suitable solvent such as ethanol or isopropanol, to be further purified ,, |

- ■ i

The benzodiazepines obtained can be treated with a inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, Phosphoric acid or chromic acid, or an organic acid such as kaleic acid, fumaric acid, succinic acid ·, formic acid or Acetic acid, to be converted into their salts. · '. ·

Examples of those producible by the method of the invention Benzodiazepines and their salts of the general formula I are: 1- (N-methylcarbamoyl) -5-phenyl-i, 3-dihydro-2H-l, ^ benzodiazepines 2-on,. . j

1- (N-methylcarbamoyl) -5-phenyl-7-chloro-l, 3-dihydro-2H-l, U-

'. ■ - ■ I

benzodiazepin-2-one,.:

1- (N-methylcarbamoyl) -5-phenyl-7 ~ bromo-1,3-dihydro-2fi-1,4

benzodiazepin-2-one,
1- (N-methylcarbamoyl) -5-phenyl-7-nitro-1,3-dlhydro-2H-lJ4-benzo-

diazepin-2-one, Γ

1- (N * -Methylcarbamoyl) -5-phenyl-7-trifluoromethyl-1,3-dihi [dro-2H-

l _l 4-benzodiazepin-2-one, | .

009 83 3/2 0 3 1 ^ ^MMAL iN ^sPECTSD

1- (K-methylcarbaisoyl) -5-phenyl-6- (or 8) -chlor-1,3-dih.yd; ro-2H-

l, 4-benzodiazepin-2-one,
1- (K-methylcarbamoyl) -5- (oc.hlorp] ienyl) -7-chloro-1,3-d.ihyd; ro-2H-

1,4-benzodiazepin-2-one, j

l- (li-methylcarbamoyl) -5- (o-fluoropheriyl) -7-chloro-1,3-dihyd; ro-2H-

1,4-benzodiazepin-2-one,;

l- (li-methylcarbamoyl) -5- (o-fluorophenyl) -7-nitro-1,3-dihydro-2H-

1,4-benzodiazepin-2-one,;

l- (N-methylcarbamoyl) -5- (o-chlorophenyl) -7-nitro-1,3-dihyd ^: ro ~ 2H-

1,4-benzodiazepin-2-one,
l- (N-methylcarbamoyl) -5- (p-chlorophenyl) -7-chloro-1,3-dihydro-2H-

l, 4-benzodiazepin-2-one,!

l- (N-methylcarbamoyl) -5- (p-bromophenyl) -7-clilor-1,3-dihydrO-2H-

1,4-benzodiazepin-2-one, ■

l- (N-Ethylcarbamoyl) -5-plienyl-7-chloro-1,3-dihydro-2H-l _} 4-! benzo-

■ »

diazepin-2-one,;

l- (li-propylcarbainoyl) -5-plienyl-7-chloro-1,3-dihydro-2H-1,4

benzodiazepin-2-one, J.

l- (N-Butylcarbamoyl) -5-piienyl-7-chloro-1,3-dihydro-2H-1,4-benzo-

diazepin-2-one, *;

1- (N-Benzylcarbamoyl) -5-phenyl-7-chloro-1,3-dihydro-2H-1,4r

benzodiazepin-2-one,!,

l- (N-Phenylcarbamoyl) -5-phenyl-7-chloro-1,3-dihydro-2H-1,4-ben-

zodiazepin-2-one, ■

l- / li_ (ni-chlorophenyl) -carbaraoyl / -5-phenyl-7-chloro-1,3-dihydro-2H-

l, 4-benzodiazepin-2-one and j

l_ / N -. (p-Chlorophenyl) -carbamoyl7-5-phenyl-7-chloro-1,3-dihyüro-2H-

1,4-benzodia2epin-2-one. '

ORIGINAL INSPECfrfiD

009833/2031 i '

The examples illustrate the invention. ■ i ■

.Example 'j - · - _. . ,; ■. "t ■

In a mixture of 2 g of 1- (N-methylcarbamoyl) -2-aminomethy1-3-phenyl-5-ehloz'indole hydrochloride and 30 ml of acetic acid, about 2 hours at 15 to 20 C without stirring, ozone-containing oxygen initiated. Then the reaction mixture with 'aqueous Ammonia neutralized with ice cooling and with methylene chloride extracted. The combined methylene chloride extracts were washed with water and dried over sodium sulfate. That Solvent is distilled off under reduced pressure and the residue rubbed with petroleum ether <>. The crystals · become filtered off and recrystallized from ethanol. You get! the

-l, 3-dlhydro ^ 2H-l, 4-benzo-

diazepin-2-one from F. * rl55 to. 158 ⁰ C.. ]

' Example 2 ■ I-

A solution of 3 g of chromic acid anhydride in 3 ml of water is added dropwise to a mixture of 3.5 g of 1- (N-methylcarbamoyl) -2-aminomethyl-S-phenyl-S-chlorindole hydrochloride and 40 ml ^: vinegar -

acid given below 20 G. The mixture is stirred for 15 hours at room temperature, then diluted with water, made alkaline with aqueous ammonia solution and extracted with methylene chloride. The combined methylene chloride extracts are washed with water and dried over sodium sulfate. i) the solvent is distilled off under reduced pressure . The residue is worked up according to Example 1. The same product is obtained with a temperature of 155 to 150 ° G. j

009833/2031

When using 1- (N-methylcarbamoyl) -2-aminomethyl-3-phenylindole sulfate in the process according to Example 2, the corresponding 1- (N-methylcarbamoyl) -5-phenyl-1,3-dihydro-2H-l is obtained , 4-benzodiazepin-2-one from P. 151 to 152 ⁰ C.:

When using 1- (N-methylcarbamoyl) -2-aminomethyl-3-phenyl-5-nitroindole hydrochloride in the process of Example 2, the corresponding 1- (li-methylcarbamoyl) -5-phenyl-7-nitro-1 is obtained , 3-dihydro-2H-1,4-benzodiazepin-2-one from I ¹ . l60 to 161 ⁰ C:

"When using 1- (N-benzylcarbamoyl) -2-aminomethyl-3-phenyl-

5-chloroindole hydrochloride or l- (N-phenylcarbamoyl) -2-aminoniethyl-3-phenyl-5-chloroindole hydrochloride and with chromic anhydride in acetic acid according to Example 2, the corresponding l-benzylearbamoyl-S-phenyl-T-chlorine is obtained -l, 3-dihydro-2H-l, 4-benzodiazepin-2-one with a melting point of 114 to 116 C or 1-phenylcarbamoyl-'5-phenyl-7-chloro-1,3-dihydro-2H-l , 4-benzodiazepin-2-one from. F. 209 to 212 ⁰ C.

Example 3
A solution of 3 g of chromic anhydride in 3 ml of v / water is added dropwise to a mixture of 3.6 g of 1- (N-ethylcarbamoyl) -2-aminomethyl-3-phenyl-5-chloroindole hydrochloride and 40 ml of acetic acid below 2O ⁰ C given. When the addition is complete, the mixture is stirred for 15 hours, then poured into water, made alkaline with aqueous ammonia solution and extracted with methylene chloride. The combined methylene chloride extracts are washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is dissolved in ethanol and an ethanol solution of hydrogen chloride is added.

009833/2031 '

ORIGINAL INSPECTSD

■ - ■ 9 -

20-5292

The solvent is then distilled off under reduced pressure. The residue is recrystallized from ether. The 1- (N-ethylcarbamoyl) -5-phenyl-7-chloro-1,3-dihydiro-2H-1,4-benzodiazepin-2-one hydrochloride from F ₀ 158 is obtained

° n

ORIGINAL INSPECTSD

0 09833/2031

Claims (5)

20Q529? Claims 1. Process for the preparation of benzodiazepines of the general Formula I. I) COMR _n in which R _{1 is} an alkyl radical having 1 to 4 carbon atoms, a benzyl or phenyl group or a halogen-substituted phenyl group or a phenyl group substituted by lower alkyl radicals, R _{2 is} a hydrogen or halogen atom or an alkyl radical having 1 to 4 C-ato men and R, a hydrogen or halogen atom, a nitro or trifluoromethyl group, and their acid addition salts, characterized in that one .2-aminomethylindole of the general formula II j. (II) in which R-,, R "and R have the above meaning, or its Treated salt with an oxidizing agent in at least a stoehiometric amount and optionally the free base obtained transferred into the acid addition roomζ by reaction with an inorganic or organic acid. ! 009833/2031 ORIGINAL 2. The method according to claim 1, characterized in that g e k e η η a ei c h "n et, · that the oxidizing agent ozone, hydrogen peroxide, performic acid, peracetic acid, perbenzoic acid or chromic acid used * ί ■ '- ■■■ - j 3. A method according to claim 1, characterized ge ke -η η ζ η e ty verifiable that the reaction is carried out at temperatures from O to about 10O ⁰ C performs. : 4. The method according to claim 3, d a d u r c h g e k e h η draw t that the reaction in the presence of a solvent and at temperatures from 0 to about 100 C or at the boiling point of the solvent used. 5. The method according to claim 4, d a d u r α h g e k e h n, -z e i η e t that, as a solvent, water, acetone, Carbon tetrachloride, formic acid, acetic acid or sulfuric acid are used. . '. • 6. Method according to Claim 1, characterized in that g e k 'e; n η ζ e i c h η e t that you have the 2-aminomethylindole in the form of his Hydrochloride, hydrobromide, sulfate or phosphate, is used. ■ -. ..: ... · ..- :. I. 00 9833/20 3 1