KR880002088B1 - Process for preparation of pyrrolodiazepines - Google Patents

Abstract

A method for prepg. pyrrolodiazepines having formula (I) comprises (i) hydrogenation of benzylaminoacetamide pyrrol derivs. in a lower alkanol i.e. MeOH, EtOH in the presence of catalyst i.e. Pt, Pd-C, Raney nickel at room temp. to produce amino derivs., (ii) reducing pressure to eliminate solvent and (iii) ring-closing with acid in the presence of catalyst i.e. sulfuric acid, HCl or p-toluene sulfonic acid. R=H, C1-4 alkyl, R1=H, C1-2 alkyl or Ph, R2=Me, R3=H, C1-2 alkyl, halogen or OH.

Description

Process for preparing pyrrolodiazepine compound

The present invention relates to a method for producing a pyrrolodiazepine compound represented by the following general formula (I).

(Wherein R is hydrogen or alkyl having 1-4 carbon atoms, R ₁ is hydrogen, alkyl group having 1-2 carbon atoms or phenyl group, R ₂ is methyl group, R _{3 is} hydrogen, alkyl group having 1-2 carbon atoms, halogen or- It is an OH group.)

3,7-dihydro-6-methyl-5-phenylpyro [3, 4-e], wherein R and R ₁ are CH ₃ and R ₂ and R ₃ are hydrogen in the general formula (I). Diazepine-2 (IH) -one (common name: premazepam) has the same anti-anxiety action as a benzodiazepine derivative and is being developed as a pharmaceutical. There is US Patent No. 4,022,766, but there is a high risk of explosion due to the use of anhydrous hydrazine in the removal of the protecting group there was an extremely difficult disadvantage in the reaction operation.

Accordingly, the present invention is to provide a novel production method that can solve the disadvantages of the conventional method as described above, as well as obtain a compound of the general formula (I) in a good yield by performing a safe and simple reaction operation. .

That is, according to the present invention, the compound of formula (II) is subjected to catalytic hydrogenation in a lower alkanol using a metal catalyst, and then the compound of formula (III) is closed by heating with an acid to give the desired formula (I). It is to prepare a compound of.

Wherein R, R ₁ , R ₂ , R ₃ are as described above and R ₄ is a benzyl group)

Catalytic hydrogenation is carried out by reaction with hydrogen at room temperature in an alcohol such as methanol, ethanol or isopropanol using platinum, palladium carbon, ranic nickel, etc. as a metal catalyst. Alternatively, a mineral acid such as hydrochloric acid, P-toluene sulfonic acid, or the like is added, followed by non-refluxing.

The compound of formula (II), which is a starting material of the present invention, is prepared by reacting a compound of formula (IV) with benzylamine (V) in the presence of a base, wherein the reaction is carried out in lower alkanols such as methanol and ethanol. It is carried out while refluxing.

Wherein R, R ₁ , R ₂ , R ₃ are as defined above and X is a halogen atom)

Since the compound of Formula (II) thus prepared is an oily crude product, it is purified by silica gel chromatography (developing phase: chloroform: methanol = 50: 1) and used as a starting material.

The present invention will be described in more detail in the following examples.

Example 1

Preparation of 3-benzoyl-4- [3- (benzylamino) -acetamide] -1,2-dimethylpyrrole

29 g (0.1 mol) of 3-benzoyl-4- (3-chloroacetamide) -1,2-dimethylpyrrole, 11 g (0.1 mol) of benzylamine and 17.6 g (0.055 mol) of potassium carbonate were suspended in 200 ml of methanol and 2 hours After refluxing, the solvent was removed under reduced pressure to obtain the crude product of the title compound which was purified by silica gel chromatography (chloroform: methanol = 50: 1) to obtain white needle crystals.

a) melting point 247-8 ° C. (decomposition)

b) Assay (C ₂₂ H ₂₃ N ₃ O ₂ )

Calculated Value (%): C: 73.11, H: 6.41, N: 11.63

Found (%): C: 72.96, H: 6.43, N: 11.78

C) NMR (δ, DMSO-d ₆ )

Example 2

Preparation of 3,7-dihydro-6-methyl-5-phenylpyrrolo [3, 4-e] [1, 4] -diazepin-2 (1H) -one

36 g (0.1 mole) of 3-benzoyl-4- [3- (benzylamino) acetamide] -1,2-dimethylpyrrole prepared in Example 1 was dissolved in 400 ml of methanol, 2 g of 5% palladium was added, and then at room temperature. Hydrogen gas was sucked while stirring to contact hydrogenation.

After absorbing about 2.5 L of hydrogen, the solvent was removed under reduced pressure when the reaction was completed. 50 ml of concentrated hydrochloric acid was added to the residue, followed by non-refluxing for 2 hours, then cooled and the reaction was filtered. The filtrate was made alkaline in aqueous sodium hydroxide solution.

The precipitate was crystallized with methanol to give 19 g of the title compound.

a) Condensation point 270 ° C (decomposition)

b) analysis (C ₁₅ H ₁₅ N ₃ O)

Calculated Value (%): C: 71.13, H: 6.39, N: 16.76

Found (%): C: 71.38, H: 6.31, N: 16.47

C) NMR (δ, DMSO-d ₆ )

Claims (1)

Next, the benzyl amino acetamide pyrrole derivative of formula (II) was catalytically hydrogenated at room temperature in a lower alkanol using a metal catalyst to prepare an amino derivative of formula (III), and the solvent was removed under reduced pressure, and then heated with an acid. Method for producing a pyrrolodiazepine compound of the general formula (I) characterized by ring closure.

(Wherein R is hydrogen, an alkyl group having 1-4 carbon atoms, R ₁ is an alkyl group or phenyl group having 1-2 hydrogen atoms, R ₂ is a methyl group, R ₃ is hydrogen, an alkyl group having 1-2 carbon atoms, halogen or -OH Group and R ₄ is a benzyl group).