Chemical process

Details Chemical process Chemical process

2003-02-19

2004-01-06

Kifle, Bruck (Department: 1629)

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

Reexamination Certificate

active

06673921

ABSTRACT:

The present invention relates to an improved process for preparing an intermediate for use in the synthesis of Cholecystokinin (CCK) agonists.
WO94/24149 describes a class of 1,5-benzodiazepine derivatives having an agonist action at the CCK-A receptor.
A particular interesting group of 1,5-benzodiazepine derivatives described therein may be represented by the general formula (A)
The compounds of formula A are conveniently prepared from the 3-amino derivative (I).
WO94/24149 teaches that such 3-amino-1,5-benzodiazepine derivatives may be prepared by reduction of the corresponding phenylhydrazone and the preparation of the compound of formula (I) by the reduction of the corresponding phenylhydrazone (B), is specifically described in intermediate 11 therein.
Reduction of the hydrazone (B) to give the amine (I) also results in the formation of aniline. This is a highly toxic product, the generation of which should be avoided if at all possible in a commercial process and thus there is a need to find an alternative synthesis to the primary amine (I) which avoids the generation of aniline and provides the required product in good yield.
We have now found that the required amine (I) can be prepared in high yield and without the consequential generation of toxic by products by concomitant reduction and hydrogenolysis of the corresponding oxime (II), wherein R is an optionally substituted benzyl group.
Thus the present invention provides for a process for preparing the amine (I) by concomitant reduction and hydrogenolysis of the oxime (II) followed, if desired, by isolation of the compound as an acid addition salt thereof.
The concomitant reduction and hydrogenolysis is conveniently carried out using a Palladium catalyst e.g. Palladium on charcoal catalyst in the presence of hydrogen or ammonium formate in a solvent such as an alkanol e.g. ethanol, isopropanol or an aqueous ethanol, e.g. aqueous ethanol, or tetrahydrofuran
For the reaction the group R is conveniently benzyl or a substituted benzyl group e.g. p-methoxybenzyl or benzhydryl. Preferably R is benzyl
The oxime (II) may conveniently be prepared by reaction of the ortho-phenylene diamine derivative (III)
with an activated derivative of the di-acid (IV), wherein R is an optionally substituted benzyl group.
Conveniently, the activated derivative of the di acid (IV) is the corresponding diacylhalide e.g. chloride and this is prepared in situ by reaction of the di-acid (IV) with an oxalyl halide e.g. oxalyl chloride. The reaction is conveniently carried out in an aprotic solvent such as an ester e.g. ethyl acetate, dichloromethane, toluene, or dimethoxyether or mixtures thereof, and in the presence of dimethylformamide.
The di acid (IV) is conveniently prepared by reaction of a dialkyl ketomalonate e.g. diethyl ketomalonate with the corresponding hydroxylamine derivative RONH
2
in a solvent such as an alkanol or industrial methylated spirits and in the presence of a base e.g. pyridine, or sodium hydroxide followed, if required, by reaction with aqueous sodium hydroxide.
The following examples, which are non-limiting, illustrate the invention.
In the Examples the abbreviations EtOAc=ethyl acetate; MeOH=methanol, DMF=N,N-dimethylformamide; IPA=isopropyl alcohol; IMS=industrial methylated spirits.
Intermediate 1
Diethyl 2-[(benzyloxy)imino]malonate
Di-ethylketomalonate (60 g) was added at 20° C. to a stirred suspension of O-benzylhydroxylamine (57.8 g) in IMS (500 ml) containing pyridine (30 ml). The reaction was heated at 75° C. for 4 hr. The reaction was cooled and solvents removed under reduced pressure. The residue was partitioned between EtOAc (500 ml) and water (300 ml) and the organic layer separated, washed with water (250 ml) and dried over MgSO
4
. Solvents were evaporated to give the title compound 95.3 g, as a colourless oil (99% th, ca 3% w/w residual EtOAc) which was used without further purification.
1H NMR (300 MHz, CDCl
3
) 7.4 (m, 5H), 5.35 (s, 2H), 4.35 (m, 4H), 1.3 (m, 6H).
Intermediate 2
Method A
2-[(benzyloxy)imino]malonic acid
To a solution of Intermediate 1 (40 g) in MeOH (80 ml) was added 2M NaOH (200 ml) over 20 mins. The reaction was stirred at room temperature for 2 hr. MeOH was removed under reduced pressure and the residual solution was acidified to pH 2 by dropwise addition of conc.HCl (~30 ml) while cooling to maintain the temperature below 35° C. A thick white slurry was formed which was diluted with water (50 ml) to aid mobility. The solids were collected by filtration, washed with chilled water (25 ml) and dried in vacuo at 55° C. to give the title compound as a white solid (17 g) found to contain ca.10% w/w residual inorganic salts. Corrected yield ~45% th. Used without further purification.
1H NMR (300 MHz, D
2
O) 7.4 (m, 5H), 5.2 (s, 2H)
Method B
2-[(Benzyloxy)imino]malonic acid
To a solution of sodium hydroxide (5.74 g) in water (50 ml) and IMS (80 ml) was added benzylhydroxylamine hydrochloride (22.9 g). Diethyl ketomalonate (25 g,) was added and the mixture warmed to 60° C. and stirred for 4 h. The mixture was cooled to 30° C. and then added over ~10 minutes to a solution of sodium hydroxide (16.1 g) in water (180 ml) maintaining the internal temperature between 25-30° C. The mixture was stirred at 25° C. for ~1 h. This solution was added to a mixture of conc. hydrochloric acid (50 ml) in ethyl acetate (160 ml) and water (20 ml) at 10° C. The rate of addition is controlled to maintain the internal temperature below 15° C. The mixture was allowed to warm to 25° C., and the phases were separated. The aqueous phase was extracted with ethyl acetate (200 ml) and this wash was combined with the organic phase. The solution was concentrated to ~100 ml by distillation under reduced pressure. Toluene (50 ml) was added and the mixture concentrated under reduced pressure to ~100 ml. Further toluene (150 ml) was added and the mixture concentrated under reduced pressure to ~100 ml and precipitation of a white solid was observed. The solid was collected by filtration and washed with toluene. The solid was dried in vacuo at 40° C. to give the title compound (24.4 g).
Intermediate 3
2-[-3-[(Benzyloxy)imino]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinyl)-N-isopropyl-N-phenylacetamide
Method A
Oxalyl chloride (38.3 g) was added dropwise (~1 hr) to a stirred suspension of Intermediate 2 (40 g, corrected for salt content to 31.4 g) in EtOAc (200 ml) containing DMF (0.5 ml, 5 mol %). The mixture was stirred at 25° C. for 0.5 hour then filtered through a pad of Dicalite, washing with EtOAc (40 ml) to give a clear yellow solution. The solution was added (~5 mins) to a stirred slurry of N-isopropyl-N-phenyl-2-(2-phenylaminophenylamino)-acetamide (50 g) in EtOAc (120 ml) at 25° C. The mixture was warmed to 60° C. and a dark purple solution formed. After 1 hr, EtOAc (200 ml) was removed by atmospheric distillation. IPA (120 ml) and water (40 ml) were added and the mixture distilled further to remove more solvent (80 ml). IPA (40 ml) and water (40 ml) were added and a further amount of solvent was distilled out (80 ml). The reaction mixture was cooled to 25° C. over 1.5 hr and the solids collected by filtration. The solids were washed with IPA (2×120 ml), water (1×120 ml) and finally IPA again (1×40 ml) then dried in vacuo at 55° C. to give the title compound as a powder (56.6 g).
1H NMR (300 MHz, CDCl
3
) 2:1 mixture of isomers about the oxime 7.6-6.95 (m. 18H), 6.9 (t 1H), 5.3 (m, 2H), 4.95 (m, H), 4.65 (d, 0.33H), 4.4 (d, 0.67H), 4.1 (d, 0.67H), 4.0 (d, 0.33H), 0.95 (m, 6H)
Method B
Oxalyl chloride (143 g) was added dropwise over ~1 h to a stirred solution of 2-[(benzyloxy)imino]malonic acid (123 g) in ethyl acetate (250 ml) containing N,N-dimethylformamide (1.2 g) at 25° C. The homogeneous mixture was stirred for 2 hr. The solution was added over ~1 h to a stirred slurry of N-isopropyl-N-phenyl-2-(2-phenylamino)-acetamide (198 g) in ethyl acetate (800 ml) at 60° C. The reaction mixture w

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