CA1044232A - Benzodiazepine - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The 7-chloro-1-[2-diethylamino-ethyl]-5-(o-fluoro-phenyl)-1,3-dihydro-2H-1,4-benzodiazepinone which is a hypnotic drug is produced by a Gringnard reaction of 7-chloro-1-[2-diethyl-amino) ethyl]-1,3-dihydro-2H-1,4-benzodiazepin-2-one-4-oxide with o-fluorophenyl magnesium bromide in situ in the presence of 1,2-dibromoethane followed by dehydration of the product obtained.

Description

This invention relates to a process for the production of 7-chIoro-l~C2-(diethylamino)-ethyl]-5-~o-fluoropheny~ ,3-dihydro-2H-1,4-benzodiazepin-2-one of the formula ~`~

CH2CH2N(C2H5)2 ,~N C ~ O
/~\\ C - N (I) C 1 ¦ F

~`, 10 1 1~

which is a known compound useful as a hypnotic drug.
The production of similar benzodiazepinones by subject-; ing a benzodiazepinon-4-oxide to a Grignard reaction is known, ~, but when applying the known pxocedure to the production of the ~ compound of formula I, a yield of less than 5% was obtained, ,"
;~ probably because carrying out a Grignard reaction with ortho-bromo-halobenzenes in the normal way results in the formation of large amounts of benzyne which is very reactive and causes side reactions reducting the yield of the desired compound.
~ It has now been found that the compound of formula `~; I can be produced in high yield with a minimum of side reactions by carrying out the Grignard reaction in a special way.
;~ Thus, according to the invention, the compound of formula (I) is produced by subjecting 7-chloro-1-~2-(diethylamino) -ethyl]-1,3-dihydro-2H-1,4-benzodiaæepin-2-one-4-oxide (II) to a ~;
Grignard reaction with _-fluorophenyl magnesium bromide in situ in the presence of 1,2-dibromoethane and subjecting the resulting 7-chloro-1-~2-(diethylamino)-ethyl]-5-(o-fluorophenyl)-1,3,4,5-tetrahydro-4-hydroxy-2H-1,4-benzodiazepin-2-one (III) to a dehydration.

The followin~ schème o~ reactions is illustrative of the pFesent process - 1 -,.~ j ~4~'~3~ `

NH - C = O
~ \C + Cl-C~12-C~2 N~C2H5)2 Cl CH - N
O .
fH2CH2N~C2H5)2 10~ ~2 +
Cl CH = N ~ F
~ O ' ,.
!~
CH2CEl2N(c2H5)2 ,~1 I .
, N--~ C - O

. ~ C~l~ ~ N = ~ =

. Cl CH - N \
F OH

1, III ~

In a preferred embodiment of the present process, the synthes;s is Garried out without isolating any intermediate product.
The Grignard reaction is preferably carried out at a temperature between 40 and 60C, and more preEerably at about 40-42C, as this has proved to result in a minimum of impurities in the resulting product. ;~
? In the production of the Grignard agent from l-bromo-2 ' `' `'l 5' 30 fluorobenzene, an excess of the latter amounting to between 25 and ;i~i 50~ preferably 30-46%, should be used to ensure maximum yield :
~' ~ithout unduly increasing impurities in the resulting intermediate ., ~:; product (III).

2 -"'j5 Z3'~

Using an excess of magnesium in relation to the total -;~amo~nt of 2-bromofluorbenzene and 1,2-chloromethane on a mole basis ensures a uniform reaction throughout in the Grignard reaction.
The starting material (II) is a hitherto unknown ~ 7 .. ~, . .. . .
.. . . .
.. . .. .
. , . ,~ 10 ~ /

.''".1 .,.'~ / ~
.''1 , / ':

.'.. ',.~1 ~ .
.,.. ;, ~

''~j~ /
'; ~1 , /
' :: ' . /

,,,.~: ~ I :

`;, 1 ~ ~

.`.`'.',,~ ~ , ' ~ 2a -, : ., ', ,, ~, .
,....~.,~
' - ' !

3~

compound, which is prepared from the known 7-chloro-1,3-dihydro-2H-1,4-benzodiazepin~2 one-4-oxide and 2-chloroethyl-diethylamine.
The dehydration of the compound (III) is preferably carried out by means of phenyl isocyanate.
Other dehydrating agents, which may be used in the pre-., .
ent process, are sodium methoxide dissolved in methanol, and 1~4-dimethylpiperazine.
:. ~
The present invention will be further illustrated by way of the following Examples.
. , ` 10 Example l .
~ 7-Chloro-~2_(diethylamino)-ethyl]-1,3-dihydro-2H-1,4-benzodiazepin-: ,, .',7~ 2 one-4-oxide (II) 7-Chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one-4-oxide ~`~ (80.0 g, 0.380 mole) was added to a solution of sodium methoxide ~ (from 9.66 g of sodium (0.420 mole) and 200 ml o~ methanol, .~4, followed by evaporation of 150 ml methanol) in methanol (50 ml) and N,N-dimethylformamide (800 ml). The clear solution, which became turbid after 30 seconds, was stirred for 30 minutes at -;~
room temperature. A solution of 2-chlorotriethylamine (prepared from the hydrochloride (72.3 g, 0.420mole)) in dry toluene (440 ml) at 5C was added in one portion to the resulting light yellow ;~ suspension. The mixture was heated with stirring for 1 hour on `~, the water bath (100C). The resulting light orange suspension was evaporated to dryness under reduced pressure from a water ;l; bath (70C). Methylene chloride (300 ml) was added to the res- -~
idue, and the resulting suspension was poured onto a mixture of ice (1000 g), water (1000 ml), and 3N hydrochloric acid (133 ml, 0.400 mole). The aqueous phase was removed, washed with methylene ~ chloride (200 + 200 ml), and adjusted to pH 9-10 at 0C with 3N
`~ 30 sodium hydroxide (133 ml, 0.400 mole). The oil, which separated,;:
~`1 r~ was extracted with methylene chloride (200 + 200 + 200 ml). The rc~Of~ rnocrk 3 ~ combined methylene chloride-extracts were dried with Drierite `l t .,.",.,~
~ -;
, . . .

, - 3 -....
, ~
.: .:,i (Sikkon Flu]ca). Removal of the methylene chloride by distill-ation from a water bath (40C), at last under 15 mm, gave 99.3 g (84~) of II as a tea-coloured oil.
The oil (99.3 g) was dissolved in warm ether (200 ml), cooled, and left for 48 hours at -30C. The resulting cake of crystals was isolated hy decantation of the superna~ant, ethereal parent liquor, washed with cold ether (15 + 15 ml), and dissolved in warm methanol (30 ml). Ether (300 ml) was added, and the solution was left overnight at -20C. The resulting crystalline . :- .
10 precipitate was isolated by filtration, washed with cold ether ~ (25 + 25 ml), and dried (20C, 0.5 mm Hg) to give 48.0 g of II

''"i (41%) as white crystals with m.p. 87-89C. The parent liquor '~ and washings were evapora~ed to dryness from a water bath (45C) -:~ under reduced pressure, and the residue was crystallized from ~' ether (100 ml) at -20C and isolated as above to give another ~' 23.4 g of II (20%) as slightly yellow crystals with m.p. 86-88C.
: . ~
The total yield of II was thus 71.4 g (61%). A sample melting ~'~ at 88-90~C was analyzed.

~ Calculated for C15H2oClN3O2(309.8): C 58.1, H 6.5, N 13.6, Cl 11.4 ;~' 20 Found : C 58.3, H 6.7, N 13.5, Cl 11.5 i~ 7-Chloro-1-[2-(diethylamino)-ethyl]-5-(o-fluorophenyl)-~' 1,3,4,5-tetrahydro-4-hydroxy-'2H-1,4-benzodiaz'epin-2-one (III) : .;.
~ A stirred suspension of magnesium turnings (1.32 g, '~ 0.055 mole) in a mixture of 1,2-dibromoethane (1.0 g, 0.005 mole), ' '~ and tetrahydrofuran (10 ml) was heated in a dry flask to about ~ 60C to initiate evolution of ethylene. A solution of (II) (4.7 '~ g, 0.015 mole) in a mixture of 1,2-dibromoethane (4.6 g, 0.025 1 mole), 1-bromo-2-fluorobenzene (3.5 g, 0.02 mole), and tetra-j~ hydrofuran (30 ml) was then added dropwise with stirring at 5Ç-~ 30 58C over a period of 35 minutes. The resulting dark-red-brown -~ solution was stirred and cooled to 30C over a period of 1 hour.

'~ The resulting viscous mixture was added in one portion with

4 --: ,' , ,., . . . . . , . ~ .

3~
stirring to 0.5N hydrochloric acid (300 ml t 0.15 mole) at 5C.
The resulting almost clear, red-brown solution was adjusted to pH 10 with 40~ sodium hydroxide (15 ml). The resulting emulsion was extracted with ether (100 + 100 + 100 ml), and the combined ethereal extracts dried over anhydrous magnesium sulfate. The brown filtrate was evaporated to dxyness to give an oily material (5.4 g). This oil was dissolved in chloroform-methanol (9:1) to give a solution containing 0.10 g per ml. 4 ml of this solution was applied on four preparative thin layer chromatography plates Q ~r~f~R~k,,) ` ~ 10 (20 x 20 cm, 2 mm layer of Merck silica gel F 254). The develop-;~ ment was performed with ether-triethylamine (19:1) for about 3 hours. The appropriate band was removed and extracted with ~`~ chloro~orm-methanol (9:1) (100 ~ 100 + 100 ml). The filtrate was evaporated to dryness to give a brownish semi-crystalline ' oil (0.33 g~.
:, :
Calculated for C21H25ClFN3O2(405.9): C 62.1, H 6.2, Cl 8.7, N 10.4 . ;.
;~ Found : C 62.0, H 6.5, Cl 8.7, N 10.2 ~ '-7-Chloro 1-[2-(diethy'l'amino)-ethyl]-5-(o-fluoropheny~

1,3-dihydro-2H-1,4-benzodiazepin-2-one,dihydrochloride (I~

~ 20 III (0.240 g, 0.590 mmole) was dissolved in dry pyri-'-~ dine (2.0 ml) at 20C. Freshly distilled isocyanic acid phenyl ~ ester (0.13 ml, 1.2 mmole) was added in one portion with stirring.

"' The clear solution was heated under reflux, until evolution of ; carbon dioxide ceased (about 40 minutes). The clear, light tea-3 coloured solution was evaporated to dryness under reduced pressure from a water bath (60C). The light brown, semi-crystalline res-idue was stirred for 5 minutes with methylene chloride (3 ml).

The suspension was filtered, and the crystals were washed with ~';, methylene chloride (0.3 + 0.3 ml) and dried (80C) to give 0.110 g '~ 30 of carbanilid~ (8B%), m.p. 243C. The filtrate and washings were . . .-- .
subjected to preparative thin-layer chromatography on a 1.50 mm '-~ layer of Merck silica gel PF 254 on a glass plate (height: 200 mm, , :, .
;,` - 5 -. . .
;~.

width: 450 mm), which had~een activated by heating for 30 minutes at 120C. The development was performed with ether-triekhylamine - (95:5), whereby at least 4 compounds were separated. The 30 mm .. . .
broad, colourless band in the middle of the chromatogram (posi-~'`` tion identified in UV) was removed from the plate and extracted for 3 hours with ether in a Soxleth-type apparatus. The ethereal :
extract was dried over magnesium sulfate, filtered, and evaporated to dryness under reduced pressure from a water bath (45C)o The resulting oil (0.214 g) was dried overnight at 50C under 0.4 mm Hg to give 0.208 of I (91%) as a light yellow oil. The IR spect-,;, rum of this sample (5~ in CHC13) was identical with that of an ` authentic sample.

100 mg (0.258 mmole) of the oil was dissolved in O.99N
.: .. 1. .
;i methanolic hydrogen chloride solution (0.58 ml, 0.57 mmole).
. ., ,1 Addition of dry ether (5 ml) and stirring for 90 minut~s ga~e a ; ,.,~
~ white suspension. The crystals were isolated by filtration, .. .~
washed with dry ether (1 + 1 ml). and dried (50C, 0.5 mm Hg, 2 hours) to give 102 mg of I (86~). Melting point and mixed melting point with an authentic sample 196-206C (dec.), (liter-~ o ature value m.p. 190~220C (dec.)). The IR spectrum (in KBr) was ;~ identical with that of the authentic sample.

~j Calculated for C21H23ClFN3O,2HC1(460.8):

.. ,;, :
C 54.7, H 5.5, N 9.1, Cl total 23.1, Cl ionog. 15.4 Found: C 54.5, H 5.6, N 8.9, Cl total 22.6, Cl ionog. 14.9.

Example 2 This example illustrates the production of the dihydro-,~, . .
chloride of the compound of formula I without isolation of the intermediates.
The stirred suspension of magnesium turnings (1.18 g, `~', 30 0.049 mole) in a mixture of 1,2-dibromoethane (1.5 g, 0.008 mole) and tetrahydrofuran (20 ml, absolutely free from water and pero-~; xide) was heated under nitrogen in a dry flask to about 60C to ;~ - 6 ~

~ ,~4'~ rz initiate evolution of ethylene. A solution of 7-chloro-1-[2-(diethylamino)ethyl]-1,3-dihydro-2H~1,4-benzodiazepin-2-one-4-oxide (1.49 g, 0.0048 mole) in a mixture of lr2-dibromoethane (2.5 g, 0.013 mole), 1-bromo-2-fluorobenzene (1.22 g, 0.007 mole), and tetrahydrofuran (20 ml, absolutely free from water and pero-xide) was then added dropwise with stirring at 40-42C over a period of 45 minutes. The resulting dark, red-brown solution was heated to 50C and stirred at this temperature for 30 minutes.
.~ . .
~; The resulting viscous mixture was added in one portion to iced 0.14N hydrochloric acid (150 ml, 0.021 mole). The resulting red-yellow, turbid solution was filtered to remove unreacted magnesium (0.4 g recovered). The pH of the solution was adjusted to about

5 with 3N NaOH (2 ml), and then extracted continuously with ~ methylene chloride for 6 hours.
y; The methylene chloride extract was washed with 20 , ~ KHC03 (50 ml + 50 ml) and dried over anhydrous calcium sulfate.

,.~'f The light brown filtrate was evaporated to about 150 ml. Methanol ,' .~`~f (50 ml) was added. Carbon black (0.2 g) was added, and the sus-.
pension was stirred under gentle reflux for 40 minutes. The fil-k J
` f ~0 trate was stirred with silica gel (3 g, Merck type G~f for 16 ~; minutes. The filtrate was evaporated to dryness (70C, 10 mm Hg).

I The remaining oil was dissolved in dry pyridine (12 ml) at 20C. Freshly distilled phenylisocyanate (1.0 ml, 0.009 mole) ~`~ was added to the stirred solution in one portion. The dark-brown-.~f ish solution was slowly heated to reflux (45 minutes) under nitro- ` ;

gen with stirring. Evolution of carbon dioxide started at about ;

80C. Reflux was maintained for 30 minutes, and then the solution ; was evaporated to dryness on a water bath (70C, 10 mm Hg) for 10 ~;~ minutes. The suspension was filtered, and the crystals were ' 3Q washed with methylene chIoride (3 ~ 3 ml) and dried (100C, 10 mm ~ Hg) to give 0.64 g of slightly reddish carbanilide, m.p. 238-"~f 241C. The filtrate was evaporated to dryness on a water bath i~ (70C, 10 mm Hg).
. ~s ~ - 7 -..''f ,`'':
~: The remaining oil was dissolved in 2-propanol (10 ml) by gentle heating. To the stirred dark-brown solu-tion was added 4.6N 2-propanolic hydrochloride acid solution (5 ml) in one por-, tion. Diethylether (about 15 ml) was slowly added to the stirred solution. When precipitation started as a brownish tar, the , -~, addition of ether was stopped, a few crystals of the compound of formula I were added, and the mixture was refluxed for a few .:
minutes with stirring until the precipitate had dissolved. The , ~i stirring w~s continued, and after a few minutes precipitation ., ~',!, 10 of the dihydrochloride of I started. Ether (S ml) was added ~- slowly, and the suspension was stirred for 1 hour. Filtration and washings with cold 2-propanol - ether (1:1) (2 + 2 ml) and ~- ether (2 + 2 ml), respectively, followed by drying (100C, 10 mm .- , "
` Hg, 4 hours) gave 1.00 g of slightly coloured crystals, m.p. 199-203C, representing an over~ll yield of 46~.
. ~

:1,:,, ' '';S
i'~

:~ 20 : .. :,:

:, i ,,..,~
.,,,.
....:~
. ,~
. i .
~;, -- 8 --

Claims (8)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the production of 7-chloro-1-[2-(die-thylamino)-ethyl]-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzo-diazepin-2-one, comprising reacting 7-chloro-1-[2-(diethylamino)-ethyl]-1,3-dihydro-2H-1,4-benzodiazepin-2-one-4-oxide in a suit-able solvent with a Grignard reagent, which is produced in situ from magnesium and at least 25% more than the theoretical amount of 2-bromo-fluorobenzene in the presence of 1,2-dibromoethane, the magnesium being used in an excess of at least 10% and dehyd-rating the resulting 7-chloro-1-[2-(diethylamino)-ethyl]-5-(o-fluorophenyl)-1,3,4,5-tetrahydro-4-hydroxy-2H-1,4-benzodiazepin-2-one.

2. The process of claim 1, which is carried out with-out isolating any intermediate product.

3. The process of claim 1, in which the Grignard reaction is carried out at a temperature between 40° and 60°C.

4. The process of claim 3, in which the Grignard reaction is carried out at a temperature from 40 - 42°C.

5. The process of claim 1, in which the Grignard reagent is produced using an excess of 25-50% of 1-bromo-2-fluorobenzene with respect to the reactant benzodiazepin-4-oxide.

6. The process of claim 5, in which the excess of 1-bromo-2-fluorobenzene is from 30-46% with respect to the reactant benzodiazepin-4-oxide.

7. The process of any of claim 1, 2 or 3, in which the dehydration product is carried out with phenyl isocyanate, sodium methoxide in methanol, or 1,4-dimethylpiperazine.

8. A process as claimed in claim 1, 2 or 3 in which the product is isolated in the form of a pharmaceutically accept-able salt.