CA1088528A - Method of producing 2-halomethyl-1,4-benzodiazepines - Google Patents
Method of producing 2-halomethyl-1,4-benzodiazepinesInfo
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- CA1088528A CA1088528A CA237,301A CA237301A CA1088528A CA 1088528 A CA1088528 A CA 1088528A CA 237301 A CA237301 A CA 237301A CA 1088528 A CA1088528 A CA 1088528A
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- halomethyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
1-alkyl-2-halomethyl-1,4-benzodiazepines corresponding to the formula
1-alkyl-2-halomethyl-1,4-benzodiazepines corresponding to the formula
Description
10~S;~8 BACKGROUNl) )F THE INVENTI(-)N
The pre~ent invention r-late~ to a proce~s for pre-paring 2-halomethyl-1,4-benzodiazepine~ corresponding to the following formula I:
f R3 1~ N--C j ~ R2 and acid addition compounds thereof, whereln Rl represents an alkyl group having from 1 to 4 car-bon atoms, R2 represents a hydrogen atom, a halogen atom or a trifluoromethyl group, R3 repre~ents a hydrogen atom or a halogen atom, and ~-~ X represents a chlorine or bromlne atom.
Particularly ~uitable halogen atom~ for R2 and R3 are }~ fluorine, chlorine and bromine. The alkyl groups r~presentod by ; Rl are principally methyl, ethyl, propyl, isopropyl, butyl and econdary butyl groups.
Compounds of the abovo formula I are described in the published specification of Canadian Letters Patent 984,388 . Those substances possess valusble pharmacological propertiss which characterise them as tranquilizer~. Addi-.; . .; . , .
tional}y, those compounas are useful intermediates for thepreparation of other substances whlch have anticonvul~lve, dative, muscle-relaxing, anxiety-relieving and anti-aggressive propertles for use ln the treatm nt of psychically di~turbed '~ ', ' . ~
lO~S;~
patients. According to Canadian Letters Patent No. 984,388 such useful derivatives can be obtained from compounds of the general formula I above, for ex~mple, by replacing the X group by various other group3, ~uch as hydroxyl, alkoxy, cyano, and amino groups. Furthenmore, the compound~ corresponding to the general formula I can be converted accordlng to Canadian Letters Patent 1,008,857 by suitable oxidant~ into lactams having the following formula Il~
~1 :' R3 ~ C - N II
,.
wherein Rl, R2 and R3 are as previously defined. These com- -;
pounds include substances of accepted therapeutic util~ty, such as, for example, 7-chloro-2H-1,3-dihydro-1-methyl-5-phenyl-1, -4-benzodiazepin-2-one.
It will now be understood that the 2-halomethyl-1,4-benzodiazepines of general formula I have extremely useful properties and are particularly ~uitable for the preparation of other valuable pharmaceutical products.
According to the teaching of Canadian~Letters Patent No. 984,388, the 2-halomethyl-1,4-benzodiazepines of :~ formula I can be produced by cyclising acyldiamines having the following formula III:
The pre~ent invention r-late~ to a proce~s for pre-paring 2-halomethyl-1,4-benzodiazepine~ corresponding to the following formula I:
f R3 1~ N--C j ~ R2 and acid addition compounds thereof, whereln Rl represents an alkyl group having from 1 to 4 car-bon atoms, R2 represents a hydrogen atom, a halogen atom or a trifluoromethyl group, R3 repre~ents a hydrogen atom or a halogen atom, and ~-~ X represents a chlorine or bromlne atom.
Particularly ~uitable halogen atom~ for R2 and R3 are }~ fluorine, chlorine and bromine. The alkyl groups r~presentod by ; Rl are principally methyl, ethyl, propyl, isopropyl, butyl and econdary butyl groups.
Compounds of the abovo formula I are described in the published specification of Canadian Letters Patent 984,388 . Those substances possess valusble pharmacological propertiss which characterise them as tranquilizer~. Addi-.; . .; . , .
tional}y, those compounas are useful intermediates for thepreparation of other substances whlch have anticonvul~lve, dative, muscle-relaxing, anxiety-relieving and anti-aggressive propertles for use ln the treatm nt of psychically di~turbed '~ ', ' . ~
lO~S;~
patients. According to Canadian Letters Patent No. 984,388 such useful derivatives can be obtained from compounds of the general formula I above, for ex~mple, by replacing the X group by various other group3, ~uch as hydroxyl, alkoxy, cyano, and amino groups. Furthenmore, the compound~ corresponding to the general formula I can be converted accordlng to Canadian Letters Patent 1,008,857 by suitable oxidant~ into lactams having the following formula Il~
~1 :' R3 ~ C - N II
,.
wherein Rl, R2 and R3 are as previously defined. These com- -;
pounds include substances of accepted therapeutic util~ty, such as, for example, 7-chloro-2H-1,3-dihydro-1-methyl-5-phenyl-1, -4-benzodiazepin-2-one.
It will now be understood that the 2-halomethyl-1,4-benzodiazepines of general formula I have extremely useful properties and are particularly ~uitable for the preparation of other valuable pharmaceutical products.
According to the teaching of Canadian~Letters Patent No. 984,388, the 2-halomethyl-1,4-benzodiazepines of :~ formula I can be produced by cyclising acyldiamines having the following formula III:
2 OH
-C-NH-CH2-1H-CH2-N ~ R3 ` III
Rl :
- 10~8S28 wherein Rl, R2 and ~3 are as previously defined, using cycli-sing a~ents, such as phosphorus oxyhalides alone or in mixture with phosphorus pentoxide or phosphorus pentachloride at tem-peratures of between 100 and 150C Under the stated reaction conditions, cyclisation accompanied by ring contraction occurs and th~ hitherto unknown 1,4-benzodiazepines of the above gen-eral formula I substituted in the 2-position are obtained SIJ MMARY OF THE INVF~NTION
It has now been found that the 2-halomethyl-1,4-benzodiazepines of formula I can also be obtained by a two-stage process which involves first reacting an acyldiamine corresponding to formula III
~; <\ ~ ~ NH-CH2-CN-CH2-N ~ R3 ~ ' ' . .
wherein Rl, R2 and R3 are as already defined, with a phosphorus halide, such ~- phosphoru~ pentachloride and phosphoru~
pentabromide, in an inert solvent, such as benzene, toluene, carbon tetr~chloride, 1,2-dichloroethane or chloroform, at the boiling point of such a ~olvent so a8 to form an imidoyl halide corresponding to the follow~ng formula IV - ~-~ ~ T N-CH2 CH C~2 7 ~ R3 IV
~
X R
wherein X repr-scnt- a c~lorine or bromine atom driYing off the .
~olvent and the pbos~horu- oxyhalide which is formed, and then -`
dissolving the r~ulting residue ~n a suit~ble inert solvent, ~H such as nitromethan~, nitroethane, tetramet~ylene sulphone preferably nitrobenz~ne, ~nd cycli~ing the imidoyl halide of :;
~ ~ 3 ~
~., .
10l~S;~8 formula IV in the presence of a Lewis acid which can be used as a Friedel-Crafts catalyst, such as boron trifluoride, boron trichloride,aluminum chloride, aluminum bromide, titanium ' tetrachloride, tin tetrachloride, antimony pentachloride, iron(III) chloride or zinc chloride, at a temperature of from about 20C and about 80C, and finally isolating the 2-halo-methyl-1,4-benzodiazepine of formula I in the form of the base or an acid addition compound thereof.
The further working up of~ the reaction products and -the isolation and purification of the 2-halomethyl-1,4-benzo-diazepines of formula I can be carried out in a conventional manner. For instance, the reaction solution may be decomposed -by the addition of ice, and the organic phase separated from the aqueous phase. From such an organic phase, the hydrochlo--ride of the product can then be extracted using dilute hydro-chloric acid. The free base can be separated from these solu~
- tions by adding a solution of sodium hydroxide until thé reac-tion is alkaline.
; For further purification, the 2-halomethyl-1,4-benzo-diazepine of formula I can be dissolved in a suitable solvent, such as ether, the solution washed with a saturated solution of common salt, the solvent distilled off, the residue taken up ~ .
in a suitable solvent, such as acetone, and the corresponding hydrochloride precipitated by adding a solution of gaseous HCl in ether. The hydrochloride may then be further recrystallised ~. ~
from a suitable solvent, such as ethanol, isopropanol, acetone or ethyl acetate or from a mixture of such solvents.
For the purpose of purifylng the raw base o~tained as described above, an alternative would be a conventional chroma-
-C-NH-CH2-1H-CH2-N ~ R3 ` III
Rl :
- 10~8S28 wherein Rl, R2 and ~3 are as previously defined, using cycli-sing a~ents, such as phosphorus oxyhalides alone or in mixture with phosphorus pentoxide or phosphorus pentachloride at tem-peratures of between 100 and 150C Under the stated reaction conditions, cyclisation accompanied by ring contraction occurs and th~ hitherto unknown 1,4-benzodiazepines of the above gen-eral formula I substituted in the 2-position are obtained SIJ MMARY OF THE INVF~NTION
It has now been found that the 2-halomethyl-1,4-benzodiazepines of formula I can also be obtained by a two-stage process which involves first reacting an acyldiamine corresponding to formula III
~; <\ ~ ~ NH-CH2-CN-CH2-N ~ R3 ~ ' ' . .
wherein Rl, R2 and R3 are as already defined, with a phosphorus halide, such ~- phosphoru~ pentachloride and phosphoru~
pentabromide, in an inert solvent, such as benzene, toluene, carbon tetr~chloride, 1,2-dichloroethane or chloroform, at the boiling point of such a ~olvent so a8 to form an imidoyl halide corresponding to the follow~ng formula IV - ~-~ ~ T N-CH2 CH C~2 7 ~ R3 IV
~
X R
wherein X repr-scnt- a c~lorine or bromine atom driYing off the .
~olvent and the pbos~horu- oxyhalide which is formed, and then -`
dissolving the r~ulting residue ~n a suit~ble inert solvent, ~H such as nitromethan~, nitroethane, tetramet~ylene sulphone preferably nitrobenz~ne, ~nd cycli~ing the imidoyl halide of :;
~ ~ 3 ~
~., .
10l~S;~8 formula IV in the presence of a Lewis acid which can be used as a Friedel-Crafts catalyst, such as boron trifluoride, boron trichloride,aluminum chloride, aluminum bromide, titanium ' tetrachloride, tin tetrachloride, antimony pentachloride, iron(III) chloride or zinc chloride, at a temperature of from about 20C and about 80C, and finally isolating the 2-halo-methyl-1,4-benzodiazepine of formula I in the form of the base or an acid addition compound thereof.
The further working up of~ the reaction products and -the isolation and purification of the 2-halomethyl-1,4-benzo-diazepines of formula I can be carried out in a conventional manner. For instance, the reaction solution may be decomposed -by the addition of ice, and the organic phase separated from the aqueous phase. From such an organic phase, the hydrochlo--ride of the product can then be extracted using dilute hydro-chloric acid. The free base can be separated from these solu~
- tions by adding a solution of sodium hydroxide until thé reac-tion is alkaline.
; For further purification, the 2-halomethyl-1,4-benzo-diazepine of formula I can be dissolved in a suitable solvent, such as ether, the solution washed with a saturated solution of common salt, the solvent distilled off, the residue taken up ~ .
in a suitable solvent, such as acetone, and the corresponding hydrochloride precipitated by adding a solution of gaseous HCl in ether. The hydrochloride may then be further recrystallised ~. ~
from a suitable solvent, such as ethanol, isopropanol, acetone or ethyl acetate or from a mixture of such solvents.
For the purpose of purifylng the raw base o~tained as described above, an alternative would be a conventional chroma-
3~ tographic separation on 10 to 30 times the quantity of alumina .
1~8S;~8 or silica gel of suitable activity with a solvent ~uch a8 benzene, toluene, ether or chloroform.
It is also within the scope of this in~ention to per-form the halogenation of the acyl diamines of formula III to the imidoyl halides of formula IV in two stages. This can be done by converting an acyl diamine corresponding to formula III~
~2 OH
C-NH-CH2-CH-CH2-N ~ 3 III
Rl at a temperature of from about 20C to about 80C into a corres-ponding haloacyldiamine corresponding to the following formula V: R2 X
~C-N~-C~2-1~-C~2-~ V
O . Rl : `
in which Rl, R2,-R3 and X are as hereinbefore defined, using a ; halogenation agent, such as phosphorus oxychloride, phosphorus -~ trichloride, thionyl chloride, phosphorus oxybromide and phos- -~-phorus tribromide, in an invert solvent, such as benzenè, toluene, xylene or 1,2-dichlor~ethane, or in an excess of such a halogena--~ ` tion agent, and removing the halogenation agent and the solvent by distillation. The haloacyldiamine residue is then treated with a phosphorus halide, such as phosphorus pentachloride or :
phosphorus pentabromide, to form the corresponding imidoyl halide of formula IV. For this reaction`, 1,2-dichloroethane, , . ~
carbon tetrachloride and chloroform are especially suitable sol~ents and temperatures between about 20C and the boilinq point of the solvent may be maintained.
One ~dvantage of this procedure ls that ~t per,mits secondary products to be removed by an intermediate purific~-tion of the haloacyldiamine, for example, by recrystallization ~, from a suitable solvent.
Compared to the process described in German PatentApplication No. 2,221,558, the process of th~ invent~on has the advantage that it can be performed at lower temperatures and more quickly. Generally, the cyclisation will require from ~ ' about two to about four hour~. The reaction time is conse- , quently as much a8 twenty hours less than that of the previous~
; ly proposed proce~s and gives rise to fewer undesirable secon-~ dary reactions which reduce the yield. This can be demonstra-i~ ted in a convincing manner by the following comparison of -yields. For example, if an acyldiamine having the followinq formula VI: ~ OH '~ ~' ~C~NN~c~2_1~ C~2 1 ~ Cl VI
is cyclised to form the corresponding 1,4-benzodia~epine derivative having the following formul~ VII:
` ~: f 3 ~ 2Cl Cl ~ > CH2 , C ~ N VII
F
by the method de~cribed in ~erman P~tent Application No.
. ~ ~
'~ 2,221,SS8, the product i~ obtained ~ith a yield of 25.5~.
By contrast a y~eld of 50~2~, l.e~ twice thQ ~bovo, i~ obtained ~,.
. .,~;
10~8~;~8 by the proce~s according to thl~ invention as hereinafter specifically de~cribed ~n Example 1.
The proces~ of this invention will now be described in more detail and merely by way of illu~tration in the following Examples.
Example 1 20 g of Nl-(2'-fluorobenzoyl)-N2-methyl-~2-(4'-chlorophenyl)--2-hydroxy-1,3-diaminopropane having a melting point between lOS
and 107C were dissolved in 100 ml of 1,2-dichloroethane and the resulting solution was refluxed for two hours with 12.6 g of phosphoruQ pentachloride. The solvent and the phosphoru~
oxychloride which was formed were then distilled off in vacuo.
The resulting residue was then dissolved in 100 ml of nitrobenzene and heated at 70 to ?5C for four hours after 16.6 g of aluminum chloride had been added.
After cooling, the reaction solution wa~ poured onto a mixture of 100 g of ice and 100 ml water and then diluted ~ with 200 ml of ether. After the addition of 50 ml of concen-,~ trated hydrochloric acid, the layers were separated and the organic phase waæ extracted three times each with 50 ml of 10% hydrochloric acid. The combined aqueous hydrochloxic solu-tions were then extracted with 100 ml of ether and next ren-dered alkaline by the addition of a 25~ solution of caustic oda while being cooled with ice. The separated base was then t~ken up in 200 ml of ether, washed with a saturated solution of common salt and dried o~er 90dium ~ulphate. After the ~ solvent had been distilled off, 15 g of residue remained and -~ that residue wa~ then dissolved in acetone and treated with a solution of HCl ga~ in ether. T~e precipitated hydrochloride was next recrystallised from acetone. 11.1 g corresponding to ~ _ 7 _ . .
, ., 1~8S;~8 a yield of 50.2~ of 7-chloro-1-methyl-2-chloromethyl-5-(2'-fluorophenyl)-lH-2,3-dihydro-1,4-benzodiazepine hydro-chloride were obtained. The product had the followin~ phy~i-cal properties:
Melting point: 220 - 222C
~R-spectrum ~in KBr):- æ ~ t 2200-3000 cm 1 C'N : 1621 cm 1 W -spectrum (~n alkaline CH30H):- ~ = 236 m~
max ~ = 269 m~
max - 366 m~
max According to German Patent Application No. 2,221,558, a derivati~e of thi~ compound melts between 161 and 165C.
~ Example 2 .t~ Nl-(2'-chlorobenzoyl)-N2-methyl-N2-(4'-chlorophenyl)-2-hydroxy-1,3-diaminopropane having a melting point between 113 and 115C was halogenated using phosphoru~ pentabromide ~: in 1,2-dichloroethane ~nd cyclised u~ing aluminum bromide in i~ ., .
nitrobenzene in the manner described in Example 1 to give 7-chloro-l-methyl-2-bromomethyl-S-(2'-chlorophenyl)-lH-2,3-dihydro-1,4-benzodiazepine hydrochloride having ~ melting point of 186 to 188C.
Example 3 ~: Nl-~2'-tr$fluoromethylbenzoyl)-N2-methyl-N2-(4'-chlorophenyl)-2-hydroxy-1,3-diam~nopropane havin~ a mel~ing point between 107 and 109C wa~ halogenated using phosphorus pentachloride in 1,2-dichloroethane and cyclised using alumin-1~`
um chloride in nitrobenzene in the manner de~cribed in Example 1 to give 7-chloro-1-methyl-2-chloromethyl-5-t2'-trifluoro-~; methylphenyl)-lH-2,3-dihydro-1,4-benzodiazepine in the form of la~ss;~
an oily base showin~ an IR-absorpt-on band (oil) at 1640 cm 1 indicating a C=N linkaqe.
Example 4 Nl-(2'-chlorobenzoyl)-N2-methyl-N2-(4'-fluorophenyl)-2-hydroxy-l,3-diaminopropane having a melting point between 92 and 94C was halogenated using phosphorus pentachloride in 1,2-dichloroethane and cyclised using aluminum chloride in the manner described in Example l in nitrobenze~e to give 7-fluoro-l-methyl-2-chloromethyl-S-(2'-chlorophenyl)-lH-2,3-dihydro-1,4-benzodiazepine hydrochloride having a melting point of 180 to 184C.
Example S
20 g of Nl-(2'-chlorobenzoyl)-N2-methyl-N2-(4'-chloro-phenyl)-2-hydroxy-1,3-diaminopropane were dissolved at room temperature, while being cooled with ice, in 100 ml of phos-phorus oxychloride and then heated at 70C for S.5 hours.
The phosphorus oxychloride was then distilled off in vacuo and the resulting residue was dissolved in 100 ml of chloroform and thoroughly mixed by stirring with 100 g of ice and 100 ml of water. The chloroform solution was then separa-ted off, washed twice with water and finally thoroughly stirred ~ -for 30 minutes with a 10% solution of sodium hydroxide. The chloroform phase was then separated, washed until neutral with water and dried over sodium sulphate. After the solvent had been distilled off, the residue was recrystallised from lS0 ml of toluene. 17 g corresponding to a yield of 81~ of Nl-(2'-chlorobenzoyl)-N2-methyl-N2-(4'-chlorophenyl)-2-~hl~ro-1,3-diaminopropane melting between 137 and 139C were obtained.
11 g of this haloacyl diamine compound were next dis-solved in 50 ml of 1,2-dichloroethane and refluxed for 3 hours _ g _ i.~l 1~8852t~
together with 3.5 g of phosphorus pentachloride. The ~olvent and the phosphoru~ oxychloride were then distilled off in vacuo and the residue dissolved in S0 ml of nitrobenzene and heated at 70C for 4 hours with 8.3 g of aluminum chloride.
The product was then purified and recovered in the manner de~-cribed in Example 1. From the ether/nitrobenzene phase, 5.5 g of the product could be recovered but, after the purification procedure, 4.0 g, corresponding to a yield of 62.8%, based on -the weight of the starting material, of 7-chloro-1-methyl-2-: 10 chloromethyl-5-(2'-chlorophenyl)-lH-2,3-dihydro-1,4-benzodiaze-pine hydrochloride were obtained. ~he reaction product had the following phy~ical properties:
Melt~ng point: 178 - 180 C
~: IR-~pectrum (in KBr~ N-H 2 2128-3125 cm 1 C-N : 1642 cm 1 W -~pectrum (in alkal~ne C~30R):- ~ ~ 233 n~
max A - 270 n~ -l~ A - 355 ny .~ max ExamPle 6 t;" Nl-benzoyl-N2-methyl-N2-(4'-chlorophenyl)-2-chloro-3-diaminopropane having a melting point between 87 and 90C
was prepared from Nl-benzoyl-N2-methyl-N2-(4'-chlorophenyl)-2-hydroxy-1,3-diaminopropane having a melting point between 136 and 137C using pho~phoru~ oxychloride at 70C ~nd then ~`~; treated first with pho~phorus pentachloride in 1,2-dichloro-~ ethane and then with aluminum chloride in nitrobenzene in the ,r`~ manner described in Example 5. 7-chloro-1-methyl-2-chloro-~ methyl-5-phenyl-lH-2,3-dihydro-1,4-bensodiazepine hydrochloride j~ 30 was obtained and the cry~talline product contained one mole of i ~i - 10 -8S;~8 isopropanol and had a melting point of 110 to 112C.
Example 7 In the manner described in Example 5, Nl-(2'-fluoro-benzoy~)-N2-ethyl-N2-(4'-chlorophenyl)-2-hydroxy-1,3-diamino-propane having a melting point between 88 and 92C wa~ treated with phosphorus oxychloride at 70C to give an oily product comprising Nl-(2'-fluorobenzoyl)-N2-ethyl-N2-(4'-chlorophenyl)-2-chloro-1,3-diaminopropane. The latter product was then treated first with phosphorus pentachloride in 1,2-dichloro-ethane and then with aluminum chloride in nitrobenzene e~sen-tially as described in Example 5 to give 7-chloro-1-ethyl-2-chloromethyl-5-(2'-fluorophenyl)-lH-2.3-dihydro-1,4-benzodiaze-pine in the form of an oily phase showing an IR-absorption band (oil) at 1640 cm 1 indicating a C=N linkage.
Example 8 Similarly, Nl-(2'-fluorobenzoyl)-N2-methyl-N2-phenyl-2-chloro-1,3-diaminopropane, an oily product, wa~ prepared in the manner described in Example 5 from Nl-(2'-fluorobenzoyl)- `~-~:~ N2-methyl-N2-phenyl-2-hydroxy-1,3-diaminopropane having a melt-ing point of 89 to 91C using phosphorus oxychloride at 70C
and that intermediate wa~ then treated first with phosphorus pentachloride in 1,2-dichloroethane and then with aluminum chloride in nitrobenzene as described in Example 5 to give : l-methyl-2-chloromethyl-5-(2'-fluorophenyl)-lH-2,3-dihydro-1,4-benzodiazepine in the form of an oily base having an IR-ab~orp-tion band (oil) at 1640 cm 1 indicating a C=N linka~e.
~ Example 9 : 6.8 g of Nl-benzoyl-N2-methyl-N2-(4'-chlorophenyl)-2-chloro-1,3-diaminopropane having a melting point between 87 and 90C were obtained from Nl-benzoyl-N2-methyl-N2-~4'-chloro-~.
,.._,j 10~
phenyl)-2-hydroxy-1,3-diaminopropane by treatment of the latter with phosphorus oxychloride at 70C and were then dissolved in 35 ml of 1,2-dichloroethane and refluxed for 2 hours with 4.3 g of phosphorus pentachloride. The solvent and the phosphorus oxychloride which had formed were distilled off in vacuo. The resulting residue was then dissolved in 35 ml of nitrobenzene and heated for 4 hours at 70C with 4.8 ml of tin(~V) chloride.
After cooling, the reaction solution was poured into a mixture of 100 g of ice and 100 ml of water and then alkalised with a concentrated solution of sodium hydroxide. The resulting aqueous alkaline solution was extracted with 200 ml of toluene and the toluene solution was then extracted four times with 100 ml of a dilute (20%) hydrochloric acid. A water-insoluble oil separated which together with the aqueous hydrochloric acid was alkalised by the addition of a concentrated solution of sodium hydroxide, with cooling. The separated base was then extracted three times each with 100 ml of ether, the ether phase being washed with a saturated solution of common salt, dried over sodium sulphate and the ether distilled off in ~acuo. The residue was then taken up in isopropanol and a solution of gaseous HCl in ether added. The hydrochloride precipitated and was recrystallised from isopropanol, giving . ~ .
3.1 g corresponding to a yield of 37~ of 7-chloro-1-methyl-2-chloromethyl-S-phenyl-lH-2,3-dihydro-1,4-benzodiazepine hydro-` ~:
chloride. The product contained 1 mole of isopropanol and had a melting point of 110 to 112C.
Example 10 ;``e `~ ~ 10.1 g of Nl-(2'-fluorobenzoyl)-N2-methyl-N2-(4'-, ~
chlorophenyl)-2-chloro-1,3-diaminopropane having a melting 30 point between 88 and 90C were obtained from ~1-(2'-fluoro-10t~8S;~8 benzoyl)-N2-methyl-N2-(4'-chlorophenyl)-2-hydroxy-1,3-diamino-propane by treatment of the latter with phosphor~s oxychloride at 70C and were then refluxed for 2 hours in S0 ml of 1,2-di-chloroethane with 3.1 g of phosphorus pentachloride. The sol-vent and the phosphorus oxychloride that had formed were dis-tilled off and the residue was disQolved in 50 ml of nitroben-zene and heated at 70C for four hours with 8.2 g of zinc chloride. The pro~uct was purified and recovered as described in Example 1. 7-chloro-1-methyl-2-chloromethyl-5-(2'-fluoro-phenyl)-lH-2,3-dihydro-1,4-benzodiazepine hydrochloride was obtained and had the following physical properties:
IR-spectrum (in XBr):- -=N-H :2200-3000 cm 1 ; C=N :1621 cm 1 Melting point: 220 - 222C.
; 20 . :
1~8S;~8 or silica gel of suitable activity with a solvent ~uch a8 benzene, toluene, ether or chloroform.
It is also within the scope of this in~ention to per-form the halogenation of the acyl diamines of formula III to the imidoyl halides of formula IV in two stages. This can be done by converting an acyl diamine corresponding to formula III~
~2 OH
C-NH-CH2-CH-CH2-N ~ 3 III
Rl at a temperature of from about 20C to about 80C into a corres-ponding haloacyldiamine corresponding to the following formula V: R2 X
~C-N~-C~2-1~-C~2-~ V
O . Rl : `
in which Rl, R2,-R3 and X are as hereinbefore defined, using a ; halogenation agent, such as phosphorus oxychloride, phosphorus -~ trichloride, thionyl chloride, phosphorus oxybromide and phos- -~-phorus tribromide, in an invert solvent, such as benzenè, toluene, xylene or 1,2-dichlor~ethane, or in an excess of such a halogena--~ ` tion agent, and removing the halogenation agent and the solvent by distillation. The haloacyldiamine residue is then treated with a phosphorus halide, such as phosphorus pentachloride or :
phosphorus pentabromide, to form the corresponding imidoyl halide of formula IV. For this reaction`, 1,2-dichloroethane, , . ~
carbon tetrachloride and chloroform are especially suitable sol~ents and temperatures between about 20C and the boilinq point of the solvent may be maintained.
One ~dvantage of this procedure ls that ~t per,mits secondary products to be removed by an intermediate purific~-tion of the haloacyldiamine, for example, by recrystallization ~, from a suitable solvent.
Compared to the process described in German PatentApplication No. 2,221,558, the process of th~ invent~on has the advantage that it can be performed at lower temperatures and more quickly. Generally, the cyclisation will require from ~ ' about two to about four hour~. The reaction time is conse- , quently as much a8 twenty hours less than that of the previous~
; ly proposed proce~s and gives rise to fewer undesirable secon-~ dary reactions which reduce the yield. This can be demonstra-i~ ted in a convincing manner by the following comparison of -yields. For example, if an acyldiamine having the followinq formula VI: ~ OH '~ ~' ~C~NN~c~2_1~ C~2 1 ~ Cl VI
is cyclised to form the corresponding 1,4-benzodia~epine derivative having the following formul~ VII:
` ~: f 3 ~ 2Cl Cl ~ > CH2 , C ~ N VII
F
by the method de~cribed in ~erman P~tent Application No.
. ~ ~
'~ 2,221,SS8, the product i~ obtained ~ith a yield of 25.5~.
By contrast a y~eld of 50~2~, l.e~ twice thQ ~bovo, i~ obtained ~,.
. .,~;
10~8~;~8 by the proce~s according to thl~ invention as hereinafter specifically de~cribed ~n Example 1.
The proces~ of this invention will now be described in more detail and merely by way of illu~tration in the following Examples.
Example 1 20 g of Nl-(2'-fluorobenzoyl)-N2-methyl-~2-(4'-chlorophenyl)--2-hydroxy-1,3-diaminopropane having a melting point between lOS
and 107C were dissolved in 100 ml of 1,2-dichloroethane and the resulting solution was refluxed for two hours with 12.6 g of phosphoruQ pentachloride. The solvent and the phosphoru~
oxychloride which was formed were then distilled off in vacuo.
The resulting residue was then dissolved in 100 ml of nitrobenzene and heated at 70 to ?5C for four hours after 16.6 g of aluminum chloride had been added.
After cooling, the reaction solution wa~ poured onto a mixture of 100 g of ice and 100 ml water and then diluted ~ with 200 ml of ether. After the addition of 50 ml of concen-,~ trated hydrochloric acid, the layers were separated and the organic phase waæ extracted three times each with 50 ml of 10% hydrochloric acid. The combined aqueous hydrochloxic solu-tions were then extracted with 100 ml of ether and next ren-dered alkaline by the addition of a 25~ solution of caustic oda while being cooled with ice. The separated base was then t~ken up in 200 ml of ether, washed with a saturated solution of common salt and dried o~er 90dium ~ulphate. After the ~ solvent had been distilled off, 15 g of residue remained and -~ that residue wa~ then dissolved in acetone and treated with a solution of HCl ga~ in ether. T~e precipitated hydrochloride was next recrystallised from acetone. 11.1 g corresponding to ~ _ 7 _ . .
, ., 1~8S;~8 a yield of 50.2~ of 7-chloro-1-methyl-2-chloromethyl-5-(2'-fluorophenyl)-lH-2,3-dihydro-1,4-benzodiazepine hydro-chloride were obtained. The product had the followin~ phy~i-cal properties:
Melting point: 220 - 222C
~R-spectrum ~in KBr):- æ ~ t 2200-3000 cm 1 C'N : 1621 cm 1 W -spectrum (~n alkaline CH30H):- ~ = 236 m~
max ~ = 269 m~
max - 366 m~
max According to German Patent Application No. 2,221,558, a derivati~e of thi~ compound melts between 161 and 165C.
~ Example 2 .t~ Nl-(2'-chlorobenzoyl)-N2-methyl-N2-(4'-chlorophenyl)-2-hydroxy-1,3-diaminopropane having a melting point between 113 and 115C was halogenated using phosphoru~ pentabromide ~: in 1,2-dichloroethane ~nd cyclised u~ing aluminum bromide in i~ ., .
nitrobenzene in the manner described in Example 1 to give 7-chloro-l-methyl-2-bromomethyl-S-(2'-chlorophenyl)-lH-2,3-dihydro-1,4-benzodiazepine hydrochloride having ~ melting point of 186 to 188C.
Example 3 ~: Nl-~2'-tr$fluoromethylbenzoyl)-N2-methyl-N2-(4'-chlorophenyl)-2-hydroxy-1,3-diam~nopropane havin~ a mel~ing point between 107 and 109C wa~ halogenated using phosphorus pentachloride in 1,2-dichloroethane and cyclised using alumin-1~`
um chloride in nitrobenzene in the manner de~cribed in Example 1 to give 7-chloro-1-methyl-2-chloromethyl-5-t2'-trifluoro-~; methylphenyl)-lH-2,3-dihydro-1,4-benzodiazepine in the form of la~ss;~
an oily base showin~ an IR-absorpt-on band (oil) at 1640 cm 1 indicating a C=N linkaqe.
Example 4 Nl-(2'-chlorobenzoyl)-N2-methyl-N2-(4'-fluorophenyl)-2-hydroxy-l,3-diaminopropane having a melting point between 92 and 94C was halogenated using phosphorus pentachloride in 1,2-dichloroethane and cyclised using aluminum chloride in the manner described in Example l in nitrobenze~e to give 7-fluoro-l-methyl-2-chloromethyl-S-(2'-chlorophenyl)-lH-2,3-dihydro-1,4-benzodiazepine hydrochloride having a melting point of 180 to 184C.
Example S
20 g of Nl-(2'-chlorobenzoyl)-N2-methyl-N2-(4'-chloro-phenyl)-2-hydroxy-1,3-diaminopropane were dissolved at room temperature, while being cooled with ice, in 100 ml of phos-phorus oxychloride and then heated at 70C for S.5 hours.
The phosphorus oxychloride was then distilled off in vacuo and the resulting residue was dissolved in 100 ml of chloroform and thoroughly mixed by stirring with 100 g of ice and 100 ml of water. The chloroform solution was then separa-ted off, washed twice with water and finally thoroughly stirred ~ -for 30 minutes with a 10% solution of sodium hydroxide. The chloroform phase was then separated, washed until neutral with water and dried over sodium sulphate. After the solvent had been distilled off, the residue was recrystallised from lS0 ml of toluene. 17 g corresponding to a yield of 81~ of Nl-(2'-chlorobenzoyl)-N2-methyl-N2-(4'-chlorophenyl)-2-~hl~ro-1,3-diaminopropane melting between 137 and 139C were obtained.
11 g of this haloacyl diamine compound were next dis-solved in 50 ml of 1,2-dichloroethane and refluxed for 3 hours _ g _ i.~l 1~8852t~
together with 3.5 g of phosphorus pentachloride. The ~olvent and the phosphoru~ oxychloride were then distilled off in vacuo and the residue dissolved in S0 ml of nitrobenzene and heated at 70C for 4 hours with 8.3 g of aluminum chloride.
The product was then purified and recovered in the manner de~-cribed in Example 1. From the ether/nitrobenzene phase, 5.5 g of the product could be recovered but, after the purification procedure, 4.0 g, corresponding to a yield of 62.8%, based on -the weight of the starting material, of 7-chloro-1-methyl-2-: 10 chloromethyl-5-(2'-chlorophenyl)-lH-2,3-dihydro-1,4-benzodiaze-pine hydrochloride were obtained. ~he reaction product had the following phy~ical properties:
Melt~ng point: 178 - 180 C
~: IR-~pectrum (in KBr~ N-H 2 2128-3125 cm 1 C-N : 1642 cm 1 W -~pectrum (in alkal~ne C~30R):- ~ ~ 233 n~
max A - 270 n~ -l~ A - 355 ny .~ max ExamPle 6 t;" Nl-benzoyl-N2-methyl-N2-(4'-chlorophenyl)-2-chloro-3-diaminopropane having a melting point between 87 and 90C
was prepared from Nl-benzoyl-N2-methyl-N2-(4'-chlorophenyl)-2-hydroxy-1,3-diaminopropane having a melting point between 136 and 137C using pho~phoru~ oxychloride at 70C ~nd then ~`~; treated first with pho~phorus pentachloride in 1,2-dichloro-~ ethane and then with aluminum chloride in nitrobenzene in the ,r`~ manner described in Example 5. 7-chloro-1-methyl-2-chloro-~ methyl-5-phenyl-lH-2,3-dihydro-1,4-bensodiazepine hydrochloride j~ 30 was obtained and the cry~talline product contained one mole of i ~i - 10 -8S;~8 isopropanol and had a melting point of 110 to 112C.
Example 7 In the manner described in Example 5, Nl-(2'-fluoro-benzoy~)-N2-ethyl-N2-(4'-chlorophenyl)-2-hydroxy-1,3-diamino-propane having a melting point between 88 and 92C wa~ treated with phosphorus oxychloride at 70C to give an oily product comprising Nl-(2'-fluorobenzoyl)-N2-ethyl-N2-(4'-chlorophenyl)-2-chloro-1,3-diaminopropane. The latter product was then treated first with phosphorus pentachloride in 1,2-dichloro-ethane and then with aluminum chloride in nitrobenzene e~sen-tially as described in Example 5 to give 7-chloro-1-ethyl-2-chloromethyl-5-(2'-fluorophenyl)-lH-2.3-dihydro-1,4-benzodiaze-pine in the form of an oily phase showing an IR-absorption band (oil) at 1640 cm 1 indicating a C=N linkage.
Example 8 Similarly, Nl-(2'-fluorobenzoyl)-N2-methyl-N2-phenyl-2-chloro-1,3-diaminopropane, an oily product, wa~ prepared in the manner described in Example 5 from Nl-(2'-fluorobenzoyl)- `~-~:~ N2-methyl-N2-phenyl-2-hydroxy-1,3-diaminopropane having a melt-ing point of 89 to 91C using phosphorus oxychloride at 70C
and that intermediate wa~ then treated first with phosphorus pentachloride in 1,2-dichloroethane and then with aluminum chloride in nitrobenzene as described in Example 5 to give : l-methyl-2-chloromethyl-5-(2'-fluorophenyl)-lH-2,3-dihydro-1,4-benzodiazepine in the form of an oily base having an IR-ab~orp-tion band (oil) at 1640 cm 1 indicating a C=N linka~e.
~ Example 9 : 6.8 g of Nl-benzoyl-N2-methyl-N2-(4'-chlorophenyl)-2-chloro-1,3-diaminopropane having a melting point between 87 and 90C were obtained from Nl-benzoyl-N2-methyl-N2-~4'-chloro-~.
,.._,j 10~
phenyl)-2-hydroxy-1,3-diaminopropane by treatment of the latter with phosphorus oxychloride at 70C and were then dissolved in 35 ml of 1,2-dichloroethane and refluxed for 2 hours with 4.3 g of phosphorus pentachloride. The solvent and the phosphorus oxychloride which had formed were distilled off in vacuo. The resulting residue was then dissolved in 35 ml of nitrobenzene and heated for 4 hours at 70C with 4.8 ml of tin(~V) chloride.
After cooling, the reaction solution was poured into a mixture of 100 g of ice and 100 ml of water and then alkalised with a concentrated solution of sodium hydroxide. The resulting aqueous alkaline solution was extracted with 200 ml of toluene and the toluene solution was then extracted four times with 100 ml of a dilute (20%) hydrochloric acid. A water-insoluble oil separated which together with the aqueous hydrochloric acid was alkalised by the addition of a concentrated solution of sodium hydroxide, with cooling. The separated base was then extracted three times each with 100 ml of ether, the ether phase being washed with a saturated solution of common salt, dried over sodium sulphate and the ether distilled off in ~acuo. The residue was then taken up in isopropanol and a solution of gaseous HCl in ether added. The hydrochloride precipitated and was recrystallised from isopropanol, giving . ~ .
3.1 g corresponding to a yield of 37~ of 7-chloro-1-methyl-2-chloromethyl-S-phenyl-lH-2,3-dihydro-1,4-benzodiazepine hydro-` ~:
chloride. The product contained 1 mole of isopropanol and had a melting point of 110 to 112C.
Example 10 ;``e `~ ~ 10.1 g of Nl-(2'-fluorobenzoyl)-N2-methyl-N2-(4'-, ~
chlorophenyl)-2-chloro-1,3-diaminopropane having a melting 30 point between 88 and 90C were obtained from ~1-(2'-fluoro-10t~8S;~8 benzoyl)-N2-methyl-N2-(4'-chlorophenyl)-2-hydroxy-1,3-diamino-propane by treatment of the latter with phosphor~s oxychloride at 70C and were then refluxed for 2 hours in S0 ml of 1,2-di-chloroethane with 3.1 g of phosphorus pentachloride. The sol-vent and the phosphorus oxychloride that had formed were dis-tilled off and the residue was disQolved in 50 ml of nitroben-zene and heated at 70C for four hours with 8.2 g of zinc chloride. The pro~uct was purified and recovered as described in Example 1. 7-chloro-1-methyl-2-chloromethyl-5-(2'-fluoro-phenyl)-lH-2,3-dihydro-1,4-benzodiazepine hydrochloride was obtained and had the following physical properties:
IR-spectrum (in XBr):- -=N-H :2200-3000 cm 1 ; C=N :1621 cm 1 Melting point: 220 - 222C.
; 20 . :
Claims (4)
1. A process for producing 2-halomethyl-1, 4-benzodiazepines corresponding to the formula:
and acid addition compounds thereof, and wherein:
R1 represents an alkyl group having from 1 to 4 carbon atoms, R2 represents a hydrogen atom, a halogen atom or a trifluoromethyl group, R3 represents a hydrogen atom or a halogen atom, and X represents a chlorine or bromine atom, and which process comprises halogenating an acyldiamine corresponding to the formula:
wherein R1, R2 and R3 have the specified meanings, by reaction with phosphorus pentachloride or phosphorus pentabromide in an inert solvent at the boiling point of that solvent to form an intermediate product; distilling off the solvent and the product formed from the halogenating agent; dissolving the resulting residue in an inert solvent;
and cyclising such intermediate product at a temperature of from about 20°C to about 80°C in the presence of a Lewis acid which can be used as a Friedel-Crafts catalyst; and isolating the resulting 2-halomethyl-1, 4-benzodiazepine in the form of the base or an acid addition compound thereof.
and acid addition compounds thereof, and wherein:
R1 represents an alkyl group having from 1 to 4 carbon atoms, R2 represents a hydrogen atom, a halogen atom or a trifluoromethyl group, R3 represents a hydrogen atom or a halogen atom, and X represents a chlorine or bromine atom, and which process comprises halogenating an acyldiamine corresponding to the formula:
wherein R1, R2 and R3 have the specified meanings, by reaction with phosphorus pentachloride or phosphorus pentabromide in an inert solvent at the boiling point of that solvent to form an intermediate product; distilling off the solvent and the product formed from the halogenating agent; dissolving the resulting residue in an inert solvent;
and cyclising such intermediate product at a temperature of from about 20°C to about 80°C in the presence of a Lewis acid which can be used as a Friedel-Crafts catalyst; and isolating the resulting 2-halomethyl-1, 4-benzodiazepine in the form of the base or an acid addition compound thereof.
2. A process as claimed in Claim 1 and in which said halogenation is performed in solution in benzene, toluene, carbon tetrachloride, 1,2-dichloroethane or chloroform.
3. A process as claimed in either of Claims 1 and 2 and in which said Lewis acid is boron trifluoride, boron trichloride, aluminum chloride, aluminum bromide, titanium tetrachloride, tin tetrachloride, antimony pentachloride, iron (III) chloride or zinc chloride.
4. A process as claimed in either of Claims 1 and 2 and in which said inert solvent in which the cyclisation reaction is performed is nitromethane, nitroethane, nitrobenzene or sulfolane.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP2448259.5 | 1974-10-10 | ||
| DE19742448259 DE2448259A1 (en) | 1974-10-10 | 1974-10-10 | PROCESS FOR THE PREPARATION OF 2-HALOGENMETHYL-1,4-BENZODIAZEPINES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1088528A true CA1088528A (en) | 1980-10-28 |
Family
ID=5927957
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA237,301A Expired CA1088528A (en) | 1974-10-10 | 1975-10-06 | Method of producing 2-halomethyl-1,4-benzodiazepines |
Country Status (13)
| Country | Link |
|---|---|
| JP (1) | JPS5165786A (en) |
| AR (1) | AR205941A1 (en) |
| AT (1) | AT346340B (en) |
| CA (1) | CA1088528A (en) |
| CH (1) | CH614199A5 (en) |
| CS (2) | CS184800B2 (en) |
| DD (1) | DD121788A5 (en) |
| DE (1) | DE2448259A1 (en) |
| FI (1) | FI752802A (en) |
| GR (1) | GR58594B (en) |
| HU (1) | HU173342B (en) |
| NL (1) | NL7511724A (en) |
| SE (1) | SE422206B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES469020A1 (en) * | 1977-05-10 | 1979-09-01 | Kali Chemie Pharma Gmbh | N1-acyl-N2-phenyldiaminopropanols and pharmaceutical compositions thereof |
| DE2720968C2 (en) * | 1977-05-10 | 1986-05-07 | Kali-Chemie Pharma Gmbh, 3000 Hannover | N? 1? -Acyl-2-hydroxy-1,3-diaminopropanes and drugs |
| US8426761B2 (en) | 2009-10-21 | 2013-04-23 | Fanuc Ltd | Method of detection of welding workpiece position using movable electrode |
-
1974
- 1974-10-10 DE DE19742448259 patent/DE2448259A1/en active Pending
-
1975
- 1975-01-01 AR AR260551A patent/AR205941A1/en active
- 1975-10-06 CH CH1295375A patent/CH614199A5/en not_active IP Right Cessation
- 1975-10-06 CA CA237,301A patent/CA1088528A/en not_active Expired
- 1975-10-06 NL NL7511724A patent/NL7511724A/en not_active Application Discontinuation
- 1975-10-07 CS CS7600007796A patent/CS184800B2/en unknown
- 1975-10-07 CS CS7500006793A patent/CS184790B2/en unknown
- 1975-10-08 FI FI752802A patent/FI752802A/fi not_active Application Discontinuation
- 1975-10-08 GR GR49075A patent/GR58594B/en unknown
- 1975-10-09 AT AT772175A patent/AT346340B/en not_active IP Right Cessation
- 1975-10-09 DD DD188775A patent/DD121788A5/xx unknown
- 1975-10-09 JP JP50122359A patent/JPS5165786A/en active Granted
- 1975-10-09 SE SE7511324A patent/SE422206B/en unknown
- 1975-10-09 HU HU75KA1447A patent/HU173342B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GR58594B (en) | 1977-11-10 |
| CS184790B2 (en) | 1978-09-15 |
| SE422206B (en) | 1982-02-22 |
| ATA772175A (en) | 1978-03-15 |
| HU173342B (en) | 1979-04-28 |
| JPS5165786A (en) | 1976-06-07 |
| SE7511324L (en) | 1976-04-12 |
| FI752802A (en) | 1976-04-11 |
| NL7511724A (en) | 1976-04-13 |
| CH614199A5 (en) | 1979-11-15 |
| AT346340B (en) | 1978-11-10 |
| DE2448259A1 (en) | 1976-04-22 |
| CS184800B2 (en) | 1978-09-15 |
| DD121788A5 (en) | 1976-08-20 |
| JPS6218554B2 (en) | 1987-04-23 |
| AR205941A1 (en) | 1976-06-15 |
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