US3546212A - Oxidation of benzodiazepines with ruthenium tetroxide - Google Patents

Oxidation of benzodiazepines with ruthenium tetroxide Download PDF

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Publication number
US3546212A
US3546212A US736250A US3546212DA US3546212A US 3546212 A US3546212 A US 3546212A US 736250 A US736250 A US 736250A US 3546212D A US3546212D A US 3546212DA US 3546212 A US3546212 A US 3546212A
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Prior art keywords
ruthenium tetroxide
dihydro
phenyl
benzodiazepin
added
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Expired - Lifetime
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US736250A
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Inventor
Arthur Martin Felix
Rodney Ian Fryer
Leo Henryk Sternbach
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F Hoffmann La Roche AG
Hoffmann La Roche Inc
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F Hoffmann La Roche AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/30—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • D—TEXTILES; PAPER
    • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
    • D06P—DYEING OR PRINTING TEXTILES; DYEING LEATHER, FURS OR SOLID MACROMOLECULAR SUBSTANCES IN ANY FORM
    • D06P1/00—General processes of dyeing or printing textiles, or general processes of dyeing leather, furs, or solid macromolecular substances in any form, classified according to the dyes, pigments, or auxiliary substances employed
    • D06P1/44—General processes of dyeing or printing textiles, or general processes of dyeing leather, furs, or solid macromolecular substances in any form, classified according to the dyes, pigments, or auxiliary substances employed using insoluble pigments or auxiliary substances, e.g. binders
    • D—TEXTILES; PAPER
    • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
    • D06P—DYEING OR PRINTING TEXTILES; DYEING LEATHER, FURS OR SOLID MACROMOLECULAR SUBSTANCES IN ANY FORM
    • D06P3/00—Special processes of dyeing or printing textiles, or dyeing leather, furs, or solid macromolecular substances in any form, classified according to the material treated
    • D06P3/80—Inorganic fibres
    • D—TEXTILES; PAPER
    • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
    • D06P—DYEING OR PRINTING TEXTILES; DYEING LEATHER, FURS OR SOLID MACROMOLECULAR SUBSTANCES IN ANY FORM
    • D06P3/00—Special processes of dyeing or printing textiles, or dyeing leather, furs, or solid macromolecular substances in any form, classified according to the material treated
    • D06P3/82—Textiles which contain different kinds of fibres
    • D06P3/854—Textiles which contain different kinds of fibres containing modified or unmodified fibres, i.e. containing the same type of fibres having different characteristics, e.g. twisted and not-twisted fibres

Definitions

  • the present invention relates to the oxidation of benzodiazepines with ruthenium tetroxide.
  • the present invention relates to a process which comprises oxidizing a compound of the formula:
  • the present invention relates to oxidizing compounds of the formula:
  • Illustrative of typical radicals represented by the character R which are stable under the oxidation conditions described herein to effect the preparation of compounds of the Formula II above are the hydrogen radical, the lower alkyl radical, the halo lower alkyl radical, e.g. chloropropyl, bromoethyl and the like, a basic side chain containing radical such as the dilower alkyl-amino-lower alkyl radical (dimethylaminoethyl, diethylaminoethyl, dimethylaminopropyl and the like), or any other radical which would be stable under the oxidation conditions utilized; that is to say, that would be uneffected by oxidation in the manner described herein utilizing ruthenium tetroxide.
  • lower alkyl as utilized herein, both branched and straight chain C -C preferably C -C hydrocarbon groups are contemplated such as methyl, ethyl propyl, isobutyl and the like.
  • halogen as utilized herein, all four forms thereof are contemplated unless otherwise specified, e.g. chlorine, bromine, iodine and fluorine.
  • a particularly advantageous process aspect of the present invention results in the preparation of compounds of the Formula II above wherein R and R are hydrogen and B is phenyl or halophenyl, preferably, 2-halophenyl, most preferentially, 2-fluorophenyl.
  • R R and B are as above and R is halogen, preferably chlorine or bromine, most preferably, chlorine.
  • R, R and R represent the groups preferred above
  • B is the phenyl group
  • R is selected from the group consisting of hydrogen, lower alkyl, most preferentially, methyl and dilower alkyl amino lower alkyl, most preferentially, diethylaminoethyl. If B is pyridyl, a 2-pyridyl radical is preferred.
  • the oxidation with ruthenium tetroxide proceeds readily and facily to the desired product of the Formula II above.
  • ruthenium tetroxide is added to the reaction zone in a molar excess.
  • the re action is effected at below room temperature, e.g., at a temperature range of from about -20 to about 15, most preferably, from about 0 to about 10.
  • the reaction proceeds most suitably in the presence of an inert inorganic solvent and among the many solvents suitable for the purposes of the present invention there may be included halogenated aliphatic hydrocarbons such as chloroform, dichloromethane and the like.
  • any suitable reagent may be added to the reaction medium to destroy any excess ruthenium tetroxide present therein.
  • a preferred reagent for this purpose is a lower alkanol such as Z-propanol.
  • the compounds of the Formula II above are known compounds and are useful as anticonvulsants, muscle relaxants and sedative agents. Their pharmacological usefulness is well document in the literature.
  • R, R R and B are as above.
  • an excess of ruthenium tetroxide is preferentially utilized in the preferred embodiment. If a slight excess is utilized, the compound of the Formula II is the major product and its preparation is preferred. If a great excess of ruthenium tetroxide is utilized, the compound of the Formula IV can be obtained in major amounts. The amount of ruthenium tetroxide utilized to achieve the desired end is readily ascertainable by those skilled in the art. As the particularly preferred embodiment of this invention relates to the preparation of a compound of the Formula II above, it is of course evi dent that a slight excess of ruthenium tetroxide is preferentially utilized for the purposes of the present invention.
  • the process of the present invention in a preferred embodiment therefore relates to a novel oxidation procedure for efiecting the conversion of certain benzodiazepines into other 2,3-dihydro-1,4-benzodiazepin-2-ones in unexpectedly good yields and in a facile and convenient manner.
  • EXAMPLE 1 Into a 500 ml. 3-necked round bottom flask equipped with magnetic stirrer and immersed in an ice-salt bath at l was placed 7-chloro-2,3-dihydro-5-phenyl-1H-l,4- benzodiazepine (642 mg., 2.5 mmoles). A chloroform solution of ruthenium tetroxide (158 ml. of 0.07 M, 11 mmole, 4.4 equivalents) was added dropwise over a 30 minute period and stirred for an additional period of 30 minutes. 2-propanol ml.) was added to the re- 4 action medium and the reaction mixture was filtered.
  • 7-chloro-2,3-dihydro-5-phenyl-1H-l,4- benzodiazepine (642 mg., 2.5 mmoles).
  • a chloroform solution of ruthenium tetroxide 158 ml. of 0.07 M, 11 mmole, 4.4 equivalent
  • EXAMPLE 2 Into a 500 ml. 3-necked round bottom flask equipped with magnetic stirrer and immersed in an ice-salt bath at 10 was placed 7-chloro-2,3-dihydro-1-methyl-5- phenyl-lH-l,4-benzodiazepine (732 mg., 2.7 mmole). A solution of ruthenium tetroxide (180 m1. of 0.054 M, 9.7 mmole, 3.6 equivalents) was added dropwise over a 30 minute period and stirred for an additional 30 minutes. 2-propanol (5 ml.) and water (200 ml.) was added to the reaction medium and the mixture was filtered through Celite.
  • the starting material 2,3-dihydro-1-methyl-7-nitro-5 (Z-pyrimidinyl)-1H-1,4-benzodiazepine is not part of the present invention, but its preparation is disclosed herein in order that the disclosure may be complete.
  • EXAMPLE 6 Into a 500 ml. 3-necked round bottom flask equipped with magnetic stirrer and immersed in an ice-salt bath at -10 was placed 7-ch1oro-1,3,4,5-tetrahydro-5-phenyl- 2H-1,4-benzodiazepin-2-one (681 mg., 2.5 mmole). A solution of ruthenium tctroxide ml. of 0.067 M, 7.0 mmole, 2.8 equivalents) was added dropwise over a 30 minute period and stirred for an additional 30 minutes.
  • EXAMPLE 7 A stirred solution of 0.5 g. (0.00166 M) of 7-chloro- 1,3 dihydro 3 hydroxy 1 methyl 5 phenyl 2H- 1,4-benzodiazepin-2-one in 12 ml. of chloroform cooled in an ice bath was treated with the dropwise addition of 51 m1. (0.00332 M) of a 0.0647 M ruthenium tctroxide solution. After 18 hrs., 15 ml, of water was added and the mixture was filtered through celite. The chloroform layer was separated, dried over anhydrous sodium sulfate and evaporated to dryness. To the oil so obtained there was added a mixture of dichloromethane and hexane (2x).
  • EXAMPLE 8 A stirred suspension of 3 g. (0.0105 M) of 7-chloro-1,3- dihydro 3 hydroxy 5 phenyl 2H 1,4 benzodiazcpin-2-one in 10 ml. of CHCl in an ice bath was treated with 200 ml. (0.013 M) of a 0.0647 M solution of ruthenium tctroxide in chloroform. After 18 hrs. at room temperature, 25 ml. of water was added and the solution was filtered through celite.
  • EXAMPLE 9 A solution of 1 g. (0.00348 M) of 7-chloro-l,3,4,5- tetrahydro 1 methyl 5 phenyl 2H 1,4 benzodi azepin-Z-one in 25 ml. of chloroform was stirred in an ice bath and was treated with 108 ml. (0.00696 M) of a 0.0047 M solution of ruthenium tctroxide in chloroform over a 10-minute period. After standing 18 hours at room temperature an additional 75 ml. (0.00485 M) of ruthenium tetroxide was added and the reaction was allowed to stand for an additional 18 hours. Water (50 ml.) was added and the mixture was filtered through Celite.
  • Z is selected from the group consisting of carbonyl and methylene
  • A is selected from the group consisting of with the proviso that when Z is carbonyl, A is with ruthenium tetroxide whereby to prepare the corresponding compound of the formula:
  • a process as defined in claim 1 which comprises oxidizing 7-halo-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine with ruthenium tetroxide whereby to obtain 7-halo- 2,3-dihydro-5-phenyl-2H 1,4-benzodiazepin-2-one.
  • a process as defined in claim 1 which comprises oxidizing 7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine with ruthenium tetroxide whereby to obtain 7- chloro-Z,3-dihydro-5-phenyl-2H-l ,4-benzodiazepin-2-one.
  • process as defined in claim 1 which comprises oxidizing 7-halo-2,3-dihydro-l-methyl-S-phenyl-IH-1,4- benzodiazepine with ruthenium tetroxide whereby to obtain 7-halo-2,3-dihydro-l-methyl-S-phenyl-ZH-1,4-benzodiazepin-Z-one.
  • a process as defined in claim 1 which comprises oxidizing 2,3 dihydro-7-nitro-5-phenyl-lH-1,4 benzodiazepine with ruthenium tetroxide whereby to obtain 2,3- dihydro7-nitro-5-pheny1-2H-1,4-benzodiazepin-2-one.
  • a process as defined in claim 1 which comprises oxidizing a compound of the formula 7-halo-l,3,4,5- tetrahydro-S-phenyl-ZH-1,4-benzodiazepin-2-one with ruthenium tetroxide whereby to prepare 7-halo-2,3-dihydro- 5-phenyl-2I-I-1,4-benzodiazepin-2-one.
  • a process as defined in claim 1 which comprises oxidizing a compound of the formula 7-chlor0-1,3,4,5- tetrahydro-S-phenyl-ZH-1,4-benzodiazepin-2-one with ruthenium tetroxide whereby to prepare 7-chloro-2,3-dihydro-S-phenyl-ZH-l,4-benzodiazepin-2-one.

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  • Chemical & Material Sciences (AREA)
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  • Engineering & Computer Science (AREA)
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US736250A 1968-06-12 1968-06-12 Oxidation of benzodiazepines with ruthenium tetroxide Expired - Lifetime US3546212A (en)

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US73625068A 1968-06-12 1968-06-12
US80346169A 1969-02-28 1969-02-28

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US (1) US3546212A (de)
AT (2) AT289125B (de)
BE (1) BE734376A (de)
CA (1) CA950453A (de)
CH (3) CH523267A (de)
DE (1) DE1929910A1 (de)
ES (1) ES368239A1 (de)
FR (1) FR2010744A1 (de)
GB (1) GB1239380A (de)
IE (1) IE33286B1 (de)
NL (3) NL143927B (de)
SE (1) SE347510B (de)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3723414A (en) * 1970-02-13 1973-03-27 Schering Corp 1-polyfluoroalkyl benzodiazepines
US3896109A (en) * 1971-09-30 1975-07-22 Upjohn Co 2,3-dehydro-1h-1,4-benzodiazepines
US4083948A (en) * 1977-04-04 1978-04-11 Hoffmann-La Roche, Inc. Benzodiazepine radioimmunoassay using I125-label
US4280993A (en) * 1978-01-19 1981-07-28 Claus Braestrup Process for determining the concentration of benzodiazepines in a body fluid
US4497740A (en) * 1981-06-19 1985-02-05 Kali-Chemie Pharma Gmbh 2-Azidomethyl-1,4-benzodiazepine compounds
US5137564A (en) * 1989-07-27 1992-08-11 Schering Agrochemicals Limited Pyrimidinyl herbicides

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3621551C1 (en) * 1986-06-27 1987-07-02 Eckard 5810 Witten De Feller Cutting tool for lathe - has carrier arm and screw cooperating to retain lower packer plate and upper cutting insert in tool
DE3836538A1 (de) * 1988-10-27 1990-05-03 Christian Rinke Verpackungsbehaelter, insbesondere flasche
KR950703537A (ko) * 1992-10-16 1995-09-20 시모무라 도오루 피리미딘 유도체(pyrimidine derivative)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3371085A (en) * 1959-12-10 1968-02-27 Hoffmann La Roche 5-aryl-3h-1,4-benzodiazepin-2(1h)-ones

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3371085A (en) * 1959-12-10 1968-02-27 Hoffmann La Roche 5-aryl-3h-1,4-benzodiazepin-2(1h)-ones

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3723414A (en) * 1970-02-13 1973-03-27 Schering Corp 1-polyfluoroalkyl benzodiazepines
US3896109A (en) * 1971-09-30 1975-07-22 Upjohn Co 2,3-dehydro-1h-1,4-benzodiazepines
US4083948A (en) * 1977-04-04 1978-04-11 Hoffmann-La Roche, Inc. Benzodiazepine radioimmunoassay using I125-label
US4280993A (en) * 1978-01-19 1981-07-28 Claus Braestrup Process for determining the concentration of benzodiazepines in a body fluid
US4497740A (en) * 1981-06-19 1985-02-05 Kali-Chemie Pharma Gmbh 2-Azidomethyl-1,4-benzodiazepine compounds
US5137564A (en) * 1989-07-27 1992-08-11 Schering Agrochemicals Limited Pyrimidinyl herbicides

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SE347510B (de) 1972-08-07
NL143927B (nl) 1974-11-15
DE1929910A1 (de) 1970-01-02
NL6908658A (de) 1969-12-16
FR2010744A1 (de) 1970-02-20
ES368239A1 (es) 1971-06-16
IE33286B1 (en) 1974-05-15
CH523898A (de) 1972-06-15
IE33286L (en) 1969-12-12
BE734376A (de) 1969-12-11
AT289125B (de) 1971-04-13
AT299960B (de) 1972-07-10
NL6908966A (de) 1969-12-16
GB1239380A (de) 1971-07-14
CA950453A (en) 1974-07-02
CH523267A (de) 1972-05-31
CH550185A (de) 1974-06-14
NL6908866A (de) 1969-12-22

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