US3364228A - 3-hydroxymethyl-4-(indol-3-yl)-hexahydro-1h-azepines and method of preparation - Google Patents

3-hydroxymethyl-4-(indol-3-yl)-hexahydro-1h-azepines and method of preparation Download PDF

Info

Publication number
US3364228A
US3364228A US466101A US46610165A US3364228A US 3364228 A US3364228 A US 3364228A US 466101 A US466101 A US 466101A US 46610165 A US46610165 A US 46610165A US 3364228 A US3364228 A US 3364228A
Authority
US
United States
Prior art keywords
alkyl
methyl
indol
acid
carbon atoms
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US466101A
Other languages
English (en)
Inventor
Jr Jackson B Hester
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia and Upjohn Co
Original Assignee
Upjohn Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Upjohn Co filed Critical Upjohn Co
Priority to US466101A priority Critical patent/US3364228A/en
Priority to IL25766A priority patent/IL25766A/en
Priority to NL6608201A priority patent/NL6608201A/xx
Priority to GB26525/66A priority patent/GB1150932A/en
Priority to FR66283A priority patent/FR1484225A/fr
Priority to DE19661620635 priority patent/DE1620635A1/de
Priority to CH901166A priority patent/CH469016A/de
Application granted granted Critical
Publication of US3364228A publication Critical patent/US3364228A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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

Definitions

  • This invention relates to novel 3-hydroxymethyl-4-(indol-3-yl)-hexah,ydro-lH-azepines and to processes for making the same.
  • novel 3-hydroxymethyl-4-(indol-3-yl)-hexahydrolH-azepines of the present invention can be represented by the following formula:
  • R, R and R are hydrogen or alkyl of not more than 4 carbon atoms, and R is hydrogen, alkyl of not more than 4 carbon atoms, alkoxy of not more than 4 carbon atoms, or halogen.
  • alkyl of not more than 4 carbon atoms are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, and tertiary butyl.
  • alkoxy are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, and tertiary butoxy.
  • halogen are fluoro, chloro, and bromo.
  • novel compounds of the invention are nitrogenous bases and, as such, can exist in the protonated and nonprotonated forms according to the pH of the environment.
  • R alkyl
  • the nonprotonated form can be oxidized, with hydrogen peroxide, for example, to form the N- oxide.
  • the N-oxide can exist in both the protonated and nonprotonated forms according to the pH of the environment.
  • the protonated forms can be isolated as acid addition salts which are useful in upgrading the free base and the free base N-oxide forms, that is, the nonprotonated forms.
  • Suitable acids for this purpose include hydrochloric acid, sulfuric acid, phosphoric acid, thiocyanic acid, fluosilicic acid, picric acid, Reineckes acid, azobenzenesulfonic acid, palmitic acid, acetic acid, maleic acid, and cyclohexanesulfamic acid.
  • the acid addition salt can be formed by neutralizing the free base or free base N-oxide with the appropriate acid or by metathesis of a simple acid addition salt such as the hydrochloride or sulfate with another salt of the desired acid.
  • the novel compounds of the invention are useful intermediates, thus, the condensation products obtained from thiocyanic acid addition salts and formaldehyde, according to U.S. Patents 2,425,320 and 2,606,155, are useful as pickling inhibitors, and the fluosilicic acid addition salts are useful as mothproofing agents according to U.S. Patents 1,915,334 and 2,075,359.
  • Novel compounds of the invention wherein R is alkyl can also exist in the form of quaternary ammonium salts such, for example, as those obtained by coordinating the free base form with a loweralkyl halide, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl chloride, bromide, or iodide, including the isomeric forms thereof.
  • the quaternary ammonium salts are useful for forming the corresponding quaternary ammonium fluosilicic acid salts which are useful as mothproofing agents.
  • fluosilicic acid salts can be formed by metathesis of a quaternary ammonium salt with an inorganic flu-osilicate or by liberating the free base, that is, the quaternary ammonium hydroxide (by treating the quaternary ammonium salt with an equivalent of base, for example, sodium hydroxide) and neutralizing with fluosilicic acid.
  • alkyl halides up to 18 carbon atoms, for example, where the alkyl group is nonyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, and the isomeric forms thereof, are surface-active compounds useful as wetting agents and as disinfectants.
  • the compounds of the invention can be prepared by reducing with lithium aluminum hydride a compound of the following formula:
  • R, R R and R are as given above, and R is alkyl, for example, methyl, ethyl, propyl, butyl, and the isomeric forms thereof.
  • the lithium aluminum hydride reduction can be effected in the manner already known in the art using, for example, ether, dioxane, or tetrahydrofuran as an inert solvent.
  • the starting compounds or intermediates of Formula II can be prepared by reacting with dialkyl malonate, for example, diethyl malonate, a compound of the following formula:
  • reaction is carried out in the presence of a strong base, for example, sodium hydroxide, and in an inert solvent, for example, xylene.
  • a strong base for example, sodium hydroxide
  • inert solvent for example, xylene.
  • suitable strong bases include sodium, sodium hydride, and potassium hydroxide.
  • suitable inert solvents include toluene, chlorobenzene, and decahydronaphthalene.
  • the reaction mixture can be worked up for the recovery of the product by neutralization of the base followed by solvent extraction and/or chromatography and like methods already known in the art. In some instances, two isomeric forms of the compounds of Formula II are obtained.
  • the starting 3-(2-pyrrolidinyl)indoles of Formula III can be prepared by processes already known in the art, for example, Youngdale et al., J. Med. Chem, 7, 415 (1964).
  • Typical 3-(2-pyrrolidinyl)indoles which can be thus prepared and which can be used as starting compounds for the process of the invention include 3-(2-pyrrolidinyl) indole, 1-methyl-3-(2-pyrrolidinyl)indole, 3-(1-methyl-2- pyrrolidinyl)indole, 3-(1-ethyl 2-pyrrolidiny1)indole, 1- methyl-3- l-methyl-2-pyrrolidinyl) indole, 5 -methyl-3-( 1- methyl-Z-pyrrolidinyl)indole, 7-methyl-3-( 1-methyl-2-pyrrolidinyl)indole, 5 methoxy-3-(l-methyl-2-pyrrolidinyl) indole, 4 chloro-3-(1-methyl-2-pyrrolidinyl)indole, 5-
  • the 3-(l-methyl-Z-pyrrolidinyl) indole can be substituted by any of the 3-(2-pyrrolidinyl) indoles embraced in Formula III, e.g., those given above.
  • the diethyl malonate can be substituted by other dialkyl malonates, for example, dimethyl, dipropyl, diisopropyl, dibutyl, diisobutyl, disec.butyl, and di-tert.butyl malonates.
  • R, R and R are members of the group consisting of hydrogen and alkyl of not more than 4 carbon atoms, and R is a member of the group consisting of hydrogen, alkyl of not more than 4 carbon atoms, alkoxy of not more than 4 carbon atoms, and halogen, and the acid addition salts thereof, the N-oxides thereof where R is alkyl and the acid addition salts thereof, and the alkyl quaternary ammonium salts thereof where R is alkyl.
  • R, R and R are hydrogen or alkyl of not more than 4 carbon atoms, and R is hydrogen, alkyl of not more than 4 carbon atoms, alkoxy of not more than 4 carbon atoms, or halogen.
  • R, R and R are hydrogen or alkyl of not more than 4 carbon atoms, and R is hydrogen, alkyl of not more than 4 carbon atoms, alkoxy of not more than 4 carbon atoms, or halogen, which comprises reacting with 6 a dialkyl malonate in the presence or a strong base a compound having the following formula:
  • R, R R and R are as given above, and R is alkyl, and reducing the resulting compound with lithium aluminum hydride.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
US466101A 1965-06-22 1965-06-22 3-hydroxymethyl-4-(indol-3-yl)-hexahydro-1h-azepines and method of preparation Expired - Lifetime US3364228A (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
US466101A US3364228A (en) 1965-06-22 1965-06-22 3-hydroxymethyl-4-(indol-3-yl)-hexahydro-1h-azepines and method of preparation
IL25766A IL25766A (en) 1965-06-22 1966-05-13 3-hydroxymethyl-4-(indol-3-yl)-hexahydro-1h-azepines and process for their preparation
NL6608201A NL6608201A (en, 2012) 1965-06-22 1966-06-14
GB26525/66A GB1150932A (en) 1965-06-22 1966-06-14 Improvements in or relating to Heterocyclic Compounds and the Manufacture thereof
FR66283A FR1484225A (fr) 1965-06-22 1966-06-21 Nouvelles azépines et leur procédé de préparation
DE19661620635 DE1620635A1 (de) 1965-06-22 1966-06-21 Verfahren zur Herstellung von 3-Hydroxymethyl-4-(indol-3-yl)-hexahydro-1H-azepine
CH901166A CH469016A (de) 1965-06-22 1966-06-22 Verfahren zur Herstellung von 3-Hydroxymethyl-4-(indol-3-yl)-hexahydro-1H-azepinen

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US466101A US3364228A (en) 1965-06-22 1965-06-22 3-hydroxymethyl-4-(indol-3-yl)-hexahydro-1h-azepines and method of preparation

Publications (1)

Publication Number Publication Date
US3364228A true US3364228A (en) 1968-01-16

Family

ID=23850471

Family Applications (1)

Application Number Title Priority Date Filing Date
US466101A Expired - Lifetime US3364228A (en) 1965-06-22 1965-06-22 3-hydroxymethyl-4-(indol-3-yl)-hexahydro-1h-azepines and method of preparation

Country Status (6)

Country Link
US (1) US3364228A (en, 2012)
CH (1) CH469016A (en, 2012)
DE (1) DE1620635A1 (en, 2012)
GB (1) GB1150932A (en, 2012)
IL (1) IL25766A (en, 2012)
NL (1) NL6608201A (en, 2012)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3214438A (en) * 1963-10-14 1965-10-26 Upjohn Co 3-substituted indoles

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3214438A (en) * 1963-10-14 1965-10-26 Upjohn Co 3-substituted indoles

Also Published As

Publication number Publication date
GB1150932A (en) 1969-05-07
CH469016A (de) 1969-02-28
NL6608201A (en, 2012) 1966-12-23
DE1620635A1 (de) 1970-08-20
IL25766A (en) 1970-02-19

Similar Documents

Publication Publication Date Title
DE69723846T2 (de) Verfahren zur Herstellung von Sildenafil
SU446966A1 (ru) Способ получени производных сложных эфиров 1,2,3,6-тетрагидро4-пиридилметилкарбоновой кислоты
Sommer et al. Alkylation of amines. New method for the synthesis of quaternary ammonium compounds from primary and secondary amines
JPS582946B2 (ja) ８− チオメチルエルゴリンルイノ セイホウ
NO118914B (en, 2012)
EP0251308B1 (de) 4-Chinolon-3-carbonsäurederivate, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Präparate
DE69629341T2 (de) Pyrrolocarbazolderivate
US3364228A (en) 3-hydroxymethyl-4-(indol-3-yl)-hexahydro-1h-azepines and method of preparation
DE2318852A1 (de) 7-acylamido-3-halogen-3-methyl-cepham4-carbonsaeure-verbindungen, verfahren zu deren herstellung und diese verbindungen enthaltende arzneipraeparate
US3235555A (en) 7-amino-3-cyanoethyl-1-methyl-2, 4-dioxo-1, 2, 3, 4, 5, 6-hexahydropyrido[2, 3-d] pyrimidine and related compounds
KR20000052891A (ko) 에세레톨로부터 피소스티그민 카르바메이트 유도체를 제조하는방법
US3347866A (en) 4-(indol-3-yl)-hexahydro-1h-azepines and their method of preparation
US3201406A (en) Pyridylcoumarins
Pilli et al. Reaction of N-(p-tolylsulfonyl) diphenylcyclopropenimine with pyridinium and isoquinolinium ylides
US3396160A (en) 2-oxo-4-(indol-3-yl)-hexahydro-1h-azepines and processes for their preparation
CH622518A5 (en) Process for the preparation of novel ergoline compounds
US4540701A (en) 2-Nitroxymethyl and 2,6-bis-nitroxymethyl-pyridine compounds having vasodilating activity
US3314942A (en) 3, 4, 5, 6-tetrahydro-1h-azepino(4, 3, 2-cd) indoles
DE2642608C2 (de) Verfahren zur Herstellung eines 4-Hydroxymethyl-2-pyrrolidinons
US5198553A (en) Process for the production of gramine derivatives
DE2453212A1 (de) 3-disubstituierte aminoisothiazol eckige klammer auf 3,4-d eckige klammer zu pyrimidine
EP0198190B1 (en) Compounds having antiplatelet aggregation activity, a process for the preparation thereof and pharmaceutical compositions containing them
Hurst et al. 22. 2-Bromomethylnicotinates: reaction with nucleophilic reagents
Gibson et al. Reissert compound studies. Cyclization of N‐(ω‐chloroalkanoyl) reissert compounds
DE69303847T2 (de) Indolderivate